PGE1, dexamethasone, U-74389G, or Bt2-cAMP as an additive to promote protection by UW solution in I/R injury.

PubMed

Chiang, C H; Hsu, K; Yan, H C; Harn, H J; Chang, D M

1997-08-01

A method to reduce ischemia-reperfusion (I/R) injury can be an important criterion to improve the preservation solution. Although University of Wisconsin solution (UW) works as a lung preservation solution, its attenuation effect on I/R injury has not been investigated. We attempted to determine whether, by adding various protective agents, modified UW solutions will enhance the I/R attenuation by UW. We examined the I/R injury in an isolated rat lung model. Various solutions, e.g., physiological salt solution (PSS), UW, and modified UW solutions containing various protective agents such as prostaglandin E1, dexamethasone, U-74389G, or dibutyryl adenosine 3',5'-cyclic monophosphate were perfused individually to evaluate the I/R injury. Isolated rat lung experiments, with ischemia for 45 min, then reperfusion for 60 min, were conducted in a closed circulating system. Hemodynamic changes, lung weight gain (LWG), capillary filtration coefficient (Kfc), protein content of lavage fluid, concentration of cytokines, and lung histopathology were analyzed. Results showed that the acute I/R lung injury with immediate permeability pulmonary edema was associated with an increase in tumor necrosis factor-alpha (TNF-alpha) production. A significant correlation existed between TNF-alpha and Kfc (r = 0.8, P < 0.0001) and TNF-alpha and LWG (r = 0. 9, P < 0.0001), indicating that TNF-alpha is an important cytokine modulating early I/R injury. Significantly lower levels of Kfc, LWG, TNF-alpha, and protein concentration of lung lavage (P < 0.05) were found in the UW-perfused group than in the control group perfused with PSS. Modified UW promoted the protective effect of UW to further decrease Kfc, LWG, and TNF-alpha (P < 0.05). Histopathological observations also substantiated this evidence. In the UW+U-74389G group, bronchial alveolar lavage fluid contained lowest protein concentration. We conclude that the UW solution attenuates I/R injury of rat lung and that the modified UW solutions further enhance the effect of UW in reducing I/R injury. Among modified solutions, UW+U-74389G is the best. Further investigation of the improved effects of the modified UW solutions would be beneficial in lung transplantation.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Whinnery, J.E.; Young, J.T.

Albumin lung-scanning agents have a proven high degree of safety, with the only contraindication to their use being allergic hypersensitivity. We have used these agents to investigate the physiologic effects of high G/sub z/ acceleratory forces on pulmonary perfusion using the miniature swine. Multiple doses of human macroaggregated albumin and human-albumin microspheres were given to a miniature swine at various levels of centrifugal acceleration over a 6-wk period. The dosages given were the same per kilogram as those used for routine clinical human studies. The animal subsequently died from a severe granulomatous interstitial pneumonia. The granulomatous lesions suggest that themore » pathogenesis may have involved a cell-mediated delayed hypersensitivity. This interstitial pneumonia may represent the end point in a chronic hypersensitivity response to the human-albumin lung-scanning agents.« less

Ex Vivo Lung Perfusion: Establishment and Operationalization in Iran.

PubMed

Shafaghi, Shadi; Abbasi Dezfuli, Azizollah; Ansari Aval, Zahra; Sheikhy, Kambiz; Farzanegan, Behrooz; Mortaz, Esmaeil; Emami, Habib; Aigner, Clemens; Hosseini-Baharanchi, Fatemeh Sadat; Najafizadeh, Katayoun

2017-02-01

Although the number of lung transplants is limited because of general shortage of organ donors, ex vivo lung perfusion is a novel method with 2 main benefits, including better evaluation of lung potential and recovery of injured lungs. The main aim of this study was to establish and operationalize ex vivo lung perfusion as the first experience in Iran. This was a prospective operational research study on 5 cases, including 1 pig from Vienna Medical University and 4 patients from Masih Daneshvari Hospital. All organ donations from brain dead donors were evaluated according to lung transplant or ex vivo lung perfusion criteria from May 2013 to July 2015 in Tehran, Iran. If a donor did not have any sign of severe chest trauma or pneumonia but had poor oxygenation due to possible atelectasis or neurogenic pulmonary edema, their lungs were included for ex vivo lung perfusion. A successful trend in the difference between the pulmonary arterial Po2 and the left atrial Po2 was observed, as well as an increasing pattern in other functional parameters, including dynamic lung compliance and a decreasing trend in pulmonary vascular resistance. These initial trials indicate that ex vivo lung perfusion can lead to remarkable progress in lung transplant in Iran. They also provide several important pieces of guidance for successful ex vivo lung perfusion, including the necessity of following standard lung retrieval procedures and monitoring temperature and pressure precisely. The development of novel methods can provide opportunities for further research studies on lungs of deceased donors and lead to undiscovered findings. By keeping this science up to date in Iran and developing such new and creative methods, we can reveal effective strategies to promote the quality of donor lungs to support patients on transplant wait lists.

Relation between lung perfusion defects and intravascular clots in acute pulmonary thromboembolism: assessment with breath-hold SPECT-CT pulmonary angiography fusion images.

PubMed

Suga, Kazuyoshi; Yasuhiko, Kawakami; Iwanaga, Hideyuki; Tokuda, Osamu; Matsunaga, Naofumi

2008-09-01

The relation between lung perfusion defects and intravascular clots in acute pulmonary thromboembolism (PTE) was comprehensively assessed on deep-inspiratory breath-hold (DIBrH) perfusion SPECT-computed tomographic pulmonary angiography (CTPA) fusion images. Subjects were 34 acute PTE patients, who had successfully performed DIBrH perfusion SPECT using a dual-headed SPECT and a respiratory tracking system. Automated DIBrH SPECT-CTPA fusion images were used to assess the relation between lung perfusion defects and intravascular clots detected by CTPA. DIBrH SPECT visualized 175 lobar/segmental or subsegmental defects in 34 patients, and CTPA visualized 61 intravascular clots at variable locations in 30 (88%) patients, but no clots in four (12%) patients. In 30 patients with clots, the fusion images confirmed that 69 (41%) perfusion defects (20 segmental, 45 subsegmental and 4 lobar defects) of total 166 defects were located in lung territories without clots, although the remaining 97 (58%) defects were located in lung territories with clots. Perfusion defect was absent in lung territories with clots (one lobar branch and three segmental branches) in four (12%) of these patients. In four patients without clots, nine perfusion defects including four segmental ones were present. Because of unexpected dissociation between intravascular clots and lung perfusion defects, the present fusion images will be a useful adjunct to CTPA in the diagnosis of acute PTE.

Profiling inflammation and tissue injury markers in perfusate and bronchoalveolar lavage fluid during human ex vivo lung perfusion

PubMed Central

Andreasson, Anders S.I.; Karamanou, Danai M.; Gillespie, Colin S.; Özalp, Faruk; Butt, Tanveer; Hill, Paul; Jiwa, Kasim; Walden, Hannah R.; Green, Nicola J.; Borthwick, Lee A.; Clark, Stephen C.; Pauli, Henning; Gould, Kate F.; Corris, Paul A.; Ali, Simi; Dark, John H.

2017-01-01

Abstract OBJECTIVES: Availability of donor lungs suitable for transplant falls short of current demand and contributes to waiting list mortality. Ex vivo lung perfusion (EVLP) offers the opportunity to objectively assess and recondition organs unsuitable for immediate transplant. Identifying robust biomarkers that can stratify donor lungs during EVLP to use or non-use or for specific interventions could further improve its clinical impact. METHODS: In this pilot study, 16 consecutive donor lungs unsuitable for immediate transplant were assessed by EVLP. Key inflammatory mediators and tissue injury markers were measured in serial perfusate samples collected hourly and in bronchoalveolar lavage fluid (BALF) collected before and after EVLP. Levels were compared between donor lungs that met criteria for transplant and those that did not. RESULTS: Seven of the 16 donor lungs (44%) improved during EVLP and were transplanted with uniformly good outcomes. Tissue and vascular injury markers lactate dehydrogenase, HMGB-1 and Syndecan-1 were significantly lower in perfusate from transplanted lungs. A model combining IL-1β and IL-8 concentrations in perfusate could predict final EVLP outcome after 2 h assessment. In addition, perfusate IL-1β concentrations showed an inverse correlation to recipient oxygenation 24 h post-transplant. CONCLUSIONS: This study confirms the feasibility of using inflammation and tissue injury markers in perfusate and BALF to identify donor lungs most likely to improve for successful transplant during clinical EVLP. These results support examining this issue in a larger study. PMID:28082471

Successful prolonged ex vivo lung perfusion for graft preservation in rats.

PubMed

Noda, Kentaro; Shigemura, Norihisa; Tanaka, Yugo; Bhama, Jay K; D'Cunha, Jonathan; Luketich, James D; Bermudez, Christian A

2014-03-01

Ex vivo lung perfusion (EVLP) strategies represent a new frontier in lung transplantation technology, and there have been many clinical studies of EVLP in lung transplantation. The establishment of a reliable EVLP model in small animals is crucial to facilitating translational research using an EVLP strategy. The main objective of this study was to develop a reproducible rat EVLP (R-EVLP) model that enables prolonged evaluation of the explanted lung during EVLP and successful transplantation after EVLP. The donor heart-lung blocks were procured with cold low-potassium dextran solution and immersed in the solution for 1 h at 4 °C. And then, the heart-lung blocks were flushed retrogradely and warmed up to 37 °C in a circuit perfused antegradely with acellular perfusate. The perfusate was deoxygenated with a gas mixture (6% O2, 8% CO2, 86% N2). The perfusion flow was maintained at 20% of the entire cardiac output. At 37 °C, the lungs were mechanically ventilated and perfusion continued for 4 h. Every hour, the perfused lung was evaluated for gas exchange, dynamic lung compliance (Cdyn) and pulmonary vascular resistance (PVR). R-EVLP was performed for 4 h. Pulmonary oxygenation ability (pO2/pCO2) was stable for 4 h during EVLP. It was noted that Cdyn and PVR were also stable. After 4 h of EVLP, pO2 was 303 ± 19 mmHg, pCO2 was 39.6 ± 1.2 mmHg, PVR was 1.75 ± 0.10 mmHg/ml/min and Cdyn was 0.37 ± 0.03 ml/cmH2O. Lungs that were transplanted after 2 h of R-EVLP resulted in significantly better post-transplant oxygenation and compliance when compared with those after standard cold static preservation. Our R-EVLP model maintained stable lung oxygenation, compliance and vascular resistance for up to 4 h of perfusion duration. This reliable model should facilitate further advancement of experimental work using EVLP.

Utilization of the organ care system as ex-vivo lung perfusion after cold storage transportation.

PubMed

Mohite, P N; Maunz, O; Popov, A-F; Zych, B; Patil, N P; Simon, A R

2015-11-01

The Organ Care System (OCS) allows perfusion and ventilation of the donor lungs under physiological conditions. Ongoing trials to compare preservation with OCS Lung with standard cold storage do not include donor lungs with suboptimal gas exchange and donor lungs treated with OCS following cold storage transportation. We present a case of a 48-yr-old man who received such lungs after cold storage transportation treated with ex-vivo lung perfusion utilizing OCS. © The Author(s) 2015.

Amiodarone causes acute oxidant lung injury in ventilated and perfused rabbit lungs.

PubMed

Kennedy, T P; Gordon, G B; Paky, A; McShane, A; Adkinson, N F; Peters, S P; Friday, K; Jackman, W; Sciuto, A M; Gurtner, G H

1988-07-01

Amiodarone (ADR), a new antiarrhythmic drug for life-threatening cardiac arrhythmias, causes pneumonitis or lung fibrosis in a sizeable minority of patients. The cause of lung damage is not known. We have shown that infusion of 10 mg amiodarone into the inflow circuit of ventilated and perfused rabbit lungs causes immediate increase in pulmonary artery pressure (mean +/- SEM) (from 13.6 +/- 1.2 to 40.6 +/- 9.5 mm Hg, p less than 0.01) and pulmonary edema with marked increase in the pulmonary generation of thromboxane and leukotrienes C4 and/or D4. Albumin (2 g%) in the perfusate prevents any increase in lung perfusion pressure or edema formation. When lung perfusion pressure increase is blocked with the combined cyclooxygenase and lipoxygenase inhibitor enolicam sodium (CG5391B, 35 microM in perfusate), significant lung edema still occurs after amiodarone, indicating that amiodarone causes increased alveolar-capillary membrane permeability. Addition of catalase (100 U/ml) or superoxide dismutase and catalase (100 U/ml each) to perfusate fails to protect from amiodarone lung injury. Immediate infusion of amiodarone (10 mg) into lungs ventilated with room air (ADR + RA) causes an increase in lung weight gain from baseline (delta W) of 5.7 +/- 1.5 g/min. Compared with ADR + RA, ventilation of lungs with 4% O2 (delta W = 0.7 +/- 0.3 g/min, p less than 0.05), pretreatment of rabbits for 3 days with butylated hydroxyanisole (BHA, 100 mg/kg/day i.p., delta W = 0.05 +/- 0.02 g/min, p less than 0.01), pretreatment of rabbits for 3 days with vitamin E (Vit E, 300 U/day orally, delta W = 0.6 +/- 0.2 g/min, p less than 0.05), or addition of N-acetylcysteine to the lung perfusate (NAC, 5 mM, delta W = 0.1 +/- 0.08 g/min, p less than 0.01) all protect from lung edema formation after amiodarone. Amiodarone (100 mg) also caused a marked increase in luminol-enhanced lung chemiluminescence, lung production of superoxide anion (O2-), and tissue levels of lung glutathione disulfide. These results suggest that amiodarone causes lung injury by an oxidant mechanism.

Reproducibility of Lobar Perfusion and Ventilation Quantification Using SPECT/CT Segmentation Software in Lung Cancer Patients.

PubMed

Provost, Karine; Leblond, Antoine; Gauthier-Lemire, Annie; Filion, Édith; Bahig, Houda; Lord, Martin

2017-09-01

Planar perfusion scintigraphy with 99m Tc-labeled macroaggregated albumin is often used for pretherapy quantification of regional lung perfusion in lung cancer patients, particularly those with poor respiratory function. However, subdividing lung parenchyma into rectangular regions of interest, as done on planar images, is a poor reflection of true lobar anatomy. New tridimensional methods using SPECT and SPECT/CT have been introduced, including semiautomatic lung segmentation software. The present study evaluated inter- and intraobserver agreement on quantification using SPECT/CT software and compared the results for regional lung contribution obtained with SPECT/CT and planar scintigraphy. Methods: Thirty lung cancer patients underwent ventilation-perfusion scintigraphy with 99m Tc-macroaggregated albumin and 99m Tc-Technegas. The regional lung contribution to perfusion and ventilation was measured on both planar scintigraphy and SPECT/CT using semiautomatic lung segmentation software by 2 observers. Interobserver and intraobserver agreement for the SPECT/CT software was assessed using the intraclass correlation coefficient, Bland-Altman plots, and absolute differences in measurements. Measurements from planar and tridimensional methods were compared using the paired-sample t test and mean absolute differences. Results: Intraclass correlation coefficients were in the excellent range (above 0.9) for both interobserver and intraobserver agreement using the SPECT/CT software. Bland-Altman analyses showed very narrow limits of agreement. Absolute differences were below 2.0% in 96% of both interobserver and intraobserver measurements. There was a statistically significant difference between planar and SPECT/CT methods ( P < 0.001) for quantification of perfusion and ventilation for all right lung lobes, with a maximal mean absolute difference of 20.7% for the right middle lobe. There was no statistically significant difference in quantification of perfusion and ventilation for the left lung lobes using either method; however, absolute differences reached 12.0%. The total right and left lung contributions were similar for the two methods, with a mean difference of 1.2% for perfusion and 2.0% for ventilation. Conclusion: Quantification of regional lung perfusion and ventilation using SPECT/CT-based lung segmentation software is highly reproducible. This tridimensional method yields statistically significant differences in measurements for right lung lobes when compared with planar scintigraphy. We recommend that SPECT/CT-based quantification be used for all lung cancer patients undergoing pretherapy evaluation of regional lung function. © 2017 by the Society of Nuclear Medicine and Molecular Imaging.

Perfusion lung imaging in the adult respiratory distress syndrome

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pistolesi, M.; Miniati, M.; Di Ricco, G.

1986-07-01

In 29 perfusion lung scans (PLS) of 19 patients with ARDS, 20 of which were obtained within six days from the onset of respiratory symptoms, perfusion abnormalities were the rule. These included focal, nonsegmental defects, mostly peripheral and dorsal, and perfusion redistribution away from the dependent lung zones. PLS were scored for the presence and intensity of perfusion abnormalities and the scores of perfusion redistribution were validated against numerical indices of blood flow distribution per unit lung volume. PLS scores were correlated with arterial blood gas values, hemodynamic parameters, and chest radiographic scores of ARDS. Arterial oxygen tension correlated withmore » the scores of both perfusion defects and redistribution. Perfusion defects correlated better with the radiographic score of ARDS, and perfusion redistribution with PAP and vascular resistance. ARDS patients exhibit peculiar patterns of PLS abnormalities not observed in other disorders. Thus, PLS may help considerably in the detection and evaluation of pulmonary vascular injury in ARDS.« less

TU-G-BRA-01: Assessing Radiation-Induced Reductions in Regional Lung Perfusion Following Stereotactic Radiotherapy for Lung Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

McGurk, R; Green, R; Lawrence, M

2015-06-15

Purpose: The dose-dependent nature of radiation therapy (RT)-induced lung injury following hypo-fractionated stereotactic RT is unclear. We herein report preliminary results of a prospective study assessing the magnitude of RT-induced reductions in regional lung perfusion following hypo-fractionated stereotactic RT. Methods: Four patients undergoing hypo-fractionated stereotactic lung RT (SBRT: 12 Gy x 4 fractions or 10 Gy x 5 fractions) had a pre-treatment SPECT (single-photon emission computed tomography) perfusion scan providing a 3D map of regional lung perfusion. Scans were repeated 3–6 months post-treatment. Pre- and post SPECT scans were registered to the planning CT scan (and hence the 3D dosemore » data). Changes in regional perfusion (counts per cc on the pre-post scans) were computed in regions of the lung exposed to different doses of radiation (in 5 Gy intervals), thus defining a dose-response function. SPECT scans were internally normalized to the regions receiving <5 Gy. Results: At 3 months post-RT, the changes in perfusion are highly variable. At 6 months, there is a consistent dose-dependent reduction in regional perfusion. The average percent decline in regional perfusion was 10% at 15–20 Gy, 20% at 20–25 Gy, and 30% at 25–30 Gy representing a relatively linear dose response with an approximate 2% reduction per Gray for doses in excess of 10 Gy. There was a subtle increase in perfusion in the lung receiving <10 Gy. Conclusion: Hypo-fractionated stereotactic RT appears to cause a dose-dependent reduction in regional lung perfusion. There appears to be a threshold effect with no apparent perfusion loss at doses <10 Gy, though this might be in part due to the normalization technique used. Additional data is needed from a larger number of patients to better assess this issue. This sort of data can be used to assist optimizing RT treatment plans that minimize the risk of lung injury. Partly supported by the NIH (CA69579) and the Lance Armstrong Foundation.« less

Perfusion scintigraphy and patient selection for lung volume reduction surgery.

PubMed

Chandra, Divay; Lipson, David A; Hoffman, Eric A; Hansen-Flaschen, John; Sciurba, Frank C; Decamp, Malcolm M; Reilly, John J; Washko, George R

2010-10-01

It is unclear if lung perfusion can predict response to lung volume reduction surgery (LVRS). To study the role of perfusion scintigraphy in patient selection for LVRS. We performed an intention-to-treat analysis of 1,045 of 1,218 patients enrolled in the National Emphysema Treatment Trial who were non-high risk for LVRS and had complete perfusion scintigraphy results at baseline. The median follow-up was 6.0 years. Patients were classified as having upper or non-upper lobe-predominant emphysema on visual examination of the chest computed tomography and high or low exercise capacity on cardiopulmonary exercise testing at baseline. Low upper zone perfusion was defined as less than 20% of total lung perfusion distributed to the upper third of both lungs as measured on perfusion scintigraphy. Among 284 of 1,045 patients with upper lobe-predominant emphysema and low exercise capacity at baseline, the 202 with low upper zone perfusion had lower mortality with LVRS versus medical management (risk ratio [RR], 0.56; P = 0.008) unlike the remaining 82 with high perfusion where mortality was unchanged (RR, 0.97; P = 0.62). Similarly, among 404 of 1,045 patients with upper lobe-predominant emphysema and high exercise capacity, the 278 with low upper zone perfusion had lower mortality with LVRS (RR, 0.70; P = 0.02) unlike the remaining 126 with high perfusion (RR, 1.05; P = 1.00). Among the 357 patients with non-upper lobe-predominant emphysema (75 with low and 282 with high exercise capacity) there was no improvement in survival with LVRS and measurement of upper zone perfusion did not contribute new prognostic information. Compared with optimal medical management, LVRS reduces mortality in patients with upper lobe-predominant emphysema when there is low rather than high perfusion to the upper lung.

Lung cancer perfusion: can we measure pulmonary and bronchial circulation simultaneously?

PubMed

Yuan, Xiaodong; Zhang, Jing; Ao, Guokun; Quan, Changbin; Tian, Yuan; Li, Hong

2012-08-01

To describe a new CT perfusion technique for assessing the dual blood supply in lung cancer and present the initial results. This study was approved by the institutional review board. A CT protocol was developed, and a dual-input CT perfusion (DI-CTP) analysis model was applied and evaluated regarding the blood flow fractions in lung tumours. The pulmonary trunk and the descending aorta were selected as the input arteries for the pulmonary circulation and the bronchial circulation respectively. Pulmonary flow (PF), bronchial flow (BF), and a perfusion index (PI, = PF/ (PF + BF)) were calculated using the maximum slope method. After written informed consent was obtained, 13 consecutive subjects with primary lung cancer underwent DI-CTP. Perfusion results are as follows: PF, 13.45 ± 10.97 ml/min/100 ml; BF, 48.67 ± 28.87 ml/min/100 ml; PI, 21 % ± 11 %. BF is significantly larger than PF, P < 0.001. There is a negative correlation between the tumour volume and perfusion index (r = 0.671, P = 0.012). The dual-input CT perfusion analysis method can be applied successfully to lung tumours. Initial results demonstrate a dual blood supply in primary lung cancer, in which the systemic circulation is dominant, and that the proportion of the two circulation systems is moderately dependent on tumour size. A new CT perfusion technique can assess lung cancer's dual blood supply. A dual blood supply was confirmed with dominant bronchial circulation in lung cancer. The proportion of the two circulations is moderately dependent on tumour size. This new technique may benefit the management of lung cancer.

Profiling inflammation and tissue injury markers in perfusate and bronchoalveolar lavage fluid during human ex vivo lung perfusion.

PubMed

Andreasson, Anders S I; Karamanou, Danai M; Gillespie, Colin S; Özalp, Faruk; Butt, Tanveer; Hill, Paul; Jiwa, Kasim; Walden, Hannah R; Green, Nicola J; Borthwick, Lee A; Clark, Stephen C; Pauli, Henning; Gould, Kate F; Corris, Paul A; Ali, Simi; Dark, John H; Fisher, Andrew J

2017-03-01

Availability of donor lungs suitable for transplant falls short of current demand and contributes to waiting list mortality. Ex vivo lung perfusion (EVLP) offers the opportunity to objectively assess and recondition organs unsuitable for immediate transplant. Identifying robust biomarkers that can stratify donor lungs during EVLP to use or non-use or for specific interventions could further improve its clinical impact. In this pilot study, 16 consecutive donor lungs unsuitable for immediate transplant were assessed by EVLP. Key inflammatory mediators and tissue injury markers were measured in serial perfusate samples collected hourly and in bronchoalveolar lavage fluid (BALF) collected before and after EVLP. Levels were compared between donor lungs that met criteria for transplant and those that did not. Seven of the 16 donor lungs (44%) improved during EVLP and were transplanted with uniformly good outcomes. Tissue and vascular injury markers lactate dehydrogenase, HMGB-1 and Syndecan-1 were significantly lower in perfusate from transplanted lungs. A model combining IL-1β and IL-8 concentrations in perfusate could predict final EVLP outcome after 2 h assessment. In addition, perfusate IL-1β concentrations showed an inverse correlation to recipient oxygenation 24 h post-transplant. This study confirms the feasibility of using inflammation and tissue injury markers in perfusate and BALF to identify donor lungs most likely to improve for successful transplant during clinical EVLP. These results support examining this issue in a larger study. © The Author 2016. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery.

Cytokine filtration modulates pulmonary metabolism and edema formation during ex vivo lung perfusion.

PubMed

Iskender, Ilker; Cosgun, Tugba; Arni, Stephan; Trinkwitz, Michael; Fehlings, Stefan; Yamada, Yoshito; Cesarovic, Nikola; Yu, Keke; Frauenfelder, Thomas; Jungraithmayr, Wolfgang; Weder, Walter; Inci, Ilhan

2017-05-20

Ex vivo lung perfusion (EVLP) has improved the process of donor lung management. Cytokine accumulation during EVLP has been shown to correlate with worse outcome after lung transplantation. Our objective in this study was to test the safety and efficacy of cytokine filtration during EVLP in a large animal model. Pig donor lungs were preserved for 24 hours at 4°C, followed by 12 hours of EVLP, according to the Toronto protocol. The perfusate was continuously run through an absorbent device (CytoSorb) via a veno-venous shunt from the reservoir in the filter group. EVLP was performed according to the standard protocol in the control group (n = 5 each). EVLP physiology, lung X-ray, perfusate biochemistry, inflammatory response and microscopic injury were assessed. Cytokine filtration significantly improved airway pressure and dynamic compliance during the 12-hour perfusion period. Lung X-rays acquired at the end of perfusion showed increased consolidation in the control group. Electrolyte imbalance, determined by increased hydrogen, potassium and calcium ion concentrations in the perfusate, was markedly worsened in the control group. Glucose consumption and lactate production were markedly reduced, along with the lactate/pyruvate ratio in the filter group. Cytokine expression profile, tissue myeloperoxidase activity and microscopic lung injury were significantly reduced in the filter group. Continuous perfusate filtration through sorbent beads is effective and safe during prolonged EVLP. Cytokine removal decreased the development of pulmonary edema and electrolyte imbalance through the suppression of anaerobic glycolysis and neutrophil activation in this setting. Further studies are needed to test the beneficial effect of cytokine filtration on post-transplant lung function. Copyright © 2017 International Society for the Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

Hypercapnic acidosis modulates inflammation, lung mechanics, and edema in the isolated perfused lung.

PubMed

De Smet, Hilde R; Bersten, Andrew D; Barr, Heather A; Doyle, Ian R

2007-12-01

Low tidal volume (V(T)) ventilation strategies may be associated with permissive hypercapnia, which has been shown by ex vivo and in vivo studies to have protective effects. We hypothesized that hypercapnic acidosis may be synergistic with low V(T) ventilation; therefore, we studied the effects of hypercapnia and V(T) on unstimulated and lipopolysaccharide-stimulated isolated perfused lungs. Isolated perfused rat lungs were ventilated for 2 hours with low (7 mL/kg) or moderately high (20 mL/kg) V(T) and 5% or 20% CO(2), with lipopolysaccharide or saline added to the perfusate. Hypercapnia resulted in reduced pulmonary edema, lung stiffness, tumor necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6) in the lavage and perfusate. The moderately high V(T) did not cause lung injury but increased lavage IL-6 and perfusate IL-6 as well as TNF-alpha. Pulmonary edema and respiratory mechanics improved, possibly as a result of a stretch-induced increase in surfactant turnover. Lipopolysaccharide did not induce significant lung injury. We conclude that hypercapnia exerts a protective effect by modulating inflammation, lung mechanics, and edema. The moderately high V(T) used in this study stimulated inflammation but paradoxically improved edema and lung mechanics with an associated increase in surfactant release.

Suppression of pulmonary vasculature in lung perfusion MRI using correlation analysis.

PubMed

Risse, Frank; Kuder, Tristan A; Kauczor, Hans-Ulrich; Semmler, Wolfhard; Fink, Christian

2009-11-01

The purpose of the study was to evaluate the feasibility of suppressing the pulmonary vasculature in lung perfusion MRI using cross-correlation analysis (CCA). Perfusion magnetic resonance imaging (MRI) (3D FLASH, TR/TE/flip angle: 0.8 ms/2.1 ms/40 degrees ) of the lungs was performed in seven healthy volunteers at 1.5 Tesla after injection of Gd-DTPA. CCA was performed pixel-wise in lung segmentations using the signal time-course of the main pulmonary artery and left atrium as references. Pixels with high correlation coefficients were considered as arterial or venous and excluded from further analysis. Quantitative perfusion parameters [pulmonary blood flow (PBF) and volume (PBV)] were calculated for manual lung segmentations separately, with the entire left and right lung with all intrapulmonary vessels (IPV) included, excluded manually or excluded using CCA. The application of CCA allowed reliable suppression of hilar and large IPVs. Using vascular suppression by CCA, perfusion parameters were significantly reduced (p

Histogram based analysis of lung perfusion of children after congenital diaphragmatic hernia repair.

PubMed

Kassner, Nora; Weis, Meike; Zahn, Katrin; Schaible, Thomas; Schoenberg, Stefan O; Schad, Lothar R; Zöllner, Frank G

2018-05-01

To investigate a histogram based approach to characterize the distribution of perfusion in the whole left and right lung by descriptive statistics and to show how histograms could be used to visually explore perfusion defects in two year old children after Congenital Diaphragmatic Hernia (CDH) repair. 28 children (age of 24.2±1.7months; all left sided hernia; 9 after extracorporeal membrane oxygenation therapy) underwent quantitative DCE-MRI of the lung. Segmentations of left and right lung were manually drawn to mask the calculated pulmonary blood flow maps and then to derive histograms for each lung side. Individual and group wise analysis of histograms of left and right lung was performed. Ipsilateral and contralateral lung show significant difference in shape and descriptive statistics derived from the histogram (Wilcoxon signed-rank test, p<0.05) on group wise and individual level. Subgroup analysis (patients with vs without ECMO therapy) showed no significant differences using histogram derived parameters. Histogram analysis can be a valuable tool to characterize and visualize whole lung perfusion of children after CDH repair. It allows for several possibilities to analyze the data, either describing the perfusion differences between the right and left lung but also to explore and visualize localized perfusion patterns in the 3D lung volume. Subgroup analysis will be possible given sufficient sample sizes. Copyright © 2017 Elsevier Inc. All rights reserved.

Functional mechanism of lung mosaic CT attenuation: assessment with deep-inspiration breath-hold perfusion SPECT-CT fusion imaging and non-breath-hold Technegas SPECT.

PubMed

Suga, K; Yasuhiko, K; Iwanaga, H; Tokuda, O; Matsunaga, N

2009-01-01

The functional mechanism of lung mosaic computed tomography attenuation (MCA) in pulmonary vascular disease (PVD) and obstructive airway disease (OAD) has not yet been fully clarified. To clarify the mechanism of MCA in these diseases by assessing the relationship between regional lung function and CT attenuation change at MCA sites with the use of automated deep-inspiratory breath-hold (DIBrH) perfusion single-photon emission computed tomography (SPECT)-CT fusion images and non-breath-hold Technegas SPECT. Subjects were 42 PVD patients (31 pulmonary thromboembolism, four primary/two secondary pulmonary hypertension, and five Takayasu arteritis), 12 OAD patients (five acute asthma, four obliterative bronchiolitis, and three bronchiectasis), and 12 normal controls, all of whom had MCA on DIBrH CT. The relationship between regional lung function and CT attenuation change at the lung slices with MCA was assessed using DIBrH perfusion SPECT-CT fusion images and non-breath-hold Technegas SPECT. The severity of perfusion defects with or without MCA was quantified by regions-of-interest analysis. On DIBrH CT and perfusion SPECT, in contrast to no noticeable CT attenuation abnormality and fairly uniform perfusion in controls, 60 MCA and 274 perfusion defects in PVD patients, and 18 MCA and 61 defects in OAD patients were identified, with a total of 77 ventilation defects on Technegas SPECT in all patients. SPECT-CT correlation showed that, throughout the 78 MCA sites of all patients, lung perfusion was persistently decreased at low CT attenuation and preserved at intervening high CT attenuation, while lung ventilation was poorly correlated with CT attenuation change. The radioactivity ratios of reduced perfusion and the intervening preserved perfusion at the 78 perfusion defects with MCA were significantly lower than those at the remaining 257 defects without MCA (P<0.0001). Although further validation is required, our results indicate that heterogeneous pulmonary arterial perfusion may be a dominant mechanism of MCA in PVD and OAD.

Airway pressure release ventilation during ex vivo lung perfusion attenuates injury.

PubMed

Mehaffey, J Hunter; Charles, Eric J; Sharma, Ashish K; Money, Dustin T; Zhao, Yunge; Stoler, Mark H; Lau, Christine L; Tribble, Curtis G; Laubach, Victor E; Roeser, Mark E; Kron, Irving L

2017-01-01

Critical organ shortages have resulted in ex vivo lung perfusion gaining clinical acceptance for lung evaluation and rehabilitation to expand the use of donation after circulatory death organs for lung transplantation. We hypothesized that an innovative use of airway pressure release ventilation during ex vivo lung perfusion improves lung function after transplantation. Two groups (n = 4 animals/group) of porcine donation after circulatory death donor lungs were procured after hypoxic cardiac arrest and a 2-hour period of warm ischemia, followed by a 4-hour period of ex vivo lung perfusion rehabilitation with standard conventional volume-based ventilation or pressure-based airway pressure release ventilation. Left lungs were subsequently transplanted into recipient animals and reperfused for 4 hours. Blood gases for partial pressure of oxygen/inspired oxygen fraction ratios, airway pressures for calculation of compliance, and percent wet weight gain during ex vivo lung perfusion and reperfusion were measured. Airway pressure release ventilation during ex vivo lung perfusion significantly improved left lung oxygenation at 2 hours (561.5 ± 83.9 mm Hg vs 341.1 ± 136.1 mm Hg) and 4 hours (569.1 ± 18.3 mm Hg vs 463.5 ± 78.4 mm Hg). Likewise, compliance was significantly higher at 2 hours (26.0 ± 5.2 mL/cm H 2 O vs 15.0 ± 4.6 mL/cm H 2 O) and 4 hours (30.6 ± 1.3 mL/cm H 2 O vs 17.7 ± 5.9 mL/cm H 2 O) after transplantation. Finally, airway pressure release ventilation significantly reduced lung edema development on ex vivo lung perfusion on the basis of percentage of weight gain (36.9% ± 14.6% vs 73.9% ± 4.9%). There was no difference in additional edema accumulation 4 hours after reperfusion. Pressure-directed airway pressure release ventilation strategy during ex vivo lung perfusion improves the rehabilitation of severely injured donation after circulatory death lungs. After transplant, these lungs demonstrate superior lung-specific oxygenation and dynamic compliance compared with lungs ventilated with standard conventional ventilation. This strategy, if implemented into clinical ex vivo lung perfusion protocols, could advance the field of donation after circulatory death lung rehabilitation to expand the lung donor pool. Copyright © 2016 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.

Contribution of the bronchial circulation to lung preservation.

PubMed

LoCicero, J; Massad, M; Matano, J; Greene, R; Dunn, M; Michaelis, L L

1991-05-01

Short preservation time still severely limits lung transplantation. To determine the effect of bronchial arterial flush preservation, we studied 54 dogs using the isolated perfused working lung model. After baseline measurements, lungs were flushed with lactated Ringer's solution (60 ml/kg at 8 degrees C) by one of three methods: pulmonary artery perfusion, bronchial artery perfusion through a 15 cm closed aortic segment, or simultaneous pulmonary-bronchial artery perfusion. These groups were further subdivided and tested after 0, 4, and 17 hours of storage at 4 degrees C (n = 6 each). Lungs were ventilated (flow rate 140 ml/kg/min; inspired oxygen fraction 0.21) and continuously reperfused with normothermic deoxygenated autologous blood in a closed loop. Measured variables were hemodynamics, aerodynamics, and leukocytes in bronchoalveolar lavage. Survival time was determined from initial reperfusion to failure of the lung to oxygenate. After 0 and 4 hours of storage, there was no significant difference in survival times. After 17 hours, lungs subjected to pulmonary-bronchial artery perfusion survived longer than those perfused via either the pulmonary or bronchial arteries alone (120 +/- 24 versus 38 +/- 14 or 52 +/- 16 minutes; p less than 0.01). Pulmonary artery pressure and resistance in all groups except at failure were never different from baseline values in the intact animal. Shunts in the pulmonary-bronchial artery perfusion groups were closest to baseline at onset (8% +/- 4%) and remained lower throughout reperfusion than in the groups subjected to pulmonary or bronchial artery perfusion alone. After 17 hours, static compliance of pulmonary artery-perfused lungs was worse than baseline (1.1 +/- 0.2 x 10(-2) versus 3.2 +/- 0.7 x 10(-2) L/cm H2O/sec; p less than 0.05), whereas compliance in the pulmonary-bronchial artery perfusion groups remained constant (3.6 +/- 1.5 x 10(-2) L/cm H2O/sec). Elastic work performed by lungs subjected to pulmonary-bronchial artery flushing at onset was significantly lower when these lungs were reperfused immediately (201 +/- 14 versus 295 +/- 35 gm-m/min for pulmonary artery-flushed lungs) or after 4 hours of storage (229 +/- 30 versus 290 +/- 24 gm-m/min for pulmonary artery-flushed lungs). Bronchoalveolar lavage after 17 hours in the group subjected to pulmonary bronchial artery flushing demonstrated leukocyte counts similar to those of intact lungs (45 +/- 5 versus 29 +/- 8/mm3) and significantly less than in lungs subjected to pulmonary or bronchial artery flushing (137 +/- 18 or 82 +/- 10/mm3, respectively).(ABSTRACT TRUNCATED AT 400 WORDS)

Perfusion-related stimuli for compensatory lung growth following pneumonectomy

PubMed Central

Dane, D. Merrill; Yilmaz, Cuneyt; Gyawali, Dipendra; Iyer, Roshni; Ravikumar, Priya; Estrera, Aaron S.

2016-01-01

Following pneumonectomy (PNX), two separate mechanical forces act on the remaining lung: parenchymal stress caused by lung expansion, and microvascular distension and shear caused by increased perfusion. We previously showed that parenchymal stress and strain explain approximately one-half of overall compensation; the remainder was presumptively attributed to perfusion-related factors. In this study, we directly tested the hypothesis that perturbation of regional pulmonary perfusion modulates post-PNX lung growth. Adult canines underwent banding of the pulmonary artery (PAB) to the left caudal (LCa) lobe, which caused a reduction in basal perfusion to LCa lobe without preventing the subsequent increase in its perfusion following right PNX while simultaneously exaggerating the post-PNX increase in perfusion to the unbanded lobes, thereby creating differential perfusion changes between banded and unbanded lobes. Control animals underwent sham pulmonary artery banding followed by right PNX. Pulmonary function, regional pulmonary perfusion, and high-resolution computed tomography of the chest were analyzed pre-PNX and 3-mo post-PNX. Terminally, the remaining lobes were fixed for detailed morphometric analysis. Results were compared with corresponding lobes in two control (Sham banding and normal unoperated) groups. PAB impaired the indices of post-PNX extravascular alveolar tissue growth by up to 50% in all remaining lobes. PAB enhanced the expected post-PNX increase in alveolar capillary formation, measured by the prevalence of double-capillary profiles, in both unbanded and banded lobes. We conclude that perfusion distribution provides major stimuli for post-PNX compensatory lung growth independent of the stimuli provided by lung expansion and parenchymal stress and strain. PMID:27150830

Perfusion Scintigraphy and Patient Selection for Lung Volume Reduction Surgery

PubMed Central

Chandra, Divay; Lipson, David A.; Hoffman, Eric A.; Hansen-Flaschen, John; Sciurba, Frank C.; DeCamp, Malcolm M.; Reilly, John J.; Washko, George R.

2010-01-01

Rationale: It is unclear if lung perfusion can predict response to lung volume reduction surgery (LVRS). Objectives: To study the role of perfusion scintigraphy in patient selection for LVRS. Methods: We performed an intention-to-treat analysis of 1,045 of 1,218 patients enrolled in the National Emphysema Treatment Trial who were non–high risk for LVRS and had complete perfusion scintigraphy results at baseline. The median follow-up was 6.0 years. Patients were classified as having upper or non–upper lobe–predominant emphysema on visual examination of the chest computed tomography and high or low exercise capacity on cardiopulmonary exercise testing at baseline. Low upper zone perfusion was defined as less than 20% of total lung perfusion distributed to the upper third of both lungs as measured on perfusion scintigraphy. Measurements and Main Results: Among 284 of 1,045 patients with upper lobe–predominant emphysema and low exercise capacity at baseline, the 202 with low upper zone perfusion had lower mortality with LVRS versus medical management (risk ratio [RR], 0.56; P = 0.008) unlike the remaining 82 with high perfusion where mortality was unchanged (RR, 0.97; P = 0.62). Similarly, among 404 of 1,045 patients with upper lobe–predominant emphysema and high exercise capacity, the 278 with low upper zone perfusion had lower mortality with LVRS (RR, 0.70; P = 0.02) unlike the remaining 126 with high perfusion (RR, 1.05; P = 1.00). Among the 357 patients with non–upper lobe–predominant emphysema (75 with low and 282 with high exercise capacity) there was no improvement in survival with LVRS and measurement of upper zone perfusion did not contribute new prognostic information. Conclusions: Compared with optimal medical management, LVRS reduces mortality in patients with upper lobe–predominant emphysema when there is low rather than high perfusion to the upper lung. PMID:20538961

Ex vivo lung perfusion: a comprehensive review of the development and exploration of future trends.

PubMed

Roman, Marius A; Nair, Sukumaran; Tsui, Steven; Dunning, John; Parmar, Jasvir S

2013-09-01

There is a critical mismatch between the number of donor lungs available and the demand for lungs for transplantation. This has created unacceptably high waiting-list mortality for lung transplant recipients. Currently (2012) in the United Kingdom, there are 216 patients on the lung transplant waiting list and 17 on heart and lung transplant list. The waiting times for suitable lungs average 412 days, with an increasing mortality and morbidity among the patients on the lung transplant list. Ex vivo lung perfusion (EVLP) has emerged as a technique for the assessment, resuscitation, and potential repair of suboptimal donor lungs. This is a rapidly developing field with significant clinical implications. In this review article, we critically appraise the background developments that have led to our current clinical practice. In particular, we focus on the human and animal experience, the different perfusion-ventilation strategies, and the impact of different perfusates and leukocyte filters. Finally, we examine EVLP as a potential research tool. This will provide insight into EVLP and its future development in the field of clinical lung transplantation.

Graft downsizing during ex vivo lung perfusion: case report and technical notes.

PubMed

Nosotti, M; Rosso, L; Mendogni, P; Tosi, D; Palleschi, A; Righi, I; Froio, S; Valenza, F; Santambrogio, L

2014-09-01

Among patients with respiratory insufficiency awaiting lung transplantation, small adult patients have a lower opportunity of receiving size-matched pulmonary grafts, because of the shortage of donors, particularly those of small size. Reducing the size of an oversized graft is one of the methods to increase the donor pool; similarly, ex vivo lung perfusion is an emerging technique aimed toward the same purpose. We describe how we combined the 2 techniques (lobar transplantation plus contralateral nonanatomic graft reduction during ex vivo lung perfusion) to overcome graft shortage in a clinical case. For the 1st time, this case report demonstrates that surgical manipulation during ex vivo lung perfusion does not affect the functional improvement in a lung previously judged to be not suitable for transplantation. The 6-month follow-up results are similar to those of standard bilateral lung transplantation. Copyright © 2014 Elsevier Inc. All rights reserved.

Quantitative lung perfusion evaluation using Fourier decomposition perfusion MRI.

PubMed

Kjørstad, Åsmund; Corteville, Dominique M R; Fischer, Andre; Henzler, Thomas; Schmid-Bindert, Gerald; Zöllner, Frank G; Schad, Lothar R

2014-08-01

To quantitatively evaluate lung perfusion using Fourier decomposition perfusion MRI. The Fourier decomposition (FD) method is a noninvasive method for assessing ventilation- and perfusion-related information in the lungs, where the perfusion maps in particular have shown promise for clinical use. However, the perfusion maps are nonquantitative and dimensionless, making follow-ups and direct comparisons between patients difficult. We present an approach to obtain physically meaningful and quantifiable perfusion maps using the FD method. The standard FD perfusion images are quantified by comparing the partially blood-filled pixels in the lung parenchyma with the fully blood-filled pixels in the aorta. The percentage of blood in a pixel is then combined with the temporal information, yielding quantitative blood flow values. The values of 10 healthy volunteers are compared with SEEPAGE measurements which have shown high consistency with dynamic contrast enhanced-MRI. All pulmonary blood flow (PBF) values are within the expected range. The two methods are in good agreement (mean difference = 0.2 mL/min/100 mL, mean absolute difference = 11 mL/min/100 mL, mean PBF-FD = 150 mL/min/100 mL, mean PBF-SEEPAGE = 151 mL/min/100 mL). The Bland-Altman plot shows a good spread of values, indicating no systematic bias between the methods. Quantitative lung perfusion can be obtained using the Fourier Decomposition method combined with a small amount of postprocessing. Copyright © 2013 Wiley Periodicals, Inc.

Normal versus sickle red blood cells: hemodynamic and permeability characteristics in reperfusion lung injury.

PubMed

Haynes, J; Seibert, A; Shah, A; Taylor, A

1990-01-01

Decreased deformability and increased internal viscosity of the sickle red blood cell (SRBC) contribute to abnormal flow in the microcirculation. Since the lungs are commonly affected in sickle cell disease, we compared the hemodynamics of the normal human red blood cell (NRBC) with the SRBC in the pulmonary circulation. The SRBC has decreased antioxidant enzyme activities compared with the NRBC. Thus, using the capillary filtration coefficient (Kfc), we determined the ability of the NRBC and the SRBC to attenuate the increased permeability and resulting edema seen in the oxidant stress of reperfusion lung injury (RLI). We found that lungs perfused with a 5% SRBC perfusate had higher pulmonary arterial pressures (Ppa) and resistances than lungs perfused with a 5% NRBC perfusate. Lungs made ischemic and reperfused with a physiologic cell-free perfusate resulted in a significant increase (P less than .05) in Kfc compared with the preischemic Kfc (.45 +/- .06 to 1.4 +/- 22 mL.min-1.cm H2O.100 g-1). In lungs reperfused with 5% RBC-containing perfusates, the Kfc did not change from preischemic Kfc with NRBCs and decreased from the preischemic Kfc with SRBCs. These findings suggest that the SRBC causes physiologically significant increases in Ppa and resistances and the SRBC, like the NRBC, offers apparent protection in RLI.

Effects of Constant Flow vs. Constant Pressure Perfusion on Fluid Filtration in Severe Hypothermic Isolated Blood-Perfused Rat Lungs.

PubMed

Halsøy, Kathrine; Kondratiev, Timofey; Tveita, Torkjel; Bjertnaes, Lars J

2016-01-01

Victims of severe accidental hypothermia are prone to fluid extravasation but rarely develop lung edema. We hypothesize that combined hypothermia-induced increase in pulmonary vascular resistance (PVR) and a concomitant fall in cardiac output protect the lungs against edema development. Our aim was to explore in hypothermic-isolated blood-perfused rat lungs whether perfusion at constant pressure influences fluid filtration differently from perfusion at constant flow. Isolated blood-perfused rat lungs were hanging freely in a weight transducer for measuring weight changes (ΔW). Fluid filtration coefficient (Kfc), was determined by transiently elevating left atrial pressure (Pla) by 5.8 mmHg two times each during normothermia (37°C) and during hypothermia (15°C). The lung preparations were randomized to two groups. One group was perfused with constant flow (Constant flow group) and the other group with constant pulmonary artery pressure (Constant PPA group). Microvascular pressure (Pmv) was determined before and during elevation of Pla (ΔPmv) by means of the double occlusion technique. Kfc was calculated with the formula Kfc = ΔW/ΔPmv/min. All Kfc values were normalized to predicted lung weight (P LW ), which was based on body weight (BW) according to the formula: P LW  = 0.0053 BW - 0.48 and presented as Kfc PLW in mg/min/mmHg/g. At cessation, bronchoalveolar lavage (BAL) fluid/perfusate protein concentration (B/P) ratio was determined photometrically. Data were analyzed with parametric or non-parametric tests as appropriate. p  < 0.05 considered as significant. Perfusate flow remained constant in the Constant flow group, but was more than halved during hypothermia in the Constant PPA group concomitant with a more fold increase in PVR. In the Constant flow group, Kfc PLW and B/P ratio increased significantly by more than 10-fold during hypothermia concerted by visible signs of edema in the trachea. Hemoglobin and hematocrit increased within the Constant flow group and between the groups at cessation of the experiments. In hypothermic rat lungs perfused at constant flow, fluid filtration coefficient per gram P LW and B/P ratio increased more than 10-fold concerted by increased hemoconcentration, but the changes were less in hypothermic lungs perfused at constant PPA.

Tumor Vessel Compression Hinders Perfusion of Ultrasonographic Contrast Agents1

PubMed Central

Galiè, Mirco; D'Onofrio, Mirko; Montani, Maura; Amici, Augusto; Calderan, Laura; Marzola, Pasquina; Benati, Donatella; Merigo, Flavia; Marchini, Cristina; Sbarbati, Andrea

2005-01-01

Abstract Contrast-enhanced ultrasound (CEUS) is an advanced approach to in vivo assessment of tumor vascularity and is being increasingly adopted in clinical oncology. It is based on 1- to 10 µm-sized gas microbubbles, which can cross the capillary beds of the lungs and are effective echo enhancers. It is known that high cell density, high transendothelial fluid exchange, and poorly functioning lymphatic circulation all provoke solid stress, which compresses vessels and drastically reduces tumor blood flow. Given their size, we supposed that the perfusion of microbubbles is affected by anatomic features of tumor vessels more than are contrast agents traditionally used in dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Here, we compared dynamic information obtained from CEUS and DCE-MRI on two experimental tumor models exhibiting notable differences in vessel anatomy. We found that tumors with small, flattened vessels show a much higher resistance to microbubble perfusion than to MRI contrast agents, and appear scarcely vascularized at CEUS examination, despite vessel volume adequate for normal function. Thus, whereas CEUS alone could induce incorrect diagnosis when tumors have small or collapsed vessels, integrated analysis using CEUS and DCE-MRI allows in vivo identification of tumors with a vascular profile frequently associated with malignant phenotypes. PMID:15967105

Scintigraphy at 3 months after single lung transplantation and observations of primary graft dysfunction and lung function.

PubMed

Belmaati, Esther Okeke; Iversen, Martin; Kofoed, Klaus F; Nielsen, Michael B; Mortensen, Jann

2012-06-01

Scintigraphy has been used as a tool to detect dysfunction of the lung before and after transplantation. The aims of this study were to evaluate the development of the ventilation-perfusion relationships in single lung transplant recipients in the first year, at 3 months after transplantation, and to investigate whether scintigraphic findings at 3 months were predictive for the outcome at 12 months in relation to primary graft dysfunction (PGD) and lung function. A retrospective study was carried out on all patients who prospectively and consecutively were referred for a routine lung scintigraphy procedure 3 months after single lung transplantation (SLTX). A total of 41 patients were included in the study: 20 women and 21 men with the age span of patients at transplantation being 38-66 years (mean ± SD: 54.2 ± 6.0). Patient records also included lung function tests and chest X-ray images. We found no significant correlation between lung function distribution at 3 months and PGD at 72 h. There was also no significant correlation between PGD scores at 72 h and lung function at 6 and 12 months. The same applied to scintigraphic scores for heterogeneity at 3 months compared with lung function at 6 and 12 months. Fifty-five percent of all patients had decreased ventilation function measured in the period from 6 to 12 months. Forty-nine percent of the patients had normal perfusion evaluations, and 51% had abnormal perfusion evaluations at 3 months. For ventilation evaluations, 72% were normal and 28% were abnormal. There was a significant difference in the normal versus abnormal perfusion and ventilation scintigraphic images evaluated from the same patients. Ventilation was distributed more homogenously in the transplanted lung than perfusion in the same lung. The relative distribution of perfusion and ventilation to the transplanted lung of patients with and without a primary diagnosis of fibrosis did not differ significantly from each other. We conclude that PGD defined at 72 h does not lead to recognizable changes in ventilation-perfusion scintigrapy at 3 months, and scintigraphic findings do not correlate with development in lung function in the first 12 months.

Pulmonary Perfusion Changes as Assessed by Contrast-Enhanced Dual-Energy Computed Tomography after Endoscopic Lung Volume Reduction by Coils.

PubMed

Lador, Frédéric; Hachulla, Anne-Lise; Hohn, Olivia; Plojoux, Jérôme; Ronot, Maxime; Montet, Xavier; Soccal, Paola M

2016-01-01

Endoscopic lung volume reduction by coils (LVRC) is a recent treatment approach for severe emphysema. Furthermore, dual-energy computed tomography (DECT) now offers a combined assessment of lung morphology and pulmonary perfusion. The aim of our study was to assess the impact of LVRC on pulmonary perfusion with DECT. Seventeen patients (64.8 ± 6.7 years) underwent LVRC. DECT was performed prior to and after LVRC. For each patient, lung volumes and emphysema quantification were automatically calculated. Then, 6 regions of interest (ROIs) on the iodine perfusion map were drawn in the anterior, mid, and posterior right and left lungs at 4 defined levels. The ROI values were averaged to obtain lung perfusion as assessed by the lung's iodine concentration (CLung, μg·cm-3). The CLung values were normalized using the left atrial iodine concentration (CLA) to take into account differences between successive DECT scans. The 6-min walk distance (6MWD) improved significantly after the procedure (p = 0.0002). No lung volume changes were observed between successive DECT scans for any of the patients (p = 0.32), attesting the same suspended inspiration. After LVRC, the emphysema index was significantly reduced in the treated lung (p = 0.0014). Lung perfusion increased significantly adjacent to the treated areas (CLung/CLA from 3.4 ± 1.7 to 5.6 ± 2.2, p < 0.001) and in the ipsilateral untreated areas (from 4.1 ± 1.4 to 6.6 ± 1.7, p < 0.001), corresponding to a mean 65 and 61% increase in perfusion, respectively. No significant difference was observed in the contralateral upper and lower areas (from 4.4 ± 1.9 to 4.8 ± 2.1, p = 0.273, and from 4.9 ± 2.0 to 5.2 ± 1.7, p = 0.412, respectively). A significant correlation between increased 6MWD and increased perfusion was found (p = 0.0027, R2 = 0.3850). Quantitative analysis based on DECT acquisition revealed that LVRC results in a significant increase in perfusion in the coil-free areas adjacent to the treated ones, as well as in the ipsilateral untreated areas. This suggests a possible role for LVRC in the improvement of the ventilation/perfusion relationship. © 2016 S. Karger AG, Basel.

Perfusion CT of the Brain and Liver and of Lung Tumors: Use of Monte Carlo Simulation for Patient Dose Estimation for Examinations With a Cone-Beam 320-MDCT Scanner.

PubMed

Cros, Maria; Geleijns, Jacob; Joemai, Raoul M S; Salvadó, Marçal

2016-01-01

The purpose of this study was to estimate the patient dose from perfusion CT examinations of the brain, lung tumors, and the liver on a cone-beam 320-MDCT scanner using a Monte Carlo simulation and the recommendations of the International Commission on Radiological Protection (ICRP). A Monte Carlo simulation based on the Electron Gamma Shower Version 4 package code was used to calculate organ doses and the effective dose in the reference computational phantoms for an adult man and adult woman as published by the ICRP. Three perfusion CT acquisition protocols--brain, lung tumor, and liver perfusion--were evaluated. Additionally, dose assessments were performed for the skin and for the eye lens. Conversion factors were obtained to estimate effective doses and organ doses from the volume CT dose index and dose-length product. The sex-averaged effective doses were approximately 4 mSv for perfusion CT of the brain and were between 23 and 26 mSv for the perfusion CT body protocols. The eye lens dose from the brain perfusion CT examination was approximately 153 mGy. The sex-averaged peak entrance skin dose (ESD) was 255 mGy for the brain perfusion CT studies, 157 mGy for the lung tumor perfusion CT studies, and 172 mGy for the liver perfusion CT studies. The perfusion CT protocols for imaging the brain, lung tumors, and the liver performed on a 320-MDCT scanner yielded patient doses that are safely below the threshold doses for deterministic effects. The eye lens dose, peak ESD, and effective doses can be estimated for other clinical perfusion CT examinations from the conversion factors that were derived in this study.

The effect of lung deformation on the spatial distribution of pulmonary blood flow.

PubMed

Arai, Tatsuya J; Theilmann, Rebecca J; Sá, Rui Carlos; Villongco, Michael T; Hopkins, Susan R

2016-11-01

Pulmonary perfusion measurement using magnetic resonance imaging combined with deformable image registration enabled us to quantify the change in the spatial distribution of pulmonary perfusion at different lung volumes. The current study elucidated the effects of tidal volume lung inflation [functional residual capacity (FRC) + 500 ml and FRC + 1 litre] on the change in pulmonary perfusion distribution. Changes in hydrostatic pressure distribution as well as transmural pressure distribution due to the change in lung height with tidal volume inflation are probably bigger contributors to the redistribution of pulmonary perfusion than the changes in pulmonary vasculature resistance caused by lung tissue stretch. Tidal volume lung inflation results in structural changes in the pulmonary circulation, potentially affecting pulmonary perfusion. We hypothesized that perfusion is recruited to regions receiving the greatest deformation from a tidal breath, thus ensuring ventilation-perfusion matching. Density-normalized perfusion (DNP) magnetic resonance imaging data were obtained in healthy subjects (n = 7) in the right lung at functional residual capacity (FRC), FRC+500 ml, and FRC+1.0 l. Using deformable image registration, the displacement of a sagittal lung slice acquired at FRC to the larger volumes was calculated. Registered DNP images were normalized by the mean to estimate perfusion redistribution (nDNP). Data were evaluated across gravitational regions (dependent, middle, non-dependent) and by lobes (upper, RUL; middle, RML; lower, RLL). Lung inflation did not alter mean DNP within the slice (P = 0.10). The greatest expansion was seen in the dependent region (P < 0.0001: dependent vs non-dependent, P < 0.0001: dependent vs middle) and RLL (P = 0.0015: RLL vs RUL, P < 0.0001: RLL vs RML). Neither nDNP recruitment to RLL [+500 ml = -0.047(0.145), +1 litre = 0.018(0.096)] nor to dependent lung [+500 ml = -0.058(0.126), +1 litre = -0.023(0.106)] were found. Instead, redistribution was seen in decreased nDNP in the non-dependent [+500 ml = -0.075(0.152), +1 litre = -0.137(0.167)) and increased nDNP in the gravitational middle lung [+500 ml = 0.098(0.058), +1 litre = 0.093(0.081)] (P = 0.01). However, there was no significant lobar redistribution (P < 0.89). Contrary to our hypothesis, based on the comparison between gravitational and lobar perfusion data, perfusion was not redistributed to the regions of the most inflation. This suggests that either changes in hydrostatic pressure or transmural pressure distribution in the gravitational direction are implicated in the redistribution of perfusion away from the non-dependent lung. © 2016 The Authors. The Journal of Physiology © 2016 The Physiological Society.

The effect of lung deformation on the spatial distribution of pulmonary blood flow

PubMed Central

Arai, Tatsuya J.; Theilmann, Rebecca J.; Sá, Rui Carlos; Villongco, Michael T.

2016-01-01

Key points Pulmonary perfusion measurement using magnetic resonance imaging combined with deformable image registration enabled us to quantify the change in the spatial distribution of pulmonary perfusion at different lung volumes.The current study elucidated the effects of tidal volume lung inflation [functional residual capacity (FRC) + 500 ml and FRC + 1 litre] on the change in pulmonary perfusion distribution.Changes in hydrostatic pressure distribution as well as transmural pressure distribution due to the change in lung height with tidal volume inflation are probably bigger contributors to the redistribution of pulmonary perfusion than the changes in pulmonary vasculature resistance caused by lung tissue stretch. Abstract Tidal volume lung inflation results in structural changes in the pulmonary circulation, potentially affecting pulmonary perfusion. We hypothesized that perfusion is recruited to regions receiving the greatest deformation from a tidal breath, thus ensuring ventilation–perfusion matching. Density‐normalized perfusion (DNP) magnetic resonance imaging data were obtained in healthy subjects (n = 7) in the right lung at functional residual capacity (FRC), FRC+500 ml, and FRC+1.0 l. Using deformable image registration, the displacement of a sagittal lung slice acquired at FRC to the larger volumes was calculated. Registered DNP images were normalized by the mean to estimate perfusion redistribution (nDNP). Data were evaluated across gravitational regions (dependent, middle, non‐dependent) and by lobes (upper, RUL; middle, RML; lower, RLL). Lung inflation did not alter mean DNP within the slice (P = 0.10). The greatest expansion was seen in the dependent region (P < 0.0001: dependent vs non‐dependent, P < 0.0001: dependent vs middle) and RLL (P = 0.0015: RLL vs RUL, P < 0.0001: RLL vs RML). Neither nDNP recruitment to RLL [+500 ml = −0.047(0.145), +1 litre = 0.018(0.096)] nor to dependent lung [+500 ml = −0.058(0.126), +1 litre = −0.023(0.106)] were found. Instead, redistribution was seen in decreased nDNP in the non‐dependent [+500 ml = −0.075(0.152), +1 litre = −0.137(0.167)) and increased nDNP in the gravitational middle lung [+500 ml = 0.098(0.058), +1 litre = 0.093(0.081)] (P = 0.01). However, there was no significant lobar redistribution (P < 0.89). Contrary to our hypothesis, based on the comparison between gravitational and lobar perfusion data, perfusion was not redistributed to the regions of the most inflation. This suggests that either changes in hydrostatic pressure or transmural pressure distribution in the gravitational direction are implicated in the redistribution of perfusion away from the non‐dependent lung. PMID:27273807

Magnetic Resonance Imaging of Ventilation and Perfusion in the Lung

NASA Technical Reports Server (NTRS)

Prisk, Gordon Kim (Inventor); Hopkins, Susan Roberta (Inventor); Pereira De Sa, Rui Carlos (Inventor); Theilmann, Rebecca Jean (Inventor); Buxton, Richard Bruce (Inventor); Cronin, Matthew Vincent (Inventor)

2017-01-01

Methods, devices, and systems are disclosed for implementing a fully quantitative non-injectable contrast proton MRI technique to measure spatial ventilation-perfusion (VA/Q) matching and spatial distribution of ventilation and perfusion. In one aspect, a method using MRI to characterize ventilation and perfusion in a lung includes acquiring an MR image of the lung having MR data in a voxel and obtaining a breathing frequency parameter, determining a water density value, a specific ventilation value, and a perfusion value in at least one voxel of the MR image based on the MR data and using the water density value to determine an air content value, and determining a ventilation-perfusion ratio value that is the product of the specific ventilation value, the air content value, the inverse of the perfusion value, and the breathing frequency.

Pre- and postjunctional inhibitory effects of fenspiride on guinea-pig bronchi.

PubMed

Girard, V; Naline, E; Crambes, O; Malbezin, M; Malmström, R E; Lundberg, J M; Advenier, C

1997-05-01

Fenspiride is a drug with potential benefits in the treatment of obstructive airways disease. It has antibronchoconstriction and anti-inflammatory properties. The aim of this study was to investigate the effect of this drug on the contractions induced in the guinea-pig isolated main bronchus and perfused lung by electrical field stimulation (EFS) or exogenously added agents. Bronchi were stimulated transmurally in the presence of indomethacin 10(-6) M and propranolol 10(-6) M, and isometric tension was measured. In the perfused lung model calcitonin gene-related peptide (CGRP) release was determined in the perfusate fractions as a measure of neuropeptide production. Two successive contractile responses were observed: a rapid cholinergic contraction, followed by a long-lasting contraction due to local release of neuropeptides from C-fibre endings. Fenspiride (10(-6) to 10(-4) M) inhibited the nonadrenergic, noncholinergic (NANC) component of the contraction of the guinea-pig isolated main bronchus induced by EFS. Fenspiride significantly affected contractions induced by exogenously added substance P or [Nle10]-NKA(4-10) only at concentrations higher than 10(-3) M. In the guinea-pig perfused lung, fenspiride inhibited low pH- but not capsaicin-evoked release of CGRP. At higher concentrations (10(-4) M to 3x10(-4) M) fenspiride exhibited a significant inhibitory effect both on the cholinergic component of contractile response induced by EFS in the guinea-pig isolated main bronchus and on exogenously added acetylcholine. In conclusion, the result of this study suggests that fenspiride, in moderate concentrations, reduces the release of neuropeptides, including tachykinins, from sensory nerve endings at a prejunctional level. At higher concentrations, postjunctional actions on bronchial smooth muscle are also present.

Distribution of perfusion.

PubMed

Glenny, Robb; Robertson, H Thomas

2011-01-01

Local driving pressures and resistances within the pulmonary vascular tree determine the distribution of perfusion in the lung. Unlike other organs, these local determinants are significantly influenced by regional hydrostatic and alveolar pressures. Those effects on blood flow distribution are further magnified by the large vertical height of the human lung and the relatively low intravascular pressures in the pulmonary circulation. While the distribution of perfusion is largely due to passive determinants such as vascular geometry and hydrostatic pressures, active mechanisms such as vasoconstriction induced by local hypoxia can also redistribute blood flow. This chapter reviews the determinants of regional lung perfusion with a focus on vascular tree geometry, vertical gradients induced by gravity, the interactions between vascular and surrounding alveolar pressures, and hypoxic pulmonary vasoconstriction. While each of these determinants of perfusion distribution can be examined in isolation, the distribution of blood flow is dynamically determined and each component interacts with the others so that a change in one region of the lung influences the distribution of blood flow in other lung regions. © 2011 American Physiological Society.

Implementation and evaluation of a new workflow for registration and segmentation of pulmonary MRI data for regional lung perfusion assessment.

PubMed

Böttger, T; Grunewald, K; Schöbinger, M; Fink, C; Risse, F; Kauczor, H U; Meinzer, H P; Wolf, Ivo

2007-03-07

Recently it has been shown that regional lung perfusion can be assessed using time-resolved contrast-enhanced magnetic resonance (MR) imaging. Quantification of the perfusion images has been attempted, based on definition of small regions of interest (ROIs). Use of complete lung segmentations instead of ROIs could possibly increase quantification accuracy. Due to the low signal-to-noise ratio, automatic segmentation algorithms cannot be applied. On the other hand, manual segmentation of the lung tissue is very time consuming and can become inaccurate, as the borders of the lung to adjacent tissues are not always clearly visible. We propose a new workflow for semi-automatic segmentation of the lung from additionally acquired morphological HASTE MR images. First the lung is delineated semi-automatically in the HASTE image. Next the HASTE image is automatically registered with the perfusion images. Finally, the transformation resulting from the registration is used to align the lung segmentation from the morphological dataset with the perfusion images. We evaluated rigid, affine and locally elastic transformations, suitable optimizers and different implementations of mutual information (MI) metrics to determine the best possible registration algorithm. We located the shortcomings of the registration procedure and under which conditions automatic registration will succeed or fail. Segmentation results were evaluated using overlap and distance measures. Integration of the new workflow reduces the time needed for post-processing of the data, simplifies the perfusion quantification and reduces interobserver variability in the segmentation process. In addition, the matched morphological data set can be used to identify morphologic changes as the source for the perfusion abnormalities.

Positron emission tomography to assess hypoxia and perfusion in lung cancer

PubMed Central

Verwer, Eline E; Boellaard, Ronald; van der Veldt, Astrid AM

2014-01-01

In lung cancer, tumor hypoxia is a characteristic feature, which is associated with a poor prognosis and resistance to both radiation therapy and chemotherapy. As the development of tumor hypoxia is associated with decreased perfusion, perfusion measurements provide more insight into the relation between hypoxia and perfusion in malignant tumors. Positron emission tomography (PET) is a highly sensitive nuclear imaging technique that is suited for non-invasive in vivo monitoring of dynamic processes including hypoxia and its associated parameter perfusion. The PET technique enables quantitative assessment of hypoxia and perfusion in tumors. To this end, consecutive PET scans can be performed in one scan session. Using different hypoxia tracers, PET imaging may provide insight into the prognostic significance of hypoxia and perfusion in lung cancer. In addition, PET studies may play an important role in various stages of personalized medicine, as these may help to select patients for specific treatments including radiation therapy, hypoxia modifying therapies, and antiangiogenic strategies. In addition, specific PET tracers can be applied for monitoring therapy. The present review provides an overview of the clinical applications of PET to measure hypoxia and perfusion in lung cancer. Available PET tracers and their characteristics as well as the applications of combined hypoxia and perfusion PET imaging are discussed. PMID:25493221

Static inflation attenuates ischemia/reperfusion injury in an isolated rat lung in situ.

PubMed

Kao, Shang Jyh; Wang, David; Yeh, Diana Yu-Wung; Hsu, Kang; Hsu, Yung Hsiang; Chen, Hsing I

2004-08-01

Ischemia (I)/reperfusion (R) lung injury is an important clinical issue in lung transplantation. In the present study, we observed the effects of lung static inflation, different perfusates, and ventilatory gas with nitrogen or oxygen on the I/R-induced pulmonary damage. A total of 96 male Sprague-Dawley rats were used. The lung was isolated in situ. In an isolated lung, the capillary filtration coefficient (Kfc), lung weight gain (LWG), lung weight (LW)/body weight (BW) ratio, and protein concentration in BAL fluid (PCBAL) were measured or calculated to evaluate the degree of lung injury. Histologic examinations with hematoxylin-eosin staining were performed. I/R caused lung injury, as reflected by increases in Kfc, LWG, LW/BW, and PCBAL. The histopathologic picture revealed the presence of hyaline membrane formation and the infiltration of inflammatory cells. These values were significantly attenuated by static lung inflation. The I/R lung damage appeared to be less in the lung perfused with whole blood than in the lung perfused with an isotonic solution. Therapy with ventilatory air (ie, nitrogen or oxygen) did not alter the I/R lung damage. The data suggest that lung inflation is protective to I/R injury, irrespective of the type of ventilatory air used for treatment. The preservation of the lung for transplantation is better kept at a static inflation state and perfused with whole blood instead of an isotonic physiologic solution.

The role of interleukin-1β as a predictive biomarker and potential therapeutic target during clinical ex vivo lung perfusion.

PubMed

Andreasson, Anders S I; Borthwick, Lee A; Gillespie, Colin; Jiwa, Kasim; Scott, Jonathan; Henderson, Paul; Mayes, Jonny; Romano, Rosalba; Roman, Marius; Ali, Simi; Fildes, James E; Marczin, Nandor; Dark, John H; Fisher, Andrew J

2017-09-01

Extended criteria donor lungs deemed unsuitable for immediate transplantation can be reconditioned using ex vivo lung perfusion (EVLP). Objective identification of which donor lungs can be successfully reconditioned and will function well post-operatively has not been established. This study assessed the predictive value of markers of inflammation and tissue injury in donor lungs undergoing EVLP as part of the DEVELOP-UK study. Longitudinal samples of perfusate, bronchoalveolar lavage, and tissue from 42 human donor lungs undergoing clinical EVLP assessments were analyzed for markers of inflammation and tissue injury. Levels were compared according to EVLP success and post-transplant outcomes. Neutrophil adhesion to human pulmonary microvascular endothelial cells (HPMECs) conditioned with perfusates from EVLP assessments was investigated on a microfluidic platform. The most effective markers to differentiate between in-hospital survival and non-survival post-transplant were perfusate interleukin (IL)-1β (area under the curve = 1.00, p = 0.002) and tumor necrosis factor-α (area under the curve = 0.95, p = 0.006) after 30 minutes of EVLP. IL-1β levels in perfusate correlated with upregulation of intracellular adhesion molecule-1 in donor lung vasculature (R 2 = 0.68, p < 0.001) and to a lesser degree upregulation of intracellular adhesion molecule-1 (R 2 = 0.30, p = 0.001) and E-selectin (R 2 = 0.29, p = 0.001) in conditioned HPMECs and neutrophil adhesion to conditioned HPMECs (R 2 = 0.33, p < 0.001). Neutralization of IL-1β in perfusate effectively inhibited neutrophil adhesion to conditioned HPMECs (91% reduction, p = 0.002). Donor lungs develop a detectable and discriminatory pro-inflammatory signature in perfusate during EVLP. Blocking the IL-1β pathway during EVLP may reduce endothelial activation and subsequent neutrophil adhesion on reperfusion; this requires further investigation in vivo. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Interpretation of indeterminate lung scintigrams. [/sup 99m/Tc, /sup 133/Xe

DOE Office of Scientific and Technical Information (OSTI.GOV)

Biello, D.R.; Mattar, A.G.; Osei-Wusu, A.

1979-10-01

Lung scintigrams and pulmonary angiograms of 111 patients with suspected pulmonary embolism who had matching perfusion defects and radiographic abnormalities (infiltrate, atelectasis, or effusion) were reviewed. In 14 patients perfusion defects were substantially smaller than the corresponding radiographic opacity; only 1 (7%) had pulmonary embolism. In 77 the opacities and perfusion defects were of similar size; the abnormality was due to embolism in 20 (26%). In 18 patients perfusion defects were substantially larger than the radiographic opacities and were not associated with matching ventilation abnormalities; of these, 16 (89%) had pulmonary embolism. Evaluation of the relative size of perfusion defectsmore » and radiographic abnormalities occurring in the same region improves the ability of lung scintigrams to predict pulmonary emboli.« less

Importance of the lung perfusion scintigraphy in single lung transplantation.

PubMed

Rodríguez Mesa, N V; Guerrero Cancio, M C; Cordero Jiménez, M D; Alvarez Velázquez, I K

2012-01-01

Lung perfusion scintigraphy (LPS) with (99m)Tc-MAA gives valuable information about patients who will undergo a single lung transplantation. This technique makes it possible to evaluate and quantify the relative function of both lungs to select the organ to be transplanted. Once the surgery has been performed, the LPS represents a diagnostic method to study the status of the transplanted organ. Two patients who underwent single lung transplantation were studied in our hospital. In both cases, a pre-operative LPS was performed before surgery for selection of the organ to be transplanted and the scintigraphy study was performed a few months after transplantation to establish the perfusion function of the transplanted lung. Copyright © 2011 Elsevier España, S.L. y SEMNIM. All rights reserved.

PREOPERATIVE PREDICTION OF LUNG FUNCTION IN PNEUMONECTOMY BY SPIROMETRY AND LUNG PERFUSION SCINTIGRAPHY

PubMed Central

Cukic, Vesna

2012-01-01

Introduction: Nowadays an increasing number of lung resections are being done because of the rising prevalence of lung cancer that occurs mainly in patients with limited lung function, what is caused by common etiologic factor - smoking cigarettes. Loss of lung tissue in such patients can worsen much the postoperative pulmonary function. So it is necessary to asses the postoperative pulmonary function especially after maximal resection, i.e. pneumonectomy. Objective: To check over the accuracy of preoperative prognosis of postoperative lung function after pneumonectomy using spirometry and lung perfusion scinigraphy. Material and methods: The study was done on 17 patients operated at the Clinic for thoracic surgery, who were treated previously at the Clinic for Pulmonary Diseases “Podhrastovi” in the period from 01. 12. 2008. to 01. 06. 2011. Postoperative pulmonary function expressed as ppoFEV1 (predicted postoperative forced expiratory volume in one second) was prognosticated preoperatively using spirometry, i.e.. simple calculation according to the number of the pulmonary segments to be removed and perfusion lung scintigraphy. Results: There is no significant deviation of postoperative achieved values of FEV1 from predicted ones obtained by both methods, and there is no significant differences between predicted values (ppoFEV1) obtained by spirometry and perfusion scintigraphy. Conclusion: It is necessary to asses the postoperative pulmonary function before lung resection to avoid postoperative respiratory failure and other cardiopulmonary complications. It is absolutely necessary for pneumonectomy, i.e.. maximal pulmonary resection. It can be done with great possibility using spirometry or perfusion lung scintigraphy. PMID:23378687

DOE Office of Scientific and Technical Information (OSTI.GOV)

Crocetti, Laura, E-mail: l.crocetti@med.unipi.it; Lencioni, Riccardo; Bozzi, Elena

The purpose of this study was to investigate the feasibility and safety of lung radiofrequency (RF) ablation by using low-perfusion-rate, expandable, multitined electrodes in an in vivo animal model. Ten New Zealand White rabbits underwent RF ablation using low-perfusion-rate, expandable, multitined electrodes (Starburst Talon; RITA Medical Systems, Mountain View, CA) and a 200-W RF generator. The electrode was positioned under fluoroscopy guidance and a single percutaneous RF ablation was performed. Saline perfusate was doped with nonionic iodinated contrast agent to render it visible on computed tomography (CT). The pump infused the saline doped with contrast agent into the lateral tinesmore » at a rate of 0.1ml/min. The planned ablation was of 3 min, with the hooks deployed to 2 cm at a target temperature of 105{sup o}C. An immediate posttreatment CT scan documented the distribution of the doped saline and the presence of immediate complications. The animals were monitored for delayed complications and sacrificed within 72 h (n = 4), 2 weeks (n = 3), or 4 weeks (n = 3). Assessment of ablation zone and adjacent structures was done at autopsy. Major complications consisted of pneumothorax requiring drainage (n = 2) and skin burn (n = 1). Immediately after the procedure the area of ablation was depicted at CT as a round, well-demarcated area, homogeneously opacified by iodinated contrast medium (mean size, 2.3 {+-} 0.8 cm). The presence of a sharply demarcated area of coagulation necrosis (mean size, 2.1 {+-} 0.4 cm) without severe damage to adjacent structures was confirmed at autopsy. In one case, euthanized at 4 weeks, in whom pneumothorax and pleural effusion were depicted, pleural fibrinous adhesions were demonstrated at autopsy. In conclusion, lung RF ablation performed in an in vivo animal model using low-perfusion-rate, expandable, multitined electrodes is feasible and safe. No severe damage to adjacent structures was demonstrated.« less

Identifying the heterogeneity of COPD by V/P SPECT: a new tool for improving the diagnosis of parenchymal defects and grading the severity of small airways disease.

PubMed

Bajc, M; Chen, Y; Wang, J; Li, X Y; Shen, W M; Wang, C Z; Huang, H; Lindqvist, A; He, X Y

2017-01-01

Airway obstruction and possible concomitant pulmonary diseases in COPD cannot be identified conventionally with any single diagnostic tool. We aimed to diagnose and grade COPD severity and identify pulmonary comorbidities associated with COPD with ventilation/perfusion single-photon emission computed tomography (V/P SPECT) using Technegas as the functional ventilation imaging agent. 94 COPD patients (aged 43-86 years, Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages I-IV) were examined with V/P SPECT and spirometry. Ventilation and perfusion defects were analyzed blindly according to the European guidelines. Penetration grade of Technegas in V SPECT measured the degree of obstructive small airways disease. Total preserved lung function and penetration grade of Technegas in V SPECT were assessed by V/P SPECT and compared to GOLD stages and spirometry. Signs of small airway obstruction in the ventilation SPECT images were found in 92 patients. Emphysema was identified in 81 patients. Two patients had no signs of COPD, but both of them had a pulmonary embolism, and in one of them we also suspected a lung tumor. The penetration grade of Technegas in V SPECT and total preserved lung function correlated significantly to GOLD stages ( r =0.63 and -0.60, respectively, P <0.0001). V/P SPECT identified pulmonary embolism in 30 patients (32%). A pattern typical for heart failure was present in 26 patients (28%). Parenchymal changes typical for pneumonia or lung tumor were present in several cases. V/P SPECT, using Technegas as the functional ventilation imaging agent, is a new tool to diagnose COPD and to grade its severity. Additionally, it revealed heterogeneity of COPD caused by pulmonary comorbidities. The characteristics of these comorbidities suggest their significant impact in clarifying symptoms, and also their influence on the prognosis.

Active Oxygen Metabolites and Thromboxane in Phorbol Myristate Acetate Toxicity to the Isolated, Perfused Rat Lung.

NASA Astrophysics Data System (ADS)

Carpenter, Laurie Jean

When administered intravenously or intratracheally to rats, rabbits and sheep, phorbol myristate acetate (PMA) produces changes in lung morphology and function are similar to those seen in humans with the adult respiratory distress syndrome (ARDS). Therefore, it is thought that information about the mechanism of ARDS development can be gained from experiments using PMA-treated animals. Currently, the mechanisms by which PMA causes pneumotoxicity are unknown. Results from other studies in rabbits and in isolated, perfused rabbit lungs suggest that PMA-induced lung injury is mediated by active oxygen species from neutrophils (PMN), whereas studies in sheep and rats suggest that PMN are not required for the toxic response. The role of PMN, active oxygen metabolites and thromboxane (TxA_2) in PMA-induced injury to isolated, perfused rat lungs (IPLs) was examined in this thesis. To determine whether PMN were required for PMA to produce toxicity to the IPL, lungs were perfused for 30 min with buffer containing various concentrations of PMA (in the presence or absence of PMN). When concentrations >=q57 ng/ml were added to medium devoid of added PMN, perfusion pressure and lung weight increased. When a concentration of PMA (14-28 ng/ml) that did not by itself cause lungs to accumulate fluid was added to the perfusion medium containing PMN (1 x 10 ^8), perfusion pressure increased, and lungs accumulated fluid. These results indicate that high concentrations of PMA produce lung injury which is independent of PMN, whereas injury induced by lower concentrations is PMN-dependent. To examine whether active oxygen species were involved in mediating lung injury induced by PMA and PMN, lungs were coperfused with the oxygen radical scavengers SOD and/or catalase. Coperfusion with either or both of these enzymes totally protected lungs against injury caused by PMN and PMA. These results suggest that active oxygen species (the hydroxyl radical in particular), mediate lung injury in this model. To determine whether TxA_2 was involved in toxicity induced by PMN and PMA, lungs were coperfused with the cyclooxygenase inhibitor, indomethacin or the thromboxane synthase inhibitor, Dazmegrel. Experiments were also performed using lungs and/or PMN that had been pretreated with aspirin. These drug treatments had little effect, if any, on the pressure increase; however, they protected lungs against edema development. These results suggest that TxA_2 may participate in the pathogenesis of edema by some other mechanism than by increasing vascular pressure. In conclusion, results from studies performed in this thesis suggest that both active oxygen species and thromboxane are involved in toxicity to the isolated rat lung induced by PMA and PMN. How both of these interact to produce lung injury is a question which remains to be answered.

Protective agents used as additives in University of Wisconsin solution to promote protection against ischaemia-reperfusion injury in rat lung.

PubMed

Chiang, C H; Wu, K; Yu, C P; Perng, W C; Yan, H C; Wu, C P; Chang, D M; Hsu, K

1998-09-01

1. An intervention to reduce ischaemia-reperfusion lung injury will be an important advance in transplant medicine. Although the mechanisms associated with producing ischaemia-reperfusion endothelial injury have not been completely elucidated, many of the injury mediators have been studied in detail. While no single pharmacological therapy is likely to be totally effective in eliminating this complex injury, we have developed a mixture of agents that are known to block pathways involved in producing ischaemia-reperfusion-associated lung vascular injury.2. The present study modified University of Wisconsin solution (UW) by adding one of the protective agents prostaglandin E1 (PGE1), dexamethasone (Dex) or dibutyryl cAMP (Bt2-cAMP), or a combination of these, to the perfusate of rat lungs exposed to 4 h of cold ischaemia followed by 1 h of reperfusion. Nine modified UW solutions were studied: (1) UW+Dex, (2) UW+PGE1, (3) UW+Bt2-cAMP, (4) UW+Dexx3, (5) UW+PGE1x3, (6) UW+Bt2-cAMPx3, (7) UW+Dex+PGE1, (8) UW+Dex+Bt2-cAMP, (9) UW+PGE1+Bt2-cAMP. These solutions were utilized in individual experiments to assess haemodynamic changes, lung weight gain, the capillary filtration coefficient (Kfc) and pathology in all lungs.3. The results indicate that lung weight gain and Kfc values were significantly lower than with UW alone in groups 1, 2 and 3, which contained only one additional protective agent. In groups 4, 5 and 6, which contain three times the concentration of each protective agent, both Kfc and lung weight gain were similar to those measured in groups 1, 2 and 3, i.e. lungs were protected but the protection was not dose dependent. In groups 7, 8 and 9, which contained two protective agents, lung weight gain and Kfc were greatly reduced compared with UW alone. Histopathological studies showed similar decreases in the injury profiles of lungs.4. Although UW contains several antioxidant protective agents such as allopurinol and glutathione, it did not provide effective protection in our ischaemia-reperfusion lung injury model. UW modified with an additive of PGE1, Dex or Bt2-cAMP attenuated ischaemia-reperfusion injury. Furthermore, UW containing two of these protective agents augmented the protection. Among the modified solutions, it appears that UW+PGE1+Bt2-cAMP protects the lungs to a greater extent than all other solutions used in our study. We suggest that preservation solutions containing PGE1-Bt2-cAMP will provide additional protective effects to organs stored for transplantation.

Hemofiltration in ex vivo lung perfusion-a study in experimentally induced pulmonary edema.

PubMed

Nilsson, Tobias; Hansson, Christoffer; Wallinder, Andreas; Malm, Carl-Johan; Silverborn, Martin; Ricksten, Sven-Erik; Dellgren, Göran

2016-02-01

Ex vivo lung perfusion (EVLP) can potentially reduce pulmonary edema. In a pig model with induced pulmonary edema, we evaluated the effect of hemofiltration (HF) during EVLP on lung function, perfusate oncotic pressure, and lung weight. In anesthetized pigs (n = 14), pulmonary edema was induced by a balloon in the left atrium, combined with crystalloid infusion (20 mL/kg), for 2 hours. The lungs were harvested, stored cold for 2 hours, and randomized to EVLP, with or without a hemofilter (HF and noHF groups, respectively, n = 7 for each). EVLP was performed with cellular perfusate at a hematocrit of 10% to 15%. Oncotic pressure, lung performance, and weight were measured before and after 180 minutes of EVLP reconditioning with or without HF. After in vivo induction of edema, arterial oxygen tension (Pao2)/inspired oxygen fraction (Fio2), and compliance decreased by 63% and 16%, respectively. Pao2/Fio2 was considerably improved at first evaluation ex vivo in both groups. HF increased oncotic pressure by 43% and decreased lung weight by 15%. The effects were negligible in the noHF group. Compliance decreased in both groups during reconditioning, although less so in the HF group (P < .05). Pao2/Fio2, shunt fraction, and oxygen saturation remained unchanged in both groups. Pulmonary flow index decreased in both groups, and was partially reversed by nitroglycerin. Dorsal atelectatic consolidations were seen in both groups. In this lung-edema model, EVLP reconditioning with hyperoncotic solution did not affect the degree of lung edema. HF during EVLP increased perfusate oncotic pressure, decreased lung weight with beneficial effects on compliance, but did not improve lung oxygenation capacity. Copyright © 2016 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.

Kinetics of lactate metabolism during acellular normothermic ex vivo lung perfusion.

PubMed

Koike, Terumoto; Yeung, Jonathan C; Cypel, Marcelo; Rubacha, Matthew; Matsuda, Yasushi; Sato, Masaaki; Waddell, Thomas K; Liu, Mingyao; Keshavjee, Shaf

2011-12-01

Plasma lactate has been used as a marker of poor prognosis in clinical conditions. However, the relationship between lactate production and lung function during acellular normothermic ex vivo lung perfusion (EVLP) is unclear. We investigated the kinetics of lactate metabolism during EVLP and the correlation of this marker with outcomes after transplant. Human donor lungs in our clinical EVLP trial (CLs; n = 28) and rejected donor lungs for experimental use (Els; n = 8) were perfused ex vivo using the Toronto technique. Lactate level, lactate/pyruvate (L/P) ratio, and glucose level in the perfusate were measured. In CLs, we examined the relationship between lactate metabolism during EVLP and early post-transplant outcomes. The hypoxia-inducible factor 1 sub-unit 1α (HIF-1α) level in lung tissue was examined in ELs. We performed double-lung EVLP in CLs and single-lung EVLP in ELs. In CLs, the lactate and L/P ratios at the end of EVLP had no correlation with early post-transplant outcomes despite lactate elevation during EVLP. Although lactate elevation was also present in all ELs, we were able to identify 2 groups based on L/P ratio at the end of EVLP. The group with the high L/P ratio had higher airway pressure during EVLP and higher HIF-1α in lung tissue at the end of EVLP. Lactate increases seen in the EVLP perfusate most often represent physiologic lactate production by the lung in a setting with reduced lactate clearance. Thus, patients who underwent transplantation after EVLP had good outcomes despite lactate elevation during EVLP. Copyright © 2011 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

The metabolism of 5-hydroxytryptamine and beta-phenylethylamine in perfused rat lung and in vitro.

PubMed Central

Bakhle, Y S; Youdim, M B

1979-01-01

1 Metabolism of 5-hydroxytryptamine (5-HT) and beta-phenylethylamine (PHE) by monoamine oxidase (MAO) was investigated in rat isolated lungs and in mitochondrial preparations from rat lung. 2. In perfused lungs 5-HT metabolism had an apparent Km of 2 microgram and PHE metaoblism a Km of 54 microgram, whereas in vitro the Km values were 330 microgram and 28 microgram respectively. 3 In vitro, MAO activity had substrate and inhibitor specificities compatible with the presence of A and B types of MAO. 4 In perfused lung, metabolism of 5-HT but not that of PHE was inhibited by desmethylimipramine. 5 These results show that PHE metabolism in perfused lung, unlike that of other metabolized amines, is not limited by transport and the transport process for PHE is unlike that of 5-HT or noradrenaline. 6 These results also show that the kinetic parameters obtained for MAO activity in vitro do not generally apply to the isolated lung where transport of substrate can be the deciding factor. This discrepancy emphasizes that the enzymic properties of the whole organ cannot relaibly be deduced from its enzymic content. PMID:32944

Enhanced perfusion defect clarity and inhomogeneity in smokers' lungs with deep-inspiratory breath-hold perfusion SPECT images.

PubMed

Suga, Kazuyoshi; Yasuhiko, Kawakami; Iwanaga, Hideyuki; Hayashi, Norio; Yamashita, Tomio; Matsunaga, Naofumi

2005-09-01

Deep-inspiratory breath-hold (DIBrH) Tc-99m-macroaggregated albumin (MAA) SPECT images were developed to accurately evaluate perfusion impairment in smokers' lungs. DIBrH SPECT was performed in 28 smokers with or without low attenuation areas (LAA) on CT images, using a triple-headed SPECT system and a laser light respiratory tracking device. DIBrH SPECT images were reconstructed from every 4 degrees projection of five adequate 360 degrees projection data sets with almost the same respiratory dimension at 20 sec DIBrH. Perfusion defect clarity was assessed by the lesion (defect)-to-contralateral normal lung count ratios (L/N ratios). Perfusion inhomogeneity was assessed by the coefficient of variation (CV) values of pixel counts and correlated with the diffusing capacity of the lungs for carbon monoxide/alveolar volume (DLCO/VA) ratios. The results were compared with those on conventional images. Five DIBrH projection data sets with minimal dimension differences of 2.9+/-0.6 mm were obtained in all subjects. DIBrH images enhanced perfusion defects compared with conventional images, with significantly higher L/N ratios (P<0.0001), and detected a total of 109 (26.9%) additional detects (513 vs. 404), with excellent inter-observer agreement (kappa value of 0.816). CV values in the smokers' lungs on DIBrH images were also significantly higher compared with those on conventional images (0.31+/-0.10 vs. 0.19+/-0.06, P<0.0001). CV values in smokers on DIBrH images showed a significantly closer correlation with DLCO/VA ratios compared with conventional images (R = 0.872, P<0.0001 vs. R=0.499, P<0.01). By reducing adverse effect of respiratory motion, DIBrH SPECT images enhance perfusion defect clarity and inhomogeneity, and provide more accurate assessment of impaired perfusion in smokers' lungs compared with conventional images.

Pressure- and flow-controlled media perfusion differently modify vascular mechanics in lung decellularization.

PubMed

da Palma, Renata K; Campillo, Noelia; Uriarte, Juan J; Oliveira, Luis V F; Navajas, Daniel; Farré, Ramon

2015-09-01

Organ biofabrication is a potential future alternative for obtaining viable organs for transplantation. Achieving intact scaffolds to be recellularized is a key step in lung bioengineering. Perfusion of decellularizing media through the pulmonary artery has shown to be effective. How vascular perfusion pressure and flow vary throughout lung decellularization, which is not well known, is important for optimizing the process (minimizing time) while ensuring scaffold integrity (no barotrauma). This work was aimed at characterizing the pressure/flow relationship at the pulmonary vasculature and at how effective vascular resistance depends on pressure- and flow-controlled variables when applying different methods of media perfusion for lung decellularization. Lungs from 43 healthy mice (C57BL/6; 7-8 weeks old) were investigated. After excision and tracheal cannulation, lungs were inflated at 10 cmH2O airway pressure and subjected to conventional decellularization with a solution of 1% sodium dodecyl sulfate (SDS). Pressure (PPA) and flow (V'PA) at the pulmonary artery were continuously measured. Decellularization media was perfused through the pulmonary artery: (a) at constant PPA=20 cmH2O or (b) at constant V'PA=0.5 and 0.2 ml/min. Effective vascular resistance was computed as Rv=PPA/V'PA. Rv (in cmH2O/(ml/min)); mean±SE) considerably varied throughout lung decellularization, particularly for pressure-controlled perfusion (from 29.1±3.0 in baseline to a maximum of 664.1±164.3 (p<0.05), as compared with flow-controlled perfusion (from 49.9±3.3 and 79.5±5.1 in baseline to a maximum of 114.4±13.9 and 211.7±70.5 (p<0.05, both), for V'PA of 0.5 and 0.2 ml/min respectively. Most of the media infused to the pulmonary artery throughout decellularization circulated to the airways compartment across the alveolar-capillary membrane. This study shows that monitoring perfusion mechanics throughout decellularization provides information relevant for optimizing the process time while ensuring that vascular pressure is kept within a safety range to preserve the organ scaffold integrity. Copyright © 2015 Elsevier Ltd. All rights reserved.

Selective Heart, Brain and Body Perfusion in Open Aortic Arch Replacement.

PubMed

Maier, Sven; Kari, Fabian; Rylski, Bartosz; Siepe, Matthias; Benk, Christoph; Beyersdorf, Friedhelm

2016-09-01

Open aortic arch replacement is a complex and challenging procedure, especially in post dissection aneurysms and in redo procedures after previous surgery of the ascending aorta or aortic root. We report our experience with the simultaneous selective perfusion of heart, brain, and remaining body to ensure optimal perfusion and to minimize perfusion-related risks during these procedures. We used a specially configured heart-lung machine with a centrifugal pump as arterial pump and an additional roller pump for the selective cerebral perfusion. Initial arterial cannulation is achieved via femoral artery or right axillary artery. After lower body circulatory arrest and selective antegrade cerebral perfusion for the distal arch anastomosis, we started selective lower body perfusion simultaneously to the selective antegrade cerebral perfusion and heart perfusion. Eighteen patients were successfully treated with this perfusion strategy from October 2012 to November 2015. No complications related to the heart-lung machine and the cannulation occurred during the procedures. Mean cardiopulmonary bypass time was 239 ± 33 minutes, the simultaneous selective perfusion of brain, heart, and remaining body lasted 55 ± 23 minutes. One patient suffered temporary neurological deficit that resolved completely during intensive care unit stay. No patient experienced a permanent neurological deficit or end-organ dysfunction. These high-risk procedures require a concept with a special setup of the heart-lung machine. Our perfusion strategy for aortic arch replacement ensures a selective perfusion of heart, brain, and lower body during this complex procedure and we observed excellent outcomes in this small series. This perfusion strategy is also applicable for redo procedures.

Effects of the oestrous cycle and exogenous ovarian steroids on metabolism of beta-phenylethylamine in rat lung.

PubMed Central

Bakhle, Y. S.; Ben-Harari, R. R.

1979-01-01

1 Metabolism of [14C]-beta-phenylethylamine (PEN), a substrate for monoamine oxidase-B (MAO-B), was measured in lung homogenates and in perfused lungs during the 4 day oestrous cycle of the rat. 2 Metabolism in vitro was high during met-oestrus and di-oestrus and low during pro-oestrus and oestrus; this variation in activity correlated with changes in Vmax of the enzyme without changes in Km. 3 PEN metabolism in lung homogenates was also altered by treatment of rats with 17 beta-oestradiol but not by progesterone treatment. 4 Metabolism of [14C]-PEN in perfused lungs was the same during either pro-oestrus or met-oestrus. Uptake of [14C]-PEN in perfused lung measured directly was also the same at these two stages. 5 These results demonstrate that in lungs MAO-B activity was affected by endogenous changes in steroid level but that such changes in enzymic activity were not reflected in the metabolic properties of whole lung. PMID:574038

Assessment of branch pulmonary artery stenosis in children after repair of tetralogy of Fallot using lung perfusion scintigraphy comparison with echocardiography.

PubMed

Chien, Kuang-Jen; Huang, Hurng-Wern; Huang, Ta-Cheng; Lee, Cheng-Liang; Weng, Ken-Pen; Lin, Chu-Chuan; Shieh, Po-Chuen; Wu, Ming-Ting; Hsieh, Kai-Sheng

2016-01-01

The aim of this study was to compare the usefulness of lung perfusion scintigraphy and echocardiogram in the evaluation of the branch pulmonary arteries stenosis in children with tetralogy of Fallot (TOF). From February 2006 to November 2008, 74 children (mean age 7.8 years, range 1–18 years) who underwent repair of TOF at ages from 10 months to 13 years were suspected to have unilateral or bilateral branch pulmonary artery stenosis. In all patients, cardiac angiography was performed to confirm the diagnosis of branch pulmonary artery stenosis. Lung perfusion scintigraphy and two-dimensional transthoracic echocardiography were performed in all patients to compare their abilities to diagnose branch pulmonary artery stenosis. Of the 74 patients, 51 cases were found to have branch pulmonary artery stenosis by cardiac angiography. There was agreement between the scintigraphic and angiographic findings in 44 (86%) patients and there were discrepancies in 11 (15%) patients. The positive predictive value of our lung perfusion scintigraphy in detecting the branch pulmonary artery stenosis was 92 %. The positive and negative likelihood ratios of lung perfusion scintigraphy were 4.96 and 0.17, respectively. There was conformity between the echocardiographic and angiographic findings in 40 (78%) patients with discrepancies in 16 (21%) patients. The positive predictive value of our echocardiography in detecting the branch pulmonary artery stenosis was 89%. The positive and negative likelihood ratios of echocardiography were 3.61 and 0.28, respectively. Lung perfusion scintigraphy is a valuable, non-invasive screening tool in the assessment of branch pulmonary artery stenosis in children after TOF.

Niacinamide mitigated the acute lung injury induced by phorbol myristate acetate in isolated rat's lungs

PubMed Central

2012-01-01

Background Phorbol myristate acetate (PMA) is a strong neutrophil activator and has been used to induce acute lung injury (ALI). Niacinamide (NAC) is a compound of B complex. It exerts protective effects on the ALI caused by various challenges. The purpose was to evaluate the protective effects of niacinamide (NAC) on the PMA-induced ALI and associated changes. Methods The rat's lungs were isolated in situ and perfused with constant flow. A total of 60 isolated lungs were randomized into 6 groups to received Vehicle (DMSO 100 μg/g), PMA 4 μg/g (lung weight), cotreated with NAC 0, 100, 200 and 400 mg/g (lung weight). There were 10 isolated lungs in each group. We measured the lung weight and parameters related to ALI. The pulmonary arterial pressure and capillary filtration coefficient (Kfc) were determined in isolated lungs. ATP (adenotriphosphate) and PARP [poly(adenosine diphophate-ribose) polymerase] contents in lung tissues were detected. Real-time PCR was employed to display the expression of inducible and endothelial NO synthases (iNOS and eNOS). The neutrophil-derived mediators in lung perfusate were determined. Results PMA caused increases in lung weight parameters. This agent produced pulmonary hypertension and increased microvascular permeability. It resulted in decrease in ATP and increase in PARP. The expression of iNOS and eNOS was upregulated following PMA. PMA increased the neutrophil-derived mediators. Pathological examination revealed lung edema and hemorrhage with inflammatory cell infiltration. Immunohistochemical stain disclosed the presence of iNOS-positive cells in macrophages and endothelial cells. These pathophysiological and biochemical changes were diminished by NAC treatment. The NAC effects were dose-dependent. Conclusions Our results suggest that neutrophil activation and release of neutrophil-derived mediators by PMA cause ALI and associated changes. NO production through the iNOS-producing cells plays a detrimental role in the PMA-induced lung injury. ATP is beneficial, while PARP plays a deteriorative effect on the PMA-induced ALI. NAC exerts protective effects on the inflammatory cascade leading to pulmonary injury. This B complex compound may be applied for clinical usage and therapeutic regimen. PMID:22375599

Niacinamide mitigated the acute lung injury induced by phorbol myristate acetate in isolated rat's lungs.

PubMed

Lin, Chia-Chih; Hsieh, Nan-Kuang; Liou, Huey Ling; Chen, Hsing I

2012-03-01

Phorbol myristate acetate (PMA) is a strong neutrophil activator and has been used to induce acute lung injury (ALI). Niacinamide (NAC) is a compound of B complex. It exerts protective effects on the ALI caused by various challenges. The purpose was to evaluate the protective effects of niacinamide (NAC) on the PMA-induced ALI and associated changes. The rat's lungs were isolated in situ and perfused with constant flow. A total of 60 isolated lungs were randomized into 6 groups to received Vehicle (DMSO 100 μg/g), PMA 4 μg/g (lung weight), cotreated with NAC 0, 100, 200 and 400 mg/g (lung weight). There were 10 isolated lungs in each group. We measured the lung weight and parameters related to ALI. The pulmonary arterial pressure and capillary filtration coefficient (Kfc) were determined in isolated lungs. ATP (adenotriphosphate) and PARP [poly(adenosine diphophate-ribose) polymerase] contents in lung tissues were detected. Real-time PCR was employed to display the expression of inducible and endothelial NO synthases (iNOS and eNOS). The neutrophil-derived mediators in lung perfusate were determined. PMA caused increases in lung weight parameters. This agent produced pulmonary hypertension and increased microvascular permeability. It resulted in decrease in ATP and increase in PARP. The expression of iNOS and eNOS was upregulated following PMA. PMA increased the neutrophil-derived mediators. Pathological examination revealed lung edema and hemorrhage with inflammatory cell infiltration. Immunohistochemical stain disclosed the presence of iNOS-positive cells in macrophages and endothelial cells. These pathophysiological and biochemical changes were diminished by NAC treatment. The NAC effects were dose-dependent. Our results suggest that neutrophil activation and release of neutrophil-derived mediators by PMA cause ALI and associated changes. NO production through the iNOS-producing cells plays a detrimental role in the PMA-induced lung injury. ATP is beneficial, while PARP plays a deteriorative effect on the PMA-induced ALI. NAC exerts protective effects on the inflammatory cascade leading to pulmonary injury. This B complex compound may be applied for clinical usage and therapeutic regimen.

Accuracy and Utility of Deformable Image Registration in {sup 68}Ga 4D PET/CT Assessment of Pulmonary Perfusion Changes During and After Lung Radiation Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hardcastle, Nicholas, E-mail: nick.hardcastle@gmail.com; Centre for Medical Radiation Physics, University of Wollongong, Wollongong; Hofman, Michael S.

2015-09-01

Purpose: Measuring changes in lung perfusion resulting from radiation therapy dose requires registration of the functional imaging to the radiation therapy treatment planning scan. This study investigates registration accuracy and utility for positron emission tomography (PET)/computed tomography (CT) perfusion imaging in radiation therapy for non–small cell lung cancer. Methods: {sup 68}Ga 4-dimensional PET/CT ventilation-perfusion imaging was performed before, during, and after radiation therapy for 5 patients. Rigid registration and deformable image registration (DIR) using B-splines and Demons algorithms was performed with the CT data to obtain a deformation map between the functional images and planning CT. Contour propagation accuracy andmore » correspondence of anatomic features were used to assess registration accuracy. Wilcoxon signed-rank test was used to determine statistical significance. Changes in lung perfusion resulting from radiation therapy dose were calculated for each registration method for each patient and averaged over all patients. Results: With B-splines/Demons DIR, median distance to agreement between lung contours reduced modestly by 0.9/1.1 mm, 1.3/1.6 mm, and 1.3/1.6 mm for pretreatment, midtreatment, and posttreatment (P<.01 for all), and median Dice score between lung contours improved by 0.04/0.04, 0.05/0.05, and 0.05/0.05 for pretreatment, midtreatment, and posttreatment (P<.001 for all). Distance between anatomic features reduced with DIR by median 2.5 mm and 2.8 for pretreatment and midtreatment time points, respectively (P=.001) and 1.4 mm for posttreatment (P>.2). Poorer posttreatment results were likely caused by posttreatment pneumonitis and tumor regression. Up to 80% standardized uptake value loss in perfusion scans was observed. There was limited change in the loss in lung perfusion between registration methods; however, Demons resulted in larger interpatient variation compared with rigid and B-splines registration. Conclusions: DIR accuracy in the data sets studied was variable depending on anatomic changes resulting from radiation therapy; caution must be exercised when using DIR in regions of low contrast or radiation pneumonitis. Lung perfusion reduces with increasing radiation therapy dose; however, DIR did not translate into significant changes in dose–response assessment.« less

Prediction of Therapeutic Effect of Chemotherapy for NSCLC Using Dual-Input Perfusion CT Analysis: Comparison among Bevacizumab Treatment, Two-Agent Platinum-based Therapy without Bevacizumab, and Other Non-Bevacizumab Treatment Groups.

PubMed

Yabuuchi, Hidetake; Kawanami, Satoshi; Iwama, Eiji; Okamoto, Isamu; Kamitani, Takeshi; Sagiyama, Koji; Yamasaki, Yuzo; Honda, Hiroshi

2018-02-01

Purpose To determine whether dual-input perfusion computed tomography (CT) can predict therapeutic response and prognosis in patients who underwent chemotherapy for non-small cell lung cancer (NSCLC). Materials and Methods The institutional review board approved this study and informed consent was obtained. Sixty-six patients with stage III or IV NSCLC (42 men, 24 women; mean age, 63.4 years) who underwent chemotherapy were enrolled. Patients were separated into three groups: those who received chemotherapy with bevacizumab (BV) (n = 20), those who received two-agent platinum-based therapy without BV (n = 25), and those who received other non-BV treatment (n = 21). Before treatment, pulmonary artery perfusion (PAP) and bronchial artery perfusion (BAP) of the tumors were calculated. Predictors of tumor reduction after two courses of chemotherapy and prognosis were identified by using univariate and multivariate analyses. Covariates included were age, sex, patient's performance status, baseline maximum diameter of the tumor, clinical stage, pretreatment PAP, and pretreatment BAP. For multivariate analyses, multiple linear regression analysis for tumor reduction rate and Cox proportional hazards model for prognosis were performed, respectively. Results Pretreatment BAP was independently correlated with tumor reduction rate after two courses of chemotherapy in the BV treatment group (P = .006). Pretreatment BAP was significantly associated with a highly cumulative risk of death (P = .006) and disease progression after chemotherapy (P = .015) in the BV treatment group. Pretreatment PAP and clinical parameters were not significant predictors of therapeutic effect or prognosis in three treatment groups. Conclusion Pretreatment BAP derived from dual-input perfusion CT seems to be a promising tool to help predict responses to chemotherapy with BV in patients with NSCLC. © RSNA, 2017.

Sickle erythrocytes and platelets augment lung leukotriene synthesis with downregulation of anti-inflammatory proteins: relevance in the pathology of the acute chest syndrome

PubMed Central

Opene, Michael; Kurantsin-Mills, Joseph; Husain, Sumair

2014-01-01

Abstract Initiation, progression, and resolution of vaso-occlusive pain episodes in sickle cell disease (SCD) have been recognized as reperfusion injury, which provokes an inflammatory response in the pulmonary circulation. Some 5-lipoxygenase (5-lox) metabolites are potent vasoconstrictors in the pulmonary circulation. We studied stimulation of production of the inflammatory eicosanoids leukotrienes (LTs) and prostaglandin E2 (PGE2) by isolated rat lungs perfused with sickle (HbSS) erythrocytes. Our hypothesis is that HbSS erythrocytes produce more LTs than normal (HbAA) erythrocytes, which can induce vaso-occlusive episodes in SCD patients. Lung perfusates were collected at specific time points and purified by high-pressure liquid chromatography, and LTC4 and PGE2 contents were measured by enzyme-linked immunosorbent assay (ELISA). Rat lung explants were also cultured with purified HbAA and HbSS peptides, and 5-lox, cyclooxygenase 1/2, and platelet-activating factor receptor (PAFR) proteins were measured by Western blotting, while prostacyclin and LTs produced by cultured lung explants were measured by ELISA. Lung weight gain and blood gas data were not different among the groups. HbSS-perfused lungs produced more LTC4 and PGE2 than HbAA-perfused lungs: 10.40 ± 0.62 versus 0.92 ± 0.2 ng/g dry lung weight (mean ± SEM; P = 0.0001) for LTC4. Inclusion of autologous platelets (platelet-rich plasma) elevated LTC4 production to 12.6 ± 0.96 and 7 ± 0.60 ng/g dry lung weight in HbSS and HbAA perfusates, respectively. HbSS lungs also expressed more 5-lox and PAFR. The data suggest that HbSS erythrocytes and activated platelets in patient’s pulmonary microcirculation will enhance the synthesis and release of the proinflammatory mediators LTC4 and PGE2, both of which may contribute to onset of the acute chest syndrome in SCD. PMID:25621162

State-of-the-art radiological techniques improve the assessment of postoperative lung function in patients with non-small cell lung cancer.

PubMed

Ohno, Yoshiharu; Koyama, Hisanobu; Nogami, Munenobu; Takenaka, Daisuke; Onishi, Yumiko; Matsumoto, Keiko; Matsumoto, Sumiaki; Maniwa, Yoshimasa; Yoshimura, Masahiro; Nishimura, Yoshihiro; Sugimura, Kazuro

2011-01-01

The purpose of this study was to compare predictive capabilities for postoperative lung function in non-small cell lung cancer (NSCLC) patients of the state-of-the-art radiological methods including perfusion MRI, quantitative CT and SPECT/CT with that of anatomical method (i.e. qualitative CT) and traditional nuclear medicine methods such as planar imaging and SPECT. Perfusion MRI, CT, nuclear medicine study and measurements of %FEV(1) before and after lung resection were performed for 229 NSCLC patients (125 men and 104 women). For perfusion MRI, postoperative %FEV(1) (po%FEV(1)) was predicted from semi-quantitatively assessed blood volumes within total and resected lungs, for quantitative CT, it was predicted from the functional lung volumes within total and resected lungs, for qualitative CT, from the number of segments of total and resected lungs, and for nuclear medicine studies, from uptakes within total and resected lungs. All SPECTs were automatically co-registered with CTs for preparation of SPECT/CTs. Predicted po%FEV(1)s were then correlated with actual po%FEV(1)s, which were measured %FEV(1)s after operation. The limits of agreement were also evaluated. All predicted po%FEV(1)s showed good correlation with actual po%FEV(1)s (0.83≤r≤0.88, p<0.0001). Perfusion MRI, quantitative CT and SPECT/CT demonstrated better correlation than other methods. The limits of agreement of perfusion MRI (4.4±14.2%), quantitative CT (4.7±14.2%) and SPECT/CT (5.1±14.7%) were less than those of qualitative CT (6.0±17.4%), planar imaging (5.8±18.2%), and SPECT (5.5±16.8%). State-of-the-art radiological methods can predict postoperative lung function in NSCLC patients more accurately than traditional methods. Copyright © 2009 Elsevier Ireland Ltd. All rights reserved.

Postmortem and ex vivo carbon monoxide ventilation reduces injury in rat lungs transplanted from non-heart-beating donors.

PubMed

Dong, Boming; Stewart, Paul W; Egan, Thomas M

2013-08-01

We sought to determine whether ventilation of lungs after death in non-heart-beating donors with carbon monoxide during warm ischemia and ex vivo lung perfusion and after transplant would reduce ischemia-reperfusion injury and improve lung function. One hour after death, Sprague-Dawley rats were ventilated for another hour with 60% oxygen (control group) or 500 ppm carbon monoxide in 60% oxygen (CO-vent group; n=6/group). Then, lungs were flushed with 20 mL cold Perfadex, stored cold for 1 hour, then warmed to 37 °C in an ex vivo lung perfusion circuit perfused with Steen solution. At 37 °C, lungs were ventilated for 15 minutes with alveolar gas with or without 500 ppm carbon monoxide, then perfusion-cooled to 20 °C, flushed with cold Perfadex and stored cold for 2 hours. The left lung was transplanted using a modified cuff technique. Recipients were ventilated with 60% oxygen with or without carbon monoxide. One hour after transplant, we measured blood gases from the left pulmonary vein and aorta, and wet-to-dry ratio of both lungs. The RNA and protein extracted from graft lungs underwent real-time polymerase chain reaction and Western blotting, and measurement of cyclic guanosine monophosphate by enzyme-linked immunosorbent assay. Carbon monoxide ventilation begun 1 hour after death reduced wet/dry ratio after ex vivo lung perfusion. After transplantation, the carbon monoxide-ventilation group had better oxygenation; higher levels of tissue cyclic guanosine monophosphate, heme oxidase-1 expression, and p38 phosphorylation; reduced c-Jun N-terminal kinase phosphorylation; and reduced expression of interleukin-6 and interleukin-1β messenger RNA. Administration of carbon monoxide to the deceased donor and non-heart-beating donor lungs reduces ischemia-reperfusion injury in rat lungs transplanted from non-heart-beating donors. Therapy to the deceased donor via the airway may improve post-transplant lung function. Copyright © 2013 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.

Automated scoring of regional lung perfusion in children from contrast enhanced 3D MRI

NASA Astrophysics Data System (ADS)

Heimann, Tobias; Eichinger, Monika; Bauman, Grzegorz; Bischoff, Arved; Puderbach, Michael; Meinzer, Hans-Peter

2012-03-01

MRI perfusion images give information about regional lung function and can be used to detect pulmonary pathologies in cystic fibrosis (CF) children. However, manual assessment of the percentage of pathologic tissue in defined lung subvolumes features large inter- and intra-observer variation, making it difficult to determine disease progression consistently. We present an automated method to calculate a regional score for this purpose. First, lungs are located based on thresholding and morphological operations. Second, statistical shape models of left and right children's lungs are initialized at the determined locations and used to precisely segment morphological images. Segmentation results are transferred to perfusion maps and employed as masks to calculate perfusion statistics. An automated threshold to determine pathologic tissue is calculated and used to determine accurate regional scores. We evaluated the method on 10 MRI images and achieved an average surface distance of less than 1.5 mm compared to manual reference segmentations. Pathologic tissue was detected correctly in 9 cases. The approach seems suitable for detecting early signs of CF and monitoring response to therapy.

Lung bioengineering: physical stimuli and stem/progenitor cell biology interplay towards biofabricating a functional organ.

PubMed

Nonaka, Paula N; Uriarte, Juan J; Campillo, Noelia; Oliveira, Vinicius R; Navajas, Daniel; Farré, Ramon

2016-11-28

A current approach to obtain bioengineered lungs as a future alternative for transplantation is based on seeding stem cells on decellularized lung scaffolds. A fundamental question to be solved in this approach is how to drive stem cell differentiation onto the different lung cell phenotypes. Whereas the use of soluble factors as agents to modulate the fate of stem cells was established from an early stage of the research with this type of cells, it took longer to recognize that the physical microenvironment locally sensed by stem cells (e.g. substrate stiffness, 3D architecture, cyclic stretch, shear stress, air-liquid interface, oxygenation gradient) also contributes to their differentiation. The potential role played by physical stimuli would be particularly relevant in lung bioengineering since cells within the organ are physiologically subjected to two main stimuli required to facilitate efficient gas exchange: air ventilation and blood perfusion across the organ. The present review focuses on describing how the cell mechanical microenvironment can modulate stem cell differentiation and how these stimuli could be incorporated into lung bioreactors for optimizing organ bioengineering.

The protective effect of dexmedetomidine in a rat ex vivo lung model of ischemia-reperfusion injury.

PubMed

Zhou, Yan; Zhou, Xinqiao; Zhou, Wenjuan; Pang, Qingfeng; Wang, Zhiping

2018-01-01

To investigate the effect of dexmedetomidine (Dex) in a rat ex vivo lung model of ischemia-reperfusion injury. An IL-2 ex vivo lung perfusion system was used to establish a rat ex vivo lung model of ischemia-reperfusion injury. Drugs were added to the perfusion solution for reperfusion. Lung injury was assessed by histopathological changes, airway pressure (Res), lung compliance (Compl), perfusion flow (Flow), pulmonary venous oxygen partial pressure (PaO2), and lung wet/dry (W/D) weight ratio. The levels of superoxide dismutase (SOD), malondialdehyde (MDA), 78 kDa glucose-regulated protein (GRP78) and CCAAT/enhancer-binding protein homologous protein (CHOP) were measured, respectively. The introduction of Dex attenuated the post-ischemia-reperfusion lung damage and MDA level, improved lung histology, W/D ratio, lung injury scores and SOD activity. Decreased mRNA and protein levels of GRP78 and CHOP compared with the IR group were observed after Dex treatment. The effect of Dex was dosage-dependence and a high dose of Dex (10 nM) was shown to confer the strongest protective effect against lung damage (P<0.05). Yohimbine, an α2 receptor antagonist, significantly reversed the protective effect of Dex in lung tissues (P<0.05). Dex reduced ischemia-reperfusion injury in rat ex vivo lungs.

Modeling of Tracer Transport Delays for Improved Quantification of Regional Pulmonary 18F-FDG Kinetics, Vascular Transit Times, and Perfusion

PubMed Central

Wellman, Tyler J.; Winkler, Tilo; Vidal Melo, Marcos F.

2015-01-01

18F-FDG-PET is increasingly used to assess pulmonary inflammatory cell activity. However, current models of pulmonary 18F-FDG kinetics do not account for delays in 18F-FDG transport between the plasma sampling site and the lungs. We developed a three-compartment model of 18F-FDG kinetics that includes a delay between the right heart and the local capillary blood pool, and used this model to estimate regional pulmonary perfusion. We acquired dynamic 18F-FDG scans in 12 mechanically ventilated sheep divided into control and lung injury groups (n=6 each). The model was fit to tracer kinetics in three isogravitational regions-of-interest to estimate regional lung transport delays and regional perfusion. 13NN bolus infusion scans were acquired during a period of apnea to measure regional perfusion using an established reference method. The delayed input function model improved description of 18F-FDG kinetics (lower Akaike Information Criterion) in 98% of studied regions. Local transport delays ranged from 2.0–13.6s, averaging 6.4±2.9s, and were highest in non-dependent regions. Estimates of regional perfusion derived from model parameters were highly correlated with perfusion measurements based on 13NN-PET (R2=0.92, p<0.001). By incorporating local vascular transports delays, this model of pulmonary 18F-FDG kinetics allows for simultaneous assessment of regional lung perfusion, transit times, and inflammation. PMID:25940652

Correlation of iodine uptake and perfusion parameters between dual-energy CT imaging and first-pass dual-input perfusion CT in lung cancer.

PubMed

Chen, Xiaoliang; Xu, Yanyan; Duan, Jianghui; Li, Chuandong; Sun, Hongliang; Wang, Wu

2017-07-01

To investigate the potential relationship between perfusion parameters from first-pass dual-input perfusion computed tomography (DI-PCT) and iodine uptake levels estimated from dual-energy CT (DE-CT).The pre-experimental part of this study included a dynamic DE-CT protocol in 15 patients to evaluate peak arterial enhancement of lung cancer based on time-attenuation curves, and the scan time of DE-CT was determined. In the prospective part of the study, 28 lung cancer patients underwent whole-volume perfusion CT and single-source DE-CT using 320-row CT. Pulmonary flow (PF, mL/min/100 mL), aortic flow (AF, mL/min/100 mL), and a perfusion index (PI = PF/[PF + AF]) were automatically generated by in-house commercial software using the dual-input maximum slope method for DI-PCT. For the dual-energy CT data, iodine uptake was estimated by the difference (λ) and the slope (λHU). λ was defined as the difference of CT values between 40 and 70 KeV monochromatic images in lung lesions. λHU was calculated by the following equation: λHU = |λ/(70 - 40)|. The DI-PCT and DE-CT parameters were analyzed by Pearson/Spearman correlation analysis, respectively.All subjects were pathologically proved as lung cancer patients (including 16 squamous cell carcinoma, 8 adenocarcinoma, and 4 small cell lung cancer) by surgery or CT-guided biopsy. Interobserver reproducibility in DI-PCT (PF, AF, PI) and DE-CT (λ, λHU) were relatively good to excellent (intraclass correlation coefficient [ICC]Inter = 0.8726-0.9255, ICCInter = 0.8179-0.8842; ICCInter = 0.8881-0.9177, ICCInter = 0.9820-0.9970, ICCInter = 0.9780-0.9971, respectively). Correlation coefficient between λ and AF, and PF were as follows: 0.589 (P < .01) and 0.383 (P < .05). Correlation coefficient between λHU and AF, and PF were as follows: 0.564 (P < .01) and 0.388 (P < .05).Both the single-source DE-CT and dual-input CT perfusion analysis method can be applied to assess blood supply of lung cancer patients. Preliminary results demonstrated that the iodine uptake relevant parameters derived from DE-CT significantly correlated with perfusion parameters derived from DI-PCT.

How to optimize the lung donor.

PubMed

Sales, Gabriele; Costamagna, Andrea; Fanelli, Vito; Boffini, Massimo; Pugliese, Francesco; Mascia, Luciana; Brazzi, Luca

2018-02-01

Over the last two decades, lung transplantation emerged as the standard of care for patients with advanced and terminal lung disease. Despite the increment in lung transplantation rates, in 2016 the overall mortality while on waiting list in Italy reached 10%, whereas only 39% of the wait-list patients were successfully transplanted. A number of approaches, including protective ventilatory strategy, accurate management of fluid balance, and administration of a hormonal resuscitation therapy, have been reported to improve lung donor performance before organ retrieval. These approaches, in conjunction with the use of ex-vivo lung perfusion technique contributed to expand the lung donor pool, without affecting the harvest of other organs and the outcomes of lung recipients. However, the efficacy of issues related to the ex-vivo lung perfusion technique, such as the optimal ventilation strategy, the ischemia-reperfusion induced lung injury management, the prophylaxis of germs transmission from donor to recipient and the application of targeted pharmacologic therapies to treat specific donor lung injuries are still to be explored. The main objective of the present review is to summarize the "state-of-art" strategies to optimize the donor lungs and to present the actual role of ex-vivo lung perfusion in the process of lung transplant. Moreover, different approaches about the technique reported in literature and several issues that are under investigation to treat specific donor lung injury will be discussed.

Tezosentan reduces the microvascular filtration coefficient in isolated lungs from rats subjected to cecum ligation and puncture.

PubMed

Kuklin, Vladimir; Sovershaev, Mikhail; Andreasen, Thomas; Skogen, Vegard; Ytrehus, Kirsti; Bjertnaes, Lars

2005-01-01

We recently demonstrated that the non-selective endothelin-1 (ET-1) receptor blocker tezosentan antagonizes ovine acute lung injury (ALI) following infusion of endotoxin or ET-1 by reducing the enhanced lung microvascular pressure, although we could not exclude the possibility of a simultaneous decline in microvascular permeability. In the present study, our aim was to find out if tezosentan reverses the rise in microvascular filtration coefficient (Kfc) in rat lungs that have been isolated and perfused 12 h after cecum ligation and puncture (CLP) or infusion of ET-1. Wistar rats (n = 42) were subjected to CLP. Postoperatively, rats were randomized to a CLP group (n = 7) and a CLP + tezosentan group (n = 7); the latter received tezosentan 30 mg/kg. A sham-operated group (n = 5) underwent laparotomy without CLP. Twelve hours postoperatively, the lungs were isolated and perfused with blood from similarly treated rats that also were used to assess plasma concentration of ET-1 and protein kinase Calpha (PKCalpha) in lung tissue. Additionally, isolated blood perfused lungs from healthy rats were randomized to a control group (n = 8), an ET-1 group (n = 7) subjected to pulmonary arterial injection of ET-1 10 nM, and an ET-1 + tezosentan group (n = 7) that received tezosentan 30 mg/kg. All lung preparations received papaverine 0.1 microg/kg added to the perfusate for vasoplegia. Pulmonary hemodynamic variables, Kfc and lung compliance (CL) were assessed. After CLP, the plasma concentration of ET-1 increased. Papaverine abolished the vasoconstrictor response to ET-1 and the pulmonary vascular pressures remained close to baseline throughout the experiments. Both CLP and injection of ET-1 caused significant changes in Kfc and CL that were prevented in tezosentan-treated rats. Compared to sham-operated animals, CLP increased the content of PKCalpha by 50% and 70% in the cytosolic and the membrane fractions of lung tissue homogenates, respectively. Tezosentan prevented the upregulation of PKCalpha in the membrane fraction. In rat lungs isolated and perfused after CLP, tezosentan precludes both the increase in Kfc and the upregulation of PKCalpha in the membrane fraction of lung tissue.

The role of lung imaging in pulmonary embolism

PubMed Central

Mishkin, Fred S.; Johnson, Philip M.

1973-01-01

The advantages of lung scanning in suspected pulmonary embolism are its diagnostic sensitivity, simplicity and safety. The ability to delineate regional pulmonary ischaemia, to quantitate its extent and to follow its response to therapy provides valuable clinical data available by no other simple means. The negative scan effectively excludes pulmonary embolism but, although certain of its features favour the diagnosis of embolism, the positive scan inherently lacks specificity and requires angiographic confirmation when embolectomy, caval plication or infusion of a thrombolytic agent are contemplated. The addition of simple ventilation imaging techniques with radioxenon overcomes this limitation by providing accurate analog estimation or digital quantitation of regional ventilation: perfusion (V/Q) ratios fundamental to understanding the pathophysiologic consequences of embolism and other diseases of the lung. ImagesFig. 1Fig. 2Fig. 3Fig. 4Fig. 5Fig. 6Fig. 7p495-bFig. 8Fig. 9Fig. 10Fig. 11Fig. 12Fig. 13 PMID:4602128

The effects of exogenous surfactant administration on ventilation-induced inflammation in mouse models of lung injury.

PubMed

Puntorieri, Valeria; Hiansen, Josh Qua; McCaig, Lynda A; Yao, Li-Juan; Veldhuizen, Ruud A W; Lewis, James F

2013-11-20

Mechanical ventilation (MV) is an essential supportive therapy for acute lung injury (ALI); however it can also contribute to systemic inflammation. Since pulmonary surfactant has anti-inflammatory properties, the aim of the study was to investigate the effect of exogenous surfactant administration on ventilation-induced systemic inflammation. Mice were randomized to receive an intra-tracheal instillation of a natural exogenous surfactant preparation (bLES, 50 mg/kg) or no treatment as a control. MV was then performed using the isolated and perfused mouse lung (IPML) set up. This model allowed for lung perfusion during MV. In experiment 1, mice were exposed to mechanical ventilation only (tidal volume =20 mL/kg, 2 hours). In experiment 2, hydrochloric acid or air was instilled intra-tracheally four hours before applying exogenous surfactant and ventilation (tidal volume =5 mL/kg, 2 hours). For both experiments, exogenous surfactant administration led to increased total and functional surfactant in the treated groups compared to the controls. Exogenous surfactant administration in mice exposed to MV only did not affect peak inspiratory pressure (PIP), lung IL-6 levels and the development of perfusate inflammation compared to non-treated controls. Acid injured mice exposed to conventional MV showed elevated PIP, lung IL-6 and protein levels and greater perfusate inflammation compared to air instilled controls. Instillation of exogenous surfactant did not influence the development of lung injury. Moreover, exogenous surfactant was not effective in reducing the concentration of inflammatory cytokines in the perfusate. The data indicates that exogenous surfactant did not mitigate ventilation-induced systemic inflammation in our models. Future studies will focus on altering surfactant composition to improve its immuno-modulating activity.

Modeling of Tracer Transport Delays for Improved Quantification of Regional Pulmonary ¹⁸F-FDG Kinetics, Vascular Transit Times, and Perfusion.

PubMed

Wellman, Tyler J; Winkler, Tilo; Vidal Melo, Marcos F

2015-11-01

¹⁸F-FDG-PET is increasingly used to assess pulmonary inflammatory cell activity. However, current models of pulmonary ¹⁸F-FDG kinetics do not account for delays in ¹⁸F-FDG transport between the plasma sampling site and the lungs. We developed a three-compartment model of ¹⁸F-FDG kinetics that includes a delay between the right heart and the local capillary blood pool, and used this model to estimate regional pulmonary perfusion. We acquired dynamic ¹⁸F-FDG scans in 12 mechanically ventilated sheep divided into control and lung injury groups (n = 6 each). The model was fit to tracer kinetics in three isogravitational regions-of-interest to estimate regional lung transport delays and regional perfusion. ¹³NN bolus infusion scans were acquired during a period of apnea to measure regional perfusion using an established reference method. The delayed input function model improved description of ¹⁸F-FDG kinetics (lower Akaike Information Criterion) in 98% of studied regions. Local transport delays ranged from 2.0 to 13.6 s, averaging 6.4 ± 2.9 s, and were highest in non-dependent regions. Estimates of regional perfusion derived from model parameters were highly correlated with perfusion measurements based on ¹³NN-PET (R² = 0.92, p < 0.001). By incorporating local vascular transports delays, this model of pulmonary ¹⁸F-FDG kinetics allows for simultaneous assessment of regional lung perfusion, transit times, and inflammation.

Lung perfusion characteristics in pulmonary arterial hypertension (PAH) and peripheral forms of chronic thromboembolic pulmonary hypertension (pCTEPH): Dual-energy CT experience in 31 patients.

PubMed

Giordano, Jessica; Khung, Suonita; Duhamel, Alain; Hossein-Foucher, Claude; Bellèvre, Dimitri; Lamblin, Nicolas; Remy, Jacques; Remy-Jardin, Martine

2017-04-01

To compare lung perfusion in PAH and pCTEPH on dual-energy CT (DECT) examinations. Thirty-one patients with PAH (group 1; n = 19) and pCTEPH (group 2; n = 12) underwent a dual-energy chest CTA with reconstruction of diagnostic and perfusion images. Perfusion alterations were analysed at a segmental level. V/Q scintigraphy was available in 22 patients (group 1: 13/19; group 2: 9/12). CT perfusion was abnormal in 52.6 % of group 1 patients and in 100 % of group 2 patients (p = 0.0051). The patterns of perfusion alteration significantly differed between the two groups (p < 0.0001): (1) in group 1, 96.6 % of segments with abnormal perfusion showed patchy defects; (2) in group 2, the most frequent abnormalities consisted of patchy (58.5 %) and PE-type (37.5 %) defects. Paired comparison of CT perfusion and scintigraphy showed concordant findings in 76.9 % of group 1 (10/13) and 100 % of group 2 (9/9) patients, with a predominant or an exclusive patchy pattern in group 1 and a mixed pattern of abnormalities in group 2. Lung perfusion alterations at DECT are less frequent and more homogeneous in PAH than in pCTEPH, with a high level of concordant findings with V/Q scintigraphy. • Depiction of chronic pulmonary embolism exclusively located on peripheral arteries is difficult. • The main differential diagnosis of pCTEPH is PAH. • The pattern of DECT perfusion changes can help differentiate PAH and pCETPH. • In PAH, almost all segments with abnormal perfusion showed patchy defects. • In pCTEPH, patchy and PE-type defects were the most frequent abnormalities.

Optical imaging of tissue mitochondrial redox state in intact rat lungs in two models of pulmonary oxidative stress

PubMed Central

Sepehr, Reyhaneh; Staniszewski, Kevin; Maleki, Sepideh; Jacobs, Elizabeth R.; Audi, Said

2012-01-01

Abstract. Ventilation with enhanced fractions of O2 (hyperoxia) is a common and necessary treatment for hypoxemia in patients with lung failure, but prolonged exposure to hyperoxia causes lung injury. Ischemia-reperfusion (IR) injury of lung tissue is common in lung transplant or crush injury to the chest. These conditions are associated with apoptosis and decreased survival of lung tissue. The objective of this work is to use cryoimaging to evaluate the effect of exposure to hyperoxia and IR injury on lung tissue mitochondrial redox state in rats. The autofluorescent mitochondrial metabolic coenzymes nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FAD) are electron carriers in ATP generation. These intrinsic fluorophores were imaged for rat lungs using low-temperature fluorescence imaging (cryoimaging). Perfused lungs from four groups of rats were studied: normoxia (control), control perfused with an mitochondrial complex IV inhibitor (potassium cyanide, KCN), rats exposed to hyperoxia (85% O2) for seven days, and from rats subjected to lung IR in vivo 24 hours prior to study. Each lung was sectioned sequentially in the transverse direction, and the images were used to reconstruct a three-dimensional (3-D) rendering. In KCN perfused lungs the respiratory chain was more reduced, whereas hyperoxic and IR lung tissue have a more oxidized respiratory chain than control lung tissue, consistent with previously measured mitochondrial dysfunction in both hyperoxic and IR lungs. PMID:22559688

A General Approach to the Evaluation of Ventilation-Perfusion Ratios in Normal and Abnormal Lungs

ERIC Educational Resources Information Center

Wagner, Peter D.

1977-01-01

Outlines methods for manipulating multiple gas data so as to gain the greatest amount of insight into the properties of ventilation-perfusion distributions. Refers to data corresponding to normal and abnormal lungs. Uses a two-dimensional framework with the respiratory gases of oxygen and carbon dioxide. (CS)

Concentration of (+/-)-propranolol in isolated, perfused lungs of rat.

PubMed Central

Dollery, C T; Junod, A F

1976-01-01

1 The metabolism and the accumulation of (+/-)-propranolol have been studied in isolated lungs of the rat, perfused with an artificial medium. 2 Little or no metabolism took place during the perfusion periods (up to 10 minutes). 3 Accumulation was observed with high tissue/medium ratios for substrate concentrations of 0.2 muM to 1 mM; there was evidence for saturability, but no real plateau could be seen. The presence of two binding sites with different affinities was established. 4 Cold greatly inhibited the accumulation process at low substrate concentrations, but had no effect at 1 mM propranolol. 5 Inhibition of accumulation was measured in the presence of imipramine, desmethylimipramine, nortryptiline, chlorpromazine and of Na+-free medium. Cocaine, 5-hydroxytryptamine and noradrenaline had no effect. Lidocaine enhanced the accumulation process. Release of previously bound propranolol was accelerated in the presence of propranolol and imipramine, unaffected by a Na+-free medium and decreased by cold and by lidocaine. 6 Experiments on lung tissue slices yielded qualitatively similar results to those obtained with perfused lungs. Ouabain and KCN had no or little effect on propranolol accumulation. PMID:1276542

Feasibility of quantitative regional ventilation and perfusion mapping with phase-resolved functional lung (PREFUL) MRI in healthy volunteers and COPD, CTEPH, and CF patients.

PubMed

Voskrebenzev, Andreas; Gutberlet, Marcel; Klimeš, Filip; Kaireit, Till F; Schönfeld, Christian; Rotärmel, Alexander; Wacker, Frank; Vogel-Claussen, Jens

2018-04-01

In this feasibility study, a phase-resolved functional lung imaging postprocessing method for extraction of dynamic perfusion (Q) and ventilation (V) parameters using a conventional 1H lung MRI Fourier decomposition acquisition is introduced. Time series of coronal gradient-echo MR images with a temporal resolution of 288 to 324 ms of two healthy volunteers, one patient with chronic thromboembolic hypertension, one patient with cystic fibrosis, and one patient with chronic obstructive pulmonary disease were acquired at 1.5 T. Using a sine model to estimate cardiac and respiratory phases of each image, all images were sorted to reconstruct full cardiac and respiratory cycles. Time to peak (TTP), V/Q maps, and fractional ventilation flow-volume loops were calculated. For the volunteers, homogenous ventilation and perfusion TTP maps (V-TTP, Q-TTP) were obtained. The chronic thromboembolic hypertension patient showed increased perfusion TTP in hypoperfused regions in visual agreement with dynamic contrast-enhanced MRI, which improved postpulmonary endaterectomy surgery. Cystic fibrosis and chronic obstructive pulmonary disease patients showed a pattern of increased V-TTP and Q-TTP in regions of hypoventilation and decreased perfusion. Fractional ventilation flow-volume loops of the chronic obstructive pulmonary disease patient were smaller in comparison with the healthy volunteer, and showed regional differences in visual agreement with functional small airways disease and emphysema on CT. This study shows the feasibility of phase-resolved functional lung imaging to gain quantitative information regarding regional lung perfusion and ventilation without the need for ultrafast imaging, which will be advantageous for future clinical translation. Magn Reson Med 79:2306-2314, 2018. © 2017 International Society for Magnetic Resonance in Medicine. © 2017 International Society for Magnetic Resonance in Medicine.

PO2 modulation of paraquat-induced microvascular injury in isolated dog lungs.

PubMed

Shibamoto, T; Taylor, A E; Parker, J C

1990-05-01

We determined the effects of paraquat (PQ) concentrations ranging from 10(-3) to 10(-2) M and three levels of venous PO2 [hypoxia (41 +/- 3 Torr), normoxia (147 +/- 8 Torr), and hyperoxia (444 +/- 17 Torr)] in the presence of 4 x 10(-3) M PQ on microvascular permeability in isolated blood-perfused dog lungs. Capillary filtration coefficient (Kf,c) increased and isogravimetric capillary pressure (Pc,i) decreased 3 h after perfusion with 10(-2) M PQ (n = 7) and 5 h after perfusion with 4 x 10(-3) M PQ (n = 6) but not with 10(-3) M PQ (n = 4). In hyperoxic lungs perfused with 4 x 10(-3) M PQ, Kf,c increased to nine times the base-line value 5 h after PQ [0.15 +/- 0.01 to 1.35 +/- 0.25 (SE) ml.min-1.cmH2O-1.100 g-1]. Pc,i significantly decreased from a base-line value of 9.4 +/- 0.2 to 7.1 +/- 0.4 cmH2O at 3 h. In hypoxic lungs perfused with 4 x 10(-3) M PQ (n = 5), Pc,i and Kf,c changes were not significantly different from those in normoxic lungs treated with PQ. Thus both hyperoxia and an increased dose of PQ shortened the latent period and increased the severity of the PQ-induced microvascular permeability lesion, but hypoxia failed to prevent the PQ damage.

Vasomotor tone does not affect perfusion heterogeneity and gas exchange in normal primate lungs during normoxia

NASA Technical Reports Server (NTRS)

Glenny, R. W.; Robertson, H. T.; Hlastala, M. P.

2000-01-01

To determine whether vasoregulation is an important cause of pulmonary perfusion heterogeneity, we measured regional blood flow and gas exchange before and after giving prostacyclin (PGI(2)) to baboons. Four animals were anesthetized with ketamine and mechanically ventilated. Fluorescent microspheres were used to mark regional perfusion before and after PGI(2) infusion. The lungs were subsequently excised, dried inflated, and diced into approximately 2-cm(3) pieces (n = 1,208-1,629 per animal) with the spatial coordinates recorded for each piece. Blood flow to each piece was determined for each condition from the fluorescent signals. Blood flow heterogeneity did not change with PGI(2) infusion. Two other measures of spatial blood flow distribution, the fractal dimension and the spatial correlation, did not change with PGI(2) infusion. Alveolar-arterial O(2) differences did not change with PGI(2) infusion. We conclude that, in normal primate lungs during normoxia, vasomotor tone is not a significant cause of perfusion heterogeneity. Despite the heterogeneous distribution of blood flow, active regulation of regional perfusion is not required for efficient gas exchange.

Effect of hyperoxia on uptake and metabolism of 5-hydroxytryptamine and β-phenylethylamine in rat lung: a sex difference

PubMed Central

Ben-Harari, R.R.; Lanir, A.; Youdim, M.B.H.

1981-01-01

1 The uptake of 5-hydroxytryptamine (5—HT) and β-phenylethylamine (PEA) and their deamination by monoamine oxidase (MAO) were studied in perfused lung from male and female rats exposed to 100% O2 at 1 ATA for up to 60 h. 2 The uptake and metabolism of 5-HT in lungs from both male and female rats was not changed by exposure to O2. 3 The uptake and metabolism of PEA by lungs from male rats was unchanged. Uptake of PEA by lungs from female rats was inhibited 20% and 62% after 37 h and 50 h exposure respectively. 4 MAO activity, both in vitro and in perfused lung, was increased towards PEA after 35 h of hyperoxia. 5 Metabolism of PEA in perfused lung, measured over 30 min, was inhibited 52% after 50 h of O2 hyperoxia. 6 These results show that exposure to high concentrations of O2 damages lung, resulting in inhibition of uptake of PEA and consequently in inhibition of metabolism of PEA. 7 These results also indicate that, in lung from female rats, MAO-type B is more susceptible to changes in O2 tension than MAO type A. PMID:7236995

Cardiorespiratory Interactions in Paediatrics: 'It's (almost always) the circulation stupid!'

PubMed

Rigby, M L; Rosenthal, M

2017-03-01

The interaction of the heart and lungs is probably the most important aspect of life and survival. Fortunately, it is not difficult to understand the fundamentals. The purpose of the lungs and their ventilation is to present oxygen to the circulation via the alveoli and to receive carbon dioxide from the circulation and then expel it. The relations of the heart and lungs and the matching of blood flow to the various organs with ventilation and lung perfusion may be disrupted by a variety of congenital or acquired heart malformations. They include those giving rise to an increased or reduced pulmonary blood flow, elevated pulmonary venous pressure or external physical pressure on the airways or lung parenchyma. Respiratory disorders which compromise cardiac function include states with reduced alveolar ventilation, those with a barrier to ventilation or perfusion, ventilation/perfusion mismatch and pulmonary vascular disease. There is also a fascinating group in which congenital disorders of the heart and lung co-exist to produce very particular modes of abnormal cardiopulmonary interaction. Copyright © 2016. Published by Elsevier Ltd.

Electrical impedance tomography.

PubMed

Costa, Eduardo L V; Lima, Raul Gonzalez; Amato, Marcelo B P

2009-02-01

Electrical impedance tomography (EIT) is a noninvasive, radiation-free monitoring tool that allows real-time imaging of ventilation. The purpose of this article is to discuss the fundamentals of EIT and to review the use of EIT in critical care patients. In addition to its established role in describing the distribution of alveolar ventilation, EIT has been shown to be a useful tool to detect lung collapse and monitor lung recruitment, both regionally and on a global basis. EIT has also been used to diagnose with high sensitivity incident pneumothoraces during mechanical ventilation. Additionally, with injection of hypertonic saline as a contrast agent, it is possible to estimate ventilation/perfusion distributions. EIT is cheap, noninvasive and allows continuous monitoring of ventilation. It is gaining acceptance as a valuable monitoring tool for the care of critical patients.

Coenzyme Q(1) as a probe for mitochondrial complex I activity in the intact perfused hyperoxia-exposed wild-type and Nqo1-null mouse lung.

PubMed

Bongard, Robert D; Myers, Charles R; Lindemer, Brian J; Baumgardt, Shelley; Gonzalez, Frank J; Merker, Marilyn P

2012-05-01

Previous studies showed that coenzyme Q(1) (CoQ(1)) reduction on passage through the rat pulmonary circulation was catalyzed by NAD(P)H:quinone oxidoreductase 1 (NQO1) and mitochondrial complex I, but that NQO1 genotype was not a factor in CoQ(1) reduction on passage through the mouse lung. The aim of the present study was to evaluate the complex I contribution to CoQ(1) reduction in the isolated perfused wild-type (NQO1(+/+)) and Nqo1-null (NQO1(-)/(-)) mouse lung. CoQ(1) reduction was measured as the steady-state pulmonary venous CoQ(1) hydroquinone (CoQ(1)H(2)) efflux rate during infusion of CoQ(1) into the pulmonary arterial inflow. CoQ(1)H(2) efflux rates during infusion of 50 μM CoQ(1) were not significantly different for NQO1(+/+) and NQO1(-/-) lungs (0.80 ± 0.03 and 0.68 ± 0.07 μmol·min(-1)·g lung dry wt(-1), respectively, P > 0.05). The mitochondrial complex I inhibitor rotenone depressed CoQ(1)H(2) efflux rates for both genotypes (0.19 ± 0.08 and 0.08 ± 0.04 μmol·min(-1)·g lung dry wt(-1) for NQO1(+/+) and NQO1(-/-), respectively, P < 0.05). Exposure of mice to 100% O(2) for 48 h also depressed CoQ(1)H(2) efflux rates in NQO1(+/+) and NQO1(-/-) lungs (0.43 ± 0.03 and 0.11 ± 0.04 μmol·min(-1)·g lung dry wt(-1), respectively, P < 0.05 by ANOVA). The impact of rotenone or hyperoxia on CoQ(1) redox metabolism could not be attributed to effects on lung wet-to-dry weight ratios, perfusion pressures, perfused surface areas, or total venous effluent CoQ(1) recoveries, the latter measured by spectrophotometry or mass spectrometry. Complex I activity in mitochondria-enriched lung fractions was depressed in hyperoxia-exposed lungs for both genotypes. This study provides new evidence for the potential utility of CoQ(1) as a nondestructive indicator of the impact of pharmacological or pathological exposures on complex I activity in the intact perfused mouse lung.

Tezosentan reduces the microvascular filtration coefficient in isolated lungs from rats subjected to cecum ligation and puncture

PubMed Central

Kuklin, Vladimir; Sovershaev, Mikhail; Andreasen, Thomas; Skogen, Vegard; Ytrehus, Kirsti; Bjertnaes, Lars

2005-01-01

Introduction We recently demonstrated that the non-selective endothelin-1 (ET-1) receptor blocker tezosentan antagonizes ovine acute lung injury (ALI) following infusion of endotoxin or ET-1 by reducing the enhanced lung microvascular pressure, although we could not exclude the possibility of a simultaneous decline in microvascular permeability. In the present study, our aim was to find out if tezosentan reverses the rise in microvascular filtration coefficient (Kfc) in rat lungs that have been isolated and perfused 12 h after cecum ligation and puncture (CLP) or infusion of ET-1. Methods Wistar rats (n = 42) were subjected to CLP. Postoperatively, rats were randomized to a CLP group (n = 7) and a CLP + tezosentan group (n = 7); the latter received tezosentan 30 mg/kg. A sham-operated group (n = 5) underwent laparotomy without CLP. Twelve hours postoperatively, the lungs were isolated and perfused with blood from similarly treated rats that also were used to assess plasma concentration of ET-1 and protein kinase Cα (PKCα) in lung tissue. Additionally, isolated blood perfused lungs from healthy rats were randomized to a control group (n = 8), an ET-1 group (n = 7) subjected to pulmonary arterial injection of ET-1 10 nM, and an ET-1 + tezosentan group (n = 7) that received tezosentan 30 mg/kg. All lung preparations received papaverine 0.1 μg/kg added to the perfusate for vasoplegia. Pulmonary hemodynamic variables, Kfc and lung compliance (CL) were assessed. Results After CLP, the plasma concentration of ET-1 increased. Papaverine abolished the vasoconstrictor response to ET-1 and the pulmonary vascular pressures remained close to baseline throughout the experiments. Both CLP and injection of ET-1 caused significant changes in Kfc and CL that were prevented in tezosentan-treated rats. Compared to sham-operated animals, CLP increased the content of PKCα by 50% and 70% in the cytosolic and the membrane fractions of lung tissue homogenates, respectively. Tezosentan prevented the upregulation of PKCα in the membrane fraction. Conclusion In rat lungs isolated and perfused after CLP, tezosentan precludes both the increase in Kfc and the upregulation of PKCα in the membrane fraction of lung tissue. PMID:16280068

Platelet sequestration and activation during GalTKO.hCD46 pig lung perfusion by human blood is primarily mediated by GPIb, GPIIb/IIIa, and von Willebrand Factor.

PubMed

Burdorf, L; Riner, A; Rybak, E; Salles, I I; De Meyer, S F; Shah, A; Quinn, K J; Harris, D; Zhang, T; Parsell, D; Ali, F; Schwartz, E; Kang, E; Cheng, X; Sievert, E; Zhao, Y; Braileanu, G; Phelps, C J; Ayares, D L; Deckmyn, H; Pierson, R N; Azimzadeh, A M; Dandro, Amy; Karavi, Kasinath

2016-05-01

Here, we ask whether platelet GPIb and GPIIb/IIIa receptors modulate platelet sequestration and activation during GalTKO.hCD46 pig lung xenograft perfusion. GalTKO.hCD46 transgenic pig lungs were perfused with heparinized fresh human blood. Results from perfusions in which αGPIb Fab (6B4, 10 mg/l blood, n = 6), αGPIIb/IIIa Fab (ReoPro, 3.5 mg/l blood, n = 6), or both drugs (n = 4) were administered to the perfusate were compared to two additional groups in which the donor pig received 1-desamino-8-d-arginine vasopressin (DDAVP), 3 μg/kg (to pre-deplete von Willebrand Factor (pVWF), the main GPIb ligand), with or without αGPIb (n = 6 each). Platelet sequestration was significantly delayed in αGPIb, αGPIb+DDAVP, and αGPIb+αGPIIb/IIIa groups. Median lung "survival" was significantly longer (>240 vs. 162 min reference, p = 0.016), and platelet activation (as CD62P and βTG) were significantly inhibited, when pigs were pre-treated with DDAVP, with or without αGPIb Fab treatment. Pulmonary vascular resistance rise was not significantly attenuated in any group, and was associated with residual thromboxane and histamine elaboration. The GPIb-VWF and GPIIb/IIIa axes play important roles in platelet sequestration and coagulation cascade activation during GalTKO.hCD46 lung xenograft injury. GPIb blockade significantly reduces platelet activation and delays platelet sequestration in this xenolung rejection model, an effect amplified by adding αGPIIb/IIIa blockade or depletion of VWF from pig lung. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Lung perfusion measured using magnetic resonance imaging: New tools for physiological insights into the pulmonary circulation.

PubMed

Hopkins, Susan R; Prisk, G Kim

2010-12-01

Since the lung receives the entire cardiac output, sophisticated imaging techniques are not required in order to measure total organ perfusion. However, for many years studying lung function has required physiologists to consider the lung as a single entity: in imaging terms as a single voxel. Since imaging, and in particular functional imaging, allows the acquisition of spatial information important for studying lung function, these techniques provide considerable promise and are of great interest for pulmonary physiologists. In particular, despite the challenges of low proton density and short T2* in the lung, noncontrast MRI techniques to measure pulmonary perfusion have several advantages including high reliability and the ability to make repeated measurements under a number of physiologic conditions. This brief review focuses on the application of a particular arterial spin labeling (ASL) technique, ASL-FAIRER (flow sensitive inversion recovery with an extra radiofrequency pulse), to answer physiologic questions related to pulmonary function in health and disease. The associated measurement of regional proton density to correct for gravitational-based lung deformation (the "Slinky" effect (Slinky is a registered trademark of Pauf-Slinky incorporated)) and issues related to absolute quantification are also discussed. Copyright © 2010 Wiley-Liss, Inc.

Desflurane inhalation before ischemia increases ischemia-reperfusion-induced vascular leakage in isolated rabbit lungs.

PubMed

Oshima, Yoshiaki; Sakamoto, Seiji; Yamasaki, Kazumasa; Mochida, Shinsuke; Funaki, Kazumi; Moriyama, Naoki; Otsuki, Akihiro; Endo, Ryo; Nakasone, Masato; Takahashi, Shunsaku; Harada, Tomomi; Minami, Yukari; Inagaki, Yoshimi

2016-01-01

Isoflurane and sevoflurane protect lungs with ischemia-reperfusion (IR) injury. We examined the influence of desflurane on IR lung injury using isolated rabbit lungs perfused with a physiological salt solution. The isolated lungs were divided into three groups: IR, desflurane-treated ischemia-reperfusion (DES-IR), and ventilation/perfusion-continued control (Cont) groups (n = 6 per group). In the DES-IR group, inhalation of desflurane at 1 minimum alveolar concentration (MAC) was conducted in a stable 30-min phase. In the IR and DES-IR groups, ventilation/perfusion was stopped for 75 min after the stable phase. Subsequently, they were resumed. Each lung was placed on a balance, and weighed. Weight changes were measured serially throughout this experiment. The coefficient of filtration (K fc ) was determined immediately before ischemia and 60 min after reperfusion. Furthermore, bronchoalveolar lavage fluid (BALF) was collected from the right bronchus at the completion of the experiment. After the completion of the experiment, the left lung was dried, and the lung wet-to-dry weight ratio (W/D) was calculated. The K fc values at 60 min after perfusion were 0.40 ± 0.13 ml/min/mmHg/100 g in the DES-IR group, 0.26 ± 0.07 ml/min/mmHg/100 g in the IR group, and 0.22 ± 0.08 (mean ± SD) ml/mmHg/100 g in the Cont group. In the DES-IR group, the K fc at 60 min after the start of reperfusion was significantly higher than in the other groups. In the DES-IR group, W/D was significantly higher than in the Cont group. In the DES-IR group, the BALF concentrations of nitric oxide metabolites were significantly higher than in the other groups. In the DES-IR group, the total amount of vascular endothelial growth factor in BALF was significantly higher than in the Cont group. The pre-inhalation of desflurane at 1 MAC exacerbates pulmonary IR injury in isolated/perfused rabbit lungs.

Ex Vivo Lung Perfusion Rehabilitates Sepsis-Induced Lung Injury

PubMed Central

Mehaffey, J. Hunter; Charles, Eric J.; Sharma, Ashish K.; Salmon, Morgan; Money, Dustin; Schubert, Sarah; Stoler, Mark H; Tribble, Curtis G.; Laubach, Victor E.; Roeser, Mark E.; Kron, Irving L.

2017-01-01

Objective Sepsis is the number one cause of lung injury in adults. Ex vivo lung perfusion (EVLP) is gaining clinical acceptance for donor lung evaluation and rehabilitation, and may expand the use of marginal organs for transplantation. We hypothesized that four hours of normothermic EVLP would improve compliance and oxygenation in a porcine model of sepsis-induced lung injury. Methods We utilized a porcine lung injury model using intravenous lipopolysaccharide (LPS) to induce a systemic inflammatory response. Two groups (n=4 animals/group) received a 2-hour infusion of LPS via the external jugular vein. Serial blood gases were performed every 30 min until the PO2/FiO2 ratio dropped below 150 on two consecutive readings. Lungs were then randomized to treatment with 4 hours of normothermic EVLP with Steen solution or 4 additional hours of in vivo perfusion (Control). Airway pressures and blood gases were recorded for calculation of dynamic lung compliance and PO2/FiO2 ratios. EVLP was performed according to the NOVEL trial protocol with hourly recruitment maneuvers and oxygen challenge. Results All animals reached a PO2/FiO2 ratio < 150 mmHg within 3 hours after start of LPS infusion. Animals in the Control group had continued decline of oxygenation and compliance during the 4-hour in vivo perfusion period with three of the four animals dying within 4 hours due to severe hypoxia. The EVLP group demonstrated significant improvements in oxygenation and dynamic compliance from hour 1 to hour 4 (365.8±53.0 vs 584.4±21.0 mmHg, p=0.02; 9.0±2.8 vs 15.0±3.6, p=0.02 mL/cmH2O). Conclusions EVLP can successfully rehabilitate LPS-induced lung injury in this preclinical porcine model. Thus EVLP may provide a means to rehabilitate many types of acute lung injury. PMID:28434548

Endothelial cell membrane vesicles in the study of organ preference of metastasis.

PubMed

Johnson, R C; Augustin-Voss, H G; Zhu, D Z; Pauli, B U

1991-01-01

Many malignancies exhibit distinct patterns of metastasis that appear to be mediated by receptor/ligand-like interactions between tumor cells and organ-specific vascular endothelium. In order to study endothelial cell surface molecules involved in the binding of metastatic cells, we developed a perfusion method to isolate outside-out membrane vesicles from the lumenal surface of rat lung microvascular endothelium. Lungs were perfused in situ for 4 h at 37 degrees C with a solution of 100 mM formaldehyde, 2 mM dithiothreitol in phosphate-buffered saline to induce endothelial cell vesiculation. Radioiodinated rat lung endothelial cell membrane vesicles bound lung-metastatic tumor cells (B16F10, R323OAC-MET) in significantly higher numbers than their low or nonmetastatic counterparts (B16F0, R323OAC-LR). In contrast, leg endothelial membrane vesicle showed no binding preference for either cell line. Neuraminidase treatment of vesicles abolished specificity of adhesion of lung-derived vesicles to lung metastatic tumor cells. These results demonstrate that in situ perfusion is an appropriate technique to obtain pure endothelial cell membrane vesicles containing functionally active adhesion molecules. The preferential binding of lung-derived endothelial cell membrane vesicles by lung metastatic tumor cells is evidence of the importance of endothelial cell adhesion molecules in the formation of metastases.

Assessment of regional lung functional impairment with co-registered respiratory-gated ventilation/perfusion SPET-CT images: initial experiences.

PubMed

Suga, Kazuyoshi; Yasuhiko, Kawakami; Zaki, Mohammed; Yamashita, Tomio; Seto, Aska; Matsumoto, Tsuneo; Matsunaga, Naofumi

2004-02-01

In this study, respiratory-gated ventilation and perfusion single-photon emission tomography (SPET) were used to define regional functional impairment and to obtain reliable co-registration with computed tomography (CT) images in various lung diseases. Using a triple-headed SPET unit and a physiological synchroniser, gated perfusion SPET was performed in a total of 78 patients with different pulmonary diseases, including metastatic nodules (n = 15); in 34 of these patients, it was performed in combination with gated technetium-99m Technegas SPET. Projection data were acquired using 60 stops over 120 degrees for each detector. Gated end-inspiration and ungated images were reconstructed from 1/8 data centered at peak inspiration for each regular respiratory cycle and full respiratory cycle data, respectively. Gated images were registered with tidal inspiration CT images using automated three-dimensional (3D) registration software. Registration mismatch was assessed by measuring 3D distance of the centroid of the nine selected round perfusion-defective nodules. Gated SPET images were completed within 29 min, and increased the number of visible ventilation and perfusion defects by 9.7% and 17.2%, respectively, as compared with ungated images; furthermore, lesion-to-normal lung contrast was significantly higher on gated SPET images. In the nine round perfusion-defective nodules, gated images yielded a significantly better SPET-CT match compared with ungated images (4.9 +/- 3.1 mm vs 19.0 +/- 9.1 mm, P<0.001). The co-registered SPET-CT images allowed accurate perception of the location and extent of each ventilation/perfusion defect on the underlying CT anatomy, and characterised the pathophysiology of the various diseases. By reducing respiratory motion effects and enhancing perfusion/ventilation defect clarity, gated SPET can provide reliable co-registered images with CT images to accurately characterise regional functional impairment in various lung diseases.

Applications and interpretation of krypton 81m ventilation/technetium 99m macroaggregate perfusion lung scanning in childhood

NASA Astrophysics Data System (ADS)

Davies, Hugh Trevor Frimston

Radionuclide ventilation perfusion lung scans now play an important part in the investigation of paediatric lung disease, providing a safe, noninvasive assessment of regional lung function in children with suspected pulmonary disease. In paediatric practice the most suitable radionuclides are Krypton 81m (Kr81m) and Technetium 99m (Tc99m), which are jointly used in the Kr81m ventilation/Tc99m macroaggregate perfusion lung scan (V/Q lung scan). The Kr81m ventilation scan involves a low radiation dose, requires little or no subject cooperation and because of the very short half life of Kr81m (13 seconds) the steady state image acquired during continuous inhalation of the radionuclide is considered to reflect regional distribution of ventilation. It is now the most important noninvasive method available for the investigation of the regional abnormalities of ventilation characteristic of many congenital and acquired paediatric respiratory diseases, such as diaphragmatic hernia, pulmonary sequestration, bronchopulmonary dysplasia, foreign body inhalation and bronchiectasis. It improves diagnostic accuracy, aids clinical decision making and is used to monitor the progress of disease and response to therapy. Theoretical analysis of the steady state Kr81m ventilation image suggests that it may only reflect regional ventilation when specific ventilation (ventilation per unit volume of lung) is within or below the normal adult range (1-3 L/L/min). At higher values such as those seen in neonates and infants (8-15 L/L/min) Kr81m activity may reflect regional lung volume rather than ventilation, a conclusion supported by the studies of Ciofetta et al. There is some controversy on this issue as animal studies have demonstrated that the Kr81m image reflects ventilation over a much wider range of specific ventilation (up to 13 L/L/min). A clinical study of sick infants and very young children is in agreement with this animal work and suggests that the steady state Kr81m image still reflects regional ventilation in this age group. The doubt cast on the interpretation of the Kr81m steady state image could limit the value of V/Q lung scans in following regional lung function through childhood, a period when specific ventilation is falling rapidly as the child grows. Therefore the first aim of this study was to examine the application of this theoretical model to children and determine whether the changing specific ventilation seen through childhood significantly alters the interpretation of the steady state Kr81m image. This is a necessary first step before conducting longitudinal studies of regional ventilation and perfusion in children. The effect of posture on regional ventilation and perfusion in the adult human lung has been extensively studied. Radiotracer studies have consistently shown that both ventilation and perfusion are preferentially distributed to dependent lung regions during tidal breathing regardless of posture. There is little published information concerning the pattern in children yet there are many differences in lung and chest wall mechanics of children and adults which, along with clinical observation, have led to the hypothesis that the pattern of regional ventilation observed in adults may not be seen in children. Recent reports of regional ventilation in infants and very young children have provided support for this theory. The paper of Heaf et al demonstrated that these differences may in certain circumstances be clinically important. It is not clear however at what age children adopt the "adult pattern of ventilation". In addition to the problems referred to above, attenuation of Kr81m activity as it passes through the chest wall and the changing geometry of the chest during tidal breathing have made quantitative analysis of the image difficult although fractional ventilation and perfusion to each lung can be calculated from the steady state image. In clinical practise, therefore, ventilation and perfusion are usually assessed by inspection of the steady state image. The aims of the present study were therefore: 1. To critically assess Kr81m ventilation and Tc99m MAA perfusion images in children. 2. To derive fractional ventilation and perfusion to each lung in children with normal chest radiography and homogeneous distribution of the radionuclides. 3. To conduct further studies into the effects of gravity on regional lung function. 4. To apply the technique in clinical practise. 5. To attempt to improve quantitation of the Kr81m ventilation image.

Biomarkers for radiation pneumonitis using non-invasive molecular imaging

PubMed Central

Medhora, Meetha; Haworth, Steven; Liu, Yu; Narayanan, Jayashree; Gao, Feng; Zhao, Ming; Audi, Said; Jacobs, Elizabeth R.; Fish, Brian L.; Clough, Anne V.

2016-01-01

Rationale Our goal is to develop minimally-invasive biomarkers for predicting radiation-induced lung injury before symptoms develop. Currently there are no biomarkers that can predict radiation pneumonitis. Radiation damage to the whole lung is a serious risk in nuclear accidents or in case of radiological terrorism. Our previous studies have shown a single dose of 15 Gy X-rays to the thorax causes severe pneumonitis in rats by 6–8 weeks. We have also developed a mitigator for radiation pneumonitis and fibrosis that can be started as late as 5 weeks after radiation. Methods We used two functional single photon emission computed tomography (SPECT) probes in vivo in irradiated rat lungs. Regional pulmonary perfusion was measured by injection of technetium labeled macroaggregated albumin (99mTc-MAA). Perfused volume was determined by comparing the volume of distribution of 99mTc-MAA to the anatomical lung volume obtained by micro-CT. A second probe, technetium labeled duramycin that binds to apoptotic cells, was used to measure pulmonary cell death in the same rat model. Results Perfused volume of lung was decreased by ~25% at 1, 2 and 3 weeks after 15 Gy and 99mTc-duramycin uptake was more than doubled at 2 and 3 weeks. There was no change in body weight, breathing rate or lung histology between irradiated and non-irradiated rats at these times. Pulmonary vascular resistance and vascular permeability measured in isolated perfused lungs ex vivo increased at 2 weeks after 15 Gy. Principal conclusions Our results suggest the potential for SPECT biomarkers for predicting radiation injury to the lungs before substantial functional or histological damage is observed. Early prediction of radiation pneumonitis will benefit those receiving radiation in the context of therapy, accidents or terrorism in time to initiate mitigation. PMID:27033892

Ischemia-reperfusion injury in the isolated rat lung. Role of flow and endogenous leukocytes.

PubMed

Seibert, A F; Haynes, J; Taylor, A

1993-02-01

Microvascular lung injury caused by ischemia-reperfusion (IR) may occur via leukocyte-dependent and leukocyte-independent pathways. Leukocyte-endothelial adhesion may be a rate-limiting step in IR lung injury. Leukocyte adhesion to microvascular endothelium occurs when the attractant forces between leukocyte and endothelium are greater than the kinetic energy of the leukocyte and the vascular wall shear rate. We hypothesized (1) that isolated, buffer-perfused rat lungs are not free of endogenous leukocytes, (2) that endogenous leukocytes contribute to IR-induced microvascular injury as measured by the capillary filtration coefficient (Kfc), and (3) that a reduction of perfusate flow rate would potentiate leukocyte-dependent IR injury. Sixty lungs were divided into four groups: (1) low-flow controls, (2) high-flow controls, (3) low-flow IR, and (4) high-flow IR. Microvascular injury was linearly related to baseline perfusate leukocyte concentrations at both low (r = 0.78) and high (r = 0.82) flow rates. Kfc in the high-flow IR group (0.58 +/- 0.03 ml/min/cm H2O/100 g) was less (p < 0.05) than Kfc in the low-flow IR group (0.82 +/- 0.07), and in both groups Kfc values were significantly greater than low-flow (0.34 +/- 0.03) and high-flow (0.31 +/- 0.01) control Kfc values after 75 min. Retention of leukocytes in the lung, evaluated by a tissue myeloperoxidase assay, was greatest in the low-flow IR group. We conclude (1) that isolated, buffer-perfused rat lungs contain significant quantities of leukocytes and that these leukocytes contribute to IR lung injury, and (2) that IR-induced microvascular injury is potentiated by low flow.

Novel Flurometric Tool to Assess Mitochondrial Redox State of Isolated Perfused Rat Lungs After Exposure to Hyperoxia

PubMed Central

Audi, Said H.; Staniszewski, Kevin S.; Haworth, Steven T.; Jacobs, Elizabeth R.; Ranji, Mahsa; Zablocki, Clement J.

2013-01-01

Recently, we demonstrated the utility of optical fluorometry to detect a change in the redox status of mitochondrial autofluorescent coenzymes nicotinamide adenine dinucleotide (NADH) and oxidized form of flavin adenine dinucleotide \\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{upgreek} \\usepackage{mathrsfs} \\setlength{\\oddsidemargin}{-69pt} \\begin{document} }{}$({\\rm FADH}_{2})$\\end{document} (FAD), as a measure of mitochondrial function in isolated perfused rat lungs (IPL). The objective of this paper was to utilize optical fluorometry to evaluate the effect of rat exposure to hyperoxia (\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{upgreek} \\usepackage{mathrsfs} \\setlength{\\oddsidemargin}{-69pt} \\begin{document} }{}${>}{95\\%}~{\\rm O}_{2}$\\end{document} for 48 h) on lung tissue mitochondrial redox status of NADH and FAD in a nondestructive manner in IPL. Surface NADH and FAD signals were measured before and after lung perfusion with perfusate containing rotenone (ROT, complex I inhibitor), potassium cyanide (KCN, complex IV inhibitor), and/or pentachlorophenol (PCP, uncoupler). ROT- or KCN-induced increase in NADH signal is considered a measure of complex I activity, and KCN-induced decrease in FAD signal is considered a measure of complex II activity. The results show that hyperoxia decreased complex I and II activities by 63% and 55%, respectively, when compared to lungs of rats exposed to room air (normoxic rats). Mitochondrial complex I and II activities in lung homogenates were also lower (77% and 63%, respectively) for hyperoxic than for normoxic lungs. These results suggest that the mitochondrial matrix is more reduced in hyperoxic lungs than in normoxic lungs, and demonstrate the ability of optical fluorometry to detect a change in mitochondrial redox state of hyperoxic lungs prior to histological changes characteristic of hyperoxia. PMID:25379360

Hyperpolarized xenon magnetic resonance of the lung and the brain

NASA Astrophysics Data System (ADS)

Venkatesh, Arvind Krishnamachari

2001-04-01

Hyperpolarized noble gas Magnetic Resonance Imaging (MRI) is a new diagnostic modality that has been used successfully for lung imaging. Xenon is soluble in blood and inhaled xenon is transported to the brain via circulating blood. Xenon also accumulates in the lipid rich white matter of the brain. Hyperpolarized xenon can hence be used as a tissue- sensitive probe of brain function. The goals of this study were to identify the NMR resonances of xenon in the rat brain and evaluate the role of hyperpolarized xenon for brain MRI. We have developed systems to produce sufficient volumes of hyperpolarized xenon for in vivo brain experiments. The specialized instrumentation developed include an apparatus for optical pump-cell manufacture and high purity gas manifolds for filling cells. A hyperpolarized gas delivery system was designed to ventilate small animals with hyperpolarized xenon for transport to the brain. The T1 of xenon dissolved in blood indicates that the lifetime of xenon in the blood is sufficient for significant magnetization to be transferred to distal tissues. A variety of carrier agents for intravenous delivery of hyperpolarized xenon were tested for transport to distal tissues. Using our new gas delivery system, high SNR 129Xe images of rat lungs were obtained. Spectroscopy with hyperpolarized xenon indicated that xenon was transported from the lungs to the blood and tissues with intact magnetization. After preliminary studies that indicated the feasibility for in vivo rat brain studies, experiments were performed with adult rats and young rats with different stages of white matter development. Both in vivo and in vitro experiments showed the prominence of one peak from xenon in the rat brain, which was assigned to brain lipids. Cerebral brain perfusion was calculated from the wash-out of the hyperpolarized xenon signal in the brain. An increase in brain perfusion during maturation was observed. These experiments showed that hyperpolarized xenon MRI can be used to develop unique approaches to studying white matter and gray matter in the brain. Some of the possible applications of hyperpolarized xenon MRI in the brain are clinical diagnosis of white matter diseases, functional MRI (fMRI) and measurement of cerebral blood perfusion.

Ischemia and reperfusion of the lung tissues induced increase of lung permeability and lung edema is attenuated by dimethylthiourea (PP69).

PubMed

Chen, K H; Chao, D; Liu, C F; Chen, C F; Wang, D

2010-04-01

This study sought to determine whether oxygen radical scavengers of dimethylthiourea (DMTU), superoxide dismutase (SOD), or catalase (CAT) pretreatment attenuated ischemia-reperfusion (I/R)-induced lung injury. After isolation from a Sprague-Dawley rat, the lungs were perfused through the pulmonary artery cannula with rat whole blood diluted 1:1 with a physiological salt solution. An acute lung injury was induced by 10 minutes of hypoxia with 5% CO2-95% N2 followed by 65 minutes of ischemia and then 65 minutes of reperfusion. I/R significantly increased microvascular permeability as measured by the capillary filtration coefficient (Kfc), lung weight-to-body weight ratio (LW/BW), and protein concentration in bronchoalveolar lavage fluid (PCBAL). DMTU pretreatment significantly attenuated the acute lung injury. The capillary filtration coefficient (P<.01), LW/BW (P<.01) and PCBAL (P<.05) were significantly lower among the DMTU-treated rats than hosts pretreated with SOD or CAT. The possible mechanisms of the protective effect of DMTU in I/R-induced lung injury may relate to the permeability of the agent allowing it to scavenge intracellular hydroxyl radicals. However, whether superoxide dismutase or catalase antioxidants showed protective effects possibly due to their impermeability of the cell membrane not allowing scavenging of intracellular oxygen radicals. Copyright (c) 2010 Elsevier Inc. All rights reserved.

Ventilation/Perfusion Positron Emission Tomography—Based Assessment of Radiation Injury to Lung

DOE Office of Scientific and Technical Information (OSTI.GOV)

Siva, Shankar, E-mail: shankar.siva@petermac.org; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville; Hardcastle, Nicholas

2015-10-01

Purpose: To investigate {sup 68}Ga-ventilation/perfusion (V/Q) positron emission tomography (PET)/computed tomography (CT) as a novel imaging modality for assessment of perfusion, ventilation, and lung density changes in the context of radiation therapy (RT). Methods and Materials: In a prospective clinical trial, 20 patients underwent 4-dimensional (4D)-V/Q PET/CT before, midway through, and 3 months after definitive lung RT. Eligible patients were prescribed 60 Gy in 30 fractions with or without concurrent chemotherapy. Functional images were registered to the RT planning 4D-CT, and isodose volumes were averaged into 10-Gy bins. Within each dose bin, relative loss in standardized uptake value (SUV) was recorded for ventilation andmore » perfusion, and loss in air-filled fraction was recorded to assess RT-induced lung fibrosis. A dose-effect relationship was described using both linear and 2-parameter logistic fit models, and goodness of fit was assessed with Akaike Information Criterion (AIC). Results: A total of 179 imaging datasets were available for analysis (1 scan was unrecoverable). An almost perfectly linear negative dose-response relationship was observed for perfusion and air-filled fraction (r{sup 2}=0.99, P<.01), with ventilation strongly negatively linear (r{sup 2}=0.95, P<.01). Logistic models did not provide a better fit as evaluated by AIC. Perfusion, ventilation, and the air-filled fraction decreased 0.75 ± 0.03%, 0.71 ± 0.06%, and 0.49 ± 0.02%/Gy, respectively. Within high-dose regions, higher baseline perfusion SUV was associated with greater rate of loss. At 50 Gy and 60 Gy, the rate of loss was 1.35% (P=.07) and 1.73% (P=.05) per SUV, respectively. Of 8/20 patients with peritumoral reperfusion/reventilation during treatment, 7/8 did not sustain this effect after treatment. Conclusions: Radiation-induced regional lung functional deficits occur in a dose-dependent manner and can be estimated by simple linear models with 4D-V/Q PET/CT imaging. These findings may inform future studies of functional lung avoidance using V/Q PET/CT.« less

Recent lung imaging studies. [Effectiveness for diagnosis of chronic obstructive pulmonary disease

DOE Office of Scientific and Technical Information (OSTI.GOV)

Taplin, G.V.; Chopra, S.K.

1976-01-01

Radionuclide lung imaging procedures have been available for 11 years but only the perfusion examination has been used extensively and mainly for the diagnosis of pulmonary embolism (P.E.). Its ability to reveal localized ischemia makes it a valuable test of regional lung function as well as a useful diagnostic aid in P.E. Although it had been recognized for several years that chronic obstructive pulmonary disease (COPD) can cause lung perfusion defects which may simulate pulmonary embolism, relatively little use has been made of either the radioxenon or the radioaerosol inhalation lung imaging procedures until the last few years as amore » means of distinguishing P.E. from COPD. In this review emphasis is placed on our recent experience with both of these inhalation procedures in comparison with pulmonary function tests and roentgenography for the early detection of COPD in population studies. Equal emphasis is given to simultaneous aerosol ventilation-perfusion (V/P) imaging for a functional diagnosis of P.E. Two new developments in regional lung diffusion imaging, performed after the inhalation of radioactive gases and/or rapidly absorbed radioaerosols are described. The experimental basis for their potential clinical application in pulmonary embolism detection is presented.« less

The 'fragmented' scintigraphic lung pattern in pulmonary lymphangitic carcinomatosis secondary to breast cancer.

PubMed

Vattimo, A V; Burroni, L; Bertelli, P; Vella, A; Volterrani, D

1998-01-01

Pulmonary lymphangitic carcinomatosis (PLC) is an unusual presentation of diffuse infiltrative lung disease. In this report we present two cases secondary to breast cancer; the diagnosis was made by means of transbronchial lung biopsy or postmortem examination. The goal of this study was to analyze the scintigraphic pattern of pulmonary perfusion performed with technetium-99m macroaggregated albumin (99mTc-MAA) in the hope of achieving improved recognition of PLC and its subsequent diagnosis. Upon admission, both patients underwent routine clinical exams followed by chest X-rays. The second patient also underwent CT examination, and both were ultimately examined using pulmonary perfusion scintigraphy with 99mTc-MAA. In the various exams performed, the most reliable and easily identified diagnostic finding turned out to be a characteristic 'fragmented' lung pattern revealed with the perfusion lung scan. Unfortunately, in both cases the patients' conditions rapidly worsened and death occurred shortly following scintigraphy. We were able to conclude that the recognition of the mentioned fragmented scintigraphic lung pattern may be useful in suspected PLC, whereas the nonspecific clinical presentation of this pathology makes diagnosis extremely difficult, with the most significant results being achieved through a comparison of scintigraphic and high resolution CT data.

Locoregional intravascular viral therapy of cancer: precision guidance for Paris’s arrow?

PubMed Central

Pencavel, T; Seth, R; Hayes, A; Melcher, A; Pandha, H; Vile, R; Harrington, KJ

2013-01-01

Viral therapy of cancer includes strategies such as viral transduction of tumour cells with ‘suicide genes’, using viral infection to trigger immune-mediated tumour cell death and using oncolytic viruses for their direct anti-tumour action. However, problems still remain in terms of adequate viral delivery to tumours. A role is also emerging for single-organ isolation and perfusion. Having begun with the advent of isolated limb perfusion for extremity malignancy, experimental systems have been developed for the perfusion of other organs, particularly the liver, kidneys and lungs. These are beginning to be adopted into clinical treatment pathways. The combination of these two modalities is potentially significant. Locoregional perfusion increases the exposure of tumour cells to viral agents. In addition, the avoidance of systemic elimination through the immune and reticulo-endothelial systems should provide a mechanism for increased transduction/infection of target cells. The translation of laboratory research to clinical practice would occur within the context of perfusion programmes, which are already established in the clinic. Many of these programmes include the use of vasoactive cytokines such as tumour necrosis factor-α, which may have an effect on viral uptake. Evidence of activation of specific antitumour immunological responses by intratumoural and other existing methods of viral administration raises the intriguing possibility of a locoregional therapy, with the ability to affect distant sites of disease. In this review, we examined the state of the literature in this area and summarized current findings before indicating likely areas of continuing interest. PMID:20445580

Regional lung ventilation and perfusion by electrical impedance tomography compared to single-photon emission computed tomography.

PubMed

Hentze, Benjamin; Muders, Thomas; Luepschen, Henning; Maripuu, Enn; Hedenstierna, Göran; Putensen, Christian; Walter, Marian; Leonhardt, Steffen

2018-06-20

Electrical impedance tomography (EIT) is a noninvasive imaging modality that allows real-time monitoring of regional lung ventilation ([Formula: see text]) in intensive care patients at bedside. However, for improved guidance of ventilation therapy it would be beneficial to obtain regional ventilation-to-perfusion ratio ([Formula: see text]) by EIT. In order to further explore the feasibility, we first evaluate a model-based approach, based on semi-negative matrix factorization and a gamma-variate model, to extract regional lung perfusion ([Formula: see text]) from EIT measurements. Subsequently, a combined validation of both [Formula: see text] and [Formula: see text] measured by EIT against single-photon emission computed tomography (SPECT) is performed on data acquired as part of a porcine animal trial. Four pigs were ventilated at two different levels of positive end-expiratory pressure (PEEP 0 and 15 cm H 2 O, respectively) in randomized order. Repeated injections of an EIT contrast agent (NaCl 10%) and simultaneous SPECT measurements of [Formula: see text] (81 m Kr gas) and [Formula: see text] (99 m Tc-labeled albumin) were performed. Both [Formula: see text] and [Formula: see text] from EIT and SPECT were compared by correlation analysis. Very strong (r 2   =  0.94 to 0.95) correlations were found for [Formula: see text] and [Formula: see text] in the dorsal-ventral direction at both PEEP levels. Moderate (r 2   =  0.36 to 0.46) and moderate to strong (r 2   =  0.61 to 0.82) correlations resulted for [Formula: see text] and [Formula: see text] in the right-left direction, respectively. The results of combined validation indicate that monitoring of [Formula: see text] and [Formula: see text] by EIT is possible. However, care should be taken when trying to quantify [Formula: see text] by EIT, as imaging artefacts and model bias may void necessary spatial matching.

Preparation of Tc-99m-macroaggregated albumin from recombinant human albumin for lung perfusion imaging.

PubMed

Hunt, A P; Frier, M; Johnson, R A; Berezenko, S; Perkins, A C

2006-01-01

Human serum albumin (HSA) extracted from pooled blood taken from human donors is used in the production of (99m)Tc-labelled macroaggregated albumin (MAA) for lung perfusion imaging. However, concerns for the safety of blood-derived products due to potential contamination by infective agents (e.g. new variant CJD), make alternative production methods necessary. Recombinant DNA technology is a promising method of albumin production avoiding problems associated with human-derived HSA. This paper presents results comparing MAA prepared from recombinant human albumin (rHA, Recombumin) (rMAA) with in-house produced HSA MAA (hMAA) and commercially available MAA (cMAA). (99m)Tc-MAA was prepared using previously published production methods by heating a mixture of albumin and stannous chloride in acetate buffer (pH 5.4) at 70 degrees C for 20 min. Parameters investigated include aggregate size, radiolabelling efficiency, radiochemical and aggregate stability at 4 degrees C and in vitro (in whole human blood) at 37 degrees C and biodistribution studies. Results showed that rMAA could be produced with similar morphology, labelling efficiency and stability to hMAA and cMAA. Our findings confirm that rHA shows significant potential as a direct replacement for HSA in commercially available MAA.

Depleted energy charge and increased pulmonary endothelial permeability induced by mitochondrial complex I inhibition are mitigated by coenzyme Q1 in the isolated perfused rat lung.

PubMed

Bongard, Robert D; Yan, Ke; Hoffmann, Raymond G; Audi, Said H; Zhang, Xiao; Lindemer, Brian J; Townsley, Mary I; Merker, Marilyn P

2013-12-01

Mitochondrial dysfunction is associated with various forms of lung injury and disease that also involve alterations in pulmonary endothelial permeability, but the relationship, if any, between the two is not well understood. This question was addressed by perfusing isolated intact rat lung with a buffered physiological saline solution in the absence or presence of the mitochondrial complex I inhibitor rotenone (20 μM). Compared to control, rotenone depressed whole lung tissue ATP from 5.66 ± 0.46 (SEM) to 2.34 ± 0.15 µmol · g(-1) dry lung, with concomitant increases in the ADP:ATP and AMP:ATP ratios. Rotenone also increased lung perfusate lactate (from 12.36 ± 1.64 to 38.62 ± 3.14 µmol · 15 min(-1) perfusion · g(-1) dry lung) and the lactate:pyruvate ratio, but had no detectable impact on lung tissue GSH:GSSG redox status. The amphipathic quinone coenzyme Q1 (CoQ1; 50 μM) mitigated the impact of rotenone on the adenine nucleotide balance, wherein mitigation was blocked by NAD(P)H-quinone oxidoreductase 1 or mitochondrial complex III inhibitors. In separate studies, rotenone increased the pulmonary vascular endothelial filtration coefficient (Kf) from 0.043 ± 0.010 to 0.156 ± 0.037 ml · min(-1) · cm H2O(-1) · g(-1) dry lung, and CoQ1 protected against the effect of rotenone on Kf. A second complex I inhibitor, piericidin A, qualitatively reproduced the impact of rotenone on Kf and the lactate:pyruvate ratio. Taken together, the observations imply that pulmonary endothelial barrier integrity depends on mitochondrial bioenergetics as reflected in lung tissue ATP levels and that compensatory activation of whole lung glycolysis cannot protect against pulmonary endothelial hyperpermeability in response to mitochondrial blockade. The study further suggests that low-molecular-weight amphipathic quinones may have therapeutic utility in protecting lung barrier function in mitochondrial insufficiency. Published by Elsevier Inc.

Synergism between endotoxin priming and exotoxin challenge in provoking severe vascular leakage in rabbit lungs.

PubMed

Schütte, H; Rosseau, S; Czymek, R; Ermert, L; Walmrath, D; Krämer, H J; Seeger, W; Grimminger, F

1997-09-01

Lipopolysaccharides (LPS) of gram-negative bacteria prime rabbit lungs for enhanced thromboxane-mediated vasoconstriction upon subsequent challenge with the exotoxin Escherichia coli hemolysin (HlyA) (Walmrath et al. J. Exp. Med. 1994;180:1437-1443). We investigated the impact of endotoxin priming and subsequent HlyA challenge on lung vascular permeability while maintaining constancy of capillary pressure. Rabbit lungs were perfused in a pressure-controlled mode in the presence of the thromboxane receptor antagonist BM 13.505, with continuous monitoring of flow. Perfusion for 180 min with 10 ng/ml LPS did not provoke vasoconstriction or alteration of capillary filtration coefficient (Kfc) values. HlyA (0.021 hemolytic units/ml) induced thromboxane release and a transient decrease in perfusion flow in the absence of significant changes in Kfc. Similar results were obtained when LPS and HlyA were coapplied simultaneously. However, when the HlyA challenge was undertaken after 180 min of LPS priming, a manifold increase in Kfc values was noted, with concomitant severe lung edema formation, although capillary pressure remained unchanged. Thus, endotoxin primes the lung vasculature to respond with a severe increase in vascular permeability to a subsequent low-dose application of HlyA. Such synergism between endotoxin priming and exotoxin challenge in provoking lung vascular leakage may contribute to the pathogenesis of respiratory failure in sepsis and severe lung infection.

Beware Cold Agglutinins in Organ Donors! Ex Vivo Lung Perfusion From an Uncontrolled Donation After Circulatory-Determination-of-Death Donor With a Cold Agglutinin: A Case Report.

PubMed

Venkataraman, A; Blackwell, J W; Funkhouser, W K; Birchard, K R; Beamer, S E; Simmons, W T; Randell, S H; Egan, T M

2017-09-01

We began to recover lungs from uncontrolled donation after circulatory determination of death to assess for transplant suitability by means of ex vivo lung perfusion (EVLP) and computerized tomographic (CT) scan. Our first case had a cold agglutinin with an interesting outcome. A 60-year-old man collapsed at home and was pronounced dead by Emergency Medical Services personnel. Next-of-kin consented to lung retrieval, and the decedent was ventilated and transported. Lungs were flushed with cold Perfadex, removed, and stored cold. The lungs did not flush well. Medical history revealed a recent hemolytic anemia and a known cold agglutinin. Warm nonventilated ischemia time was 51 minutes. O 2 -ventilated ischemia time was 141 minutes. Total cold ischemia time was 6.5 hours. At cannulation for EVLP, established clots were retrieved from both pulmonary arteries. At initiation of EVLP with Steen solution, tiny red aggregates were observed initially. With warming, the aggregates disappeared and the perfusate became red. After 1 hour, EVLP was stopped because of florid pulmonary edema. The lungs were cooled to 20°C; tiny red aggregates formed again in the perfusate. Ex vivo CT scan showed areas of pulmonary edema and a pyramidal right middle lobe opacity. Dissection showed multiple pulmonary emboli-the likely cause of death. However, histology showed agglutinated red blood cells in the microvasculature in pre- and post-EVLP biopsies, which may have contributed to inadequate parenchymal preservation. Organ donors with cold agglutinins may not be suitable owing to the impact of hypothermic preservation. Copyright © 2017 Elsevier Inc. All rights reserved.

Effects of lung ventilation–perfusion and muscle metabolism–perfusion heterogeneities on maximal O2 transport and utilization

PubMed Central

Cano, I; Roca, J; Wagner, P D

2015-01-01

Previous models of O2 transport and utilization in health considered diffusive exchange of O2 in lung and muscle, but, reasonably, neglected functional heterogeneities in these tissues. However, in disease, disregarding such heterogeneities would not be justified. Here, pulmonary ventilation–perfusion and skeletal muscle metabolism–perfusion mismatching were added to a prior model of only diffusive exchange. Previously ignored O2 exchange in non-exercising tissues was also included. We simulated maximal exercise in (a) healthy subjects at sea level and altitude, and (b) COPD patients at sea level, to assess the separate and combined effects of pulmonary and peripheral functional heterogeneities on overall muscle O2 uptake ( and on mitochondrial (). In healthy subjects at maximal exercise, the combined effects of pulmonary and peripheral heterogeneities reduced arterial () at sea level by 32 mmHg, but muscle by only 122 ml min−1 (–3.5%). At the altitude of Mt Everest, lung and tissue heterogeneity together reduced by less than 1 mmHg and by 32 ml min−1 (–2.4%). Skeletal muscle heterogeneity led to a wide range of potential among muscle regions, a range that becomes narrower as increases, and in regions with a low ratio of metabolic capacity to blood flow, can exceed that of mixed muscle venous blood. For patients with severe COPD, peak was insensitive to substantial changes in the mitochondrial characteristics for O2 consumption or the extent of muscle heterogeneity. This integrative computational model of O2 transport and utilization offers the potential for estimating profiles of both in health and in diseases such as COPD if the extent for both lung ventilation–perfusion and tissue metabolism–perfusion heterogeneity is known. PMID:25640017

The effect of supine exercise on the distribution of regional pulmonary blood flow measured using proton MRI

PubMed Central

Hall, E. T.; Sá, R. C.; Holverda, S.; Arai, T. J.; Dubowitz, D. J.; Theilmann, R. J.; Prisk, G. K.

2013-01-01

The Zone model of pulmonary perfusion predicts that exercise reduces perfusion heterogeneity because increased vascular pressure redistributes flow to gravitationally nondependent lung, and causes dilation and recruitment of blood vessels. However, during exercise in animals, perfusion heterogeneity as measured by the relative dispersion (RD, SD/mean) is not significantly decreased. We evaluated the effect of exercise on pulmonary perfusion in six healthy supine humans using magnetic resonance imaging (MRI). Data were acquired at rest, while exercising (∼27% of maximal oxygen consumption) using a MRI-compatible ergometer, and in recovery. Images were acquired in most of the right lung in the sagittal plane at functional residual capacity, using a 1.5-T MR scanner equipped with a torso coil. Perfusion was measured using arterial spin labeling (ASL-FAIRER) and regional proton density using a fast multiecho gradient-echo sequence. Perfusion images were corrected for coil-based signal heterogeneity, large conduit vessels removed and quantified (in ml·min−1·ml−1) (perfusion), and also normalized for density and quantified (in ml·min−1·g−1) (density-normalized perfusion, DNP) accounting for tissue redistribution. DNP increased during exercise (11.1 ± 3.5 rest, 18.8 ± 2.3 exercise, 13.2 ± 2.2 recovery, ml·min−1·g−1, P < 0.0001), and the increase was largest in nondependent lung (110 ± 61% increase in nondependent, 63 ± 35% in mid, 70 ± 33% in dependent, P < 0.005). The RD of perfusion decreased with exercise (0.93 ± 0.21 rest, 0.73 ± 0.13 exercise, 0.94 ± 0.18 recovery, P < 0.005). The RD of DNP showed a similar trend (0.82 ± 0.14 rest, 0.75 ± 0.09 exercise, 0.81 ± 0.10 recovery, P = 0.13). In conclusion, in contrast to animal studies, in supine humans, mild exercise decreased perfusion heterogeneity, consistent with Zone model predictions. PMID:24356515

Iloprost ameliorates post-ischemic lung reperfusion injury and maintains an appropriate pulmonary ET-1 balance.

PubMed

Kawashima, Masahiro; Nakamura, Takayuki; Schneider, Sven; Vollmar, Brigitte; Lausberg, Henning F; Bauer, Michael; Menger, Michael D; Schäfers, Hans-Joachim

2003-07-01

Ischemia-reperfusion (I/R) injury of the lung involves increased pulmonary vascular resistance. Prostaglandins are thought to have a beneficial effect in lung transplantation, but their mechanism in I/R injury is unknown. We investigated whether iloprost, a stable prostacyclin analogue, prevents I/R-associated pulmonary vascular dysfunction and whether it affects endothelin-1 (ET-1) balance. In an isolated blood-perfusion model, we subjected lungs of Lewis rats to 45 minutes of ischemia at 37 degrees C and randomly allocated the lungs to 3 groups (n = 6 each): iloprost (33.3 nmol/liter) added to the perfusate before ischemia and reperfusion (ILO+IR), iloprost (33.3 nmol/liter) given only before reperfusion (ILO+R), and controls without iloprost treatment (ILO-). Reperfusion induced marked pulmonary edema in non-treated controls (ILO-), which was attenuated in ILO+R lungs and completely prevented in ILO+IR lungs. At 60 minutes reperfusion, arterial oxygen tension was significantly greater in both ILO+R and ILO+IR lungs compared with ILO- controls. Mean pulmonary artery pressure and pulmonary vascular resistance were slightly decreased in the ILO+R and significantly decreased in the ILO+IR group compared with the ILO- controls. Plasma levels of big ET-1, measured in both afferent and efferent blood, showed that I/R results in increased pulmonary venous levels of big ET-1. Interestingly, the increased venoarterial ET-1 gradient in ILO- lungs decreased significantly in the ILO+IR group. We demonstrated in an isolated lung perfusion model that iloprost ameliorates post-ischemic lung reperfusion injury and maintains an appropriate pulmonary ET-1 balance.

Spatial correspondence of 4D CT ventilation and SPECT pulmonary perfusion defects in patients with malignant airway stenosis

NASA Astrophysics Data System (ADS)

Castillo, Richard; Castillo, Edward; McCurdy, Matthew; Gomez, Daniel R.; Block, Alec M.; Bergsma, Derek; Joy, Sarah; Guerrero, Thomas

2012-04-01

To determine the spatial overlap agreement between four-dimensional computed tomography (4D CT) ventilation and single photon emission computed tomography (SPECT) perfusion hypo-functioning pulmonary defect regions in a patient population with malignant airway stenosis. Treatment planning 4D CT images were obtained retrospectively for ten lung cancer patients with radiographically demonstrated airway obstruction due to gross tumor volume. Each patient also received a SPECT perfusion study within one week of the planning 4D CT, and prior to the initiation of treatment. Deformable image registration was used to map corresponding lung tissue elements between the extreme component phase images, from which quantitative three-dimensional (3D) images representing the local pulmonary specific ventilation were constructed. Semi-automated segmentation of the percentile perfusion distribution was performed to identify regional defects distal to the known obstructing lesion. Semi-automated segmentation was similarly performed by multiple observers to delineate corresponding defect regions depicted on 4D CT ventilation. Normalized Dice similarity coefficient (NDSC) indices were determined for each observer between SPECT perfusion and 4D CT ventilation defect regions to assess spatial overlap agreement. Tidal volumes determined from 4D CT ventilation were evaluated versus measurements obtained from lung parenchyma segmentation. Linear regression resulted in a linear fit with slope = 1.01 (R2 = 0.99). Respective values for the average DSC, NDSC1 mm and NDSC2 mm for all cases and multiple observers were 0.78, 0.88 and 0.99, indicating that, on average, spatial overlap agreement between ventilation and perfusion defect regions was comparable to the threshold for agreement within 1-2 mm uncertainty. Corresponding coefficients of variation for all metrics were similarly in the range: 0.10%-19%. This study is the first to quantitatively assess 3D spatial overlap agreement between clinically acquired SPECT perfusion and specific ventilation from 4D CT. Results suggest high correlation between methods within the sub-population of lung cancer patients with malignant airway stenosis.

ENHANCED GENE DELIVERY IN PORCINE VASCULATURE TISSUE FOLLOWING INCORPORATION OF ADENO-ASSOCIATED VIRUS NANOPARTICLES INTO POROUS SILICON MICROPARTICLES

PubMed Central

McConnell, Kellie I.; Rhudy, Jessica; Yokoi, Kenji; Gu, Jianhua; Mack, Aaron; Suh, Junghae; La Francesca, Saverio; Sakamoto, Jason; Serda, Rita E.

2014-01-01

There is an unmet clinical need to increase lung transplant successes, patient satisfaction and to improve mortality rates. We offer the development of a nanovector-based solution that will reduce the incidence of lung ischemic reperfusion injury (IRI) leading to graft organ failure through the successful ex vivo treatment of the lung prior to transplantation. The innovation is in the integrated application of our novel porous silicon (pSi) microparticles carrying adeno-associated virus (AAV) nanoparticles, and the use of our ex vivo lung perfusion/ventilation system for the modulation of pro-inflammatory cytokines initiated by ischemic pulmonary conditions prior to organ transplant that often lead to complications. Gene delivery of anti-inflammatory agents to combat the inflammatory cascade may be a promising approach to prevent IRI following lung transplantation. The rationale for the device is that the microparticle will deliver a large payload of virus to cells and serve to protect the AAV from immune recognition. The microparticle-nanoparticle hybrid device was tested both in vitro on cell monolayers and ex vivo using either porcine venous tissue or a pig lung transplantation model, which recapitulates pulmonary IRI that occurs clinically post-transplantation. Remarkably, loading AAV vectors into pSi microparticles increases gene delivery to otherwise non-permissive endothelial cells. PMID:25180449

DOE Office of Scientific and Technical Information (OSTI.GOV)

Churchill, M.; Orawski, A.T.; AchutaMurthy, P.N.

Several studies have suggested that the essentially complete degradation of circulating bradykinin (BK) in lung is mediated in part by peptidase(s) other than the well-characterized angiotensin converting enzyme (ACE). The authors report here that the isolated perfused rat lung can inactivate BK by sequential N-terminal cleavage. (/sup 3/H-2, 3-Pro) BK was perfused through the lung and the products in the perfusate identified by HPLC. In the absence of inhibitors, BK was 89-100% degraded with /sup 3/H-Pro/sup 2/-Pro/sup 3/ and /sup 3/H-Pro as the major products. The dipeptidylaminopeptidase IV (DAP IV) inhibitor, diprotein A (Ile-Pro-Ile), greatly reduced the Pro-Pro and Promore » peaks and produced a prominent BK/sub 2-7/ peak (or BK/sub 2-9/ peak if the ACE inhibitor, captopril, was also present). 2-Mercapto-ethanol, a rather specific inhibitor of aminopeptidase P (AP-P), prevented the release of Arg/sup 1/, producing major BK and/or BK/sub 1-7/ peaks. The neutral metalloendopeptidase inhibitor, phosphoramidon, had no effect on the pattern of degradation of BK by the perfused rat lung by the release of Arg/sup 1/ by AP-P followed by release of Pro/sup 2/-Pro/sup 3/ by DAP IV.« less

Restoration of normal pH triggers ischemia-reperfusion injury in lung by Na+/H+ exchange activation.

PubMed

Moore, T M; Khimenko, P L; Taylor, A E

1995-10-01

The effects of acidotic extracellular pH and Na+/H+ exchange inhibition on ischemia-reperfusion (I/R)-induced microvascular injury were studied in the isolated, buffer-perfused rat lung. When lungs were subjected to 45 min of ischemia followed by 30 min of reperfusion, the capillary filtration coefficient (Kfc) increased significantly, resulting in a change in Kfc (delta Kfc) of 0.360 +/- 0.09 ml.min-1.cmH2O-1.100 g-1. Addition of hydrochloric acid to the perfusate before ischemia at a concentration sufficient to reduce perfusate pH from 7.38 +/- 0.03 to 7.09 +/- 0.04 completely prevented the increase in Kfc associated with I/R (delta Kfc = 0.014 +/- 0.034 ml.min-1.cmH2O-1.100 g-1). Addition of a Na+/H+ exchange inhibitor, 5-(N,N-dimethyl)-amiloride, to the perfusate either before ischemia or at reperfusion also prevented the I/R-induced permeability increase (delta Kfc = 0.01 +/- 0.02 and -0.001 +/- 0.02 ml.min-1.cmH2O-1.100 g-1, respectively). We conclude that restoration of flow at physiological pH to the postischemic lung activates the Na+/H+ exchange system, which may represent the "triggering mechanism" responsible for initiating reperfusion-induced microvascular injury.

Bioengineered Lungs: A Challenge and An Opportunity.

PubMed

Farré, Ramon; Otero, Jordi; Almendros, Isaac; Navajas, Daniel

2018-01-01

Lung biofabrication is a new tissue engineering and regenerative development aimed at providing organs for potential use in transplantation. Lung biofabrication is based on seeding cells into an acellular organ scaffold and on culturing them in an especial purpose bioreactor. The acellular lung scaffold is obtained by decellularizing a non-transplantable donor lung by means of conventional procedures based on application of physical, enzymatic and detergent agents. To avoid immune recipient's rejection of the transplanted bioengineered lung, autologous bone marrow/adipose tissue-derived mesenchymal stem cells, lung progenitor cells or induced pluripotent stem cells are used for biofabricating the bioengineered lung. The bioreactor applies circulatory perfusion and mechanical ventilation with physiological parameters to the lung during biofabrication. These physical stimuli to the organ are translated into the stem cell local microenvironment - e.g. shear stress and cyclic stretch - so that cells sense the physiological conditions in normally functioning mature lungs. After seminal proof of concept in a rodent model was published in 2010, the hypothesis that lungs can be biofabricated is accepted and intense research efforts are being devoted to the topic. The current experimental evidence obtained so far in animal tests and in ex vivo human bioengineered lungs suggests that the date of first clinical tests, although not immediate, is coming. Lung bioengineering is a disrupting concept that poses a challenge for improving our basic science knowledge and is also an opportunity for facilitating lung transplantation in future clinical translation. Copyright © 2017 SEPAR. Publicado por Elsevier España, S.L.U. All rights reserved.

Combined Ventilation and Perfusion Imaging Correlates With the Dosimetric Parameters of Radiation Pneumonitis in Radiation Therapy Planning for Lung Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kimura, Tomoki, E-mail: tkkimura@hiroshima-u.ac.jp; Doi, Yoshiko; Nakashima, Takeo

2015-11-15

Purpose: The purpose of this study was to prospectively investigate clinical correlations between dosimetric parameters associated with radiation pneumonitis (RP) and functional lung imaging. Methods and Materials: Functional lung imaging was performed using four-dimensional computed tomography (4D-CT) for ventilation imaging, single-photon emission computed tomography (SPECT) for perfusion imaging, or both (V/Q-matched region). Using 4D-CT, ventilation imaging was derived from a low attenuation area according to CT numbers below different thresholds (vent-860 and -910). Perfusion imaging at the 10th, 30th, 50th, and 70th percentile perfusion levels (F10-F70) were defined as the top 10%, 30%, 50%, and 70% hyperperfused normal lung, respectively.more » All imaging data were incorporated into a 3D planning system to evaluate correlations between RP dosimetric parameters (where fV20 is the percentage of functional lung volume irradiated with >20 Gy, or fMLD, the mean dose administered to functional lung) and the percentage of functional lung volume. Radiation pneumonitis was evaluated using Common Terminology Criteria for Adverse Events version 4.0. Statistical significance was defined as a P value of <.05. Results: Sixty patients who underwent curative radiation therapy were enrolled (48 patients for non-small cell lung cancer, and 12 patients for small cell lung cancer). Grades 1, 2, and ≥3 RP were observed in 16, 44, and 6 patients, respectively. Significant correlations were observed between the percentage of functional lung volume and fV20 (r=0.4475 in vent-860 and 0.3508 in F30) or fMLD (r=0.4701 in vent-860 and 0.3128 in F30) in patients with grade ≥2 RP. F30∩vent-860 results exhibited stronger correlations with fV20 and fMLD in patients with grade ≥2 (r=0.5509 in fV20 and 0.5320 in fMLD) and grade ≥3 RP (r=0.8770 in fV20 and 0.8518 in fMLD). Conclusions: RP dosimetric parameters correlated significantly with functional lung imaging.« less

Krypton-81m ventilation scanning: acute respiratory disease

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lavender, J.P.; Irving, H.; Armstrong, J.D. II

1981-02-01

From experience with 700 patients undergoing ventilation and perfusion lung scanning with krypton-81m/technetium-99m technique, 34 patients suffering from nonembolic acute respiratory disease were selected for review. In 16 patients with pneumonia, all had defects of ventilation corresponding to, or larger than, the radiologic consolidation. In 13 patients there was some preservation of perfusion in the consolidated region. In two of the three patients with matched defects, the pneumonia was of long standing. In seven patients with collapse or atelectasis and in 11 patients with acute reversible bronchial obstruction and normal volume lungs, a similar pattern or ventillation and perfusion wasmore » observed.« less

Quantitative Differences Between the First and Second Injection of Contrast Agent in Contrast-Enhanced Ultrasonography of Feline Kidneys and Spleen.

PubMed

Stock, Emmelie; Vanderperren, Katrien; Haers, Hendrik; Duchateau, Luc; Hesta, Myriam; Saunders, Jimmy H

2017-02-01

Contrast-enhanced ultrasound is a valuable and safe technique for the evaluation of organ perfusion. Repeated injections of ultrasound contrast agent are often administered during the same imaging session. However, it remains unclear if quantitative differences are present between the consecutive microbubble injections. Therefore, the first and second injection of contrast agent for the left renal cortex, renal medulla and the splenic parenchyma in healthy cats were compared. A lower peak intensity and area under the curve were observed for the first injection of contrast agent in the feline kidney, both for the renal cortex and medulla, and spleen. Moreover, for the renal cortex, the time-intensity curve was steeper after the second injection. Findings from the present study demonstrate that a second injection of contrast agent provides stronger enhancement. The exact mechanism behind our findings remains unclear; however, saturation of the lung macrophages is believed to play an important role. Copyright © 2016 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.

Quantification of lung perfusion blood volume (lung PBV) by dual-energy CT in patients with chronic thromboembolic pulmonary hypertension (CTEPH) before and after balloon pulmonary angioplasty (BPA): Preliminary results.

PubMed

Koike, Hirofumi; Sueyoshi, Eijun; Sakamoto, Ichiro; Uetani, Masataka; Nakata, Tomoo; Maemura, Kouji

2016-09-01

Balloon pulmonary angioplasty (BPA) is a treatment option for patients with chronic thromboembolic pulmonary hypertension (CTEPH). Its effect on pulmonary perfusion has not been quantified; we examined the clinical significance of pulmonary blood volume (PBV) using dual-energy computed tomography (DECT) in patients with CTEPH undergoing BPA. In this retrospective study of 16 BPAs in eight female patients with CTEPH, we evaluated both-lung (n=16), right- or left-lung (n=32), and three right- or left-segment (upper, middle, and lower) (n=96) PBVs before and after BPA, using DECT. We evaluated the relationships between improvement in lung PBV and pulmonary artery (PA) pressure (PAP), cardiac index (CI), pulmonary vascular resistance (PVR), and 6-min walking distance. We measured PA enhancement (PAenh) on DECT images and calculated lung PBV/PAenh to adjust timing. Pre- and post-BPA 6-segment lung PBV/PAenh were 0.067±0.021 and 0.077±0.019, respectively, in the treated segment (p<0.0001). There were significant positive correlations between pre- to post-BPA improvements in both-lung PBV/PAenh and PAP (R=0.69, p=0.005), PVR (R=0.56, p=0.03), and 6-min walking distance (R=0.67, p=0.01). Improved PBV after BPA, reflecting increased lung perfusion, was positively correlated with PAP, PVR, and 6-min walking distance. Lung PBV may be an indicator of BPA treatment effect. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Nitric Oxide as a Mediator of Oxidant Lung Injury Due to Paraquat

NASA Astrophysics Data System (ADS)

Berisha, Hasan I.; Pakbaz, Hedayatollah; Absood, Afaf; Said, Sami I.

1994-08-01

At low concentrations, nitric oxide is a physiological transmitter, but in excessive concentrations it may cause cell and tissue injury. We report that in acute oxidant injury induced by the herbicide paraquat in isolated guinea pig lungs, nitric oxide synthesis was markedly stimulated, as evidenced by increased levels of cyclic GMP in lung perfusate and of nitrite and L-citrulline production in lung tissue. All signs of injury, including increased airway and perfusion pressures, pulmonary edema, and protein leakage into the airspaces, were dose-dependently attenuated or totally prevented by either N^G-nitro-L-arginine methyl ester or N^ω-nitro-L-arginine, selective and competitive inhibitors of nitric oxide synthase. Protection was reversed by excess L-arginine but not by its enantiomer D-arginine. When blood was added to the lung perfusate, the paraquat injury was moderated or delayed as it was when paraquat was given to anesthetized guinea pigs. The rapid onset of injury and its failure to occur in the absence of Ca2+ suggest that constitutive rather than inducible nitric oxide synthase was responsible for the stimulated nitric oxide synthesis. The findings indicate that nitric oxide plays a critical role in the production of lung tissue injury due to paraquat, and it may be a pathogenetic factor in other forms of oxidant tissue injury.

Scintigraphic results in patients with lung transplants: a prospective comparative study.

PubMed

Humplik, B I; Sandrock, D; Aurisch, R; Richter, W-St; Ewert, R; Munz, D L

2005-04-01

We addressed the feasibility of scintigraphy in the postoperative monitoring of lung transplants. 37 patients (22 women, 15 men, 37 +/- 15 years) in good clinical condition were examined after lung transplantation. Scintigraphic procedures for assessing ventilation (133Xe), perfusion (99mTc microspheres) and aerosol-inhalation (99mTc aerosol) were performed for all patients. The findings were compared with those of established diagnostic modalities. All lung transplants showed homogeneous ventilation but with a non-physiologic difference of over 20% between both pulmonary lobes in one-third of the cases. There was a difference between the impairement of perfusion and ventilation in the presence of an impaired Euler-Liljestrand reflex in 14/37 (38%) patients. Furthermore, bronchoscopy and aerosol-inhalation scans often did not correlate, e. g. a bronchoscopically evident stenosis was not necessarily associated with an increased activity, and vice versa. Although peripheral mucociliary clearance was preserved after transplantation, stasis in central airways resulted in significantly impaired global clearance. Ventilation and perfusion scintigraphy reveal in a significant number of lung recipients pathologic findings and therefore can be recommended for postoperative monitoring. From a clinical point of view aerosol-inhalation scintigraphy (clearance) is not of any additional value.

Biomarkers for Radiation Pneumonitis Using Noninvasive Molecular Imaging.

PubMed

Medhora, Meetha; Haworth, Steven; Liu, Yu; Narayanan, Jayashree; Gao, Feng; Zhao, Ming; Audi, Said; Jacobs, Elizabeth R; Fish, Brian L; Clough, Anne V

2016-08-01

Our goal is to develop minimally invasive biomarkers for predicting radiation-induced lung injury before symptoms develop. Currently, there are no biomarkers that can predict radiation pneumonitis. Radiation damage to the whole lung is a serious risk in nuclear accidents or in radiologic terrorism. Our previous studies have shown that a single dose of 15 Gy of x-rays to the thorax causes severe pneumonitis in rats by 6-8 wk. We have also developed a mitigator for radiation pneumonitis and fibrosis that can be started as late as 5 wk after radiation. We used 2 functional SPECT probes in vivo in irradiated rat lungs. Regional pulmonary perfusion was measured by injection of (99m)Tc-macroaggregated albumin. Perfused volume was determined by comparing the volume of distribution of (99m)Tc-macroaggregated albumin to the anatomic lung volume obtained by small-animal CT. A second probe, (99m)Tc-labeled Duramycin, which binds to apoptotic cells, was used to measure pulmonary cell death in the same rat model. The perfused volume of lung was decreased by about 25% at 1, 2, and 3 wk after receipt of 15 Gy, and (99m)Tc-Duramycin uptake was more than doubled at 2 and 3 wk. There was no change in body weight, breathing rate, or lung histology between irradiated and nonirradiated rats at these times. Pulmonary vascular resistance and vascular permeability measured in isolated perfused lungs ex vivo increased at 2 wk after 15 Gy of irradiation. Our results suggest that SPECT biomarkers have the potential to predict radiation injury to the lungs before substantial functional or histologic damage is observed. Early prediction of radiation pneumonitis in time to initiate mitigation will benefit those exposed to radiation in the context of therapy, accidents, or terrorism. © 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

Abolished ventilation and perfusion of lung caused by blood clot in the left main bronchus: auto-downregulation of pulmonary arterial blood supply.

PubMed

Afzelius, P; Bergmann, A; Henriksen, J H

2015-09-15

It is generally assumed that the lungs possess arterial autoregulation associated with bronchial obstruction. A patient with pneumonia and congestive heart failure unexpectedly developed frequent haemoptysis. High-resolution CT and diagnostic CT were performed as well as ventilation/perfusion (V/Q) scintigraphy with single-photon emission CT (SPECT)/CT. V/Q SPECT/CT demonstrated abolished ventilation due to obstruction of the left main bronchus and markedly reduced perfusion of the entire left lung, a condition that was completely reversed after removal of a blood clot. We present the first pictorially documented case of hypoxia-induced pulmonary vasoconstriction and flow shift in a main pulmonary artery due to a complete intrinsic obstruction of the ipsilateral main bronchus. The condition is reversible, contingent on being relieved within a few days. 2015 BMJ Publishing Group Ltd.

New imaging technology: measurement of myocardial perfusion by contrast echocardiography

NASA Technical Reports Server (NTRS)

Rubin, D. N.; Thomas, J. D.

2000-01-01

Myocardial perfusion imaging has long been a goal for the non-invasive echocardiographic assessment of the heart. However, many factors at play in perfusion imaging have made this goal elusive. Harmonic imaging and triggered imaging with newer contrast agents have made myocardial perfusion imaging potentially practical in the very near future. The application of indicator dilution theory to the coronary circulation and bubble contrast agents is fraught with complexities and sources of error. Therefore, quantification of myocardial perfusion by non-invasive echocardiographic imaging requires further investigation in order to make this technique clinically viable.

Imaging Lung Function in Mice Using SPECT/CT and Per-Voxel Analysis

PubMed Central

Jobse, Brian N.; Rhem, Rod G.; McCurry, Cory A. J. R.; Wang, Iris Q.; Labiris, N. Renée

2012-01-01

Chronic lung disease is a major worldwide health concern but better tools are required to understand the underlying pathologies. Ventilation/perfusion (V/Q) single photon emission computed tomography (SPECT) with per-voxel analysis allows for non-invasive measurement of regional lung function. A clinically adapted V/Q methodology was used in healthy mice to investigate V/Q relationships. Twelve week-old mice were imaged to describe normal lung function while 36 week-old mice were imaged to determine how age affects V/Q. Mice were ventilated with Technegas™ and injected with 99mTc-macroaggregated albumin to trace ventilation and perfusion, respectively. For both processes, SPECT and CT images were acquired, co-registered, and quantitatively analyzed. On a per-voxel basis, ventilation and perfusion were moderately correlated (R = 0.58±0.03) in 12 week old animals and a mean log(V/Q) ratio of −0.07±0.01 and standard deviation of 0.36±0.02 were found, defining the extent of V/Q matching. In contrast, 36 week old animals had significantly increased levels of V/Q mismatching throughout the periphery of the lung. Measures of V/Q were consistent across healthy animals and differences were observed with age demonstrating the capability of this technique in quantifying lung function. Per-voxel analysis and the ability to non-invasively assess lung function will aid in the investigation of chronic lung disease models and drug efficacy studies. PMID:22870297

Analysis of decrease in lung perfusion blood volume with occlusive and non-occlusive pulmonary embolisms.

PubMed

Ikeda, Yohei; Yoshimura, Norihiko; Hori, Yoshiro; Horii, Yosuke; Ishikawa, Hiroyuki; Yamazaki, Motohiko; Noto, Yoshiyuki; Aoyama, Hidefumi

2014-12-01

The aim of this study was to determine if lung perfusion blood volume (lung PBV) with non-occlusive pulmonary embolism (PE) differs quantitatively and visually from that with occlusive PE and to investigate if lung PBV with non-occlusive PE remains the same as that without PE. Totally, 108 patients suspected of having acute PE underwent pulmonary dual-energy computed tomography angiography (DECTA) between April 2011 and January 2012. Presence of PE on DECTA was evaluated by one radiologist. Two radiologists visually evaluated the PE distribution (segmental or subsegmental) and its nature (occlusive or non-occlusive) on DECTA and classified perfusion in lung PBV as "decreased," "slightly decreased," and "preserved". Two radiologists used a lung PBV application to set a region of interest (ROI) in the center of the lesion and measured HU values of an iodine map. In the same slice as the ROI of the lesion and close to the lesion, another ROI was set in the normal perfusion area without PE, and HUs were measured. The proportion of lesions was compared between the occlusive and non-occlusive groups. HUs were compared among the occlusive, non-occlusive, and corresponding normal groups. Twenty-five patients had 80 segmental or subsegmental lesions. There were 37 and 43 lesions in the occlusive and non-occlusive groups, respectively. The proportion of decreased lesions was 73.0% (27/37) in the occlusive group, while that of preserved lesions in the non-occlusive group was 76.7% (33/43). There was a significant difference in the proportion of lesions (P<0.001) between the two groups. HUs of the iodine map were significantly higher in the non-occlusive group than in the occlusive group (33.8 ± 8.2 HU vs. 11.9 ± 6.1 HU, P<0.001). There was no significant difference in HUs for the entire lesion between the non-occlusive (33.8 ± 8.2 HU) and corresponding normal group (34.5 ± 6.8 HU; P=0.294). Iodine perfusion tended to be visually and quantitatively preserved in lungs with nonocclusive PE. Lung PBV is required to evaluate pulmonary blood flow. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Comparison of 68Ga- and fluorescence-labeled microspheres for measurement of relative pulmonary perfusion in anesthetized pigs.

PubMed

Braune, Anja; Scharffenberg, Martin; Naumann, Anne; Bluth, Thomas; de Abreu, Marcelo Gama; Kotzerke, Jörg

2018-06-01

We compared 68 Gallium ( 68 Ga)- and fluorescence-labeled microspheres for measurement of pulmonary perfusion distribution in anesthetized pigs without lung injury. In two mechanically ventilated pigs, the distribution of pulmonary perfusion was marked in vivo with 68 Ga- and fluorescence-labeled microspheres in supine and prone position. After each injection, the distribution of 68 Ga-labeled microspheres was measured in vivo with positron emission tomography/ computed tomography (PET/CT) in the position in which microspheres were injected and vice versa. The distribution of fluorescence-labeled microspheres was measured ex vivo . Perfusion distributions were compared between methods and postures within four lung regions and along the ventro-dorsal gradient. After each injection of 68 Ga-labeled microspheres, changes in ventro-dorsal perfusion gradients induced by repositioning were compared for volume- and mass-normalized PET/CT measurements. Regional and gradient analyses of in vivo and ex vivo measurements, respectively, consistently revealed higher pulmonary perfusion in dorsal than ventral regions in supine positioned animals. Both methods showed more pronounced perfusion gradients in supine compared to prone position. Changes in animal position were associated with alterations in the ventro-dorsal perfusion gradient when volume-, but not mass-normalization was conducted for PET/CT data. Ex vivo fluorescence- and in vivo 68 Ga-labeled microspheres measurements revealed similar perfusion distributions. Mass-normalized perfusion measurements by 68 Ga-labeled microspheres and PET/CT were not affected by positioning artifacts. Schattauer GmbH.

Evaluation of the preventive effect of dexpanthenol in radiation injury by lung perfusion scintigraphy: a preclinical experimental model of radiation injury.

PubMed

Koç, Zehra P; İn, Erdal; Karslioğlu, İhsan; Üçer, Özlem; Canpolat, Sinan

2015-12-01

The aim of this study was to show the preventative effects of dexpanthenol in radiation injuries caused by radiotherapy (RT) through the use of lung perfusion scintigraphy in the pre-RT and post-RT periods. Six male New Zealand rabbits (5-6 months of age and ∼2.5-3 kg in weight) were the used in this study. The animals were subjected to Tc-macroaggregated albumin lung perfusion scintigraphy in the pre-RT and post-RT (i.e. 2 weeks after treatment) periods. The scintigraphies were performed with the same dose by the same staff and the methodology used the same acquisition parameters. The rabbits were divided into two groups: group I (administered RT only) and group II (also administered intramuscular 500 mg dexpanthenol injections for 14 consecutive days after RT). Quantification was performed to compare the groups and the quantification variables were compared using a paired samples t-test, with P value less than 0.05 considered to be statistically significant. Histopathological analysis was also carried out. The post-RT scintigraphies indicated a decrease in the counts in both lungs, suggesting early post-RT injury. The difference between the counts obtained from both lungs in groups I and II was significantly different and favoured group II. Histopathological results confirmed the scintigraphy results. It is possible to estimate post-RT changes in the early period (in contrast to previous data) by lung perfusion scintigraphy. Dexpanthenol may also reduce the effects of RT to a degree. Although this is the first study to report the preventive effects of dexpanthenol on RT injuries, further studies are warranted in this area.

Propofol attenuates oxidant-induced acute lung injury in an isolated perfused rabbit-lung model.

PubMed

Yumoto, Masato; Nishida, Osamu; Nakamura, Fujio; Katsuya, Hirotada

2005-01-01

Reactive oxygen species have been strongly implicated in the pathogenesis of acute lung injury (ALI). Some animal studies suggest that free radical scavengers inhibit the onset of oxidant-induced ALI. Propofol (2,6-diisopropylphenol) is chemically similar to phenol-based free radical scavengers such as the endogenous antioxidant vitamin E. Both in vivo and in vitro studies have suggested that propofol has antioxidant potential. We hypothesized that propofol may attenuate ALI by acting as a free-radical scavenger. We investigated the effects of propofol on oxidant-induced ALI induced by purine and xanthine oxidase (XO), in isolated perfused rabbit lung, in two series of experiments. In series 1, we examined the relationship between the severity of ALI and the presence of hydrogen peroxide (H2O2). In series 2, we evaluated the effects of propofol on attenuating ALI and the dose dependence of these effects. The lungs were perfused for 90 min, and we evaluated the effects on the severity of ALI by monitoring the pulmonary capillary filtration coefficient (Kfc), pulmonary arterial pressure (Ppa), and the pulmonary capillary hydrostatic pressure (Ppc). In series 1, treatment with catalase (an H2O2 scavenger) prior to the addition of purine and XO resulted in complete prevention of ALI, suggesting that H2O2 may be involved closely in the pathogenesis of ALI. In series 2, pretreatment with propofol at concentrations in excess of 0.5 mM significantly inhibited the increases in the Kfc values, and that in excess of 0.75 mM significantly inhibited the increase in the Ppa values. Propofol attenuates oxidant-induced ALI in an isolated perfused rabbit lung model, probably due to its antioxidant action.

Strategies for safe donor expansion: donor management, donations after cardiac death, ex-vivo lung perfusion.

PubMed

Cypel, Marcelo; Keshavjee, Shaf

2013-10-01

The number of patients listed for lung transplantation largely exceeds the number of available transplantable organs because of both a shortage of organ donors and a low utilization rate of lungs from those donors. Two major innovations in recent years include the use of lungs from donations after cardiac death (DCD) and the use of ex-vivo lung perfusion (EVLP) to assess and improve injured donor lungs. DCD lung transplants now account for about 20% of lung transplants in many centres and outcomes after transplantation have been excellent with this source of donation. Clinical experience using EVLP has shown the method to be well tolerated and allow for reassessment and improvement in function from high-risk donor lungs. When these lungs were transplanted, low rates of primary graft dysfunction were achieved and long-term survival was comparable with standard transplantation. Preclinical studies have shown a great potential of EVLP as a platform for the delivery of novel therapies to repair injured donor lungs. A significant increase on the number of available lungs for transplantation is expected in the coming years with the wider use of DCD lungs and with organ-specific ex-vivo treatment strategies.

Radioisotope scanning of brain, liver, lung and bone with a note on tumour localizing agents

PubMed Central

Lavender, J. P.

1973-01-01

Radioisotopic scanning of brain, liver, lungs and the skeleton is briefly reviewed with a survey of recent developments of clinical significance. In brain scanning neoplasm detection rates of greater than 90% are claimed. The true figure is probably 70-80%. Autopsy data shows a number of false negatives, particularly with vascular lesions. Attempts to make scanning more specific in differentiating neoplasm from vascular lesions by rapid sequence blood flow studies are reviewed. In liver scanning by means of colloids again high success rate is claimed but small metastases are frequently missed and the false negative scan rate is probably quite high. Lung scanning still has its main place in investigating pulmonary embolic disease. Ventilation studies using Xenon 133 are useful, particularly combined with perfusion studies. The various radiopharmaceuticals for use in bone scanning are reviewed. The appearance of technetium labelled phosphate compounds will probably allow much wider use of total skeletal scanning. Research into tumour localizing agents continues, the most recent and interesting being Gallium citrate and labelled bleomycin. Neither agent is predictable however although Gallium may have a place in Hodgkins disease and bronchogenic neoplasm and both may have a place in the detection of cerebral tumours. ImagesFig. 1Fig. 2Fig. 3p452-bFig. 3bFig. 4Fig. 5Fig. 5bFig. 6Fig. 7Fig. 8Fig. 9Fig. 10Fig. 11Fig. 12Fig. 12c & 12dFig. 13Fig. 13 b,c,dFig. 14Fig. 14bFig. 15Fig. 15bFig. 16Fig. 17Fig. 18 PMID:4602127

Ability of anti-glycoprotein IIb/IIIa agents to dissolve platelet thrombi formed on a collagen surface under blood flow conditions.

PubMed

Goto, Shinya; Tamura, Noriko; Ishida, Hideyuki

2004-07-21

We examined the lytic effects of anti-glycoprotein (GP) IIb/IIIa agents on platelet thrombi formed on the collagen surface under blood flow conditions. Anti-GP IIb/IIIa agents may influence platelet thrombi already formed. Blood samples were anticoagulated either by the specific antithrombin Argatroban (100 microM) or by unfractionated heparin (0.1 U/ml). After platelet thrombi were formed on a collagen surface following 6-min perfusion of whole blood obtained from eight adult donors containing fluorescinated platelets at a wall shear rate of 1,500 s(-1), additional blood samples from the same donors either containing or not containing anti-GP IIb/IIIa agents (abciximab, eptifibatide, or tirofiban) were perfused on these thrombi. The three-dimensional structures of the platelet thrombi were continuously observed by laser confocal microscopy equipped with a piezo-electric motor control unit and recorded. The platelet thrombi started to dissolve after perfusion of blood containing the anti-GP IIb/IIIa agents, whereas their growth resumed after subsequent perfusion of control blood. Only a single layer of platelets having heights of 3 +/- 1 microm, 3 +/- 2 microm, and 3 +/- 1 microm, respectively, could be seen after 6-min perfusion of blood containing abciximab, eptifibatide, and tirofiban, whereas the initial height of the platelet thrombi of 8 +/- 2 microm increased to 11 +/- 4 microm after subsequent perfusion of control blood (n = 8). The volume of the platelet thrombi, which was 3,352 +/- 1,045 microm(3) before starting the second perfusion, was reduced to 778 +/- 102 microm(3), 812 +/- 122 microm(3), and 856 +/- 144 microm(3) after 6-min perfusion of blood containing abciximab, eptifibatide, and tirofiban, respectively. We have shown in this study that anti-GP IIb/IIIa agents possess the ability to dissolve platelet thrombi.

[Estimation of pulmonary hypertension in lung and valvular heart diseases by perfusion lung scintigraphy].

PubMed

Fujii, T; Tanaka, M; Yazaki, Y; Kitabayashi, H; Koizumi, T; Kubo, K; Sekiguchi, M; Yano, K

1999-06-01

To estimate pulmonary hypertension, we measured postural differences in pulmonary blood flow for the lateral decubitus positions on perfusion lung scintigrams with Tc-99 m macro-aggregated albumin, applying the method devised by Tanaka et al (Eur J Nucl Med 17: 320-326, 1990). Utilizing a scintillation camera coupled to a minicomputer system, changes in the distribution of pulmonary blood flow caused by gravitational effects, namely, changes in the total count ratios for the right lung versus the left lung in the right and left lateral decubitus positions (R/L), were obtained for 44 patients with lung disease, 95 patients with valvular heart disease, and 23 normal subjects. Mean standard deviation in the R/L ratios was 3.09 +/- 1.28 for the normal subjects, 1.97 +/- 0.89 for the patients with lung disease, and 1.59 +/- 0.59 for the patients with valvular heart disease. The R/L ratios correlated with mean pulmonary arterial pressure and cardio-thoracic ratios in the lung disease and valvular heart disease groups, with pulmonary arteriolar resistance in the former, and with pulmonary capillary wedge pressure in the latter. Defining pulmonary hypertension (> 20 mmHg) as an R/L ratio of less than 1.81, which is the mean-1 standard deviation for normal subjects, the sensitivity and the specificity of the R/L ratio for the diagnosis of pulmonary hypertension were 62.9% and 76.2%, respectively, for the lung disease patients, and 80.3% and 61.8%, respectively, for the valvular heart disease patients. This method seems to be useful for the pathophysiologic evaluation of pulmonary perfusion in cases of lung disease and valvular heart disease.

Organotypic lung culture: A new model for studying ischemia and ex vivo perfusion in lung transplantation.

PubMed

Baste, Jean-Marc; Gay, Arnaud; Smail, Hassiba; Noël, Romain; Bubenheim, Michael; Begueret, Hugues; Morin, Jean-Paul; Litzler, Pierre-Yves

2015-01-01

Donors after cardiac death (DCD) in lung transplantation is considered as a solution for organ shortage. However, it is characterized by warm ischemic period, which could be involved in severe Ischemia-Reperfusion lesion (IR) with early graft dysfunction. We describe a new hybrid model combining in vivo ischemia followed by in vitro reoxygenation using organ-specific culture. A hybrid model using in vivo ischemic period followed by in vitro lung slice reoxygenation was set up in rat to mimic DCD in lung transplantation with in vitro perfusion. Different markers (bioenergetics, oxidant stress assays, and histology) were measured to evaluate the viability of lung tissue after different ischemic times (I-0, I-1, I-2, I-4, I-15 hours) and reoxygenation times (R-0, R-1, R-4, R-24 hours). No differences were found in cell viability, ATP concentrations, extracellular LDH assays or histology, demonstrating extensive viability of up to 4 hours in lung tissue warm ischemia. We found oxidative stress mainly during the ischemic period with no burst at reoxygenation. Cytosolic anti-oxidant system was involved first (I-0,I-1,I-2) followed by mitochondrial anti-oxidant system for extensive ischemia (I-4). Histological features showed differences in this model of ischemia-reoxygenation between bronchial epithelium and lung parenchymal cells, with epithelium regeneration after 2 hours of warm ischemia and 24 hours of perfusion. The results of our hybrid model experiment suggest extensive lung viability of up to 4 hours ischemia. Our model could be an interesting tool to evaluate ex vivo reconditioning techniques after different in vivo lung insults.

Baseline regional perfusion impacts exercise response to endobronchial valve therapy in advanced pulmonary emphysema.

PubMed

Argula, Rahul G; Strange, Charlie; Ramakrishnan, Viswanathan; Goldin, Jonathan

2013-11-01

Advanced heterogeneous emphysema with hyperinflation impacts exercise tolerance in COPD. Bronchoscopic lung volume reduction using Zephyr endobronchial valves (EBVs) has been shown to improve lung function in patients with heterogeneous emphysema. It is unclear whether the target lobe perfusion of patients receiving EBV therapy impacts exercise tolerance as measured by the 6-min walk test distance (6MWTD). We performed a retrospective analysis on the treatment group of the Endobronchial Valve for Emphysema Palliation Trial (VENT) to evaluate the impact of perfusion, measured by 99mTc-MAA-perfusion scintigraphy, on the 6-month improvement in 6MWTD. A mixed-model analysis was performed for the treatment outcome, adjusting for other variables such as age, target lobe position, fissure integrity, BMI, sex, destruction score, and lobar exclusion. Dichotomized at the median, of the 169 patients who received EBV therapy, 88 had a low target lobe regional perfusion and 81 had high target lobe regional perfusion at baseline. Patients with a low target lobe regional perfusion had a significant improvement in 6MWTD when compared with those with a high baseline target lobe regional perfusion (30.24 m vs 3.72 m, P = .03). Shifts in perfusion after EBV therapy occurred only in patients with high baseline perfusion and did not correlate with improved 6MWTD. Patients having heterogeneous emphysema with a low baseline target lobe regional perfusion benefit from EBV therapy, independent of the degree of target lobe destruction. This effect is attenuated if the EBV therapy is not occlusive. Characterization of baseline perfusion may enhance clinical results of patients with emphysema undergoing EBV therapy. ClinicalTrials.gov; No.: NCT00000606; URL: www.clincialtrials.gov.

Intra-observer and inter-observer agreements for the measurement of dual-input whole tumor computed tomography perfusion in patients with lung cancer: Influences of the size and inner-air density of tumors.

PubMed

Wang, Qingle; Zhang, Zhiyong; Shan, Fei; Shi, Yuxin; Xing, Wei; Shi, Liangrong; Zhang, Xingwei

2017-09-01

This study was conducted to assess intra-observer and inter-observer agreements for the measurement of dual-input whole tumor computed tomography perfusion (DCTP) in patients with lung cancer. A total of 88 patients who had undergone DCTP, which had proved a diagnosis of primary lung cancer, were divided into two groups: (i) nodules (diameter ≤3 cm) and masses (diameter >3 cm) by size, and (ii) tumors with and without air density. Pulmonary flow, bronchial flow, and pulmonary index were measured in each group. Intra-observer and inter-observer agreements for measurement were assessed using intraclass correlation coefficient, within-subject coefficient of variation, and Bland-Altman analysis. In all lung cancers, the reproducibility coefficient for intra-observer agreement (range 26.1-38.3%) was superior to inter-observer agreement (range 38.1-81.2%). Further analysis revealed lower agreements for nodules compared to masses. Additionally, inner-air density reduced both agreements for lung cancer. The intra-observer agreement for measuring lung cancer DCTP was satisfied, while the inter-observer agreement was limited. The effects of tumoral size and inner-air density to agreements, especially between two observers, should be emphasized. In future, an automatic computer-aided segment of perfusion value of the tumor should be developed. © 2017 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.

Hypoxic pulmonary vasoconstriction in reptiles: a comparative study of four species with different lung structures and pulmonary blood pressures.

PubMed

Skovgaard, Nini; Abe, Augusto S; Andrade, Denis V; Wang, Tobias

2005-11-01

Low O2 levels in the lungs of birds and mammals cause constriction of the pulmonary vasculature that elevates resistance to pulmonary blood flow and increases pulmonary blood pressure. This hypoxic pulmonary vasoconstriction (HPV) diverts pulmonary blood flow from poorly ventilated and hypoxic areas of the lung to more well-ventilated parts and is considered important for the local matching of ventilation to blood perfusion. In the present study, the effects of acute hypoxia on pulmonary and systemic blood flows and pressures were measured in four species of anesthetized reptiles with diverse lung structures and heart morphologies: varanid lizards (Varanus exanthematicus), caimans (Caiman latirostris), rattlesnakes (Crotalus durissus), and tegu lizards (Tupinambis merianae). As previously shown in turtles, hypoxia causes a reversible constriction of the pulmonary vasculature in varanids and caimans, decreasing pulmonary vascular conductance by 37 and 31%, respectively. These three species possess complex multicameral lungs, and it is likely that HPV would aid to secure ventilation-perfusion homogeneity. There was no HPV in rattlesnakes, which have structurally simple lungs where local ventilation-perfusion inhomogeneities are less likely to occur. However, tegu lizards, which also have simple unicameral lungs, did exhibit HPV, decreasing pulmonary vascular conductance by 32%, albeit at a lower threshold than varanids and caimans (6.2 kPa oxygen in inspired air vs. 8.2 and 13.9 kPa, respectively). Although these observations suggest that HPV is more pronounced in species with complex lungs and functionally divided hearts, it is also clear that other components are involved.

REDUCTION IN INSPIRATORY FLOW ATTENUATES IL-8 RELEASE AND MAPK ACTIVATION OF LUNG OVERSTRETCH

EPA Science Inventory

Lung overstretch involves mechanical factors, including large tidal volumes (VT), which induce inflammatory responses. The current authors hypothesised that inspiratory flow contributes to ventilator-induced inflammation. Buffer-perfused rabbit lungs were ventilated for 2 h with ...

Differential roles of endothelin-1 ETA and ETB receptors and vasoactive intestinal polypeptide in regulation of the airways and the pulmonary vasculature in isolated rat lung.

PubMed

Janosi, Tibor; Peták, Ferenc; Fontao, Fabienne; Morel, Denis R; Beghetti, Maurice; Habre, Walid

2008-11-01

The available treatment strategies against pulmonary hypertension include the administration of endothelin-1 (ET-1) receptor subtype blockers (ET(A) and ET(B) antagonists); vasoactive intestinal polypeptide (VIP) has recently been suggested as a potential new therapeutic agent. We set out to investigate the ability of these agents to protect against the vasoconstriction and impairment of lung function commonly observed in patients with pulmonary hypertension. An ET(A) blocker (BQ123), ET(B) blocker (BQ788), a combination of these selective blockers (ET(A) + ET(B) blockers) or VIP (V6130) was administered into the pulmonary circulation in four groups of perfused normal rat lungs. Pulmonary vascular resistance (PVR) and forced oscillatory lung input impedance (Z(L)) were measured in all groups under baseline conditions and at 1 min intervals following ET-1 administrations. The airway resistance, inertance, tissue damping and elastance were extracted from the Z(L) spectra. While VIP, ET(A) blocker and combined ET(A) and ET(B) blockers significantly prevented the pulmonary vasoconstriction induced by ET-1, ET(B) blockade enhanced the ET-1-induced increases in PVR. In contrast, the ET(A) and ET(B) blockers markedly elevated the ET-1-induced increases in airway resistance, while VIP blunted this constrictor response. Our results suggest that VIP potently acts against the airway and pulmonary vascular constriction mediated by endothelin-1, while the ET(A) and ET(B) blockers exert a differential effect between airway resistance and PVR.

Nearly total absence of pulmonary perfusion with corresponding technetium-99m MDP and gallium-67 uptake in a patient with mediastinal neuroblastoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Garty, I.; Koren, A.; Moguilner, G.

1985-08-01

A case of unilateral nearly total hypoperfusion of the left lung in a 13-month-old girl is presented. The combination of the lung hypoperfusion and accumulation of the Tc-99m MDP and Ga-67 citrate in the same area suggested the preoperative diagnosis of mediastinal neuroblastoma. Explorative thoracotomy revealed the presence of a neuroblastoma compressing the left lung pedicle. The described scintigraphic appearance in the pediatric age group is suggested as typical of mediastinal neuroblastoma. This pathology should be included in the following gamuts in nuclear medicine: unilateral decrease or absent lung perfusion, unilateral diffuse chest uptake of Ga-67 citrate, and unilateral pulmonarymore » uptake in bone scintigraphy.« less

Evaluation of (99)  (m)TcN-MPO as a new myocardial perfusion imaging agent in normal dogs and in an acute myocardial infarction canine model: comparison with (99)  (m)Tc-sestamibi.

PubMed

Bu, Lihong; Li, Renfei; Jin, Zhongnan; Wen, Xiaofei; Liu, Shuang; Yang, Baofeng; Shen, Baozhong; Chen, Xiaoyuan

2011-02-01

(99)  (m)TcN-MPO ([(99)  (m)TcN(mpo)(PNP5)](+): mpo = 2-mercaptopyridine oxide and PNP5 = N-ethoxyethyl-N,N-bis[2-(bis(3-methoxypropyl)phosphino)ethyl]amine) is a cationic (99)  (m)Tc-nitrido complex, which has favorable biodistribution and myocardial uptake with rapid liver clearance in Sprague Dawley rats. The objective of this study was to compare the biodistribution and pharmacokinetics of (99)  (m)TcN-MPO and (99)  (m)Tc-Sestamibi in normal dogs, and to evaluate the potential of (99)  (m)TcN-MPO as a myocardial perfusion agent in canines with acute myocardial infarction. Five normal mongrel dogs were injected intravenously with (99)  (m)TcN-MPO. Venous blood samples were collected via a femoral vein catheter at 0.5, 1, 2, 3, 4, 5, 10, 20, 30, 40, 60, and 90 min post-injection (p.i.). Anterior-posterior planar images were acquired by γ-camera at 10, 20, 30, 60, 90, and 120 min p.i. Regions of interest (ROIs) were drawn around the heart, liver, and lungs. The heart/liver and heart/lung ratios were calculated by dividing the mean counts in heart ROI by the mean counts in the liver and lung ROI, respectively. For comparison, (99)  (m)Tc-sestamibi was also evaluated in the same five dogs. The interval period between the two examinations was 1 week to eliminate possible interference between these two radiotracers. In addition, single positron emission computed tomography (SPECT) images in the canine infarct model were collected 24 h after myocardial infarction at 30 and 60 min after the administration of (99)  (m)TcN-MPO (n = 4) or (99)  (m)Tc-Sestamibi (n = 4). It was found that (99)  (m)TcN-MPO and (99)  (m)Tc-Sestamibi displayed very similar blood clearance characteristics during the first 90 min p.i. Both (99)  (m)TcN-MPO and (99)  (m)Tc-Sestamibi had a rapid blood clearance with less than 50% of initial radioactivity remaining at 1 min and less than 5% at 30 min p.i. (99)  (m)TcN-MPO and (99)  (m)Tc-Sestamibi both showed good heart/lung contrast. The heart/liver ratio of (99)  (m)TcN-MPO increased with time (0.53 ± 0.06 at 10 min, 0.90 ± 0.062 at 30 min, and 1.22 ± 0.06 at 60 min p.i.), whereas the heart/liver ratio of (99)  (m)Tc-Sestamibi remained low at all time points (0.50 ± 0.03 at 10 min, 0.64 ± 0.03 at 30 min, and 0.60 ± 0.02 at 60 min p.i.). SPECT imaging studies in canines with acute myocardial infarction indicated that good visualization of the left ventricular wall and perfusion defects could be achieved at 30 min after administration of (99)  (m)TcN-MPO but not after (99)  (m)Tc-Sestamibi. The combination of reasonable heart uptake with rapid hepatobiliary excretion makes (99)  (m)TcN-MPO a promising new radiotracer for myocardial perfusion imaging.

Three-dimensional Fourier-domain optical coherence tomography of alveolar mechanics in stepwise inflated and deflated isolated and perfused rabbit lungs

NASA Astrophysics Data System (ADS)

Krueger, Alexander; Knels, Lilla; Meissner, Sven; Wendel, Martina; Heller, Axel R.; Lambeck, Thomas; Koch, Thea; Koch, Edmund

2007-07-01

Fourier domain optical coherence tomography (FD-OCT) was used to acquire three-dimensional image stacks of isolated and perfused rabbit lungs (n = 4) at different constant pulmonary airway pressures (CPAP) and during vascular fixation. After despeckling and applying a threshold, the images were segmented into air and tissue, and registered to each other to compensate for movement between CPAP steps. The air-filled cross-sectional areas were quantified using a semi-automatic algorithm. The cross-sectional area of alveolar structures taken at all three perpendicular planes increased with increasing CPAP. Between the minimal CPAP of 3 mbar and the maximum of 25 mbar the areas increased to about 140% of their initial value. There was no systematic dependency of inflation rate on initial size of the alveolar structure. During the perfusion fixation of the lungs with glutaraldehyde morphometric changes of the alveolar geometry measured with FD-OCT were negligible.

Vasoactive intestinal peptide prevents lung injury due to xanthine/xanthine oxidase.

PubMed

Berisha, H; Foda, H; Sakakibara, H; Trotz, M; Pakbaz, H; Said, S I

1990-08-01

Reactive oxygen species mediate injury and inflammation in many tissues. The addition of xanthine and xanthine oxidase to perfused rat lungs led to increases in peak airway pressure and perfusion pressure, pulmonary edema, and increased protein content in bronchoalveolar lavage fluid. Treatment with 1-10 micrograms.kg-1.min-1 of vasoactive intestinal peptide (VIP), a widely distributed neuropeptide, markedly reduced or totally prevented all signs of injury. Simultaneously, VIP also diminished or abolished the associated generation of arachidonate products. Similar protection was provided by catalase (100 micrograms/ml) but not by the VIP-related peptides secretin or glucagon. The pulmonary vasodilator papaverine (0.15 mg/ml) was also ineffective. Injured lungs that were not treated with VIP released large amounts of this peptide in the perfusate. The results indicate that VIP has potent protective activity against injury triggered by xanthine/xanthine oxidase and may be a physiological modulator of inflammatory tissue damage associated with toxic oxygen metabolites.

Regional Distribution of Pulmonary Blood Volume with Dual-Energy Computed Tomography: Results in 42 Subjects.

PubMed

Felloni, Paul; Duhamel, Alain; Faivre, Jean-Baptiste; Giordano, Jessica; Khung, Suonita; Deken, Valérie; Remy, Jacques; Remy-Jardin, Martine

2017-11-01

The noninvasive approach of lung perfusion generated from dual-energy computed tomography acquisitions has entered clinical practice. The purpose of this study was to analyze the regional distribution of iodine within distal portions of the pulmonary arterial bed on dual-source, dual-energy computed tomography examinations in a cohort of subjects without cardiopulmonary pathologies. The study population included 42 patients without cardiorespiratory disease, enabling quantitative and qualitative analysis of pulmonary blood volume after administration of a 40% contrast agent. Qualitative analysis was based on visual assessment. Quantitative analysis was obtained after semiautomatic division of each lung into 18 areas. The iodine concentration did not significantly differ between the right (R) and left (L) lungs (P = .49), with a mean attenuation of 41.35 Hounsfield units (HU) and 41.14 HU, respectively. Three regional gradients of attenuation were observed between: (a) lung bases and apices (P < .001), linked to the conditions of examination (mean Δ: 6.23 in the R lung; 5.96 in the L lung); (b) posterior and anterior parts of the lung (P < .001) due to gravity (mean Δ: 11.92 in the R lung ; 15.93 in the L lung); and (c) medullary and cortical lung zones (P < .001) (mean Δ: 9.35 in the R lung ; 8.37 in the L lung). The intensity of dependent-nondependent (r = 0.42; P < .001) and corticomedullary (r = 0.58; P < .0001) gradients was correlated to the overall iodine concentration. Distribution of pulmonary blood volume is influenced by physiological gradients and scanning conditions. Copyright © 2017 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.

Adrenergic support in septic shock: a critical review.

PubMed

Póvoa, Pedro; Carneiro, António H

2010-02-01

The definition of septic shock includes sepsis-induced hypotension despite adequate fluid resuscitation, along with the presence of organ perfusion abnormalities, and ultimately cell dysfunction. To restore adequate organ perfusion and cell homeostasis, cardiac output should be restored with volume infusion plus vasopressor agents as indicated. Appropriate arterial pressure for each individual patient and proper arterial oxygen content are key elements to restoring perfusion. Tissue perfusion can be monitored by markers of organ and mitochondrial function, namely urine output, level of consciousness, peripheral skin perfusion, central or mixed venous oxygen saturation, and lactate. The hemodynamic effects of the different vasopressor agents depend on the relative affinity to adrenergic receptors. Those with predominant alpha-agonist activity produce more vasoconstriction (inoconstrictors) while those with predominant beta-agonist stimulation increase cardiac performance (inodilators). The debate about whether one vasopressor agent is superior to another is still ongoing. The Surviving Sepsis Campaign guidelines refer to either norepinephrine or dopamine as the first-choice vasopressor agent to correct hypotension in septic shock. However, recent data from observational and controlled trials have challenged these recommendations concerning different adrenergic agents. As a result, our view on the prescription of vasopressors has changed from a probably oversimplified "one-size-fits-all" approach to a multimodal approach in vasopressor selection.

Opposing actions of TRPV4 channel activation in the lung vasculature.

PubMed

Ke, Sun-Kui; Chen, Lan; Duan, Hong-Bing; Tu, Yuan-Rong

2015-12-01

Transient receptor potential vanilloid 4 (TRPV4) calcium channels are known to promote endothelium-dependent relaxation of mouse mesenteric arteries but TRPV4's role in the pulmonary vasculature is uncertain. Thus, we characterized TRPV4 channel vascular tone regulation in mouse main pulmonary artery rings and in the isolated perfused pulmonary circulation and studied possible mechanisms behind these characterizations. Using myography and a TRPV4 specific agonist GSK1016790A in a C57BL/6 WT mouse model of isolated constant-flow lung perfusion, we studied vascular tone regulation in arterial rings from the main left and right pulmonary arteries and vascular resistance of the intra-pulmonary circulation beyond the second branches of the pulmonary arteries. Removal of the endothelium confirmed endothelial dependence. GSK1016790A relaxed the main pulmonary artery (EC50 4 × 10(-8)mol/L), which was inhibited by removal of the endothelium from main pulmonary artery rings. GSK1016790A significantly increased vascular resistance of the pulmonary circulation in isolated perfused lungs, but these effects were inhibited by a TRPV4 antagonist AB159908. A nitric oxide inhibitor NG-nitro-L-arginine methyl ester (L-NAME) and K(+) channel blockers apamin plus charybdotoxin (ChTx) significantly inhibited GSK1016790A in the main pulmonary artery and in an isolated perfused lung in vitro. Activated TRPV4 channels increase pulmonary vascular resistance and vasodilate the main pulmonary artery. Copyright © 2015 Elsevier B.V. All rights reserved.

Ventilation/perfusion SPECT/CT in patients with pulmonary emphysema. Evaluation of software-based analysing.

PubMed

Schreiter, V; Steffen, I; Huebner, H; Bredow, J; Heimann, U; Kroencke, T J; Poellinger, A; Doellinger, F; Buchert, R; Hamm, B; Brenner, W; Schreiter, N F

2015-01-01

The purpose of this study was to evaluate the reproducibility of a new software based analysing system for ventilation/perfusion single-photon emission computed tomography/computed tomography (V/P SPECT/CT) in patients with pulmonary emphysema and to compare it to the visual interpretation. 19 patients (mean age: 68.1 years) with pulmonary emphysema who underwent V/P SPECT/CT were included. Data were analysed by two independent observers in visual interpretation (VI) and by software based analysis system (SBAS). SBAS PMOD version 3.4 (Technologies Ltd, Zurich, Switzerland) was used to assess counts and volume per lung lobe/per lung and to calculate the count density per lung, lobe ratio of counts and ratio of count density. VI was performed using a visual scale to assess the mean counts per lung lobe. Interobserver variability and association for SBAS and VI were analysed using Spearman's rho correlation coefficient. Interobserver agreement correlated highly in perfusion (rho: 0.982, 0.957, 0.90, 0.979) and ventilation (rho: 0.972, 0.924, 0.941, 0.936) for count/count density per lobe and ratio of counts/count density in SBAS. Interobserver agreement correlated clearly for perfusion (rho: 0.655) and weakly for ventilation (rho: 0.458) in VI. SBAS provides more reproducible measures than VI for the relative tracer uptake in V/P SPECT/CTs in patients with pulmonary emphysema. However, SBAS has to be improved for routine clinical use.

Co-registered perfusion SPECT/CT: utility for prediction of improved postoperative outcome in lung volume reduction surgery candidates.

PubMed

Takenaka, Daisuke; Ohno, Yoshiharu; Koyama, Hisanobu; Nogami, Munenobu; Onishi, Yumiko; Matsumoto, Keiko; Yoshikawa, Takeshi; Matsumoto, Sumiaki; Sugimura, Kazuro

2010-06-01

To directly compare the capabilities of perfusion scan, SPECT, co-registered SPECT/CT, and quantitatively and qualitatively assessed MDCT (i.e. quantitative CT and qualitative CT) for predicting postoperative clinical outcome for lung volume reduction surgery (LVRS) candidates. Twenty-five consecutive candidates (19 men and six women, age range: 42-72 years) for LVRS underwent preoperative CT and perfusion scan with SPECT. Clinical outcome of LVRS for all subjects was also assessed by determining the difference between pre- and postoperative forced expiratory volume in 1s (FEV(1)) and 6-min walking distance (6MWD). All SPECT examinations were performed on a SPECT scanner, and co-registered to thin-section CT by using commercially available software. On planar imaging, SPECT and SPECT/CT, upper versus lower zone or lobe ratios (U/Ls) were calculated from regional uptakes between upper and lower lung fields in the operated lung. On quantitatively assessed CT, U/L for all subjects was assessed from regional functional lung volumes. On qualitatively assessed CT, planar imaging, SPECT and co-registered SPECT/CT, U/Ls were assessed with a 4-point visual scoring system. To compare capabilities of predicting clinical outcome, each U/L was statistically correlated with the corresponding clinical outcome. Significantly fair or moderate correlations were observed between quantitatively and qualitatively assessed U/Ls obtained with all four methods and clinical outcomes (-0.60

Nitrogen-13-labeled ammonia for myocardial imaging.

PubMed

Walsh, W F; Fill, H R; Harper, P V

1977-01-01

Cyclotron-produced nitrogen-13 (half-life 10 min), as labeled ammonia (13NH4+), has been evaluated as a myocardial perfusion imaging agent. The regional myocardial uptake of 13NH4+ has been shown to be proportional to regional tissue perfusion in animal studies. Intravenously administered 13NH4+ is rapidly cleared from the circulation, being extracted by the liver (15%), lungs, myocardium (2%-4%), brain, kidney, and bladder. Myocardial ammonia is metabolized mainly to glutamine via the glutamine synthetase pathway. Pulmonary uptake is substantial, but usually transient, except in smokers where clearance may be delayed. The position annihilation irradiation (511 keV) of 13N may be imaged with a scintillation camera, using either a specially designed tungsten collimator or a pinhole collimator. After early technical problems with collimation and the production method of 13NH4+ were overcome, reproducible high quality myocardial images were consistently obtained. The normal myocardial image was established to be of a homogeneous "doughnut" configuration. Imaging studies performed in patients with varying manifestations of ischemic and valvular heart disease showed a high incidence of localized perfusion defects, especially in patients with acute myocardial infarction. Sequential studies at short intervals in patients with acute infarction showed correlation between alterations in regional perfusion and the clinical course of the patient. It is concluded that myocardial imaging with 13NH4+ and a scintillation camera provides a valid and noninvasive means of assessing regional myocardial perfusion. This method is especially suitable for sequential studies of acute cardiac patients at short intervals. Coincidence imaging of the 511 keV annihilation irradiation provides a tomographic and potentially quantitative assessment of the regional myocardial uptake of 13NH4+.

[Nuclear cardiology with new radiopharmaceuticals].

PubMed

Bunko, H

1994-08-01

In the field of nuclear cardiology, 99mTc labeled myocardial perfusion agents such as MIBI, Tetrofosmin and Teboroxime, 111In-antimyosin for imaging of myocardial necrosis, 123I-betamethyl-iodophenylpentadecanoic acid (BMIPP) for imaging of myocardial fatty acid metabolism and 123I-metaiodobenzylguanidine (MIBG) for imaging of myocardial adrenergic function are introduced recently in Japan. Improved image quality and simultaneous evaluation of myocardial perfusion, function and wall motion can be obtained with use of 99mTc labeled myocardial perfusion agents. 111In-antimyosin enables specific imaging of myocardial necrosis which leads to the use for wide variety of heart diseases. Discrepancy of the myocardial perfusion and metabolism in case of stunned myocardium or cardiomyopathy can be evaluated by 123I-BMIPP in conjunction with perfusion agent. Recently wide variety of diseases which may have cardiac adrenergic abnormality are targeted for 123I-MIBG imaging. These new radiopharmaceuticals are expected to be powerful tool for evaluation of the pathophysiology including severity and prognosis and evaluation of the etiology of the various heart diseases.

In Search of the Optimal Heart Perfusion Ultrasound Imaging Platform.

PubMed

Grishenkov, Dmitry; Gonon, Adrian; Janerot-Sjoberg, Birgitta

2015-09-01

Quantification of myocardial perfusion by contrast echocardiography remains a challenge. Existing imaging phantoms used to evaluate the performance of ultrasound scanners do not comply with perfusion basics in the myocardium, where perfusion and motion are inherently coupled. To contribute toward an improvement, we developed a contrast echocardiographic perfusion imaging platform based on an isolated rat heart coupled to an ultrasound scanner. Perfusion was assessed by using 3 different types of contrast agents: dextran-based Promiten (Meda AB, Solna, Sweden), phospholipid-shelled SonoVue (Bracco Diagnostics, Inc, Princeton, NJ), and polymer-shelled MB-pH5-RT, developed in-house. The myocardial video intensity was monitored over time from contrast agent administration to peak, and 2 characteristic constants were calculated by using an exponential fit: A, representing capillary volume; and β, representing inflow velocity. Acquired experimental evidence demonstrates that the application of all 3 contrast agents allows sonographic estimation of myocardial perfusion in the isolated rat heart. Video intensity maps show that an increase in contrast concentration increases the late-plateau values, A, mimicking increased capillary volume. Estimated values of the flow, proportional to A × β, increase when the pressure of the perfusate column increases from 80 to 110 cm of water. This finding is in agreement with the true values of the coronary flow increase measured by a flowmeter attached to the aortic cannula. The contrast echocardiographic perfusion imaging platform described holds promise for standardized evaluation and optimization of contrast perfusion ultrasound imaging in which real-time inflow curves at low acoustic power semiquantitatively reflect coronary flow. © 2015 by the American Institute of Ultrasound in Medicine.

An in vitro lung model to assess true shunt fraction by multiple inert gas elimination.

PubMed

Varadarajan, Balamurugan; Vogt, Andreas; Hartwich, Volker; Vasireddy, Rakesh; Consiglio, Jolanda; Hugi-Mayr, Beate; Eberle, Balthasar

2017-01-01

The Multiple Inert Gas Elimination Technique, based on Micropore Membrane Inlet Mass Spectrometry, (MMIMS-MIGET) has been designed as a rapid and direct method to assess the full range of ventilation-to-perfusion (V/Q) ratios. MMIMS-MIGET distributions have not been assessed in an experimental setup with predefined V/Q-distributions. We aimed (I) to construct a novel in vitro lung model (IVLM) for the simulation of predefined V/Q distributions with five gas exchange compartments and (II) to correlate shunt fractions derived from MMIMS-MIGET with preset reference shunt values of the IVLM. Five hollow-fiber membrane oxygenators switched in parallel within a closed extracorporeal oxygenation circuit were ventilated with sweep gas (V) and perfused with human red cell suspension or saline (Q). Inert gas solution was infused into the perfusion circuit of the gas exchange assembly. Sweep gas flow (V) was kept constant and reference shunt fractions (IVLM-S) were established by bypassing one or more oxygenators with perfusate flow (Q). The derived shunt fractions (MM-S) were determined using MIGET by MMIMS from the retention data. Shunt derived by MMIMS-MIGET correlated well with preset reference shunt fractions. The in vitro lung model is a convenient system for the setup of predefined true shunt fractions in validation of MMIMS-MIGET.

Absence of Gal epitope prolongs survival of swine lungs in an ex vivo model of hyperacute rejection

PubMed Central

Nguyen, Bao-Ngoc H.; Azimzadeh, Agnes M.; Schroeder, Carsten; Buddensick, Thomas; Zhang, Tianshu; Laaris, Amal; Cochrane, Megan; Schuurman, Henk-Jan; Sachs, David H.; Allan, James S.; Pierson, Richard N.

2012-01-01

Background Galactosyl transferase gene knock-out (GalTKO) swine offer a unique tool to evaluate the role of the Gal antigen in xenogenic lung hyperacute rejection. Methods We perfused GalTKO miniature swine lungs with human blood. Results were compared with those from previous studies using wild-type and human decay-accelerating factor-transgenic (hDAF+/+) pig lungs. Results GalTKO lungs survived 132 ± 52 min compared to 10 ± 9 min for wild-type lungs (P = 0.001) and 45 ± 60 min for hDAF+/+ lungs (P = 0.18). GalTKO lungs displayed stable physiologic flow and pulmonary vascular resistance (PVR) until shortly before graft demise, similar to autologous perfusion, and unlike wild-type or hDAF+/+ lungs. Early (15 and 60 min) complement (C3a) and platelet activation and intrapulmonary platelet deposition were significantly diminished in GalTKO lungs relative to wild-type or hDAF+/+ lungs. However, GalTKO lungs adsorbed cytotoxic anti-non-Gal antibody and elaborated high levels of thrombin; their demise was associated with increased PVR, capillary congestion, intravascular thrombi and strong CD41 deposition not seen at earlier time points. Conclusions In summary, GalTKO lungs are substantially protected from injury but, in addition to anti-non-Gal antibody and complement, platelet adhesion and non-physiologic intravascular coagulation contribute to Gal-independent lung injury mechanisms. PMID:21496117

Cerebral perfusion imaging with bolus harmonic imaging (Honorable Mention Poster Award)

NASA Astrophysics Data System (ADS)

Kier, Christian; Toth, Daniel; Meyer-Wiethe, Karsten; Schindler, Angela; Cangur, Hakan; Seidel, Gunter; Aach, Til

2005-04-01

Fast visualisation of cerebral microcirculation supports diagnosis of acute stroke. However, the commonly used CT/MRI-based methods are time consuming, costly and not applicable to every patient. The bolus perfusion harmonic imaging (BHI) method is an ultrasound imaging technique which makes use of the fact, that ultrasound contrast agents unlike biological tissues resonate at harmonic frequencies. Exploiting this effect, the contrast between perfused and non-perfused areas can be improved. Thus, BHI overcomes the low signal-to-noise ratio of transcranial ultrasound and the high impedance of the skull. By analysing image sequences, visualising the qualitative characteristics of an US contrast agent bolus injection becomes possible. The analysis consists of calculating four perfusion-related parameters, Local Peak Intensity, Time To Peak, Area Under Curve, and Average Rising, from the time/intensity curve and providing them as colour-coded images. For calculating these parameters the fundamental assumption is that image intensity corresponds to contrast agent concentration which in turn shows the perfusion of the corresponding brain region. In a clinical study on patients suffering from acute ischemic stroke it is shown that some of the parameters correlate significantly to the infarction area. Thus, BHI becomes a less time-consuming and inexpensive bedside method for diagnosis of cerebral perfusion deficits.

Distribution of extravascular fluid volumes in isolated perfused lungs measured with H215O.

PubMed Central

Jones, T; Jones, H A; Rhodes, C G; Buckingham, P D; Hughes, J M

1976-01-01

The distributions per unit volume of extravascular water (EVLW), blood volume, and blood flow were measured in isolated perfused vertical dog lungs. A steady-state tracer technique was employed using oxygen-15, carbon-11, and nitrogen-13 isotopes and external scintillation counting of the 511-KeV annihilation radiation common to all three radionuclides. EVLW, and blood volume and flow increased from apex to base in all preparations, but the gradient of increasing flow exceeded that for blood and EVLW volumes. The regional distributions of EVLW and blood volume were almost identical. With increasing edema, lower-zone EVLW increased slightly relative to that in the upper zone. There was no change in the distribution of blood volume or flow until gross edema (100% wt gain) occurred when lower zone values were reduced. In four lungs the distribution of EVLW was compared with wet-to-dry ratios from lung biopsies taken immediately afterwards. Whereas the isotopically measured EVLW increased from apex to base, the wet-to-dry weight ratios remained essentially uniform. We concluded that isotopic methods measure only an "exchangeable" water pool whose volume is dependent on regional blood flow and capillary recruitment. Second, the isolated perfused lung can accommodate up to 60% wt gain without much change in the regional distribution of EVLW, volume, or flow. PMID:765354

Meta-analysis of the independent and cumulative effects of multiple genetic modifications on pig lung xenograft performance during ex vivo perfusion with human blood

PubMed Central

Harris, Donald G.; Quinn, Kevin J.; French, Beth M.; Schwartz, Evan; Kang, Elizabeth; Dahi, Siamak; Phelps, Carol J.; Ayares, David L.; Burdorf, Lars; Azimzadeh, Agnes M.; Pierson, Richard N.

2014-01-01

Background Genetically modified pigs are a promising potential source of lung xenografts. Ex-vivo xenoperfusion is an effective platform for testing the effect of new modifications, but typical experiments are limited by testing of a single genetic intervention and small sample sizes. The purpose of this study was to analyze the individual and aggregate effects of donor genetic modifications on porcine lung xenograft survival and injury in an extensive pig lung xenoperfusion series. Methods Data from 157 porcine lung xenoperfusion experiments using otherwise unmodified heparinized human blood were aggregated as either continuous or dichotomous variables. Lungs were wild type in 17 perfusions (11% of the study group), while 31 lungs (20% of the study group) had 1 genetic modification, 40 lungs (39%) had 2, and 47 lungs (30%) had 3 or more modifications. The primary endpoint was functional lung survival to 4 hours of perfusion. Secondary analyses evaluated previously identified markers associated with known lung xenograft injury mechanisms. In addition to comparison among all xenografts grouped by survival status, a subgroup analysis was performed of lungs incorporating the GalTKO.hCD46 genotype. Results Each increase in the number of genetic modifications was associated with additional prolongation of lung xenograft survival. Lungs that exhibited survival to 4 hours generally had reduced platelet activation and thrombin generation. GalTKO and the expression of hCD46, HO-1, hCD55 or hEPCR were associated with improved survival. hTBM, HLA-E, and hCD39 were associated with no significant effect on the primary outcome. Conclusion This meta-analysis of an extensive lung xenotransplantation series demonstrates that increasing the number of genetic modifications targeting known xenogeneic lung injury mechanisms is associated with incremental improvements in lung survival. While more detailed mechanistic studies are needed to explore the relationship between gene expression and pathway-specific injury, and explore why some genes apparently exhibit neutral (hTBM, HLA-E) or inconclusive (CD39) effects, GalTKO, hCD46, HO-1, hCD55, and hEPCR modifications were associated with significant lung xenograft protection. This analysis supports the hypothesis that multiple genetic modifications targeting different known mechanisms of xenograft injury will be required to optimize lung xenograft survival. PMID:25470239

Functional significance and control of release of pulmonary surfactant in the lizard lung.

PubMed

Wood, P G; Daniels, C B; Orgeig, S

1995-10-01

The amount of pulmonary surfactant in the lungs of the bearded dragon (Pogona vitticeps) increases with increasing body temperature. This increase coincides with a decrease in lung compliance. The relationship between surfactant and lung compliance and the principal stimuli for surfactant release and composition (temperature, ventilatory pattern, and autonomic neurotransmitters) were investigated. We chose to investigate ventilatory pattern (which causes mechanical deformation of the type II cells) and adrenergic agents, because they are the major stimuli for surfactant release in mammals. To examine the effects of body temperature and ventilatory pattern, isolated lungs were ventilated at either 18 or 37 degrees C at different ventilatory regimens. An isolated perfused lung preparation at 27 degrees C was used to analyze the effects of autonomic neurotransmitters. Ventilatory pattern did not affect surfactant release, composition, or lung compliance at either 18 or 37 degrees C. An increase in temperature increased phospholipid reuptake and disproportionately increased cholesterol degradation/uptake. Epinephrine and acetylcholine stimulated phospholipid but not cholesterol release. Removal of surfactant caused a decrease in compliance, regardless of the experimental temperature. Temperature appears to be the principal determinant of lung compliance in the bearded dragon, acting directly to increase the tone of the smooth muscle. Increasing the ambient temperature may result in greater surfactant turnover by increasing cholesterol reuptake/degradation directly and by increasing circulating epinephrine, thereby indirectly increasing phospholipid secretion. We suggest that changing ventilatory pattern may be inadequate as a mechanism for maintaining surfactant homeostasis, given the discontinuous, highly variable reptilian breathing pattern.

Ex Vivo Adenoviral Vector Gene Delivery Results in Decreased Vector-associated Inflammation Pre- and Post–lung Transplantation in the Pig

PubMed Central

Yeung, Jonathan C; Wagnetz, Dirk; Cypel, Marcelo; Rubacha, Matthew; Koike, Terumoto; Chun, Yi-Min; Hu, Jim; Waddell, Thomas K; Hwang, David M; Liu, Mingyao; Keshavjee, Shaf

2012-01-01

Acellular normothermic ex vivo lung perfusion (EVLP) is a novel method of donor lung preservation for transplantation. As cellular metabolism is preserved during perfusion, it represents a potential platform for effective gene transduction in donor lungs. We hypothesized that vector-associated inflammation would be reduced during ex vivo delivery due to isolation from the host immune system response. We compared ex vivo with in vivo intratracheal delivery of an E1-, E3-deleted adenoviral vector encoding either green fluorescent protein (GFP) or interleukin-10 (IL-10) to porcine lungs. Twelve hours after delivery, the lung was transplanted and the post-transplant function assessed. We identified significant transgene expression by 12 hours in both in vivo and ex vivo delivered groups. Lung function remained excellent in all ex vivo groups after viral vector delivery; however, as expected, lung function decreased in the in vivo delivered adenovirus vector encoding GFP (AdGFP) group with corresponding increases in IL-1β levels. Transplanted lung function was excellent in the ex vivo transduced lungs and inferior lung function was seen in the in vivo group after transplantation. In summary, ex vivo delivery of adenoviral gene therapy to the donor lung is superior to in vivo delivery in that it leads to less vector-associated inflammation and provides superior post-transplant lung function. PMID:22453765

Ex vivo administration of trimetazidine improves post-transplant lung function in pig model.

PubMed

Cosgun, Tugba; Iskender, Ilker; Yamada, Yoshito; Arni, Stephan; Lipiski, Miriam; van Tilburg, Koen; Weder, Walter; Inci, Ilhan

2017-07-01

Ex vivo lung perfusion (EVLP) is not only used to assess marginal donor lungs but is also used as a platform to deliver therapeutic agents outside the body. We previously showed the beneficial effects of trimetazidine (TMZ) on ischaemia reperfusion (IR) injury in a rat model. This study evaluated the effects of TMZ in a pig EVLP transplant model. Pig lungs were retrieved and stored for 24 h at 4°C, followed by 4 h of EVLP. Allografts were randomly allocated to 2 groups ( n  = 5 each). TMZ (5 mg/kg) was added to the prime solution prior to EVLP. After EVLP, left lungs were transplanted and recipients were observed for 4 h. Allograft gas exchange function and lung mechanics were recorded hourly throughout reperfusion. Microscopic lung injury and inflammatory and biochemical parameters were assessed. There was a trend towards better oxygenation during EVLP in the TMZ group ( P  = 0.06). After transplantation, pulmonary gas exchange was significantly better during the 4-h reperfusion period and after isolation of the allografts for 10 min ( P  < 0.05). Tissue thiobarbituric acid levels, myeloperoxidase activity and protein concentrations in bronchoalveolar lavage samples were significantly lower in the TMZ group at the end of EVLP ( P  < 0.05). Ex vivo treatment of donor lungs with TMZ significantly improved immediate post-transplant lung function. Further studies are warranted to understand the effect of this strategy on long-term lung function. © The Author 2017. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

Ex vivo rehabilitation of non-heart-beating donor lungs in preclinical porcine model: delayed perfusion results in superior lung function.

PubMed

Mulloy, Daniel P; Stone, Matthew L; Crosby, Ivan K; Lapar, Damien J; Sharma, Ashish K; Webb, David V; Lau, Christine L; Laubach, Victor E; Kron, Irving L

2012-11-01

Ex vivo lung perfusion (EVLP) is a promising modality for the evaluation and treatment of marginal donor lungs. The optimal timing of EVLP initiation and the potential for rehabilitation of donor lungs with extended warm ischemic times is unknown. The present study compared the efficacy of different treatment strategies for uncontrolled non-heart-beating donor lungs. Mature swine underwent hypoxic arrest, followed by 60 minutes of no-touch warm ischemia. The lungs were harvested and flushed with 4°C Perfadex. Three groups (n = 5/group) were stratified according to the preservation method: cold static preservation (CSP; 4 hours of 4°C storage), immediate EVLP (I-EVLP: 4 hours EVLP at 37°C), and delayed EVLP (D-EVLP; 4 hours of CSP followed by 4 hours of EVLP). The EVLP groups were perfused with Steen solution supplemented with heparin, methylprednisolone, cefazolin, and an adenosine 2A receptor agonist. The lungs then underwent allotransplantation and 4 hours of recipient reperfusion before allograft assessment for resultant ischemia-reperfusion injury. The donor blood oxygenation (partial pressure of oxygen/fraction of inspired oxygen ratio) before death was not different between the groups. The oxygenation after transplantation was significantly greater in the D-EVLP group than in the I-EVLP or CSP groups. The mean airway pressure, pulmonary artery pressure, and expression of interleukin-8, interleukin-1β, and tumor necrosis factor-α were all significantly reduced in the D-EVLP group. Post-transplant oxygenation exceeded the acceptable clinical levels only in the D-EVLP group. Uncontrolled non-heart-beating donor lungs with extended warm ischemia can be reconditioned for successful transplantation. The combination of CSP and EVLP in the D-EVLP group was necessary to obtain optimal post-transplant function. This finding, if confirmed clinically, will allow expanded use of nonheart-beating donor lungs. Copyright © 2012 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.

Vasoactive drugs and the gut: is there anything new?

PubMed

Woolsey, Cheryl A; Coopersmith, Craig M

2006-04-01

Systemic changes in blood pressure and cardiac output induced by pressors and inotropes do not always correlate to improvements in regional perfusion. Since the gut is often referred to as the 'motor' of the systemic inflammatory response syndrome, the impact of vasoactive agents on splanchnic perfusion has theoretical importance. This review will highlight recent studies examining secondary effects of vasoactive agents on intestinal perfusion, metabolism, and barrier function. Norepinephrine has minimal impact on mesenteric blood flow although the combination of norepinephrine and dobutamine increases splanchnic blood flow in sepsis. Dopamine also increases mesenteric blood flow although this may be associated with negative hepatic energy balance at high does. Vasopressin and epinephrine both have negative effects on splanchnic blood flow. Newer inodilators levosimendan and olprinone preferentially improve mesenteric perfusion in animal models. Secondary effects of norepinephrine and dopamine on splanchnic perfusion are minor compared with their systemic effects. While vasopressin usage is increasing in the intensive care unit, caution should be used because of its adverse effects on gut perfusion. Experimental agents for the treatment of heart failure have beneficial gut-specific effects although the clinical significance of this is currently limited by their availability.

The gravitational distribution of ventilation-perfusion ratio is more uniform in prone than supine posture in the normal human lung

PubMed Central

Sá, Rui Carlos; Theilmann, Rebecca J.; Buxton, Richard B.; Prisk, G. Kim; Hopkins, Susan R.

2013-01-01

The gravitational gradient of intrapleural pressure is suggested to be less in prone posture than supine. Thus the gravitational distribution of ventilation is expected to be more uniform prone, potentially affecting regional ventilation-perfusion (V̇a/Q̇) ratio. Using a novel functional lung magnetic resonance imaging technique to measure regional V̇a/Q̇ ratio, the gravitational gradients in proton density, ventilation, perfusion, and V̇a/Q̇ ratio were measured in prone and supine posture. Data were acquired in seven healthy subjects in a single sagittal slice of the right lung at functional residual capacity. Regional specific ventilation images quantified using specific ventilation imaging and proton density images obtained using a fast gradient-echo sequence were registered and smoothed to calculate regional alveolar ventilation. Perfusion was measured using arterial spin labeling. Ventilation (ml·min−1·ml−1) images were combined on a voxel-by-voxel basis with smoothed perfusion (ml·min−1·ml−1) images to obtain regional V̇a/Q̇ ratio. Data were averaged for voxels within 1-cm gravitational planes, starting from the most gravitationally dependent lung. The slope of the relationship between alveolar ventilation and vertical height was less prone than supine (−0.17 ± 0.10 ml·min−1·ml−1·cm−1 supine, −0.040 ± 0.03 prone ml·min−1·ml−1·cm−1, P = 0.02) as was the slope of the perfusion-height relationship (−0.14 ± 0.05 ml·min−1·ml−1·cm−1 supine, −0.08 ± 0.09 prone ml·min−1·ml−1·cm−1, P = 0.02). There was a significant gravitational gradient in V̇a/Q̇ ratio in both postures (P < 0.05) that was less in prone (0.09 ± 0.08 cm−1 supine, 0.04 ± 0.03 cm−1 prone, P = 0.04). The gravitational gradients in ventilation, perfusion, and regional V̇a/Q̇ ratio were greater supine than prone, suggesting an interplay between thoracic cavity configuration, airway and vascular tree anatomy, and the effects of gravity on V̇a/Q̇ matching. PMID:23620488

Pulmonary preservation studies: effects on endothelial function and pulmonary adenine nucleotides.

PubMed

Paik, Hyo Chae; Hoffmann, Steven C; Egan, Thomas M

2003-02-27

Lung transplantation is an effective therapy plagued by a high incidence of early graft dysfunction, in part because of reperfusion injury. The optimal preservation solution for lung transplantation is unknown. We performed experiments using an isolated perfused rat lung model to test the effect of lung preservation with three solutions commonly used in clinical practice. Lungs were retrieved from Sprague-Dawley rats and flushed with one of three solutions: modified Euro-Collins (MEC), University of Wisconsin (UW), or low potassium dextran and glucose (LPDG), then stored cold for varying periods before reperfusion with Earle's balanced salt solution using the isolated perfused rat lung model. Outcome measures were capillary filtration coefficient (Kfc), wet-to-dry weight ratio, and lung tissue levels of adenine nucleotides and cyclic AMP. All lungs functioned well after 4 hr of storage. By 6 hr, UW-flushed lungs had a lower Kfc than LPDG-flushed lungs. After 8 hr of storage, only UW-flushed lungs had a measurable Kfc. Adenine nucleotide levels were higher in UW-flushed lungs after prolonged storage. Cyclic AMP levels correlated with Kfc in all groups. Early changes in endothelial permeability seemed to be better attenuated in lungs flushed with UW compared with LPDG or MEC; this was associated with higher amounts of adenine nucleotides. MEC-flushed lungs failed earlier than LPDG-flushed or UW-flushed lungs. The content of the solution may be more important for lung preservation than whether the ionic composition is intracellular or extracellular.

[Lung scintigraphy].

PubMed

Schümichen, Carl; Schmidt, Matthias; Krause, Thomas

2018-06-01

The S1 guideline for lung scintigraphy has been updated and extended in order to emphasize the advantages oft the method in detecting acute pulmonary embolism (PE) in the periphery oft the lung (subsegmental PE), in underlying subacute and chronic pulmonary disorders, as well as in detecting chronic LE (CTEPH). Method of choice is ventilation / perfusion (V/P) SPECT or V/P SPECT/CT with even higher specificity. Because of its high sensitivity, a threshold (V/P mismatch in at least one segment or two subsegments) is introduced to avoid overtreatment. In case of a change in the therapeutic approach (observation only instead of anticoaculation) the threshold can be omitted. New data concerning the clinical and therapeutical impact of subsegmental PE are included, the chapters open questions have been extented. Other indications for V/P SPECT (secondary diagnoses, abnormalities in pulmonary perfusion, prediction of postoperative lung function) are presented with new data. Schattauer GmbH.

Activation of rho is involved in the mechanism of hydrogen-peroxide-induced lung edema in isolated perfused rabbit lung.

PubMed

Chiba, Y; Ishii, Y; Kitamura, S; Sugiyama, Y

2001-09-01

Acute lung injury is attributed primarily to increased vascular permeability caused by reactive oxygen species derived from neutrophils, such as hydrogen peroxide (H2O2). Increased permeability is accompanied by the contraction and cytoskeleton reorganization of endothelial cells, resulting in intercellular gap formation. The Rho family of Ras-like GTPases is implicated in the regulation of the cytoskeleton and cell contraction. We examined the role of Rho in H2O2-induced pulmonary edema with the use of isolated perfused rabbit lungs. To our knowledge, this is the first study to examine the role of Rho in increased vascular permeability induced by H2O2 in perfused lungs. Vascular permeability was evaluated on the basis of the capillary filtration coefficient (Kfc, ml/min/cm H2O/100 g). We found that H2O2 (300 microM) increased lung weight, Kfc, and pulmonary capillary pressure. These effects of H2O2 were abolished by treatment with Y-27632 (50 microM), an inhibitor of the Rho effector p160 ROCK. In contrast, the muscular relaxant papaverine inhibited the H2O2-induced rise in pulmonary capillary pressure, but did not suppress the increases in lung weight and Kfc. These findings indicate that H2O2 causes pulmonary edema by elevating hydrostatic pressure and increasing vascular permeability. Y-27632 inhibited the formation of pulmonary edema by blocking both of these H2O2-induced effects. Our results suggest that Rho-related pathways have a part in the mechanism of H2O2-induced pulmonary edema. Copyright 2001 Academic Press.

A neutrophil elastase inhibitor improves lung function during ex vivo lung perfusion.

PubMed

Harada, Masaaki; Oto, Takahiro; Otani, Shinji; Miyoshi, Kentaroh; Okada, Masanori; Iga, Norichika; Nishikawa, Hitoshi; Sugimoto, Seiichiro; Yamane, Masaomi; Miyoshi, Shinichiro

2015-12-01

Ex vivo lung perfusion (EVLP) has been used not only for graft evaluation but also for graft reconditioning prior to lung transplantation. Inflammatory cells such as neutrophils may cause additional graft injury during EVLP. Neutrophil elastase inhibitors protect lungs against neutrophil-induced lung injury, such as acute respiratory distress syndrome. This study aimed to investigate the effect of a neutrophil elastase inhibitor during EVLP. EVLP was performed for 4 h in bilateral pig lungs that had previously experienced warm ischemia for 2 h with or without a neutrophil elastase inhibitor (treated and control groups, respectively; n = 6). Following EVLP, the left lung was transplanted into a recipient pig, and this was followed by observation for 4 h. Pulmonary functions were observed both during EVLP and during the early post-transplant stage. During EVLP, decreases in neutrophil elastase levels (P < 0.001), the wet-dry weight ratio (P < 0.05), and pulmonary vascular resistance (P < 0.01) and increases in the PaO2/FiO2 ratio (P < 0.01) and pulmonary compliance (P < 0.05) were observed in the treated group. After transplantation, decreased pulmonary vascular resistance (P < 0.05) was observed in the treated group. A neutrophil elastase inhibitor attenuated the inflammatory response during EVLP and may decrease the incidence of lung reperfusion injury after transplantation.

Pulmonary blood flow distribution in sheep: effects of anesthesia, mechanical ventilation, and change in posture

NASA Technical Reports Server (NTRS)

Walther, S. M.; Domino, K. B.; Glenny, R. W.; Hlastala, M. P.

1997-01-01

BACKGROUND: Recent studies providing high-resolution images of pulmonary perfusion have questioned the classical zone model of pulmonary perfusion. Hence the present work was undertaken to provide detailed maps of regional pulmonary perfusion to examine the influence of anesthesia, mechanical ventilation, and posture. METHODS: Pulmonary perfusion was analyzed with intravenous fluorescent microspheres (15 microm) in six sheep studied in four conditions: prone and awake, prone with pentobarbital-anesthesia and breathing spontaneously, prone with anesthesia and mechanical ventilation, and supine with anesthesia and mechanical ventilation. Lungs were air dried at total lung capacity and sectioned into approximately 1,100 pieces (about 2 cm3) per animal. The pieces were weighed and assigned spatial coordinates. Fluorescence was read on a spectrophotometer, and signals were corrected for piece weight and normalized to mean flow. Pulmonary blood flow heterogeneity was assessed using the coefficient of variation of flow data. RESULTS: Pentobarbital anesthesia and mechanical ventilation did not influence perfusion heterogeneity, but heterogeneity increased when the animals were in the supine posture (P < 0.01). Gravitational flow gradients were absent in the prone position but present in the supine (P < 0.001 compared with zero). Pulmonary perfusion was distributed with a hilar-to-peripheral gradient in animals breathing spontaneously (P < 0.05). CONCLUSIONS: The influence of pentobarbital anesthesia and mechanical ventilation on pulmonary perfusion heterogeneity is small compared with the effect of changes in posture. Analysis of flow gradients indicate that gravity plays a small role in determining pulmonary blood flow distribution.

Effect of perfusate hematocrit on urea permeability-surface area in isolated dog lung

DOE Office of Scientific and Technical Information (OSTI.GOV)

Parker, R.E.; Roselli, R.J.; Haselton, F.R.

1986-10-01

Seven dog lower left lung lobes were statically inflated and perfused at a constant rate for each lobe with a perfusate in which the hematocrit was altered over a wide range. The permeability-surface area of urea was calculated from multiple indicator dilution curves using two separate injectates for each hematocrit level. One injectate contained only /sup 125/I-albumin as the vascular reference tracer and the other contained both /sup 51/Cr-erythrocytes and /sup 125/I-albumin as the vascular reference tracers; both contained (/sup 14/C)urea as the permeating tracer. The results strongly indicate that the phenomenon of erythrocyte trapping of urea does not affectmore » the calculation of urea permeability-surface area product provided the appropriate albumin-erythrocyte composite reference tracer is utilized in its calculation.« less

Is it possible to further improve the function of pulmonary grafts by extending the duration of lung reconditioning using ex vivo lung perfusion?

PubMed

Pierre, L; Lindstedt, S; Hlebowicz, J; Ingemansson, R

2013-07-01

The method of ex vivo lung perfusion (EVLP) has been suggested as a reliable means of differentiating between "good" and "poor" pulmonary grafts in marginal donors as, when grafts identified as good by this method are transplanted, the results do not differ from those using lungs fulfilling standard criteria. The EVLP method is also thought to improve pulmonary grafts by reducing lung edema and eliminating lung atelectasis. In the present study, we investigated whether the pulmonary graft could be further improved by extending the duration of EVLP. Six Landrace pigs were used. The lungs were reconditioned and evaluated, using the EVLP method, as double lungs. After the initial evaluation, EVLP was continued for a further 90 minutes. The arterial oxygen level (pO2) was 60.8 ± 4.8 kPa after the standard 60 minutes of EVLP and 67.1 ± 2.2 kPa after 150 minutes (p = 0.48). The pulmonary vascular resistance was 453 ± 78 dyne*s/cm(5) after 60, 90, 120 and 150 minutes of EVLP (p = 1.0). The pulmonary artery pressure was 17.8 ± 1.0 mmHg after 60, 90, 120, and 150 minutes of EVLP (p = 1.0) and the pulmonary artery flow was 3.5 ± 0.4 l/min after 60, 90, 120, and 150 minutes of EVLP (p = 1.0). The mean weight of the pulmonary grafts after harvesting was 574 ± 20 g at the beginning of EVLP 541 ± 24 g and, after 150 min of EVLP, 668 ± 33 (p = 0.011). The blood gases and hemodynamic parameters in the pulmonary grafts did not improve as a result of the extra 90 minutes of EVLP. However, the weight of the pulmonary graft increased significantly with increasing duration of EVLP, indicating lung perfusion injury.

Effects of vascular flow and PEEP in a multiple hit model of lung injury in isolated perfused rabbit lungs.

PubMed

Piacentini, Enrique; López-Aguilar, Josefina; García-Martín, Carolina; Villagrá, Ana; Saenz-Valiente, Alicia; Murias, Gastón; Fernández-Segoviano, Pilar; Hotchkiss, John R; Blanch, Lluis

2008-07-01

High vascular flow aggravates lung damage in animal models of ventilator-induced lung injury. Positive end-expiratory pressure (PEEP) can attenuate ventilator-induced lung injury, but its continued effectiveness in the setting of antecedent lung injury is unclear. The objective of the present study was to evaluate whether the application of PEEP diminishes lung injury induced by concurrent high vascular flow and high alveolar pressures in normal lungs and in a preinjury lung model. Two series of experiments were performed. Fifteen sets of isolated rabbit lungs were randomized into three groups (n = 5): low vascular flow/low PEEP; high vascular flow/low PEEP, and high vascular flow/high PEEP. Subsequently, the same protocol was applied in an additional 15 sets of isolated rabbit lungs in which oleic acid was added to the vascular perfusate to produce mild to moderate lung injury. All lungs were ventilated with peak airway pressure of 30 cm H2O for 30 minutes. Outcome measures included frequency of gross structural failure, pulmonary hemorrhage, edema formation, changes in static compliance, pulmonary vascular resistance, and pulmonary ultrafiltration coefficient. In the context of high vascular flow, application of a moderate level of PEEP reduced pulmonary rupture, edema formation, and lung hemorrhage. The protective effects of PEEP were not observed in lungs concurrently injured with oleic acid. Under these experimental conditions, PEEP attenuates lung injury in the setting of high vascular flow. The protective effect of PEEP is lost in a two-hit model of lung injury.

Tomographic digital subtraction angiography for lung perfusion estimation in rodents.

PubMed

Badea, Cristian T; Hedlund, Laurence W; De Lin, Ming; Mackel, Julie S Boslego; Samei, Ehsan; Johnson, G Allan

2007-05-01

In vivo measurements of perfusion present a challenge to existing small animal imaging techniques such as magnetic resonance microscopy, micro computed tomography, micro positron emission tomography, and microSPECT, due to combined requirements for high spatial and temporal resolution. We demonstrate the use of tomographic digital subtraction angiography (TDSA) for estimation of perfusion in small animals. TDSA augments conventional digital subtraction angiography (DSA) by providing three-dimensional spatial information using tomosynthesis algorithms. TDSA is based on the novel paradigm that the same time density curves can be reproduced in a number of consecutive injections of microL volumes of contrast at a series of different angles of rotation. The capabilities of TDSA are established in studies on lung perfusion in rats. Using an imaging system developed in-house, we acquired data for four-dimensional (4D) imaging with temporal resolution of 140 ms, in-plane spatial resolution of 100 microm, and slice thickness on the order of millimeters. Based on a structured experimental approach, we optimized TDSA imaging providing a good trade-off between slice thickness, the number of injections, contrast to noise, and immunity to artifacts. Both DSA and TDSA images were used to create parametric maps of perfusion. TDSA imaging has potential application in a number of areas where functional perfusion measurements in 4D can provide valuable insight into animal models of disease and response to therapeutics.

Quantification of the Effect of Shuttling on Computed Tomography Perfusion Parameters by Investigation of Aortic Inputs on Different Table Positions From Shuttle-Mode Scans of Lung and Liver Tumors.

PubMed

Ghosh, Payel; Chandler, Adam G; Hobbs, Brian P; Sun, Jia; Rong, John; Hong, David; Subbiah, Vivek; Janku, Filip; Naing, Aung; Hwu, Wen-Jen; Ng, Chaan S

The aim of this study was to quantify the effect of shuttling on computed tomography perfusion (CTp) parameters derived from shuttle-mode body CT images using aortic inputs from different table positions. Axial shuttle-mode CT scans were acquired from 6 patients (10 phases, 2 nonoverlapping table positions 1.4 seconds apart) after contrast agent administration. Artifacts resulting from the shuttling motion were corrected with nonrigid registration before computing CTp maps from 4 aortic levels chosen from the most superior and inferior slices of each table position scan. The effect of shuttling on CTp parameters was estimated by mean differences in mappings obtained from aortic inputs in different table positions. Shuttling effect was also quantified using 95% limits of agreement of CTp parameter differences within-table and between-table aortic positions from the interaortic mean CTp values. Blood flow, permeability surface, and hepatic arterial fraction differences were insignificant (P > 0.05) for both within-table and between-table comparisons. The 95% limits of agreement for within-table blood volume (BV) value deviations obtained from lung tumor regions were less than 4.7% (P = 0.18) compared with less than 12.2% (P = 0.003) for between-table BV value deviations. The 95% limits of agreement of within-table deviations for liver tumor regions were less than 1.9% (P = 0.55) for BV and less than 3.2% (P = 0.23) for mean transit time, whereas between-table BV and mean transit time deviations were less than 11.7% (P < 0.01) and less than 14.6% (P < 0.01), respectively. Values for normal liver tissue regions were concordant. Computed tomography perfusion parameters acquired from aortic levels within-table positions generally yielded higher agreement than mappings obtained from aortic levels between-table positions indicating differences due to shuttling effect.

Perfusion defects in pulmonary perfusion iodine maps: causes and semiology.

PubMed

Bustos Fiore, A; González Vázquez, M; Trinidad López, C; Mera Fernández, D; Costas Álvarez, M

2017-12-14

to describe the usefulness of dual-energy CT for obtaining pulmonary perfusion maps to provide morphological and functional information in patients with pulmonary embolisms. To review the semiology of perfusion defects due to pulmonary embolism so they can be differentiated from perfusion defects due to other causes: alterations outside the range used in the iodine map caused by other diseases of the lung parenchyma or artifacts. CT angiography of the pulmonary arteries is the technique of choice for the diagnosis of pulmonary embolisms. New dual-energy CT scanners are useful for detecting perfusion defects secondary to complete or partial obstruction of pulmonary arteries and is most useful for detecting pulmonary embolisms in subsegmental branches. Copyright © 2017 SERAM. Publicado por Elsevier España, S.L.U. All rights reserved.

Cardiopulmonary Bypass and Oxidative Stress

PubMed Central

Zakkar, Mustafa; Guida, Gustavo; Suleiman, M-Saadeh; Angelini, Gianni D.

2015-01-01

The development of the cardiopulmonary bypass (CPB) revolutionized cardiac surgery and contributed immensely to improved patients outcomes. CPB is associated with the activation of different coagulation, proinflammatory, survival cascades and altered redox state. Haemolysis, ischaemia, and perfusion injury and neutrophils activation during CPB play a pivotal role in oxidative stress and the associated activation of proinflammatory and proapoptotic signalling pathways which can affect the function and recovery of multiple organs such as the myocardium, lungs, and kidneys and influence clinical outcomes. The administration of agents with antioxidant properties during surgery either intravenously or in the cardioplegia solution may reduce ROS burst and oxidative stress during CPB. Alternatively, the use of modified circuits such as minibypass can modify both proinflammatory responses and oxidative stress. PMID:25722792

Selected contribution: redistribution of pulmonary perfusion during weightlessness and increased gravity

NASA Technical Reports Server (NTRS)

Glenny, R. W.; Lamm, W. J.; Bernard, S. L.; An, D.; Chornuk, M.; Pool, S. L.; Wagner, W. W. Jr; Hlastala, M. P.; Robertson, H. T.

2000-01-01

To compare the relative contributions of gravity and vascular structure to the distribution of pulmonary blood flow, we flew with pigs on the National Aeronautics and Space Administration KC-135 aircraft. A series of parabolas created alternating weightlessness and 1.8-G conditions. Fluorescent microspheres of varying colors were injected into the pulmonary circulation to mark regional blood flow during different postural and gravitational conditions. The lungs were subsequently removed, air dried, and sectioned into approximately 2 cm(3) pieces. Flow to each piece was determined for the different conditions. Perfusion heterogeneity did not change significantly during weightlessness compared with normal and increased gravitational forces. Regional blood flow to each lung piece changed little despite alterations in posture and gravitational forces. With the use of multiple stepwise linear regression, the contributions of gravity and vascular structure to regional perfusion were separated. We conclude that both gravity and the geometry of the pulmonary vascular tree influence regional pulmonary blood flow. However, the structure of the vascular tree is the primary determinant of regional perfusion in these animals.

Inhomogeneity of pulmonary perfusion during sustained microgravity on SLS-1

NASA Technical Reports Server (NTRS)

Prisk, G. Kim; Guy, Harold J. B.; Elliott, Ann R.; West, John B.

1994-01-01

We studied the effects of gravity on the inhomogeneity of pulmonary perfusion in humans by performing hyperventilation-breath-hold single-breath measurements before, during, and after 9 days of continuous exposure to microgravity during the Spacelab Life Sciences-1 (SLS-1) mission. In microgravity the indicators of inhomogeneity of perfusion, especially the size of cardiogenic oscillations in expired CO2 and the height of phase IV, were markedly reduced. Cardiogenic oscillations were reduced to approximately 60% of their preflight standing size, and the height of phase IV was between 0 and -8% (a terminal fall became a small terminal rise) of the preflight standing value. The terminal change in expired CO2 was nearly abolished in microgravity, indicating more uniformity of blood flow between lung units that close and those that remain open at the end of expiration. A possible explanation of this observation is the disappearance of gravity-dependent topographic inequality of blood flow. The residual cardiogenic oscillations in expired CO2 imply a persisting inhomogeneity of perfusion in the absence of gravity, probably in lung regions that are not within the same acinus.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Biello, D.R.

The optimal strategy for diagnostic evaluation of patients with suspected pulmonary thromboembolism (PE) is subject of controversial and often conflicting opinions. If untreated, as many as 30% of patients with PE may die. Conversely, anticoagulant therapy significantly decreases mortality from PE, but bleeding complications occur. Underdiagnosis may result in a preventable death, and overdiagnosis may lead to significant hemorrhage from unnecessary anticoagulant therapy. This article outlines a practical guide for the use of pulmonary ventilation-perfusion (V-P) scintigraphy in patients with suspected PE. Perfusion imaging involves the intravenous injection of radiolabeled particles ranging from 10 to 60 ..mu..m in diameter (technetiummore » Tc 99m macroaggregated albumin or technetium Tc 99m serum albumin microspheres); these particles are trapped in the capillaries and precapillary arterioles of the lung. The radiolabeled particles are distributed to the lungs in proportion to regional pulmonary blood flow. The correspondence of perfusion defects to bronchopulmonary segments is best appreciated in the posterior oblique views.« less

Characterization of the seven-day course of pulmonary response following unilateral lung acid injury in rats.

PubMed

Setzer, Florian; Schmidt, Barbara; Hueter, Lars; Schwarzkopf, Konrad; Sänger, Jörg; Schreiber, Torsten

2018-01-01

Aspiration of gastric acid is an important cause of acute lung injury. The time course of the pulmonary response to such an insult beyond the initial 48 hours is incompletely characterized. The purpose of this study was to comprehensively describe the pulmonary effects of focal lung acid injury over a seven day period in both directly injured and not directly injured lung tissue. Male Wistar rats underwent left-endobronchial instillation with hydrochloric acid and were sacrificed at 4, 24, 48, 96 or 168 h after the insult. Healthy non-injured animals served as controls. We assessed inflammatory cell counts and cytokine levels in right and left lung lavage fluid and blood, arterial oxygen tension, alterations in lung histology, lung wet-to-dry weight ratio and differential lung perfusion. Lung acid instillation induced an early strong inflammatory response in the directly affected lung, peaking at 4-24 hours, with only partial resolution after 7 days. A less severe response with complete resolution after 4 days was seen in the opposite lung. Alveolar cytokine levels, with exception of IL-6, only partially reflected the localization of lung injury and the time course of the functional and histologic alterations. Alveolar leucocyte subpopulations exhibited different time courses in the acid injured lung with persistent elevation of alveolar lymphocytes and macrophages. After acid instillation there was an early transient decrease in arterial oxygen tension and lung perfusion was preferentially distributed to the non-injured lung. These findings provide a basis for further research in the field of lung acid injury and for studies exploring effects of mechanical ventilation on injured lungs. Incomplete recovery in the directly injured lung 7 days after acid instillation suggests that increased vulnerability and susceptibility to further noxious stimuli are still present at that time.

Validation of fluorescent-labeled microspheres for measurement of relative blood flow in severely injured lungs

NASA Technical Reports Server (NTRS)

Hubler, M.; Souders, J. E.; Shade, E. D.; Hlastala, M. P.; Polissar, N. L.; Glenny, R. W.

1999-01-01

The aim of the study was to validate a nonradioactive method for relative blood flow measurements in severely injured lungs that avoids labor-intensive tissue processing. The use of fluorescent-labeled microspheres was compared with the standard radiolabeled-microsphere method. In seven sheep, lung injury was established by using oleic acid. Five pairs of radio- and fluorescent-labeled microspheres were injected before and after established lung injury. Across all animals, 175 pieces were selected randomly. The radioactivity of each piece was determined by using a scintillation counter. The fluorescent dye was extracted from each piece with a solvent without digestion or filtering. The fluorescence was determined with an automated fluorescent spectrophotometer. Perfusion was calculated for each piece from both the radioactivity and fluorescence and volume normalized. Correlations between flow determined by the two methods were in the range from 0.987 +/- 0.007 (SD) to 0.991 +/- 0.002 (SD) after 9 days of soaking. Thus the fluorescent microsphere technique is a valuable tool for investigating regional perfusion in severely injured lungs and can replace radioactivity.

Redistribution of pulmonary blood flow impacts thermodilution-based extravascular lung water measurements in a model of acute lung injury

PubMed Central

Easley, R. Blaine; Mulreany, Daniel G.; Lancaster, Christopher T.; Custer, Jason W.; Fernandez-Bustamante, Ana; Colantuoni, Elizabeth; Simon, Brett A.

2009-01-01

Background Studies using transthoracic thermodilution have demonstrated increased extravascular lung water (EVLW) measurements attributed to progression of edema and flooding during sepsis and acute lung injury. We hypothesize that redistribution of pulmonary blood flow can cause increased apparent EVLW secondary to increased perfusion of thermally silent tissue, not increased lung edema. Methods Anesthetized, mechanically ventilated canines were instrumented with PiCCO® (Pulsion Medical, Munich, Germany) catheters and underwent lung injury by repetitive saline lavage. Hemodynamic and respiratory physiologic data were recorded. After stabilized lung injury, endotoxin was administered to inactivate hypoxic pulmonary vasoconstriction. Computerized tomographic imaging was performed to quantify in vivo lung volume, total tissue (fluid) and air content, and regional distribution of blood flow. Results Lavage injury caused an increase in airway pressures and decreased arterial oxygen content with minimal hemodynamic effects. EVLW and shunt fraction increased after injury and then markedly following endotoxin administration. Computerized tomographic measurements quantified an endotoxin-induced increase in pulmonary blood flow to poorly aerated regions with no change in total lung tissue volume. Conclusions The abrupt increase in EVLW and shunt fraction after endotoxin administration is consistent with inactivation of hypoxic pulmonary vasoconstriction and increased perfusion to already flooded lung regions that were previously thermally silent. Computerized tomographic studies further demonstrate in vivo alterations in regional blood flow (but not lung water) and account for these alterations in shunt fraction and EVLW. PMID:19809280

Semi-quantitative assessment of pulmonary perfusion in children using dynamic contrast-enhanced MRI

NASA Astrophysics Data System (ADS)

Fetita, Catalin; Thong, William E.; Ou, Phalla

2013-03-01

This paper addresses the study of semi-quantitative assessment of pulmonary perfusion acquired from dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in a study population mainly composed of children with pulmonary malformations. The automatic analysis approach proposed is based on the indicator-dilution theory introduced in 1954. First, a robust method is developed to segment the pulmonary artery and the lungs from anatomical MRI data, exploiting 2D and 3D mathematical morphology operators. Second, the time-dependent contrast signal of the lung regions is deconvolved by the arterial input function for the assessment of the local hemodynamic system parameters, ie. mean transit time, pulmonary blood volume and pulmonary blood flow. The discrete deconvolution method implements here a truncated singular value decomposition (tSVD) method. Parametric images for the entire lungs are generated as additional elements for diagnosis and quantitative follow-up. The preliminary results attest the feasibility of perfusion quantification in pulmonary DCE-MRI and open an interesting alternative to scintigraphy for this type of evaluation, to be considered at least as a preliminary decision in the diagnostic due to the large availability of the technique and to the non-invasive aspects.

Hypoxic Pulmonary Vasoconstriction Does Not Explain All Regional Perfusion Redistribution in Asthma.

PubMed

Kelly, Vanessa J; Hibbert, Kathryn A; Kohli, Puja; Kone, Mamary; Greenblatt, Elliot E; Venegas, Jose G; Winkler, Tilo; Harris, R Scott

2017-10-01

Regional hypoventilation in bronchoconstricted patients with asthma is spatially associated with reduced perfusion, which is proposed to result from hypoxic pulmonary vasoconstriction (HPV). To determine the role of HPV in the regional perfusion redistribution in bronchoconstricted patients with asthma. Eight patients with asthma completed positron emission tomographic/computed tomographic lung imaging at baseline and after bronchoconstriction, breathing either room air or 80% oxygen (80% O 2 ) on separate days. Relative perfusion, specific ventilation (sV), and gas fraction (Fgas) in the 25% of the lung with the lowest specific ventilation (sV low ) and the remaining lung (sV high ) were quantified and compared. In the sV low region, bronchoconstriction caused a significant decrease in sV under both room air and 80% O 2 conditions (baseline vs. bronchoconstriction, mean ± SD, 1.02 ± 0.20 vs. 0.35 ± 0.19 and 1.03 ± 0.20 vs. 0.32 ± 0.16, respectively; P < 0.05). In the sV low region, relative perfusion decreased after bronchoconstriction under room air conditions and also, to a lesser degree, under 80% O 2 conditions (1.02 ± 0.19 vs. 0.72 ± 0.08 [P < 0.001] and 1.08 ± 0.19 vs. 0.91 ± 0.12 [P < 0.05], respectively). The Fgas increased after bronchoconstriction under room air conditions only (0.99 ± 0.04 vs. 1.00 ± 0.02; P < 0.05). The sV low subregion analysis indicated that some of the reduction in relative perfusion after bronchoconstriction under 80% O 2 conditions occurred as a result of the presence of regional hypoxia. However, relative perfusion was also significantly reduced in sV low subregions that were hyperoxic under 80% O 2 conditions. HPV is not the only mechanism that contributes to perfusion redistribution in bronchoconstricted patients with asthma, suggesting that another nonhypoxia mechanism also contributes. We propose that this nonhypoxia mechanism may be either direct mechanical interactions and/or unidentified intercellular signaling between constricted airways, the parenchyma, and the surrounding vasculature.

Teaching Ventilation/Perfusion Relationships in the Lung

ERIC Educational Resources Information Center

Glenny, Robb W.

2008-01-01

This brief review is meant to serve as a refresher for faculty teaching respiratory physiology to medical students. The concepts of ventilation and perfusion matching are some of the most challenging ideas to learn and teach. Some strategies to consider in teaching these concepts are, first, to build from simple to more complex by starting with a…

Reduced ischemia-reperfusion injury with isoproterenol in non-heart-beating donor lungs.

PubMed

Jones, D R; Hoffmann, S C; Sellars, M; Egan, T M

1997-05-01

Transplantation of lungs retrieved from non-heart-beating donors could expand the donor pool. Recent studies suggest that the ischemia-reperfusion injury (IRI) to the lung can be attenuated by increasing intracellular cAMP concentrations. The purpose of this study was to determine the effect of IRI on capillary permeability, as measured by Kfc, in lungs retrieved from non-heart-beating donors and reperfused with or without isoproterenol (iso). Using an in situ isolated perfused lung model, lungs were retrieved from non-heart-beating donor rats ventilated with O2 or not at varying intervals after death. The lungs were reperfused with or without iso (10 microM). Kfc, lung viability, and pulmonary hemodynamics were measured, and tissue levels of adenine nucleotides and cAMP were measured by HPLC. Iso-reperfusion decreased Kfc significantly (P < 0.05) compared to non-iso-reperfused groups at all postmortem ischemic times, irrespective of preharvest ventilation status. Pulmonary arterial pressures and resistances increased and venous resistances decreased with iso-reperfusion. Total adenine nucleotide (TAN) levels correlated with Kfc in non-iso-reperfused (r = 0.65) and iso-perfused (r = 0.84) lungs. cAMP levels increased significantly with iso-reperfusion. cAMP levels correlated with Kfc (r = 0.87) in iso-reperfused lungs. Iso-reperfusion of lungs retrieved from non-heart-beating donor rats results in decreased capillary permeability and increased lung tissue cAMP levels. Pharmacologic augmentation of tissue TAN and cAMP levels may further ameliorate the increased capillary permeability seen in lungs retrieved from non-heart-beating donors.

Non-invasive quantitative pulmonary V/Q imaging using Fourier decomposition MRI at 1.5T.

PubMed

Kjørstad, Åsmund; Corteville, Dominique M R; Henzler, Thomas; Schmid-Bindert, Gerald; Zöllner, Frank G; Schad, Lothar R

2015-12-01

Techniques for quantitative pulmonary perfusion and ventilation using the Fourier Decomposition method were recently demonstrated. We combine these two techniques and show that ventilation-perfusion (V/Q) imaging is possible using only a single MR acquisition of less than thirty seconds. The Fourier Decomposition method is used in combination with two quantification techniques, which extract baselines from within the images themselves and thus allows quantification. For the perfusion, a region assumed to consist of 100% blood is utilized, while for the ventilation the zero-frequency component is used. V/Q-imaging is then done by dividing the quantified ventilation map with the quantified perfusion map. The techniques were used on ten healthy volunteers and fifteen patients diagnosed with lung cancer. A mean V/Q-ratio of 1.15 ± 0.22 was found for the healthy volunteers and a mean V/Q-ratio of 1.93 ± 0.83 for the non-afflicted lung in the patients. Mean V/Q-ratio in the afflicted (tumor-bearing) lung was found to be 1.61 ± 1.06. Functional defects were clearly visible in many of the patient images, but 5 of 15 patient images had to be excluded due to artifacts or low SNR, indicating a lack of robustness. Non-invasive, quantitative V/Q-imaging is possible using Fourier Decomposition MRI. The method requires only a single acquisition of less than 30 seconds, but robustness in patients remains an issue. Copyright © 2015. Published by Elsevier GmbH.

Pulmonary function recovery demonstrated by ventilation-perfusion scan after posterior vertebral column resection for severe adolescent idiopathic scoliosis: a case report.

PubMed

Fujii, Takeshi; Watanabe, Kota; Toyama, Yoshiaki; Matsumoto, Morio

2014-09-01

Case report. To describe a case in which a patient regained pulmonary function, assessed by ventilation-perfusion scans, after undergoing posterior vertebral column resection (VCR) to correct severe adolescent idiopathic scoliosis (AIS) with associated pulmonary dysfunction. Pulmonary improvement after corrective surgery for AIS has been reported. Ventilation-perfusion scans are useful for assessing pulmonary function. However, these scans have not been used to examine the recovery of pulmonary function after VCR for severe AIS with pulmonary dysfunction. A patient was described in whom ventilation-perfusion scans were used to examine improvements in impaired air ventilation and blood perfusion after VCR surgery for severe AIS. The relevant literature was reviewed. An 18-year-old male came to Keio University Hospital with exertional dyspnea associated with severe AIS. Radiographs showed severe scoliosis of 91° at T6-T12, and hypokyphosis of 6° at T5-T12. Computed tomographic scans showed narrowing of the thoracic cage on the convex side of the main thoracic curve, with the vertebral bodies at the apex of the curve obstructing the right main bronchus. Pulmonary function tests revealed a percent vital capacity of 44% and percent forced expiratory volume in 1 second of 76%. A ventilation-perfusion scan showed decreased air ventilation and blood perfusion in the right lung. The patient underwent posterior correction surgery, which used segmental pedicle screws with a VCR at T9. The scoliosis was corrected to 28°, and the kyphosis to 14°. Postoperative computed tomographic scans showed expansion of the right main bronchus. A ventilation-perfusion scan conducted 1 year after surgery showed clear improvement in both ventilation and blood perfusion in the right lung. The patient's forced expiratory volume in 1 second had increased to 91%. This is the first report in which ventilation-perfusion scans were used to examine improvements in impaired air ventilation and blood perfusion after VCR surgery in a patient with severe AIS. N/A.

Metabolism of phenylethylamine in rat isolated perfused lung: evidence for monoamine oxidase 'type B' in lung.

PubMed Central

Bakhle, Y S; Youdim, M B

1976-01-01

Phenylethylamine is inactivated in a single passage through rat lung tissue by a process of uptake and deamination by a monoamine oxidase 'type B'. This enzyme is particularly susceptible to inhibition by deprenil and less sensitive to clorgyline. The monoamine oxidase of the lung, like that of other rat tissues, can be differentiated into 'type A' and 'type B' which appear to operate independently in the organized tissue. PMID:1252659

Radioaerosol lung imaging in chronic obstructive pulmonary disease. Comparison with pulmonary function tests and roentgenography. [/sup 113m/In, /sup 99m/Tc, /sup 133/Xe tracer techniques

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ramanna, L.; Tashkin, D.P.; Taplin, G.V.

1975-11-01

Seventy subjects with either no, mild, or definite evidence of pulmonary abnormality on screening studies volunteered to have detailed pulmonary function tests (PFTs), respiratory questionnaires, physical examinations, and /sup 113m/indium aerosol-inhalation lung imaging performed. Also, 22 and 52 of these subjects underwent /sup 133/xenon ventilation and lung perfusion imaging with /sup 99m/technetium-labelled macroaggregated albumin, and 56 had chest x-ray examinations performed. Results of the radionuclide lung-imaging procedures were compared with those of conventional PFTs and other clinical diagnostic procedures used to identify chronic obstructive pulmonary disease (COPD). Abnormal radioaerosol patterns were found in 32 of 33 subjects with abnormal findingsmore » on PFTs, whereas results of PFTs were abnormal in only 32 of 46 subjects with abnormal aerosol deposition. Aerosol lung images were abnormal more frequently than respiratory questionnaire responses, findings on physical examination, chest x-ray films, and perfusion lung images and with approximately the same frequency as /sup 133/xenon ventilation scintiscans. These results suggest that radioaerosol lung imaging may be a more sensitive indicator of early COPD than other diagnostic procedures, including maximal midexpiratory flow rates, single-breath nitrogen washout, and closing volume. Further studies are required to determine the physiologic and pathologic significance of isolated aerosol lung-imaging abnormalities.« less

Lung-Derived Mediators Induce Cytokine Production in Downstream Organs via an NF-κ B-Dependent Mechanism

PubMed Central

Patterson, E. K.; Yao, L. J.; Ramic, N.; Lewis, J. F.; Cepinskas, G.; McCaig, L.; Veldhuizen, R. A. W.; Yamashita, C. M.

2013-01-01

In the setting of acute lung injury, levels of circulating inflammatory mediators have been correlated with adverse outcomes. Previous studies have demonstrated that injured, mechanically ventilated lungs represent the origin of the host inflammatory response; however, mechanisms which perpetuate systemic inflammation remain uncharacterized. We hypothesized that lung-derived mediators generated by mechanical ventilation (MV) are amplified by peripheral organs in a “feed forward” mechanism of systemic inflammation. Herein, lung-derived mediators were collected from 129X1/SVJ mice after 2 hours of MV while connected to the isolated perfused mouse lung model setup. Exposure of liver endothelial cells to lung-derived mediators resulted in a significant increase in G-CSF, IL-6, CXCL-1, CXCL-2, and MCP-1 production compared to noncirculated control perfusate media (P < 0.05). Furthermore, inhibition of the NF-κB pathway significantly mitigated this response. Changes in gene transcription were confirmed using qPCR for IL-6, CXCL-1, and CXCL-2. Additionally, liver tissue obtained from mice subjected to 2 hours of in vivo MV demonstrated significant increases in hepatic gene transcription of IL-6, CXCL-1, and CXCL-2 compared to nonventilated controls. Collectively, this data demonstrates that lung-derived mediators, generated in the setting of MV, are amplified by downstream organs in a feed forward mechanism of systemic inflammation. PMID:23606793

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jens, Sjoerd, E-mail: s.jens@amc.uva.nl; Marquering, Henk A., E-mail: h.a.marquering@amc.uva.nl; Koelemay, Mark J. W., E-mail: m.j.koelemaij@amc.uva.nl

ObjectiveTo study the feasibility of 2D perfusion imaging in critical limb ischemia (CLI).Methods/ResultsPerfusion angiography is a new technology which was tested in 18 patients with CLI of the foot. A standardized protocol was used with a catheter placed at the mid-part of the popliteal artery, and a total of 9 cc of non-ionic iodinated contrast material was injected at a rate of 3 cc/sec. The technology is based on early cardiology research where iodinated contrast agents were used for imaging of cardiac perfusion. During the first pass of the contrast, there is a significant diffusion of the contrast agents into the interstitialmore » space, particularly for non-ionic and low-molecular-weight compounds.DiscussionThe original angiography data can be used to make a time–density curve, which represents the actual perfusion of the foot in time. Angiographic perfusion imaging is a post-processing modality for which no extra contrast or radiation is needed. With this technique, it is possible to get more information about the perfusion status and microcirculation of the foot. This is a step toward functional imaging in CLI patients.« less

Dynamic Chest Image Analysis: Evaluation of Model-Based Pulmonary Perfusion Analysis With Pyramid Images

DTIC Science & Technology

2001-10-25

Image Analysis aims to develop model-based computer analysis and visualization methods for showing focal and general abnormalities of lung ventilation and perfusion based on a sequence of digital chest fluoroscopy frames collected with the Dynamic Pulmonary Imaging technique 18,5,17,6. We have proposed and evaluated a multiresolutional method with an explicit ventilation model based on pyramid images for ventilation analysis. We have further extended the method for ventilation analysis to pulmonary perfusion. This paper focuses on the clinical evaluation of our method for

Critical evaluation of lung scintigraphy in cystic fibrosis: study of 113 patients

DOE Office of Scientific and Technical Information (OSTI.GOV)

Piepsz, A.; Wetzburger, C.; Spehl, M.

1980-10-01

A long-term study has been performed on 285 lung perfusion scintigrams obtained from 113 patients with cystic fibrosis. Transverse and longitudinal comparisons with clinical and radiological scores, as well as retrospective analysis of the deceased patients, were the methods used in order to evaluate the importance of the scintigraphic images. It appears that lung scintigraphy is the best index of the regional lung impairment, and contributes, as does a chest radiograph, to the early detection of lung lesions, the two methods being complementary.

Idiopathic pulmonary fibrosis. A rare cause of scintigraphic ventilation-perfusion mismatch

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pochis, W.T.; Krasnow, A.Z.; Collier, B.D.

1990-05-01

A case of idiopathic pulmonary fibrosis with multiple areas of mismatch on ventilation-perfusion lung imaging in the absence of pulmonary embolism is presented. Idiopathic pulmonary fibrosis is one of the few nonembolic diseases producing a pulmonary ventilation-perfusion mismatch. In this condition, chest radiographs may not detect the full extent of disease, and xenon-133 ventilation imaging may be relatively insensitive to morbid changes in small airways. Thus, when examining patients with idiopathic pulmonary fibrosis, one should be aware that abnormal perfusion imaging patterns without matching ventilation abnormalities are not always due to embolism. In this setting, contrast pulmonary angiography is oftenmore » needed for accurate differential diagnosis.« less

Multislice CT perfusion imaging of the lung in detection of pulmonary embolism

NASA Astrophysics Data System (ADS)

Hong, Helen; Lee, Jeongjin

2006-03-01

We propose a new subtraction technique for accurately imaging lung perfusion and efficiently detecting pulmonary embolism in chest MDCT angiography. Our method is composed of five stages. First, optimal segmentation technique is performed for extracting same volume of the lungs, major airway and vascular structures from pre- and post-contrast images with different lung density. Second, initial registration based on apex, hilar point and center of inertia (COI) of each unilateral lung is proposed to correct the gross translational mismatch. Third, initial alignment is refined by iterative surface registration. For fast and robust convergence of the distance measure to the optimal value, a 3D distance map is generated by the narrow-band distance propagation. Fourth, 3D nonlinear filter is applied to the lung parenchyma to compensate for residual spiral artifacts and artifacts caused by heart motion. Fifth, enhanced vessels are visualized by subtracting registered pre-contrast images from post-contrast images. To facilitate visualization of parenchyma enhancement, color-coded mapping and image fusion is used. Our method has been successfully applied to ten patients of pre- and post-contrast images in chest MDCT angiography. Experimental results show that the performance of our method is very promising compared with conventional methods with the aspects of its visual inspection, accuracy and processing time.

Ontogenesis of uptake and deamination of 5-hydroxytryptamine, dopamine and beta-phenylethylamine in isolated perfused lung and lung homogenates from rats.

PubMed Central

Ben-Harari, R. R.; Youdim, M. B.

1981-01-01

1. Uptake of 5-hydroxytryptamine (5-HT) and beta-phenylethylamine (PEA) was studied in perfused lung from male rats between 10 and 70 days old. 2. Monoamine oxidase (MAO) activity towards 5-HT, PEA and dopamine was studied in homogenate preparations of lung from rats aged between 5 and 80 days. 3. Uptake of 5-HT (10 microM) decreased throughout the age range studied but uptake of PEA (50 microM) increased for the first 30 days and beyond this age it decreased. Metabolites formed for both amines reflected the changes in uptake. 4. MAO activity deaminating 5-HT is well developed by day 10 and reaches its maximum by day 40. For dopamine and PEA, MAO activity remained low until day 20, and the developed rapidly, reaching a maximum by day 40 for dopamine; activity towards PEA did not reach a maximum by day 80. 5. These results show that uptake and MAO activity changes with age and thus the lung responds like other tissues. 6. These results also demonstrate the independent development of uptake and MAO activity towards 5-HT, PEA and dopamine. PMID:7284689

Effect of furosemide on pulmonary blood flow distribution in resting and exercising horses

NASA Technical Reports Server (NTRS)

Erickson, H. H.; Bernard, S. L.; Glenny, R. W.; Fedde, M. R.; Polissar, N. L.; Basaraba, R. J.; Walther, S. M.; Gaughan, E. M.; McMurphy, R.; Hlastala, M. P.

1999-01-01

We determined the spatial distribution of pulmonary blood flow (PBF) with 15-micron fluorescent-labeled microspheres during rest and exercise in five Thoroughbred horses before and 4 h after furosemide administration (0.5 mg/kg iv). The primary finding of this study was that PBF redistribution occurred from rest to exercise, both with and without furosemide. However, there was less blood flow to the dorsal portion of the lung during exercise postfurosemide compared with prefurosemide. Furosemide did alter the resting perfusion distribution by increasing the flow to the ventral regions of the lung; however, that increase in flow was abated with exercise. Other findings included 1) unchanged gas exchange and cardiac output during rest and exercise after vs. before furosemide, 2) a decrease in pulmonary arterial pressure after furosemide, 3) an increase in the slope of the relationship of PBF vs. vertical height up the lung during exercise, both with and without furosemide, and 4) a decrease in blood flow to the dorsal region of the lung at rest after furosemide. Pulmonary perfusion variability within the lung may be a function of the anatomy of the pulmonary vessels that results in a predominantly fixed spatial pattern of flow distribution.

[Gemstone computed tomography in the evaluation of material distribution in pulmonary parenchyma for pulmonary embolism].

PubMed

Zhang, Lan; Lü, Lei; Wu, Hua-wei; Zhang, Hao; Zhang, Ji-wei

2011-12-06

To present our initial experiences with pulmonary high-definition multidetector computed tomography (HDCT) in patients with acute venous thromboembolism (AVTE) to evaluate their corresponding clinical manifestations. Since December 2009 to March 2010, 23 AVTE patients underwent HDCT at our hospital. Pulmonary embolism (PE) was diagnosed based on the 3D-reconstructed images of computed tomography pulmonary angiography (CTPA). The post processed data were collected by spectral imaging system software to detect the iodine distribution maps. Perfusion defects, calculated as the values of iodine content, were compared with those of normal lung parenchymal perfusion in the absence of PE. Among them, 14 AVTE patients were definitely diagnosed with PE. Prior to anticoagulant therapy, their values of iodine content in defective perfusion area were significantly lower than those in normal perfusion area. After a 3-month anticoagulant therapy, the values of iodine content for the defective perfusion area increased significantly (P < 0.05). There was no significant correlation between the values of iodine content for segmental/subsegmental filling defect area and clinical risk score of DVT (r = 2.68, P > 0.05). But there was a significant negative correlation between the values of iodine content for segmental/subsegmental filling defection area and clinical probability score of PE (r = 0.78, P < 0.05). HDCT is a promising modality of visualizing pulmonary microvasculature as a correlative manifestation of regional perfusion. PE results in hypoperfusion with decreased values of iodine content in affected lung parenchyma. Hemodynamic changes in affected areas correlate with the severity of clinical manifestations of PE.

Pulmonary ventilation-perfusion mismatch: a novel hypothesis for how diving vertebrates may avoid the bends.

PubMed

Garcia Párraga, Daniel; Moore, Michael; Fahlman, Andreas

2018-04-25

Hydrostatic lung compression in diving marine mammals, with collapsing alveoli blocking gas exchange at depth, has been the main theoretical basis for limiting N 2 uptake and avoiding gas emboli (GE) as they ascend. However, studies of beached and bycaught cetaceans and sea turtles imply that air-breathing marine vertebrates may, under unusual circumstances, develop GE that result in decompression sickness (DCS) symptoms. Theoretical modelling of tissue and blood gas dynamics of breath-hold divers suggests that changes in perfusion and blood flow distribution may also play a significant role. The results from the modelling work suggest that our current understanding of diving physiology in many species is poor, as the models predict blood and tissue N 2 levels that would result in severe DCS symptoms (chokes, paralysis and death) in a large fraction of natural dive profiles. In this review, we combine published results from marine mammals and turtles to propose alternative mechanisms for how marine vertebrates control gas exchange in the lung, through management of the pulmonary distribution of alveolar ventilation ([Formula: see text]) and cardiac output/lung perfusion ([Formula: see text]), varying the level of [Formula: see text] in different regions of the lung. Man-made disturbances, causing stress, could alter the [Formula: see text] mismatch level in the lung, resulting in an abnormally elevated uptake of N 2 , increasing the risk for GE. Our hypothesis provides avenues for new areas of research, offers an explanation for how sonar exposure may alter physiology causing GE and provides a new mechanism for how air-breathing marine vertebrates usually avoid the diving-related problems observed in human divers. © 2018 The Authors.

[Mechanisms of tolerance to sulfur dioxide and sodium metabisulfite].

PubMed

Atzori, L; Corriga, A M; Cannas, E; Congiu, L

1997-01-01

Inhalation of sulphur dioxide (250 ppm), (SO2) or sodium metabisulfite (80 mM) (MBS) aerosol or perfusion with MBS (3 mM) induced a reduction in compliance and conductance in the isolated, perfused and ventilated guinea pig lung. Pretreatment of the lung with sodium sulfite (3 mM), a dissolution product of SO2 and MBS, reduced the bronchoconstriction induced by SO2 and MBS. Bronchoconstriction induced by SO2 and MBS in associated to increased levels of Calcitonin gene-Related Peptide (CGRP) in the perfusate effinent, indicating activation of sensory nerves. The release of CGRP induced by SO2 and MBS was not affected by sodium sulfite. Sulfite treatment did not modify lung reactivity towards acethylcholine, bradykinin, serotonin, histamine and substance P (fragment 5-11). An inhibitory effect by sulfite was observed on bronchoconstriction induced by neurokinin A (fragment 4-10). Since bronchoconstriction induced by SO2 and MBS appears to be mediated by neurokinin A release and action, sulfite may act by affecting its signal transduction pathway. In conclusion, the results indicate that during exposure to some environmental and occupational pollutants, e.g. SO2 and MBS, critical modifications of sulfhydryl groups on smooth muscle receptors may occur. We hypothesise this as a possible step in the development of tolerance and hyperreactivity.

Correlation between the clinical pretest probability score and the lung ventilation and perfusion scan probability.

PubMed

Bhoobalan, Shanmugasundaram; Chakravartty, Riddhika; Dolbear, Gill; Al-Janabi, Mazin

2013-10-01

Aim of the study was to determine the accuracy of the clinical pretest probability (PTP) score and its association with lung ventilation and perfusion (VQ) scan. A retrospective analysis of 510 patients who had a lung VQ scan between 2008 and 2010 were included in the study. Out of 510 studies, the number of normal, low, and high probability VQ scans were 155 (30%), 289 (57%), and 55 (11%), respectively. A total of 103 patients underwent computed tomography pulmonary angiography (CTPA) scan in which 21 (20%) had a positive scan, 81 (79%) had a negative scan and one (1%) had an equivocal result. The rate of PE in the normal, low-probability, and high-probability scan categories were: 2 (9.5%), 10 (47.5%), and 9 (43%) respectively. A very low correlation (Pearson correlation coefficient r = 0.20) between the clinical PTP score and lung VQ scan. The area under the curve (AUC) of the clinical PTP score was 52% when compared with the CTPA results. However, the accuracy of lung VQ scan was better (AUC = 74%) when compared with CTPA scan. The clinical PTP score is unreliable on its own; however, it may still aid in the interpretation of lung VQ scan. The accuracy of the lung VQ scan was better in the assessment of underlying pulmonary embolism (PE).

Correlation between the clinical pretest probability score and the lung ventilation and perfusion scan probability

PubMed Central

Bhoobalan, Shanmugasundaram; Chakravartty, Riddhika; Dolbear, Gill; Al-Janabi, Mazin

2013-01-01

Purpose: Aim of the study was to determine the accuracy of the clinical pretest probability (PTP) score and its association with lung ventilation and perfusion (VQ) scan. Materials and Methods: A retrospective analysis of 510 patients who had a lung VQ scan between 2008 and 2010 were included in the study. Out of 510 studies, the number of normal, low, and high probability VQ scans were 155 (30%), 289 (57%), and 55 (11%), respectively. Results: A total of 103 patients underwent computed tomography pulmonary angiography (CTPA) scan in which 21 (20%) had a positive scan, 81 (79%) had a negative scan and one (1%) had an equivocal result. The rate of PE in the normal, low-probability, and high-probability scan categories were: 2 (9.5%), 10 (47.5%), and 9 (43%) respectively. A very low correlation (Pearson correlation coefficient r = 0.20) between the clinical PTP score and lung VQ scan. The area under the curve (AUC) of the clinical PTP score was 52% when compared with the CTPA results. However, the accuracy of lung VQ scan was better (AUC = 74%) when compared with CTPA scan. Conclusion: The clinical PTP score is unreliable on its own; however, it may still aid in the interpretation of lung VQ scan. The accuracy of the lung VQ scan was better in the assessment of underlying pulmonary embolism (PE). PMID:24379532

First Danish experience with ex vivo lung perfusion of donor lungs before transplantation.

PubMed

Henriksen, Ian Sune Iversen; Møller-Sørensen, Hasse; Møller, Christian Holdfold; Zemtsovski, Mikhail; Nilsson, Jens Christian; Seidelin, Casper Tobias; Perch, Michael; Iversen, Martin; Steinbrüchel, Daniel

2014-03-01

The number of lung transplantations is limited by a general lack of donor organs. Ex vivo lung perfusion (EVLP) is a novel method to optimise and evaluate marginal donor lungs prior to transplantation. We describe our experiences with EVLP in Denmark during the first year after its introduction. The study was conducted by prospective registration of donor offers and lung transplantations in Denmark from 1 May 2012 to 30 April 2013. Donor lungs without any contraindications were transplanted in the traditional manner. Taken for EVLP were donor lungs that were otherwise considered transplantable, but failed to meet the usual criteria due to possible contusions or because they were from donors with sepsis or unable to pass the oxygenation test. In the study period, seven of 33 Danish lung transplantations were made possible due to EVLP. One patient died of non-EVLP-related causes, but all other recipients were alive with normal graft function at the end of our registration period. All lungs showed an improved PaO2/FiO2 ratio from a median 23.1 kPa (8.8-38.9) within the donor to 58.8 kPa (34.9-76.5) (FiO2 = 1.0) after EVLP, which corresponds to a 155% improved oxygenation. The median time to extubation, time in intensive care unit and the admission period were 1, 7 and 39 days, respectively. In the first year after the introduction of EVLP in Denmark, seven pairs of donor lungs that previously would have been rejected have been transplanted as a result of their improved function. EVLP seems to be a safe way to increase the use of marginal donor lungs. no funding was granted for the present paper. not relevant.

Effect of re-expansion after short-period lung collapse on pulmonary capillary permeability and pro-inflammatory cytokine gene expression in isolated rabbit lungs.

PubMed

Funakoshi, T; Ishibe, Y; Okazaki, N; Miura, K; Liu, R; Nagai, S; Minami, Y

2004-04-01

Re-expansion pulmonary oedema is a rare complication caused by rapid re-expansion of a chronically collapsed lung. Several cases of pulmonary oedema associated with one-lung ventilation (OLV) have been reported recently. Elevated levels of pro-inflammatory cytokines in pulmonary oedema fluid are suggested to play important roles in its development. Activation of cytokines after re-expansion of collapsed lung during OLV has not been thoroughly investigated. Here we investigated the effects of re-expansion of the collapsed lung on pulmonary oedema formation and pro-inflammatory cytokine expression. Lungs isolated from female white Japanese rabbits were perfused and divided into a basal (BAS) group (n=7, baseline measurement alone), a control (CONT) group (n=9, ventilated without lung collapse for 120 min) and an atelectasis (ATEL) group (n=9, lung collapsed for 55 min followed by re-expansion and ventilation for 65 min). Pulmonary vascular resistance (PVR) and the coefficient of filtration (Kfc) were measured at baseline and 60 and 120 min. At the end of perfusion, bronchoalveolar lavage fluid/plasma protein ratio (B/P), wet/dry lung weight ratio (W/D) and mRNA expressions of tumour necrosis factor (TNF)-alpha, interleukin (IL)-1beta and myeloperoxidase (MPO) were determined. TNF-alpha and IL-1beta mRNA were significantly up-regulated in lungs of the ATEL group compared with BAS and CONT, though no significant differences were noted in PVR, Kfc, B/P and W/D within and between groups. MPO increased at 120 min in CONT and ATEL groups. Pro-inflammatory cytokines were up-regulated upon re-expansion and ventilation after short-period lung collapse, though no changes were noted in pulmonary capillary permeability.

WE-FG-206-07: Assessing the Lung Function of Patients with Non-Small Cell Lung Cancer Using Hyperpolarized Xenon-129 Dissolved-Phase MRI

DOE Office of Scientific and Technical Information (OSTI.GOV)

Qing, K; Mugler, J; Chen, Q

Purpose: Hyperpolarized xenon-129 dissolved-phase MRI is the first imaging technique that allows 3-dimensional regional mapping of ventilation and gas uptake by tissue and blood the in human lung. Multiple outcome measures can be produced from this method. Existing studies in subjects with major lung diseases compared to healthy controls demonstrated high sensitivities of this method to pulmonary physiological factors including ventilation, alveolar tissue density, surface-to-volume ratio, pulmonary perfusion and gas-blood barrier thickness. The purpose of this study is to evaluate the utility of this new imaging tool to assess the lung function in patients with non-small cell lung cancer (NSCLC).more » Methods: Ten healthy controls (age: 63±10) and five patients (age: 62±13) with NSCLC underwent the xenon-129 dissolved-phase MRI, pulmonary function test (PFT) and CT for clinical purpose. Three outcome measures were produced from xenon-129 dissolved-phase MRI, including ventilation defect fraction (Vdef%) reflecting the airflow obstruction, tissue-to-gas ratio reflecting lung tissue density, and RBC-to-tissue ratio reflecting pulmonary perfusion and gas exchange. Results: Compared to healthy controls, patients with NSCLC showed more ventilation defects (NSCLC: 22±6%; control: 40±18%; P=0.01), lower tissue-to-gas (NSCLC: 0.82±0.31%; control: 1.07±0.13%; P=0.05) and RBC-to-tissue ratios (NSCLC: 0.82±0.31%; control: 1.07±0.13%; P=0.01). Maps for ventilation and gas uptake by tissue and blood were highly heterogeneous in the lungs of patients. Vdef% and RBC-to-tissue ratios in all 15 subjects correlated with corresponding global lung functional measures from PFT: FEV1/FVC (R=−0.91, P<0.001) and DLCO % predicted (R=0.54, P=0.03), respectively. The tissue-to-gas ratios correlated with tissue density (HU) measured by CT (R=0.88, P<0.001). Conclusion: With the unique ability to provide detailed information about lung function including ventilation, tissue density, perfusion and gas exchange with 3D resolution, hyperpolarized xenon-129 dissolved-phase MRI has high potential to be used as an important reference for radiotherapy treatment planning and for evaluating the side effects of the treatment. Receive research support and funding from Siemens.« less

Role of Kv7 channels in responses of the pulmonary circulation to hypoxia.

PubMed

Sedivy, Vojtech; Joshi, Shreena; Ghaly, Youssef; Mizera, Roman; Zaloudikova, Marie; Brennan, Sean; Novotna, Jana; Herget, Jan; Gurney, Alison M

2015-01-01

Hypoxic pulmonary vasoconstriction (HPV) is a beneficial mechanism that diverts blood from hypoxic alveoli to better ventilated areas of the lung, but breathing hypoxic air causes the pulmonary circulation to become hypertensive. Responses to airway hypoxia are associated with depolarization of smooth muscle cells in the pulmonary arteries and reduced activity of K(+) channels. As Kv7 channels have been proposed to play a key role in regulating the smooth muscle membrane potential, we investigated their involvement in the development of HPV and hypoxia-induced pulmonary hypertension. Vascular effects of the selective Kv7 blocker, linopirdine, and Kv7 activator, flupirtine, were investigated in isolated, saline-perfused lungs from rats maintained for 3-5 days in an isobaric hypoxic chamber (FiO2 = 0.1) or room air. Linopirdine increased vascular resistance in lungs from normoxic, but not hypoxic rats. This effect was associated with reduced mRNA expression of the Kv7.4 channel α-subunit in hypoxic arteries, whereas Kv7.1 and Kv7.5 were unaffected. Flupirtine had no effect in normoxic lungs but reduced vascular resistance in hypoxic lungs. Moreover, oral dosing with flupirtine (30 mg/kg/day) prevented short-term in vivo hypoxia from increasing pulmonary vascular resistance and sensitizing the arteries to acute hypoxia. These findings suggest a protective role for Kv7.4 channels in the pulmonary circulation, limiting its reactivity to pressor agents and preventing hypoxia-induced pulmonary hypertension. They also provide further support for the therapeutic potential of Kv7 activators in pulmonary vascular disease. Copyright © 2015 the American Physiological Society.

Lung imaging in pulmonary disease

DOE Office of Scientific and Technical Information (OSTI.GOV)

Taplin, G.V.; Chopra, S.K.

1976-01-01

Although it has been recognized for several years that chronic obstructive pulmonary disease (COPD) can cause lung perfusion defects which may simulate pulmonary embolism, relatively little use has been made of either the radioxenon or the radioaerosol inhalation lung imaging procedures until the last few years as a means of distinguishing pulmonary embolism (P.E.) from COPD is reported. Recent experience is reported with the use of both of these procedures in comparison with pulmonary function tests for the early detection of COPD in population studies and also in P.E. suspects. Equal emphasis is given to simultaneous aerosol ventilation-perfusion (V/P) imagingmore » in the differential diagnosis of P.E. Finally, this paper is concerned with new developments in regional lung diffusion imaging following the inhalation of radioactive gases and rapidly absorbed radioaerosols. Their experimental basis is presented and their potential clinical applications in pulmonary embolism are discussed. As a result of these investigations, a functional (V/P) diagnosis of pulmonary embolism in patients may be possible in the near future with a sequential radioaerosol inhalation procedure alone.« less

Comparison of 18F-Labeled Fluoroalkylphosphonium Cations with 13N-NH3 for PET Myocardial Perfusion Imaging.

PubMed

Kim, Dong-Yeon; Kim, Hyeon Sik; Reder, Sybille; Zheng, Jin Hai; Herz, Michael; Higuchi, Takahiro; Pyo, A Young; Bom, Hee-Seung; Schwaiger, Markus; Min, Jung-Joon

2015-10-01

Despite substantial advances in the diagnosis of cardiovascular disease, there is a need for 18F-labeled myocardial perfusion agents for the diagnosis of ischemic heart disease because current PET tracers for myocardial perfusion imaging have a short half-life that limits their widespread clinical use in PET. Thus, 18F-labeled fluoroalkylphosphonium derivatives (18F-FATPs), including (5-18F-fluoropentyl)triphenylphosphonium cation (18F-FPTP), (6-18F-fluorohexyl)triphenylphosphonium cation (18F-FHTP), and (2-(2-18F-fluoroethoxy)ethyl)triphenylphosphonium cation (18F-FETP), were synthesized. The myocardial extraction and image quality of the 18F-FATPs were compared with those of 13N-NH3 in rat models. The first-pass extraction fraction (EF) values of the 18F-FATPs (18F-FPTP, 18F-FHTP, 18F-FETP) and 13N-NH3 were measured in isolated rat hearts perfused with the Langendorff method (flow velocities, 0.5, 4.0, 8.0, and 16.0 mL/min). Normal and myocardial infarction rats were imaged with small-animal PET after intravenous injection of 37 MBq of 18F-FATPs and 13N-NH3. To determine pharmacokinetics, a region of interest was drawn around the heart, and time-activity curves of the 18F-FATPs and 13N-NH3 were generated to obtain the counts per pixel per second. Defect size was analyzed on the basis of polar map images of 18F-FATPs and 13N-NH3. The EF values of 18F-FATPs and 13N-NH3 were comparable at low flow velocity (0.5 mL/min), whereas at higher flows EF values of 18F-FATPs were significantly higher than those of 13N-NH3 (4.0, 8.0, and 16.0 mL/min, P<0.05). Myocardium-to-liver ratios of 18F-FPTP, 18F-FHTP, 18F-FETP, and 13N-NH3 were 2.10±0.30, 4.36±0.20, 3.88±1.03, and 0.70±0.09, respectively, 10 min after injection, whereas myocardium-to-lung ratios were 5.00±0.25, 4.33±0.20, 7.98±1.23, and 2.26±0.14, respectively. Although 18F-FATPs and 13N-NH3 sharply delineated myocardial perfusion defects, defect size on the 13N-NH3 images was significantly smaller than on the 18F-FATP images soon after tracer injection (0-10 min, P=0.027). 18F-FATPs exhibit higher EF values and more rapid clearance from the liver and lung than 13N-NH3 in normal rats, which led to excellent image quality in a rat model of coronary occlusion. Therefore, 18F-FATPs are promising new PET radiopharmaceuticals for myocardial perfusion imaging. © 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

Improved Lung Perfusion After Left Pulmonary Artery Patch Enlargement During the Norwood Operation.

PubMed

Salehi Ravesh, Mona; Scheewe, Jens; Attmann, Tim; Al Bulushi, Abdullah; Jussli-Melchers, Marka-Jill; Jerosch-Herold, Michael; Gabbert, Dominik D; Wegner, Philip; Kramer, Hans-Heiner; Rickers, Carsten

2018-05-01

Optimal pulmonary perfusion is crucial for a well-functioning Fontan circulation in patients with hypoplastic left heart syndrome (HLHS). To obtain an adequate size of the left pulmonary artery (LPA), patch enlargement is a routine part of the hemi-Fontan procedure in our center. However, LPA patch enlargement at the time of the modified Norwood procedure may have surgical advantages. Therefore, the aim of this study was to evaluate whether anatomic and functional effects of the new approach are superior. A total of 51 consecutive HLHS patients underwent a cardiovascular magnetic resonance imaging study including assessment of LPA anatomy and lung perfusion. The LPA of 20 patients was enlarged during the modified Norwood procedure (group N) and of 31 patients during the hemi-Fontan procedure (group HF). The median indexed cross-sectional area of the LPA in group N was significantly higher than in group HF (49.5 versus 27.9 mm 2 /m 2 , p < 0.0001). The regional pulmonary perfusion as measured by first-pass, contrast-enhanced signal intensity upslope was significantly improved in group N (left side 0.67 s -1 versus 0.40 s -1 , p = 0.002; right side 0.84 s -1 versus 0.52 s -1 , p = 0.01). The total hemi-Fontan bypass and procedure times were significantly shorter in group N (both p < 0.001). These first magnetic resonance imaging data show that HLHS patients after LPA patch enlargement during the modified Norwood procedure have significantly higher LPA cross-sectional areas and show improved lung perfusion and shorter overall procedure time as compared with LPA patching during second stage (hemi-Fontan). Therefore, this promising surgical technique may improve blood flow dynamics of the Fontan circulation in the long run. Copyright © 2018 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

Pectus excavatum in children: pulmonary scintigraphy before and after corrective surgery

DOE Office of Scientific and Technical Information (OSTI.GOV)

Blickman, J.G.; Rosen, P.R.; Welch, K.J.

1985-09-01

Regional distribution of pulmonary function was evaluated preoperatively and postoperatively with xenon-133 perfusion and ventilation scintigraphy in 17 patients with pectus excavatum. Ventilatory preoperative studies were abnormal in 12 of 17 patients, resolving in seven of 12 postoperatively. Perfusion scans were abnormal in ten of 17 patients preoperatively; six of ten showed improvement postoperatively. Ventilation-perfusion ratios were abnormal in ten of 17 patients, normalizing postoperatively in six of ten. Symmetry of ventilation-perfusion ratio images improved in six out of nine in the latter group. The distribution of regional lung function in pectus excavatum can be evaluated preoperatively to support indicationsmore » for surgery. Postoperative improvement can be documented by physiological changes produced by the surgical correction.« less

Ventilatory Management During Normothermic Ex Vivo Lung Perfusion: Effects on Clinical Outcomes.

PubMed

Terragni, Pier Paolo; Fanelli, Vito; Boffini, Massimo; Filippini, Claudia; Cappello, Paola; Ricci, Davide; Del Sorbo, Lorenzo; Faggiano, Chiara; Brazzi, Luca; Frati, Giacomo; Venuta, Federico; Mascia, Luciana; Rinaldi, Mauro; Ranieri, V Marco

2016-05-01

During ex vivo lung perfusion (EVLP), fixed ventilator settings and monitoring of compliance are used to prevent ventilator-induced lung injury (VILI). Analysis of the airway pressure-time curve (stress index) has been proposed to assess the presence of VILI. We tested whether currently proposed ventilator settings expose lungs to VILI during EVLP and whether the stress index could identify VILI better than compliance. Flow, volume, and airway opening pressure were collected continuously during EVLP. Durations of mechanical ventilation, intensive care unit (ICU) and hospital lengths of stay were recorded in lung recipients. Fourteen lungs underwent EVLP and were transplanted. In 5 lungs, 95 ± 2% of the stress index values were within the 0.95 to 1.05 range (protected); in the remaining nine lungs, 69 ± 1% of the values were greater than 1.05 and 15 ± 3% were less than 0.95 (nonprotected). There was a significant (P < 0.05) increase in cytokine concentrations after 4 hours of EVLP in the nonprotected lungs. Durations of mechanical ventilation, ICU, and hospital lengths of stay were shorter in recipients of protected than that of nonprotected lungs (P < 0.05). There was no correlation between compliance during EVLP and duration of mechanical ventilation or ICU and hospital lengths of stay in recipients, but the stress index during EVLP was significantly correlated with the duration of mechanical ventilation and with ICU and hospital lengths of stay (P < 0.05). This small, preliminary study shows that ventilator settings currently proposed for EVLP may expose lungs to VILI. Use of the stress index to personalize ventilator settings needs to be tested in further clinical studies.

The lung in space.

PubMed

Prisk, G Kim

2005-09-01

The lung is exquisitely sensitive to gravity, which induces gradients in ventilation, blood flow, and gas exchange. Studies of lungs in microgravity provide a means of elucidating the effects of gravity. They suggest a mechanism by which gravity serves to match ventilation to perfusion, making for a more efficient lung than anticipated. Despite predictions, lungs do not become edematous, and there is no disruption to, gas exchange in microgravity. Sleep disturbances in microgravity are not a result of respiratory-related events; obstructive sleep apnea is caused principally by the gravitational effects on the upper airways. In microgravity, lungs may be at greater risk to the effects of inhaled aerosols.

The lung in space

NASA Technical Reports Server (NTRS)

Prisk, G. Kim

2005-01-01

The lung is exquisitely sensitive to gravity, which induces gradients in ventilation, blood flow, and gas exchange. Studies of lungs in microgravity provide a means of elucidating the effects of gravity. They suggest a mechanism by which gravity serves to match ventilation to perfusion, making for a more efficient lung than anticipated. Despite predictions, lungs do not become edematous, and there is no disruption to, gas exchange in microgravity. Sleep disturbances in microgravity are not a result of respiratory-related events; obstructive sleep apnea is caused principally by the gravitational effects on the upper airways. In microgravity, lungs may be at greater risk to the effects of inhaled aerosols.

Rest-Stress Limb Perfusion Imaging in Humans with Contrast Ultrasound Using Intermediate-Power Imaging and Microbubbles Resistant to Inertial Cavitation.

PubMed

Davidson, Brian P; Hodovan, James; Belcik, J Todd; Moccetti, Federico; Xie, Aris; Ammi, Azzdine Y; Lindner, Jonathan R

2017-05-01

Contrast-enhanced ultrasound (CEU) limb perfusion imaging is a promising approach for evaluating peripheral artery disease (PAD). However, low signal enhancement in skeletal muscle has necessitated high-power intermittent imaging algorithms, which are not clinically feasible. We hypothesized that CEU using a combination of intermediate power and a contrast agent resistant to inertial cavitation would allow real-time limb stress perfusion imaging. In normal volunteers, CEU of the calf skeletal muscle was performed on separate days with Sonazoid, Optison, or Definity. Progressive reduction in the ultrasound pulsing interval was used to assess the balance between signal enhancement and agent destruction at escalating mechanical indices (MI, 0.1-0.4). Real-time perfusion imaging at MI 0.1-0.4 using postdestructive replenishment kinetics was performed at rest and during 25 W plantar flexion contractile exercise. For Optison, limb perfusion imaging was unreliable at rest due to very low signal enhancement generated at all MIs and was possible during exercise-induced hyperemia only at MI 0.1 due to agent destruction at higher MIs. For Definity, signal intensity progressively increased with MI but was offset by microbubble destruction, which resulted in modest signal enhancement during CEU perfusion imaging and distortion of replenishment curves at MI ≥ 0.2. For Sonazoid, there strong signal enhancement at MI ≥ 0.2, with little destruction detected only at MI 0.4. Accordingly, high signal intensity and nondistorted perfusion imaging was possible at MI 0.2-0.3 and detected an 8.0- ± 5.7-fold flow reserve. Rest-stress limb perfusion imaging in humans with real-time CEU, which requires only seconds to perform, is possible using microbubbles with viscoelastic properties that produce strong nonlinear signal generation without destruction at intermediate acoustic pressures. Copyright © 2016 American Society of Echocardiography. All rights reserved.

Dynamic Contrast-Enhanced Perfusion Area-Detector CT: Preliminary Comparison of Diagnostic Performance for N Stage Assessment With FDG PET/CT in Non-Small Cell Lung Cancer.

PubMed

Ohno, Yoshiharu; Fujisawa, Yasuko; Sugihara, Naoki; Kishida, Yuji; Seki, Shinichiro; Koyama, Hisanobu; Yoshikawa, Takeshi

2017-11-01

The objective of our study was to directly compare the capability of dynamic first-pass contrast-enhanced (CE) perfusion area-detector CT (ADCT) and FDG PET/CT for differentiation of metastatic from nonmetastatic lymph nodes and assessment of N stage in patients with non-small cell lung carcinoma (NSCLC). Seventy-seven consecutive patients, 45 men (mean age ± SD, 70.4 ± 5.9 years) and 32 women (71.2 ± 7.7 years), underwent dynamic first-pass CE-perfusion ADCT at two or three different positions for covering the entire thorax, FDG PET/CT, surgical treatment, and pathologic examination. From all ADCT data for each of the subjects, a whole-chest perfusion map was computationally generated using the dual- and single-input maximum slope and Patlak plot methods. For quantitative N stage assessment, perfusion parameters and the maximum standardized uptake value (SUV max ) for each lymph node were determined by measuring the relevant ROI. ROC curve analyses were performed for comparing the diagnostic capability of each of the methods on a per-node basis. N stages evaluated by each of the indexes were then statistically compared with the final pathologic diagnosis by means of chi-square and kappa statistics. The area under the ROC curve (A z ) values of systemic arterial perfusion (A z = 0.89), permeability surface (A z = 0.78), and SUV max (A z = 0.85) were significantly larger than the A z values of total perfusion (A z = 0.70, p < 0.05) and distribution volume (A z = 0.55, p < 0.05). For each of the threshold values, agreement for systemic arterial perfusion calculated using the dual-input maximum slope model was substantial (κ = 0.70, p < 0.0001), and agreement for SUV max was moderate (κ = 0.60, p < 0.0001). Dynamic first-pass CE-perfusion ADCT is as useful as FDG PET/CT for the differentiation of metastatic from nonmetastatic lymph nodes and assessment of N stage in patients with NSCLC.

Computation of ventilation-perfusion ratio with Kr-81m in pulmonary embolism

DOE Office of Scientific and Technical Information (OSTI.GOV)

Meignan, M.; Simonneau, G.; Oliveira, L.

1984-02-01

Diagnostic difficulties occur in pulmonary embolism (PE) during visual analysis of ventilation-perfusion images in matched defects or in chronic obstructive lung disease (COPD). In 44 patients with angiographically confirmed PE and in 40 patients with COPD, the regional ventilation-perfusion ratios (V/Q) were therefore computed using krypton-81m for each perfusion defect, and were displayed in a functional image. In patients with PE and mismatched defects, a high V/Q (1.96) was observed. A V/Q > 1.25 was also found in nine of 11 patients having PE and indeterminate studies (studies with perfusion abnormalities matched by radiographic abnormalities). COPD was characterized by matchedmore » defects and low V/Q. The percentage of patients correctly classified as having PE or COPD increased from 56% when considering the match or mismatched character to 88% when based on a V/Q of 1.25 in the region of the perfusion defect. This quantitative analysis, therefore, seems useful in classifying patients with scintigraphic suspicion of PE.« less

Airway Pressure Release Ventilation During Ex Vivo Lung Perfusion Attenuates Injury

PubMed Central

Mehaffey, J. Hunter; Charles, Eric J.; Sharma, Ashish K.; Money, Dustin; Zhao, Yunge; Stoler, Mark H; Lau, Christine L; Tribble, Curtis G.; Laubach, Victor E.; Roeser, Mark E.; Kron, Irving L.

2016-01-01

Objective Critical organ shortages have resulted in Ex Vivo Lung Perfusion (EVLP) gaining clinical acceptance for lung evaluation and rehabilitation to expand the use of Donation after Circulatory Death (DCD) organs for lung transplantation. We hypothesized that an innovative use of airway pressure release ventilation (APRV) during EVLP improves lung function after transplantation. Methods Two groups (n=4 animals/group) of porcine DCD donor lungs were procured after hypoxic cardiac arrest and a 2-hour period of warm ischemia, followed by a 4-hour period of EVLP rehabilitation with either standard conventional volume-based ventilation or pressure-based APRV. Left lungs were subsequently transplanted into recipient animals and reperfused for 4 hours. Blood gases for PaO2/FiO2 ratios, airway pressures for calculation of compliance, and percent wet weight gain during EVLP and reperfusion were measured. Results APRV during EVLP significantly improved left-lung oxygenation at 2-hours (561.5±83.9 vs 341.1±136.1 mmHg) and 4-hours (569.1±18.3 vs 463.5±78.4 mmHg). Similarly, compliance was significantly higher at 2-hours (26.0±5.2 vs 15.0±4.6 mL/cmH2O) and 4-hours (30.6±1.3 vs 17.7±5.9 mL/cmH2O) after transplantation. Finally, APRV significantly reduced lung edema development on EVLP based on percentage weight gain (36.9±14.6 vs 73.9±4.9%). There was no difference in additional edema accumulation 4 hours after reperfusion. Conclusions Pressure-directed APRV ventilation strategy during EVLP improves rehabilitation of severely injured DCD lungs. After transplant these lungs demonstrate superior lung-specific oxygenation and dynamic compliance compared to lungs ventilated with standard conventional ventilation. This strategy, if implemented into clinical EVLP protocols, could advance the field of DCD lung rehabilitation to expand the lung donor pool. PMID:27742245

Changes in Functional Lung Regions During the Course of Radiation Therapy and Their Potential Impact on Lung Dosimetry for Non-Small Cell Lung Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Meng, Xue; Department of Radiation Oncology, Shandong Cancer Hospital, Shandong University, Jinan; Frey, Kirk

2014-05-01

Purpose: To study changes in functional activity on ventilation (V)/perfusion (Q) single-photon emission computed tomography (SPECT) during radiation therapy (RT) and explore the impact of such changes on lung dosimetry in patients with non-small cell lung cancer (NSCLC). Methods and Materials: Fifteen NSCLC patients with centrally located tumors were enrolled. All patients were treated with definitive RT dose of ≥60 Gy. V/Q SPECT-CT scans were performed prior to and after delivery of 45 Gy of fractionated RT. SPECT images were used to define temporarily dysfunctional regions of lung caused by tumor or other potentially reversible conditions as B3. The functional lung (FL)more » was defined on SPECT by 2 separate approaches: FL1, a threshold of 30% of the maximum uptake of the patient's lung; and FL2, FL1 plus B3 region. The impact of changes in FL between initiation of RT and delivery of 45 Gy on lung dosimetry were analyzed. Results: Fourteen patients (93%) had larger FL2 volumes than FL1 pre-RT (P<.001). Dysfunctional lung became functional in 11 patients (73%) on V SPECT and in 10 patients (67%) on Q SPECT. The dosimetric parameters generated from CT-based anatomical lung had significantly lower values in FL1 than FL2, with a median reduction in the volume of lung receiving a dose of at least 20 Gy (V{sub 20}) of 3%, 5.6%, and mean lung dose of 0.95 and 1.55 on V and Q SPECT respectively. Conclusions: Regional ventilation and perfusion function improve significantly during RT in centrally located NSCLC. Lung dosimetry values vary notably between different definitions of functional lung.« less

Live Imaging of the Lung

PubMed Central

Looney, Mark R.; Bhattacharya, Jahar

2015-01-01

Live lung imaging has spanned the discovery of capillaries in the frog lung by Malpighi to the current use of single and multiphoton imaging of intravital and isolated perfused lung preparations incorporating fluorescent molecular probes and transgenic reporter mice. Along the way, much has been learned about the unique microcirculation of the lung, including immune cell migration and the mechanisms by which cells at the alveolar-capillary interface communicate with each other. In this review, we highlight live lung imaging techniques as applied to the role of mitochondria in lung immunity, mechanisms of signal transduction in lung compartments, studies on the composition of alveolar wall liquid, and neutrophil and platelet trafficking in the lung under homeostatic and inflammatory conditions. New applications of live lung imaging and the limitations of current techniques are discussed. PMID:24245941

Correlation of 68Ga Ventilation-Perfusion PET/CT with Pulmonary Function Test Indices for Assessing Lung Function.

PubMed

Le Roux, Pierre-Yves; Siva, Shankar; Steinfort, Daniel P; Callahan, Jason; Eu, Peter; Irving, Lou B; Hicks, Rodney J; Hofman, Michael S

2015-11-01

Pulmonary function tests (PFTs) are routinely used to assess lung function, but they do not provide information about regional pulmonary dysfunction. We aimed to assess correlation of quantitative ventilation-perfusion (V/Q) PET/CT with PFT indices. Thirty patients underwent V/Q PET/CT and PFT. Respiration-gated images were acquired after inhalation of (68)Ga-carbon nanoparticles and administration of (68)Ga-macroaggregated albumin. Functional volumes were calculated by dividing the volume of normal ventilated and perfused (%NVQ), unmatched and matched defects by the total lung volume. These functional volumes were correlated with forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), FEV1/FVC, and diffusing capacity for carbon monoxide (DLCO). All functional volumes were significantly different in patients with chronic obstructive pulmonary disease (P < 0.05). FEV1/FVC and %NVQ had the highest correlation (r = 0.82). FEV1 was also best correlated with %NVQ (r = 0.64). DLCO was best correlated with the volume of unmatched defects (r = -0.55). Considering %NVQ only, a cutoff value of 90% correctly categorized 28 of 30 patients with or without significant pulmonary function impairment. Our study demonstrates strong correlations between V/Q PET/CT functional volumes and PFT parameters. Because V/Q PET/CT is able to assess regional lung function, these data support the feasibility of its use in radiation therapy and preoperative planning and assessing pulmonary dysfunction in a variety of respiratory diseases. © 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

Platelet Vascular Endothelial Growth Factor is a Potential Mediator of Transfusion-Related Acute Lung Injury.

PubMed

Maloney, James P; Ambruso, Daniel R; Voelkel, Norbert F; Silliman, Christopher C

The occurrence of non-hemolytic transfusion reactions is highest with platelet and plasma administration. Some of these reactions are characterized by endothelial leak, especially transfusion related acute lung injury (TRALI). Elevated concentrations of inflammatory mediators secreted by contaminating leukocytes during blood product storage may contribute to such reactions, but platelet-secreted mediators may also contribute. We hypothesized that platelet storage leads to accumulation of the endothelial permeability mediator vascular endothelial growth factor (VEGF), and that intravascular administration of exogenous VEGF leads to extensive binding to its lung receptors. Single donor, leukocyte-reduced apheresis platelet units were sampled over 5 days of storage. VEGF protein content of the centrifuged supernatant was determined by ELISA, and the potential contribution of VEGF from contaminating leukocytes was quantified. Isolated-perfused rat lungs were used to study the uptake of radiolabeled VEGF administered intravascularly, and the effect of unlabeled VEGF on lung leak. There was a time-dependent release of VEGF into the plasma fraction of the platelet concentrates (62 ± 9 pg/ml on day one, 149 ± 23 pg/ml on day 5; mean ± SEM, p<0.01, n=8) and a contribution by contaminating leukocytes was excluded. Exogenous 125I-VEGF bound avidly and specifically to the lung vasculature, and unlabeled VEGF in the lung perfusate caused vascular leak. Rising concentrations of VEGF occur during storage of single donor platelet concentrates due to platelet secretion or disintegration, but not due to leukocyte contamination. Exogenous VEGF at these concentrations rapidly binds to its receptors in the lung vessels. At higher VEGF concentrations, VEGF causes vascular leak in uninjured lungs. These data provide further evidence that VEGF may contribute to the increased lung permeability seen in TRALI associated with platelet products.

Prophylactic Use of High-Frequency Percussive Ventilation in Patients with Inhalation Injury,

DTIC Science & Technology

1991-06-01

stabilizing such col- in burn wound management, infection control, lapsed diseased lung segments. 3- 2 In addition some in- and metabolic support increased the...confirmed in each patient by bronchoscopy and/or󈧥 Xe- 8. PCO2 < 50 mmHg but progressively increasing non ventilation-perfusion lung scan. The presence of...death for all patients admitted to the In- Inhalation injury documented by bronchoscopy or Xenon lung scan stitute of Surgical Research between January

The clinical implications of myocardial perfusion abnormalities in patients with esophageal or lung cancer after chemoradiation therapy.

PubMed

Gayed, Isis; Gohar, Salman; Liao, Zhongxing; McAleer, Mary; Bassett, Roland; Yusuf, Syed Wamique

2009-06-01

This study aims to identify the clinical implications of myocardial perfusion defects after chemoradiation therapy (CRT) in patients with esophageal and lung cancer. We retrospectively compared myocardial perfusion imaging (MPI) results before and after CRT in 16 patients with esophageal cancer and 24 patients with lung cancer. New MPI defects in the radiation therapy (RT) fields were considered related to RT. Follow-up to evaluate for cardiac complications and their relation with the results of MPI was performed. Statistical analysis identified predictors of cardiac morbidities. Eleven females and twenty nine males at a mean age of 66.7 years were included. Five patients (31%) with esophageal cancer and seven patients (29%) with lung cancer developed myocardial ischemia in the RT field at mean intervals of 7.0 and 8.4 months after RT. The patients were followed-up for mean intervals of 15 and 23 months in the esophageal and lung cancer groups, respectively. Seven patients in each of the esophageal (44%) and lung (29%) cancer patients (P = 0.5) developed cardiac complications of which one patient with esophageal cancer died of complete heart block. Six out of the fourteen patients (43%) with cardiac complication had new ischemia on MPI after CRT of which only one developed angina. The remaining eight patients with cardiac complications had normal MPI results. MPI result was not a statistically significant predictor of future cardiac complications after CRT. A history of congestive heart failure (CHF) (P = 0.003) or arrhythmia (P = 0.003) is a significant predictor of cardiac morbidity after CRT in univariate analysis but marginal predictors when multivariate analysis was performed (P = 0.06 and 0.06 for CHF and arrhythmia, respectively). Cardiac complications after CRT are more common in esophageal than lung cancer patients but the difference is not statistically significant. MPI abnormalities are frequently seen after CRT but are not predictive of future cardiac complications. A history of arrhythmia or CHF is significantly associated with cardiac complications after CRT.

Cold ischemia with selective anterograde in situ pulmonary perfusion preserves gas exchange and mitochondrial homeostasis and curbs inflammation in an experimental model of donation after cardiac death.

PubMed

Pottecher, Julien; Santelmo, Nicola; Noll, Eric; Charles, Anne-Laure; Benahmed, Malika; Canuet, Matthieu; Frossard, Nelly; Namer, Izzie J; Geny, Bernard; Massard, Gilbert; Diemunsch, Pierre

2013-10-01

The aim of this study was to assess the functional preservation of the lung graft with anterograde lung perfusion in a model of donation after cardiac death. Thirty minutes after cardiac arrest, in situ anterograde selective pulmonary cold perfusion was started in six swine. The alveolo-capillary membrane was challenged at 3, 6, and 8 h with measurements of the mean pulmonary arterial pressure (mPAP), the pulmonary vascular resistance (PVR), the PaO2 /FiO2 ratio, the transpulmonary oxygen output (tpVO2 ), and the transpulmonary CO2 clearance (tpCO2 ). Mitochondrial homeostasis was investigated by measuring maximal oxidative capacity (Vmax ) and the coupling of phosphorylation to oxidation (ACR, acceptor control ratio) in lung biopsies. Inflammation and induction of primary immune response were assessed by measurement of tumor necrosis factor alpha (TNFα), interleukine-6 (IL-6) and receptor for advanced glycation endproducts (RAGE) in bronchoalveolar lavage fluid. Data were compared using repeated measures Anova. Pulmonary hemodynamics (mPAP: P = 0.69; PVR: P = 0.46), oxygenation (PaO2 /FiO2 : P = 0.56; tpVO2 : P = 0.46), CO2 diffusion (tpCO2 : P = 0.24), mitochondrial homeostasis (Vmax : P = 0.42; ACR: P = 0.8), and RAGE concentrations (P = 0.24) did not significantly change up to 8 h after cardiac arrest. TNFα and IL-6 were undetectable. Unaffected pulmonary hemodynamics, sustained oxygen and carbon dioxide diffusion, preserved mitochondrial homeostasis, and lack of inflammation suggest a long-lasting functional preservation of the graft with selective anterograde in situ pulmonary perfusion. © 2013 Steunstichting ESOT. Published by John Wiley & Sons Ltd.

Lung Structure and the Intrinsic Challenges of Gas Exchange

PubMed Central

Hsia, Connie C.W.; Hyde, Dallas M.; Weibel, Ewald R.

2016-01-01

Structural and functional complexities of the mammalian lung evolved to meet a unique set of challenges, namely, the provision of efficient delivery of inspired air to all lung units within a confined thoracic space, to build a large gas exchange surface associated with minimal barrier thickness and a microvascular network to accommodate the entire right ventricular cardiac output while withstanding cyclic mechanical stresses that increase several folds from rest to exercise. Intricate regulatory mechanisms at every level ensure that the dynamic capacities of ventilation, perfusion, diffusion, and chemical binding to hemoglobin are commensurate with usual metabolic demands and periodic extreme needs for activity and survival. This article reviews the structural design of mammalian and human lung, its functional challenges, limitations, and potential for adaptation. We discuss (i) the evolutionary origin of alveolar lungs and its advantages and compromises, (ii) structural determinants of alveolar gas exchange, including architecture of conducting bronchovascular trees that converge in gas exchange units, (iii) the challenges of matching ventilation, perfusion, and diffusion and tissue-erythrocyte and thoracopulmonary interactions. The notion of erythrocytes as an integral component of the gas exchanger is emphasized. We further discuss the signals, sources, and limits of structural plasticity of the lung in alveolar hypoxia and following a loss of lung units, and the promise and caveats of interventions aimed at augmenting endogenous adaptive responses. Our objective is to understand how individual components are matched at multiple levels to optimize organ function in the face of physiological demands or pathological constraints. PMID:27065169

MRI of the lung: state of the art.

PubMed

Wielpütz, Mark; Kauczor, Hans-Ulrich

2012-01-01

Magnetic resonance imaging (MRI) of the lung is technically challenging due to the low proton density and fast signal decay of the lung parenchyma itself. Additional challenges consist of tissue loss, hyperinflation, and hypoxic hypoperfusion, e.g., in emphysema, a so-called "minus-pathology". However, pathological changes resulting in an increase of tissue ("plus-pathology"), such as atelectases, nodules, infiltrates, mucus, or pleural effusion, are easily depicted with high diagnostic accuracy. Although MRI is inferior or at best equal to multi-detector computed tomography (MDCT) for the detection of subtle morphological features, MRI now offers an increasing spectrum of functional imaging techniques such as perfusion assessment and measurement of ventilation and respiratory mechanics that are superior to what is possible with MDCT. Without putting patients at risk with ionizing radiation, repeated examinations allow for the evaluation of the course of lung disease and monitoring of the therapeutic response through quantitative imaging, providing a level of functional detail that cannot be obtained by any other single imaging modality. As such, MRI will likely be used for clinical applications beyond morphological imaging for many lung diseases. In this article, we review the technical aspects and protocol suggestions for chest MRI and discuss the role of MRI in the evaluation of nodules and masses, airway disease, respiratory mechanics, ventilation, perfusion and hemodynamics, and pulmonary vasculature.

Oxygen toxicity in the perfused rat liver and lung under hyperbaric conditions.

PubMed Central

Nishiki, K; Jamieson, D; Oshino, N; Chance, B

1976-01-01

1. In the lung and liver of tocopherol-deficient rats, the activities of glutathione peroxidase and glucose 6-phosphate dehydrogenase were increased substantially, suggesting an important role for both enzymes in protecting the organ against the deleterious effects of lipid peroxides. 2. Facilitation of the glutathione peroxidase reaction by infusing t-butyl hydroperoxide caused the oxidation of nicotinamide nucleotides and glutathione, resulting in a concomitant increase in the rate of release of oxidized glutathione into the perfusate. Thus the rate of production of lipid peroxide and H2O2 in the perfused organ could be compared by simultaneous measurement of the rate of glutathione release and the turnover number of the catalase reaction. 3. On hyperbaric oxygenation at 4 X 10(5)Pa, H2O2 production, estimated from the turnover of the catalase reaction, was increased slightly in the liver, and glutathione release was increased slightly, in both lung and liver. 4. Tocopherol deficiency caused a marked increase in lipid-peroxide formation as indicated by a corresponding increase in glutathione release under hyperbaric oxygenation, with a further enhancement when the tocopherol-deficient rats were also starved. 5. The study demonstrates that the primary response to hyperbaric oxygenation is an elevation of the rate of lipid peroxidation rather than of the rate of formation of H2O2 or superoxide. PMID:12754

Ventilation and cardiac related impedance changes in children undergoing corrective open heart surgery.

PubMed

Schibler, Andreas; Pham, Trang M T; Moray, Amol A; Stocker, Christian

2013-10-01

Electrical impedance tomography (EIT) can determine ventilation and perfusion relationship. Most of the data obtained so far originates from experimental settings and in healthy subjects. The aim of this study was to demonstrate that EIT measures the perioperative changes in pulmonary blood flow after repair of a ventricular septum defect in children with haemodynamic relevant septal defects undergoing open heart surgery. In a 19 bed intensive care unit in a tertiary children's hospital ventilation and cardiac related impedance changes were measured using EIT before and after surgery in 18 spontaneously breathing patients. The EIT signals were either filtered for ventilation (ΔZV) or for cardiac (ΔZQ) related impedance changes. Impedance signals were then normalized (normΔZV, normΔZQ) for calculation of the global and regional impedance related ventilation perfusion relationship (normΔZV/normΔZQ). We observed a trend towards increased normΔZV in all lung regions, a significantly decreased normΔZQ in the global and anterior, but not the posterior lung region. The normΔZV/normΔZQ was significantly increased in the global and anterior lung region. Our study qualitatively validates our previously published modified EIT filtration technique in the clinical setting of young children with significant left-to-right shunt undergoing corrective open heart surgery, where perioperative assessment of the ventilation perfusion relation is of high clinical relevance.

Metabolic studies of mammalian cells by 31P-NMR using a continuous perfusion technique.

PubMed

Knop, R H; Chen, C W; Mitchell, J B; Russo, A; McPherson, S; Cohen, J S

1984-07-20

Levels of ATP and Pi in metabolically active Chinese hamster lung fibroblasts were monitored noninvasively by 31P-NMR over many hours and under a variety of conditions. The cells were embedded in a matrix of agarose gel in the form of fine threads which were continuously perfused in a standard NMR tube. The small diameter of the thread allows rapid diffusion of metabolites and drugs into the cells. The changes in ATP and Pi levels were followed as a function of time in response to perfusion with a glucose-containing medium, with isotonic saline and with a medium containing 2,4-dinitrophenol, an uncoupler of oxidative phosphorylation. This gel-thread perfusion method should enable routine NMR studies of cellular metabolism, and may have other potential biological applications.

Utilization of the Organ Care System Lung for the assessment of lungs from a donor after cardiac death (DCD) before bilateral transplantation.

PubMed

Mohite, P N; Sabashnikov, A; García Sáez, D; Pates, B; Zeriouh, M; De Robertis, F; Simon, A R

2015-07-01

In this manuscript, we present the first experience of evaluating donation after circulatory death (DCD) lungs, using the normothermic preservation Organ Care System (OCS) and subsequent successful transplantation. The OCS could be a useful tool for the evaluation of marginal lungs from DCD donors as it allows a proper recruitment and bronchoscopy in such donations in addition to continuous ex-vivo perfusion and assessment and treatment during transport. The OCS could potentially be a standard of care in the evaluation of marginal lungs from DCD. © The Author(s) 2014.

Current management of primary pulmonary hypertension.

PubMed

Klings, E S; Farber, H W

2001-01-01

Primary pulmonary hypertension (PPH) is a rare disorder with an annual incidence of 1 to 2 per million people. The aetiology of this disorder is unknown, but it appears to result from an abnormal interaction of environmental and genetic factors leading to a vasculopathy. The pulmonary arteries in these patients exhibit a spectrum of pathological lesions ranging from the early medial hypertrophy to the end-stage fibrotic plexiform lesions. This characteristic pathology is also observed in pulmonary hypertension resulting from connective tissue disease (particularly systemic sclerosis), HIV infection, portal hypertension and certain toxins. PPH is a condition that is difficult to diagnose and treat, with a median survival of 2.8 years in historical studies. One of the difficulties in treating patients with PHH is that the subacute nature of disease presentation often prevents an accurate diagnosis during the early stages of the illness. Progressive dyspnoea on exertion is the most common presenting symptom. Diagnostic evaluation should include electrocardiography, chest radiograph and echocardiography, and laboratory and other studies to evaluate for secondary causes (e.g. pulmonary function tests, chest computed tomography and ventilation/perfusion scans, pulmonary arteriogram, cardiopulmonary testing, right heart catherisation). PHH is a disorder for which there is no known cure. Current medical and surgical treatment options for patients with PHH include anticoagulation, vasodilators and transplantation. Calcium channel antagonists are currently the oral drugs of choice for the treatment of patients with New York Heart Association (NYHA) Class II disease. These agents, in particular the dihydropyridine compounds, have beneficial effects on haemodynamics and right ventricular function, and possibly increased survival. Epoprostenol is administered by intravenous infusion, and studies have demonstrated short- and long-term improvements in symptoms, haemodynamics and survival. It is well tolerated and has become the treatment of choice for patients with NYHA Class III and IV disease. Inotropic agents are used as a bridge to transplant, which is indicated in patients who do not respond to maximal medical therapy. Experience has shown that single lung, double lung and heart-lung transplantation are approximately of equal efficacy. Currently, single lung transplant appears to be the procedure of choice. Newer agents, such as sildenafil, beraprost and bosentan, are presently being evaluated for the treatment of this disorder. Future study should include elucidation of the pathogenic mechanisms in the development of this vasculopathy, which will hopefully lead to the development of improved treatment options for patients with PHH.

Measurement of the distribution of ventilation-perfusion ratios in the human lung with proton MRI: comparison with the multiple inert-gas elimination technique.

PubMed

Sá, Rui Carlos; Henderson, A Cortney; Simonson, Tatum; Arai, Tatsuya J; Wagner, Harrieth; Theilmann, Rebecca J; Wagner, Peter D; Prisk, G Kim; Hopkins, Susan R

2017-07-01

We have developed a novel functional proton magnetic resonance imaging (MRI) technique to measure regional ventilation-perfusion (V̇ A /Q̇) ratio in the lung. We conducted a comparison study of this technique in healthy subjects ( n = 7, age = 42 ± 16 yr, Forced expiratory volume in 1 s = 94% predicted), by comparing data measured using MRI to that obtained from the multiple inert gas elimination technique (MIGET). Regional ventilation measured in a sagittal lung slice using Specific Ventilation Imaging was combined with proton density measured using a fast gradient-echo sequence to calculate regional alveolar ventilation, registered with perfusion images acquired using arterial spin labeling, and divided on a voxel-by-voxel basis to obtain regional V̇ A /Q̇ ratio. LogSDV̇ and LogSDQ̇, measures of heterogeneity derived from the standard deviation (log scale) of the ventilation and perfusion vs. V̇ A /Q̇ ratio histograms respectively, were calculated. On a separate day, subjects underwent study with MIGET and LogSDV̇ and LogSDQ̇ were calculated from MIGET data using the 50-compartment model. MIGET LogSDV̇ and LogSDQ̇ were normal in all subjects. LogSDQ̇ was highly correlated between MRI and MIGET (R = 0.89, P = 0.007); the intercept was not significantly different from zero (-0.062, P = 0.65) and the slope did not significantly differ from identity (1.29, P = 0.34). MIGET and MRI measures of LogSDV̇ were well correlated (R = 0.83, P = 0.02); the intercept differed from zero (0.20, P = 0.04) and the slope deviated from the line of identity (0.52, P = 0.01). We conclude that in normal subjects, there is a reasonable agreement between MIGET measures of heterogeneity and those from proton MRI measured in a single slice of lung. NEW & NOTEWORTHY We report a comparison of a new proton MRI technique to measure regional V̇ A /Q̇ ratio against the multiple inert gas elimination technique (MIGET). The study reports good relationships between measures of heterogeneity derived from MIGET and those derived from MRI. Although currently limited to a single slice acquisition, these data suggest that single sagittal slice measures of V̇ A /Q̇ ratio provide an adequate means to assess heterogeneity in the normal lung. Copyright © 2017 the American Physiological Society.

Transplantation after ex vivo lung perfusion: A midterm follow-up.

PubMed

Wallinder, Andreas; Riise, Gerdt C; Ricksten, Sven-Erik; Silverborn, Martin; Dellgren, Göran

2016-11-01

A large proportion of donor lungs are discarded due to known or presumed organ dysfunction. Ex vivo lung perfusion (EVLP) has proven its value as a tool for discrimination between reversible and irreversible donor lung pathology. However, the long-term outcome after transplantation of lungs after EVLP is essentially unknown. We report short-term and midterm outcomes of recipients who received transplants of EVLP-evaluated lungs. Single-center results of recipients of lungs with prior EVLP were compared with consecutive recipients of non-EVLP lungs (controls) during the same period. Short-term follow-up included time to extubation, time in the intensive care unit, and the presence of primary graft dysfunction at 72 hours postoperatively. Mortality and incidence of chronic lung allograft dysfunction were monitored for up to 4 years after discharge. During a 4-year period, 32 pairs of initially rejected donor lungs underwent EVLP. After EVLP, 22 double lungs and 5 single lungs were subsequently transplanted. During this period, 145 patients received transplants of conventional donor lungs that did not have EVLP and constituted the control group. Median time to extubation was 7 hours in the EVLP group and 6 hours in the non-EVLP control group (p = 0.45). Median intensive care unit stay was 4 days vs. 3 days, respectively (p = 0.15). Primary graft dysfunction grade > 1 was present in 14% in the EVLP group and in 12% in the non-EVLP group at 72 hours after transplant. Survival at 1 year was 92% in the EVLP group and 79% in the non-EVLP group. Cumulative survival and freedom from retransplantation or chronic rejection were also comparable between the 2 groups (p = 0.43) when monitored up to 4 years. Selected donor lungs rejected for transplantation can be used after EVLP. This technique is effective for selection of transplantable donor lungs. Patients who received lungs evaluated under EVLP have short-term and midterm outcomes comparable to recipients of non-EVLP donor lungs. Copyright © 2016 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

SU-D-202-01: Functional Lung Avoidance and Response-Adaptive Escalation (FLARE) RT: Feasibility of a Precision Radiation Oncology Strategy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bowen, S; Lee, E; Miyaoka, R

Purpose: NSCLC patient RT is planned without consideration of spatial heterogeneity in lung function or tumor response, which may have contributed to failed uniform dose escalation in a randomized trial. The feasibility of functional lung avoidance and response-adaptive escalation (FLARE) RT to reduce dose to [{sup 99m}Tc]MAA-SPECT/CT perfused lung while redistributing 74Gy within [{sup 18}F]FDG-PET/CT biological target volumes was assessed. Methods: Eight Stage IIB–IIIB NSCLC patients underwent FDG-PET/CT and MAA-SPECT/CT treatment planning scans. Perfused lung objectives were derived from scatter/collimator/attenuation-corrected MAA-SPECT uptake relative to ITV-subtracted lung to maintain <20Gy mean lung dose (MLD). Prescriptions included 60Gy to PTV and concomitantmore » boost of 74Gy mean to biological target volumes (BTV=GTV+PET margin) scaled to each BTV voxel by relative FDG-PET SUV. Dose-painting-by-numbers prescriptions were integrated into commercial TPS via previously reported ROI discretization. Dose constraints for lung, heart, cord, and esophagus were defined. FLARE RT plans were optimized with VMAT, proton pencil beam scanning (PBS) with 3%-3mm robust optimization, and combination PBS (avoidance) plus VMAT (escalation). Dosimetric differences were evaluated by Friedman non-parametric paired test with multiple sampling correction. Results: PTV and normal tissue objectives were not violated in 24 FLARE RT plans. Population median of mean BTV dose was 73.7Gy (68.5–75.5Gy), mean FDG-PET peak dose was 89.7Gy (73.5–103Gy), MLD was 12.3Gy (7.5–19.6Gy), and perfused MLD was 4.8Gy (0.9–12.1Gy). VMAT achieved higher dose to the FDG-PET peak subvolume (p=0.01), while PBS delivered lower dose to lung (p<0.001). Voxelwise linear correlation between BTV dose and FDG-PET uptake was higher for VMAT (R=0.93) and PBS+VMAT (R=0.94) compared to PBS alone (R=0.89). Conclusion: FLARE RT is feasible with VMAT and PBS. A combination of PBS for functional lung avoidance and VMAT for FDG-PET dose escalation balances target/normal tissue objective tradeoffs. These results support future testing of FLARE RT safety and efficacy within a precision radiation oncology trial. This work was supported by a Research Scholar grant from the Radiological Society of North American Research & Education Foundation.« less

Role of Aquaporin-4 in Airspace-to-Capillary Water Permeability in Intact Mouse Lung Measured by a Novel Gravimetric Method

PubMed Central

Song, Yuanlin; Ma, Tonghui; Matthay, Michael A.; Verkman, A.S.

2000-01-01

The mammalian peripheral lung contains at least three aquaporin (AQP) water channels: AQP1 in microvascular endothelia, AQP4 in airway epithelia, and AQP5 in alveolar epithelia. In this study, we determined the role of AQP4 in airspace-to-capillary water transport by comparing water permeability in wild-type mice and transgenic null mice lacking AQP1, AQP4, or AQP1/AQP4 together. An apparatus was constructed to measure lung weight continuously during pulmonary artery perfusion of isolated mouse lungs. Osmotically induced water flux (Jv) between the airspace and capillary compartments was measured from the kinetics of lung weight change in saline-filled lungs in response to changes in perfusate osmolality. Jv in wild-type mice varied linearly with osmotic gradient size (4.4 × 10−5 cm3 s−1 mOsm−1) and was symmetric, independent of perfusate osmolyte size, weakly temperature dependent, and decreased 11-fold by AQP1 deletion. Transcapillary osmotic water permeability was greatly reduced by AQP1 deletion, as measured by the same method except that the airspace saline was replaced by an inert perfluorocarbon. Hydrostatically induced lung edema was characterized by lung weight changes in response to changes in pulmonary arterial inflow or pulmonary venous outflow pressure. At 5 cm H2O outflow pressure, the filtration coefficient was 4.7 cm3 s−1 mOsm−1 and reduced 1.4-fold by AQP1 deletion. To study the role of AQP4 in lung water transport, AQP1/AQP4 double knockout mice were generated by crossbreeding of AQP1 and AQP4 null mice. Jv were (cm3 s−1 mOsm−1 × 10−5, SEM, n = 7–12 mice): 3.8 ± 0.4 (wild type), 0.35 ± 0.02 (AQP1 null), 3.7 ± 0.4 (AQP4 null), and 0.25 ± 0.01 (AQP1/AQP4 null). The significant reduction in P f in AQP1 vs. AQP1/AQP4 null mice was confirmed by an independent pleural surface fluorescence method showing a 1.6 ± 0.2-fold (SEM, five mice) reduced P f in the AQP1/AQP4 double knockout mice vs. AQP1 null mice. These results establish a simple gravimetric method to quantify osmosis and filtration in intact mouse lung and provide direct evidence for a contribution of the distal airways to airspace-to-capillary water transport. PMID:10613915

The DD genotype of the angiotensin converting enzyme gene independently associates with CMR-derived abnormal microvascular perfusion in patients with a first anterior ST-segment elevation myocardial infarction treated with thrombolytic agents.

PubMed

Bodi, Vicente; Sanchis, Juan; Nunez, Julio; Aliño, Salvador F; Herrero, Maria J; Chorro, Francisco J; Mainar, Luis; Lopez-Lereu, Maria P; Monmeneu, Jose V; Oltra, Ricardo; Chaustre, Fabian; Forteza, Maria J; Husser, Oliver; Riegger, Günter A; Llacer, Angel

2009-12-01

The role of the angiotensin converting enzyme (ACE) gene on the result of thrombolysis at the microvascular level has not been addressed so far. We analyzed the implications of the insertion/deletion (I/D) polymorphism of the ACE gene on the presence of abnormal cardiovascular magnetic resonance (CMR)-derived microvascular perfusion after ST-segment elevation myocardial infarction (STEMI). We studied 105 patients with a first anterior STEMI treated with thrombolytic agents and an open left anterior descending artery. Microvascular perfusion was assessed using first-pass perfusion CMR at 7+/-1 days. CMR studies were repeated 184+/-11 days after STEMI. The ACE gene insertion/deletion (I/D) polymorphism was determined using polymerase chain reaction amplification. Overall genotype frequencies were II-ID 58% and DD 42%. Abnormal perfusion (> or = 1 segment) was detected in 56% of patients. The DD genotype associated to a higher risk of abnormal microvascular perfusion (68% vs. 47%, p=0.03) and to a larger extent of perfusion deficit (median [percentile 25 - percentile 75]: 4 [0-6] vs. 0 [0-4] segments, p=0.003). Once adjusted for baseline characteristics, the DD genotype independently increased the risk of abnormal microvascular perfusion (odds ratio [95% confidence intervals]: 2.5 [1.02-5.9], p=0.04). Moreover, DD patients displayed a larger infarct size (35+/-17 vs. 27+/-15 g, p=0.01) and a lower ejection fraction at 6 months (48+/-14 vs. 54+/-14%, p=0.03). The DD genotype associates to a higher risk of abnormal microvascular perfusion after STEMI.

The use of carboxymethylcellulose gel to increase non-viral gene transfer in mouse airways

PubMed Central

Griesenbach, Uta; Meng, Cuixiang; Farley, Raymond; Wasowicz, Marguerite; Munkonge, Felix M; Chan, Mario; Stoneham, Charlotte; Sumner-Jones, Stephanie; Pringle, Ian A.; Gill, Deborah R.; Hyde, Stephen C.; Stevenson, Barbara; Holder, Emma; Ban, Hiroshi; Hasegawa, Mamoru; Cheng, Seng H; Scheule, Ronald K; Sinn, Patrick L; McCray, Paul B; Alton, Eric WFW

2014-01-01

We have assessed whether viscoelastic gels known to inhibit mucociliary clearance can increase lipid-mediated gene transfer. Methylcellulose or carboxymethylcellulose (0.25 to 1.5%) were mixed with complexes of the cationic lipid GL67A and plasmids encoding luciferase and perfused onto the nasal epithelium of mice. Survival after perfusion with 1% CMC or1% MC was 90 and 100%, respectively. In contrast 1.5% CMC was uniformly lethal likely due to the viscous solution blocking the airways. Perfusion with 0.5% CMC containing lipid/DNA complexes reproducibly increased gene expression by approximately 3-fold (n= 16, p<0.05). Given this benefit, likely related to increased duration of contact, we also assessed the effect of prolonging contact time of the liposome/DNA complexes by delivering our standard 80 μg DNA dose over either approximately 22 or 60 min of perfusion. This independently increased gene transfer by 6-fold (n=8, p<0.05) and could be further enhanced by the addition of 0.5% CMC, leading to an overall 25-fold enhancement (n=8, p<0.001) in gene expression. As a result of these interventions CFTR transgene mRNA transgene levels were increased several logs above background. Interestingly, this did not lead to correction of the ion transport defects in the nasal epithelium of cystic fibrosis mice nor for immunohistochemical quantification of CFTR expression. To assess if 0.5% CMC also increased gene transfer in the mouse lung, we used whole body nebulisation chambers. CMC was nebulised for 1 hr immediately before, or simultaneously with GL67A/pCIKLux. The former did not increase gene transfer, whereas co-administration significantly increased gene transfer by 4-fold (p<0.0001, n=18). This study suggests that contact time of non-viral gene transfer agents is a key factor for gene delivery, and suggests two methods which may be translatable for use in man. PMID:20022367

DCD lung donation: donor criteria, procedural criteria, pulmonary graft function validation, and preservation.

PubMed

Erasmus, Michiel E; van Raemdonck, Dirk; Akhtar, Mohammed Zeeshan; Neyrinck, Arne; de Antonio, David Gomez; Varela, Andreas; Dark, John

2016-07-01

In an era where there is a shortage of lungs for transplantation is increased utilization of lungs from donation after circulatory death (DCD) donors. We review the reports of 11 controlled and 1 uncontrolled DCD programs focusing on donor criteria, procedural criteria, graft assessment, and preservation techniques including the use of ex vivo lung perfusion. We have formulated conclusions and recommendations for each of these areas, which were presented at the 6th International Conference on Organ Donation. A table of recommendations, the grade of recommendations, and references are provided. © 2015 Steunstichting ESOT.

Perfusion redistribution after a pulmonary-embolism-like event with contrast enhanced EIT.

PubMed

Nguyen, D T; Bhaskaran, A; Chik, W; Barry, M A; Pouliopoulos, J; Kosobrodov, R; Jin, C; Oh, T I; Thiagalingam, A; McEwan, A L

2015-06-01

Recent studies showed that regional pulmonary perfusion can be reliably estimated using electrical impedance tomography (EIT) with the aid of hypertonic saline based contrast enhancement. Building on these successful studies, we studied contrast EIT for pulmonary perfusion defect caused by an artificially induced pulmonary embolism (PE) in a large ovine model (N = 8, 78 ± 7.8 kg). Furthermore, the efficacy of a less invasive contrast bolus of 0.77 ml kg(-1) of NaCl 3% was compared with a more concentrated bolus of 0.13 ml kg(-1) of NaCl 20%. Prior to the injection of each contrast bolus injection, ventilation was turned off to provide a total of 40 to 45 s of apnoea. Each bolus of impedance contrast was injected through a catheter into the right atrium. Pulmonary embolisation was performed by balloon occlusion of part of the right branch of the pulmonary trunk. Four parameters representing the kinetics of the contrast dilution in the lung were evaluated for statistical differences between baseline and PE, including peak value, maximum uptake, maximum washout and area under the curve of the averaged contrast dilution curve in each lung. Furthermore, the right lung to left lung (R2L) ratio of each the aforementioned parameters were assessed. While all of the R2L ratios yielded significantly different means between baseline and PE, it can be concluded that the R2L ratios of area under the curve and peak value of the averaged contrast dilution curve are the most promising and reliable in assessing PE. It was also found that the efficacy of the two types of impedance contrasts were not significantly different in distinguishing PE from baseline in our model.

Inhaled nitric oxide pretreatment but not posttreatment attenuates ischemia-reperfusion-induced pulmonary microvascular leak.

PubMed

Chetham, P M; Sefton, W D; Bridges, J P; Stevens, T; McMurtry, I F

1997-04-01

Ischemia-reperfusion (I/R) pulmonary edema probably reflects a leukocyte-dependent, oxidant-mediated mechanism. Nitric oxide (NO) attenuates leukocyte-endothelial cell interactions and I/R-induced microvascular leak. Cyclic adenosine monophosphate (cAMP) agonists reverse and prevent I/R-induced microvascular leak, but reversal by inhaled NO (INO) has not been tested. In addition, the role of soluble guanylyl cyclase (sGC) activation in the NO protection effect is unknown. Rat lungs perfused with salt solution were grouped as either I/R, I/R with INO (10 or 50 ppm) on reperfusion, or time control. Capillary filtration coefficients (Kfc) were estimated 25 min before ischemia (baseline) and after 30 and 75 min of reperfusion. Perfusate cell counts and lung homogenate myeloperoxidase activity were determined in selected groups. Additional groups were treated with either INO (50 ppm) or isoproterenol (ISO-10 microM) after 30 min of reperfusion. Guanylyl cyclase was inhibited with 1H-[1,2,4]Oxadiazolo[4,3-a]quinoxalin-1-one (ODQ-15 microM), and Kfc was estimated at baseline and after 30 min of reperfusion. (1) Inhaled NO attenuated I/R-induced increases in Kfc. (2) Cell counts were similar at baseline. After 75 min of reperfusion, lung neutrophil retention (myeloperoxidase activity) and decreased perfusate neutrophil counts were similar in all groups. (3) In contrast to ISO, INO did not reverse microvascular leak. (4) 8-bromoguanosine 3',5'-cyclic monophosphate (8-br-cGMP) prevented I/R-induced microvascular leak in ODQ-treated lungs, but INO was no longer effective. Inhaled NO attenuates I/R-induced pulmonary microvascular leak, which requires sGC activation and may involve a mechanism independent of inhibition of leukocyte-endothelial cell interactions. In addition, INO is ineffective in reversing I/R-induced microvascular leak.

Dual ETA/ETB blockade with macitentan improves both vascular remodeling and angiogenesis in pulmonary arterial hypertension

PubMed Central

Nadeau, Valerie; Potus, Francois; Boucherat, Olivier; Paradis, Renee; Tremblay, Eve; Iglarz, Marc; Paulin, Roxane; Bonnet, Sebastien

2017-01-01

Dysregulated metabolism and rarefaction of the capillary network play a critical role in pulmonary arterial hypertension (PAH) etiology. They are associated with a decrease in perfusion of the lungs, skeletal muscles, and right ventricle (RV). Previous studies suggested that endothelin-1 (ET-1) modulates both metabolism and angiogenesis. We hypothesized that dual ETA/ETB receptors blockade improves PAH by improving cell metabolism and promoting angiogenesis. Five weeks after disease induction, Sugen/hypoxic rats presented severe PAH with pulmonary artery (PA) remodeling, RV hypertrophy and capillary rarefaction in the lungs, RV, and skeletal muscles (microCT angiogram, lectin perfusion, CD31 staining). Two-week treatment with dual ETA/ETB receptors antagonist macitentan (30 mg/kg/d) significantly improved pulmonary hemodynamics, PA vascular remodeling, and RV function and hypertrophy compared to vehicle-treated animals (all P = 0.05). Moreover, macitentan markedly increased lung, RV and quadriceps perfusion, and microvascular density (all P = 0.05). In vitro, these effects were associated with increases in oxidative phosphorylation (oxPhox) and markedly reduced cell proliferation of PAH-PA smooth muscle cells (PASMCs) treated with macitentan without affecting apoptosis. While macitentan did not affect oxPhox, proliferation, and apoptosis of PAH–PA endothelial cells (PAECs), it significantly improved their angiogenic capacity (tube formation assay). Exposure of control PASMC and PAEC to ET-1 fully mimicked the PAH cells phenotype, thus confirming that ET-1 is implicated in both metabolism and angiogenesis abnormalities in PAH. Dual ETA/ETB receptor blockade improved the metabolic changes involved in PAH-PASMCs’ proliferation and the angiogenic capacity of PAH-PAEC leading to an increased capillary density in lungs, RV, and skeletal muscles. PMID:29064353

Lysyl oxidase-like-2 promotes tumour angiogenesis and is a potential therapeutic target in angiogenic tumours.

PubMed

Zaffryar-Eilot, Shelly; Marshall, Derek; Voloshin, Tali; Bar-Zion, Avinoam; Spangler, Rhyannon; Kessler, Ofra; Ghermazien, Haben; Brekhman, Vera; Suss-Toby, Edith; Adam, Dan; Shaked, Yuval; Smith, Victoria; Neufeld, Gera

2013-10-01

Lysyl oxidase-like 2 (LOXL2), a secreted enzyme that catalyzes the cross-linking of collagen, plays an essential role in developmental angiogenesis. We found that administration of the LOXL2-neutralizing antibody AB0023 inhibited bFGF-induced angiogenesis in Matrigel plug assays and suppressed recruitment of angiogenesis promoting bone marrow cells. Small hairpin RNA-mediated inhibition of LOXL2 expression or inhibition of LOXL2 using AB0023 reduced the migration and network-forming ability of endothelial cells, suggesting that the inhibition of angiogenesis results from a direct effect on endothelial cells. To examine the effects of AB0023 on tumour angiogenesis, AB0023 was administered to mice bearing tumours derived from SKOV-3 ovarian carcinoma or Lewis lung carcinoma (LLC) cells. AB0023 treatment significantly reduced the microvascular density in these tumours but did not inhibit tumour growth. However, treatment of mice bearing SKOV-3-derived tumours with AB0023 also promoted increased coverage of tumour vessels with pericytes and reduced tumour hypoxia, providing evidence that anti-LOXL2 therapy results in the normalization of tumour blood vessels. In agreement with these data, treatment of mice bearing LLC-derived tumours with AB0023 improved the perfusion of the tumour-associated vessels as determined by ultrasonography. Improved perfusion and normalization of tumour vessels after treatment with anti-angiogenic agents were previously found to improve the delivery of chemotherapeutic agents into tumours and to result in an enhancement of chemotherapeutic efficiency. Indeed, treatment with AB0023 significantly enhanced the anti-tumourigenic effects of taxol. Our results suggest that inhibition of LOXL2 may prove beneficial for the treatment of angiogenic tumours.

Reducing intratumour acute hypoxia through bevacizumab treatment, referring to the response of quiescent tumour cells and metastatic potential

PubMed Central

Masunaga, S; Liu, Y; Tanaka, H; Sakurai, Y; Suzuki, M; Kondo, N; Maruhashi, A; Ono, K

2011-01-01

Objectives The aim was to evaluate the influence of bevacizumab on intratumour oxygenation status and lung metastasis following radiotherapy, with specific reference to the response of quiescent (Q) cell populations within irradiated tumours. Methods B16-BL6 melanoma tumour-bearing C57BL/6 mice were continuously given 5-bromo-2-deoxyuridine (BrdU) to label all proliferating (P) cells. They received γ-ray irradiation following treatment with the acute hypoxia-releasing agent nicotinamide or local mild temperature hyperthermia (MTH) with or without the administration of bevacizumab under aerobic conditions or totally hypoxic conditions, achieved by clamping the proximal end of the tumours. Immediately after the irradiation, cells from some tumours were isolated and incubated with a cytokinesis blocker. The responses of the Q and total (P + Q) cell populations were assessed based on the frequency of micronuclei using immunofluorescence staining for BrdU. In the other tumour-bearing mice, macroscopic lung metastases were enumerated 17 days after irradiation. Results 3 days after bevacizumab administration, acute hypoxia-rich total cell population in the tumour showed a remarkably enhanced radiosensitivity to γ-rays, and the hypoxic fraction (HF) was reduced, even after MTH treatment. However, the hypoxic fraction was not reduced after nicotinamide treatment. With or without γ-ray irradiation, bevacizumab administration showed some potential to reduce the number of lung metastases as well as nicotinamide treatment. Conclusion Bevacizumab has the potential to reduce perfusion-limited acute hypoxia and some potential to cause a decrease in the number of lung metastases as well as nicotinamide. PMID:21586505

Ventilation and perfusion imaging by electrical impedance tomography: a comparison with radionuclide scanning.

PubMed

Kunst, P W; Vonk Noordegraaf, A; Hoekstra, O S; Postmus, P E; de Vries, P M

1998-11-01

Electrical impedance tomography (EIT) is a technique that makes it possible to measure ventilation and pulmonary perfusion in a volume that approximates to a 2D plane. The possibility of using EIT for measuring the left-right division of ventilation and perfusion was compared with that of radionuclide imaging. Following routine ventilation (81mKr) and perfusion scanning (99mTc-MAA), EIT measurements were performed at the third and the sixth intercostal level in 14 patients with lung cancer. A correlation (r = 0.98, p < 0.005) between the left-right division for the ventilation measured with EIT and that with 81mKr was found. For the left-right division of pulmonary perfusion a correlation of 0.95 (p < 0.005) was found between the two methods. The reliability coefficient (RC) was calculated for estimating the left-right division with EIT. The RC for the ventilation measurements was 94% and 96% for the perfusion measurements. The correlation analysis for reproducibility of the EIT measurements was 0.95 (p < 0.001) for the ventilation and 0.93 (p < 0.001) for the perfusion measurements. In conclusion, EIT can be regarded as a promising technique to estimate the left-right division of pulmonary perfusion and ventilation.

The matching of ventilation and perfusion in the lung of the Tegu lizard, Tupinambis nigropunctatus.

PubMed

Hlastala, M P; Standaert, T A; Pierson, D J; Luchtel, D L

1985-06-01

Ventilation-perfusion (VA/Q) distribution was evaluated in the Tegu lizard, Tupinambis nigropunctatus, using the multiple inert gas elimination technique (MIGET) in order to define the limitations to gas exchange in the large chambered unicameral lung. The lizards (0.52-1.1 kg) were anesthetized with halothane and ventilated. Body temperature was maintained at 35 degrees C. Arterial and sinus venosus PO2 averaged 79.4 +/- 5.9 and 47.3 +/- 6.4 torr while breathing air and 232.1 +/- 31 and 64.8 +/- 11.5 torr while breathing oxygen. VA/Q distributions were broad and right-to-left shunt averaged 21% while breathing air and 27% while breathing oxygen. Gas exchange was significantly impaired due to the presence of both shunt and VA/Q heterogeneity. The walls of the lung enclose a large axial air chamber. Microscopic examination revealed approximately three generations of septa which subdivided the wall into tubular-shaped gas-exchange chambers. Wall thickness averages 2.8 mm at the anterior end of the lung, 2.1 mm in the middle portion of the lung and 1.4 mm at the posterior end. The thickness of the blood-air barrier (epithelial-basal lamina-endothelial cell layer) ranged from 0.35 to 0.90 micron. Although this barrier is slightly thicker than in the mammalian lung (0.1-0.5 micron), it is unlikely to be a source of diffusion limitation in gas exchange at rest.

Inhibition of acid-induced lung injury by hyperosmolar sucrose in rats.

PubMed

Safdar, Zeenat; Yiming, Maimiti; Grunig, Gabriele; Bhattacharya, Jahar

2005-10-15

Acid aspiration causes acute lung injury (ALI). Recently, we showed that a brief intravascular infusion of hyperosmolar sucrose, given concurrently with airway acid instillation, effectively blocks the ensuing ALI. The objective of the present study was to determine the extent to which intravascular infusion of hyperosmolar sucrose might protect against acid-induced ALI when given either before or after acid instillation. Our studies were conducted in anesthetized rats and in isolated, blood-perfused rat lungs. We instilled HCl through the airway, and we quantified lung injury in terms of the extravascular lung water (EVLW) content, filtration coefficient (Kfc), and cell counts and protein concentration in the bronchoalveolar lavage. We infused hyperosmolar sucrose via the femoral vein. In anesthetized rats, airway HCl instillation induced ALI as indicated by a 52% increase of EVLW and a threefold increase in Kfc. However, a 15-min intravenous infusion of hyperosmolar sucrose given up to 1 h before or 30 min after acid instillation markedly blunted the increases in EVLW, as well as the increases in cell count, and in protein concentration in the bronchoalveolar lavage. Hyperosmolar pretreatment also blocked the acid-induced increase of Kfc. Studies in isolated perfused lungs indicated that the protective effect of hyperosmolar sucrose was leukocyte independent. We conclude that a brief period of vascular hyperosmolarity protects against acid-induced ALI when the infusion is administered shortly before, or shortly after, acid instillation in the airway. The potential applicability of hyperosmolar sucrose in therapy for ALI requires consideration.

Lung Metabolic Activation as an Early Biomarker of the Acute Respiratory Distress Syndrome and Local Gene Expression Heterogeneity

PubMed Central

Wellman, Tyler J.; de Prost, Nicolas; Tucci, Mauro; Winkler, Tilo; Baron, Rebecca M.; Filipczak, Piotr; Raby, Benjamin; Chu, Jen-hwa; Harris, R. Scott; Musch, Guido; dos Reis Falcao, Luiz F.; Capelozzi, Vera; Venegas, Jose; Melo, Marcos F. Vidal

2016-01-01

Background The acute respiratory distress syndrome (ARDS) is an inflammatory condition comprising diffuse lung edema and alveolar damage. ARDS frequently results from regional injury mechanisms. However, it is unknown whether detectable inflammation precedes lung edema and opacification, and whether topographically differential gene expression consistent with heterogeneous injury occurs in early ARDS. We aimed to determine the temporal relationship between pulmonary metabolic activation and density in a large animal model of early ARDS, and to assess gene expression in differentially activated regions. Methods We produced ARDS in sheep with intravenous LPS (10ng/kg/h) and mechanical ventilation for 20h. Using positron emission tomography, we assessed regional cellular metabolic activation with 2-deoxy-2-[(18)F]fluoro-D-glucose, perfusion and ventilation with 13NN-saline, and aeration using transmission scans. Species-specific micro-array technology was used to assess regional gene expression. Results Metabolic activation preceded detectable increases in lung density (as required for clinical diagnosis) and correlated with subsequent histological injury, suggesting its predictive value for severity of disease progression. Local time-courses of metabolic activation varied, with highly perfused and less aerated dependent lung regions activated earlier than non-dependent regions. These regions of distinct metabolic trajectories demonstrated differential gene expression for known and potential novel candidates for ARDS pathogenesis. Conclusions Heterogeneous lung metabolic activation precedes increases in lung density in the development of ARDS due to endotoxemia and mechanical ventilation. Local differential gene expression occurs in these early stages and reveals molecular pathways relevant to ARDS biology and of potential use as treatment targets. PMID:27611185

Lung Structure and the Intrinsic Challenges of Gas Exchange.

PubMed

Hsia, Connie C W; Hyde, Dallas M; Weibel, Ewald R

2016-03-15

Structural and functional complexities of the mammalian lung evolved to meet a unique set of challenges, namely, the provision of efficient delivery of inspired air to all lung units within a confined thoracic space, to build a large gas exchange surface associated with minimal barrier thickness and a microvascular network to accommodate the entire right ventricular cardiac output while withstanding cyclic mechanical stresses that increase several folds from rest to exercise. Intricate regulatory mechanisms at every level ensure that the dynamic capacities of ventilation, perfusion, diffusion, and chemical binding to hemoglobin are commensurate with usual metabolic demands and periodic extreme needs for activity and survival. This article reviews the structural design of mammalian and human lung, its functional challenges, limitations, and potential for adaptation. We discuss (i) the evolutionary origin of alveolar lungs and its advantages and compromises, (ii) structural determinants of alveolar gas exchange, including architecture of conducting bronchovascular trees that converge in gas exchange units, (iii) the challenges of matching ventilation, perfusion, and diffusion and tissue-erythrocyte and thoracopulmonary interactions. The notion of erythrocytes as an integral component of the gas exchanger is emphasized. We further discuss the signals, sources, and limits of structural plasticity of the lung in alveolar hypoxia and following a loss of lung units, and the promise and caveats of interventions aimed at augmenting endogenous adaptive responses. Our objective is to understand how individual components are matched at multiple levels to optimize organ function in the face of physiological demands or pathological constraints. Copyright © 2016 John Wiley & Sons, Inc.

Modification of Rat Lung Decellularization Protocol Based on Dynamic Conductometry of Working Solution.

PubMed

Kuevda, E V; Gubareva, E A; Gumenyuk, I S; Sotnichenko, A S; Gilevich, I V; Nakokhov, R Z; Rusinova, T V; Yudina, T G; Red'ko, A N; Alekseenko, S N

2017-03-01

We modified the protocol of obtaining of biological scaffolds of rat lungs based on dynamic recording of specific resistivity of working detergent solution (conductometry) during perfusion decellularization. Termination of sodium deoxycholate exposure after attaining ionic equilibrium plateau did not impair the quality of decellularization and preserved structural matrix components, which was confirmed by morphological analysis and quantitative assay of residual DNA.

Contrast-enhanced CT- and MRI-based perfusion assessment for pulmonary diseases: basics and clinical applications

PubMed Central

Ohno, Yoshiharu; Koyama, Hisanobu; Lee, Ho Yun; Miura, Sachiko; Yoshikawa, Takeshi; Sugimura, Kazuro

2016-01-01

Assessment of regional pulmonary perfusion as well as nodule and tumor perfusions in various pulmonary diseases are currently performed by means of nuclear medicine studies requiring radioactive macroaggregates, dual-energy computed tomography (CT), and dynamic first-pass contrast-enhanced perfusion CT techniques and unenhanced and dynamic first-pass contrast enhanced perfusion magnetic resonance imaging (MRI), as well as time-resolved three-dimensional or four-dimensional contrast-enhanced magnetic resonance angiography (MRA). Perfusion scintigraphy, single-photon emission tomography (SPECT) and SPECT fused with CT have been established as clinically available scintigraphic methods; however, they are limited by perfusion information with poor spatial resolution and other shortcomings. Although positron emission tomography with 15O water can measure absolute pulmonary perfusion, it requires a cyclotron for generation of a tracer with an extremely short half-life (2 min), and can only be performed for academic purposes. Therefore, clinicians are concentrating their efforts on the application of CT-based and MRI-based quantitative and qualitative perfusion assessment to various pulmonary diseases. This review article covers 1) the basics of dual-energy CT and dynamic first-pass contrast-enhanced perfusion CT techniques, 2) the basics of time-resolved contrast-enhanced MRA and dynamic first-pass contrast-enhanced perfusion MRI, and 3) clinical applications of contrast-enhanced CT- and MRI-based perfusion assessment for patients with pulmonary nodule, lung cancer, and pulmonary vascular diseases. We believe that these new techniques can be useful in routine clinical practice for not only thoracic oncology patients, but also patients with different pulmonary vascular diseases. PMID:27523813

New radionuclide agents for cardiac imaging: Description and application

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kahn, J.K.; Pippin, J.J.; Corbett, J.R.

1989-08-01

The introduction of three new radiopharmaceuticals into clinical research and practice has broadened the potential applications and scope of nuclear cardiology examinations. Technetium-99m labeled isonitrile perfusion agents have excellent imaging characteristics allowing the accurate identification of coronary artery disease. Simultaneous assessments of ventricular function are possible with these agents. Iodine-123 phenylpentadecanoic acid myocardial scintigraphy permits assessments of myocardial perfusion and fatty acid metabolism, and permits investigations of myocardial metabolism with conventional imaging equipment. Iodine-123 meta-iodobenzyl-guanidine serves as an indicator of the functional integrity of the sympathetic nervous system and permits evaluations of the effects of various disease states on catecholaminemore » handling by the heart. 58 references.« less

Contrast echocardiography: new agents.

PubMed

Miller, Andrew P; Nanda, Navin C

2004-04-01

In this report, we review the history, rationale, current status and future directions of contrast agents in echocardiography. First, we discuss the historic development of contrast agents through a review of important physical principles of microbubbles in ultrasonography. Second, we identify attributes of an ideal contrast agent and review those that are currently available or in the "pipeline" for clinical use. Third, we review indications for contrast echocardiography, including endocardial border detection, perfusion quantification and reperfusion assessment, and validate these observations by comparisons with other imaging modalities. Then, we briefly review different methodologies of performing a contrast study, including interrupted, real-time and a hybrid modality. Finally, we identify novel future applications of the newest contrast agents. These newer concepts in contrast echocardiography should form a foundation for nearly limitless application of echocardiography in improved anatomical assessment, perfusion imaging and even special applications, such as detection of vascular inflammation and site-specific drug delivery.

Lung ventilation-perfusion imbalance in pulmonary emphysema: assessment with automated V/Q quotient SPECT.

PubMed

Suga, Kazuyoshi; Kawakami, Yasuhiko; Koike, Hiroaki; Iwanaga, Hideyuki; Tokuda, Osamu; Okada, Munemasa; Matsunaga, Naofumi

2010-05-01

Tc-99m-Technegas-MAA single photon emission computed tomography (SPECT)-derived ventilation (V)/perfusion (Q) quotient SPECT was used to assess lung V-Q imbalance in patients with pulmonary emphysema. V/Q quotient SPECT and V/Q profile were automatically built in 38 patients with pulmonary emphysema and 12 controls, and V/Q distribution and V/Q profile parameters were compared. V/Q distribution on V/Q quotient SPECT was correlated with low attenuation areas (LAA) on density-mask computed tomography (CT). Parameters of V/Q profile such as the median, standard deviation (SD), kurtosis and skewness were proposed to objectively evaluate the severity of lung V-Q imbalance. In contrast to uniform V/Q distribution on V/Q quotient SPECT and a sharp peak with symmetrical V/Q distribution on V/Q profile in controls, lung areas showing heterogeneously high or low V/Q and flattened peaks with broadened V/Q distribution were frequently seen in patients with emphysema, including lung areas with only slight LAA. V/Q distribution was also often asymmetric regardless of symmetric LAA. All the proposed parameters of V/Q profile in entire lungs of patients with emphysema showed large variations compared with controls; SD and kurtosis were significantly different from controls (P < 0.0001 and P < 0.001, respectively), and a significant correlation was found between SD and A-aDO2 (P < 0.0001). V/Q quotient SPECT appears to be more sensitive to detect emphysematous lungs compared with morphologic CT in patients with emphysema. SD and kurtosis of V/Q profile can be adequate parameters to assess the severity of lung V-Q imbalance causing gas-exchange impairment in patients with emphysema.

Ex vivo lung perfusion to improve donor lung function and increase the number of organs available for transplantation.

PubMed

Valenza, Franco; Rosso, Lorenzo; Coppola, Silvia; Froio, Sara; Palleschi, Alessandro; Tosi, Davide; Mendogni, Paolo; Salice, Valentina; Ruggeri, Giulia M; Fumagalli, Jacopo; Villa, Alessandro; Nosotti, Mario; Santambrogio, Luigi; Gattinoni, Luciano

2014-06-01

This paper describes the initial clinical experience of ex vivo lung perfusion (EVLP) at the Fondazione Ca' Granda in Milan between January 2011 and May 2013. EVLP was considered if donor PaO2 /FiO2 was below 300 mmHg or if lung function was doubtful. Donors with massive lung contusion, aspiration, purulent secretions, pneumonia, or sepsis were excluded. EVLP was run with a low-flow, open atrium and low hematocrit technique. Thirty-five lung transplants from brain death donors were performed, seven of which after EVLP. EVLP donors were older (54 ± 9 years vs. 40 ± 15 years, EVLP versus Standard, P < 0.05), had lower PaO2 /FiO2 (264 ± 78 mmHg vs. 453 ± 119 mmHg, P < 0.05), and more chest X-ray abnormalities (P < 0.05). EVLP recipients were more often admitted to intensive care unit as urgent cases (57% vs. 18%, P = 0.05); lung allocation score at transplantation was higher (79 [40-84] vs. 39 [36-46], P < 0.05). After transplantation, primary graft dysfunction (PGD72 grade 3, 32% vs. 28%, EVLP versus Standard, P = 1), mortality at 30 days (0% vs. 0%, P = 1), and overall survival (71% vs. 86%, EVLP versus Standard P = 0.27) were not different between groups. EVLP enabled a 20% increase in available donor organs and resulted in successful transplants with lungs that would have otherwise been rejected (ClinicalTrials.gov number: NCT01967953). © 2014 The Authors. Transplant International published by John Wiley & Sons Ltd on behalf of Steunstichting ESOT.

Isoflurane administration before ischemia and during reperfusion attenuates ischemia/reperfusion-induced injury of isolated rabbit lungs.

PubMed

Liu, R; Ishibe, Y; Ueda, M; Hang, Y

1999-09-01

To investigate the effects of isoflurane on ischemia/ reperfusion (IR)-induced lung injury, we administered isoflurane before ischemia or during reperfusion. Isolated rabbit lungs were divided into the following groups: control (n = 6), perfused and ventilated for 120 min without ischemia; ISO-control (n = 6), 1 minimum alveolar anesthetic concentration (MAC) isoflurane was administered for 30 min before 120 min continuous perfusion; IR (n = 6), ischemia for 60 min, followed by 60 min reperfusion; IR-ISO1 and IR-ISO2, ischemia followed by reperfusion and 1 MAC (n = 6) or 2 MAC (n = 6) isoflurane for 60 min; ISO-IR (n = 6), 1 MAC isoflurane was administered for 30 min before ischemia, followed by IR. During these maneuvers, we measured total pulmonary vascular resistance (Rt), coefficient of filtration (Kfc), and lung wet to dry ratio (W/D). The results indicated that administration of isoflurane during reperfusion inhibited an IR-induced increase in Kfc and W/D ratio. Furthermore, isoflurane at 2 MAC, but not 1 MAC, significantly inhibited an IR-induced increase in Rt. The administration of isoflurane before ischemia significantly attenuated the increase in IR-induced Kfc, W/D, and Rt. Our results suggest that the administration of isoflurane before ischemia and during reperfusion protects against ischemia-reperfusion-induced injury in isolated rabbit lungs.

Case Studies in Physiology: Ventilation and perfusion in a giraffe-does size matter?

PubMed

Nyman, Görel; Röken, Bengt; Hedin, Eva-Maria; Hedenstierna, Göran

2016-12-01

The trachea in the giraffe is long but narrow, and dead space ventilation is considered to be of approximately the same size as in other mammals. Less is known about the matching between ventilation and lung blood flow. The lungs in the giraffe are large, up to 1 m high and 0.7 m wide, and this may cause considerable ventilation/perfusion (V A /Q) mismatch due to the influence of gravitational forces, which could lead to hypoxemia. We studied a young giraffe under anesthesia using the multiple inert gas elimination technique to analyze the VA/Q distribution and arterial oxygenation and compared the results with those obtained in other species of different sizes, including humans. V A /Q distribution was broad but unimodal, and the shunt of blood flow through nonventilated lung regions was essentially absent, suggesting no lung collapse. The V A /Q match was as good as in the similarly sized horse and was even comparable to that in smaller sized animals, including rabbit and rat. The match was also similar to that in anesthetized humans. Arterial oxygenation was essentially similar in all studied species. The findings suggest that the efficiency of V A /Q matching is independent of lung size in the studied mammals that vary in weight from less than 1 to more than 400 kg. Copyright © 2016 the American Physiological Society.

High Resolution Ultrasound Superharmonic Perfusion Imaging: In Vivo Feasibility and Quantification of Dynamic Contrast-Enhanced Acoustic Angiography.

PubMed

Lindsey, Brooks D; Shelton, Sarah E; Martin, K Heath; Ozgun, Kathryn A; Rojas, Juan D; Foster, F Stuart; Dayton, Paul A

2017-04-01

Mapping blood perfusion quantitatively allows localization of abnormal physiology and can improve understanding of disease progression. Dynamic contrast-enhanced ultrasound is a low-cost, real-time technique for imaging perfusion dynamics with microbubble contrast agents. Previously, we have demonstrated another contrast agent-specific ultrasound imaging technique, acoustic angiography, which forms static anatomical images of the superharmonic signal produced by microbubbles. In this work, we seek to determine whether acoustic angiography can be utilized for high resolution perfusion imaging in vivo by examining the effect of acquisition rate on superharmonic imaging at low flow rates and demonstrating the feasibility of dynamic contrast-enhanced superharmonic perfusion imaging for the first time. Results in the chorioallantoic membrane model indicate that frame rate and frame averaging do not affect the measured diameter of individual vessels observed, but that frame rate does influence the detection of vessels near and below the resolution limit. The highest number of resolvable vessels was observed at an intermediate frame rate of 3 Hz using a mechanically-steered prototype transducer. We also demonstrate the feasibility of quantitatively mapping perfusion rate in 2D in a mouse model with spatial resolution of ~100 μm. This type of imaging could provide non-invasive, high resolution quantification of microvascular function at penetration depths of several centimeters.

Pulmonary uptake of morphine (M)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Roerig, D.L.; Bunke, S.S.; Kotrly, K.J.

Previously the authors reported less than 5% of M was taken up during the first pass through the human lung. The low uptake of this basic lipophilic amine was further investigated in a single pass isolated perfused rat lung (IPL) in comparison to uptake of radiolabelled H/sub 2/O, antipyrine (A), aminopyrine (AM), nicotine (N) and phenylethylamine (P). The IPL was perfused for 5 min with each drug (5nmol/ml) and effluent collected in 10 sec fractions. Pulmonary extraction was calculated using indocyanine green dye as a non-extractable reference indicator. Accumulation of all compounds in the IPL reached an apparent equilibrium withinmore » 4 min. At equilibrium lung/perfusate conc. ratios for H/sub 2/O, A, AM, N, P and M were 1.04, 0.84, 0.85, 1.44, 2.57 and 1.13 respectively. The time course of M uptake differed from the other compounds since initial extraction of M was low (23%) compared to 75%, 53%, 35%, 82% and 86% for H/sub 2/O, A, AM, N and P respectively. Also, the half time to equilibrium for M was longer (50 sec) compared to 18, 21, 26, 19 and 22 sec for H/sub 2/O, A, AM, N and P respectively. The low initial pulmonary extraction of M compared to these compounds followed by greater M extraction during the remainder of drug infusion suggests uptake mechanisms for M different than the flow limited uptake for water and other basic amine drugs.« less

Automated interpretation of ventilation-perfusion lung scintigrams for the diagnosis of pulmonary embolism using artificial neural networks.

PubMed

Holst, H; Aström, K; Järund, A; Palmer, J; Heyden, A; Kahl, F; Tägil, K; Evander, E; Sparr, G; Edenbrandt, L

2000-04-01

The purpose of this study was to develop a completely automated method for the interpretation of ventilation-perfusion (V-P) lung scintigrams used in the diagnosis of pulmonary embolism. An artificial neural network was trained for the diagnosis of pulmonary embolism using 18 automatically obtained features from each set of V-P scintigrams. The techniques used to process the images included their alignment to templates, the construction of quotient images based on the ventilation and perfusion images, and the calculation of measures describing V-P mismatches in the quotient images. The templates represented lungs of normal size and shape without any pathological changes. Images that could not be properly aligned to the templates were detected and excluded automatically. After exclusion of those V-P scintigrams not properly aligned to the templates, 478 V-P scintigrams remained in a training group of consecutive patients with suspected pulmonary embolism, and a further 87 V-P scintigrams formed a separate test group comprising patients who had undergone pulmonary angiography. The performance of the neural network, measured as the area under the receiver operating characteristic curve, was 0.87 (95% confidence limits 0.82-0.92) in the training group and 0.79 (0.69-0.88) in the test group. It is concluded that a completely automated method can be used for the interpretation of V-P scintigrams. The performance of this method is similar to others previously presented, whereby features were extracted manually.

A polymorphism within the promoter of the TGFβ1 gene is associated with radiation sensitivity using an objective radiologic endpoint.

PubMed

Kelsey, Chris R; Jackson, Lauren; Langdon, Scott; Owzar, Kouros; Hubbs, Jessica; Vujaskovic, Zeljko; Das, Shiva; Marks, Lawrence B

2012-02-01

To evaluate whether single nucleotide polymorphisms (SNPs) in the transforming growth factor-β1 (TGFβ1) gene are associated with radiation sensitivity using an objective radiologic endpoint. Preradiation therapy and serial postradiation therapy single photon emission computed tomography (SPECT) lung perfusion scans were obtained in patients undergoing treatment for lung cancer. Serial blood samples were obtained to measure circulating levels of TGFβ1. Changes in regional perfusion were related to regional radiation dose yielding a patient-specific dose-response curve, reflecting the patient's inherent sensitivity to radiation therapy. Six TGFβ1 SNPs (-988, -800, -509, 869, 941, and 1655) were assessed using high-resolution melting assays and DNA sequencing. The association between genotype and slope of the dose-response curve, and genotype and TGFβ1 ratio (4-week/preradiation therapy), was analyzed using the Kruskal-Wallis test. 39 white patients with preradiation therapy and ≥ 6-month postradiation therapy SPECT scans and blood samples were identified. Increasing slope of the dose-response curve was associated with the C(-509)T SNP (p = 0.035), but not the other analyzed SNPs. This SNP was also associated with higher TGFβ1 ratios. This study suggests that a polymorphism within the promoter of the TGFβ1 gene is associated with increased radiation sensitivity (defined objectively by dose-dependent changes in SPECT lung perfusion). Copyright © 2012 Elsevier Inc. All rights reserved.

A Polymorphism Within the Promoter of the TGF{beta}1 Gene Is Associated With Radiation Sensitivity Using an Objective Radiologic Endpoint

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kelsey, Chris R., E-mail: kelse003@mc.duke.edu; Jackson, Lauren; Langdon, Scott

2012-02-01

Purpose: To evaluate whether single nucleotide polymorphisms (SNPs) in the transforming growth factor-{beta}1 (TGF{beta}1) gene are associated with radiation sensitivity using an objective radiologic endpoint. Methods and Materials: Preradiation therapy and serial postradiation therapy single photon emission computed tomography (SPECT) lung perfusion scans were obtained in patients undergoing treatment for lung cancer. Serial blood samples were obtained to measure circulating levels of TGF{beta}1. Changes in regional perfusion were related to regional radiation dose yielding a patient-specific dose-response curve, reflecting the patient's inherent sensitivity to radiation therapy. Six TGF{beta}1 SNPs (-988, -800, -509, 869, 941, and 1655) were assessed using high-resolutionmore » melting assays and DNA sequencing. The association between genotype and slope of the dose-response curve, and genotype and TGF{beta}1 ratio (4-week/preradiation therapy), was analyzed using the Kruskal-Wallis test. Results: 39 white patients with preradiation therapy and {>=}6-month postradiation therapy SPECT scans and blood samples were identified. Increasing slope of the dose-response curve was associated with the C(-509)T SNP (p = 0.035), but not the other analyzed SNPs. This SNP was also associated with higher TGF{beta}1 ratios. Conclusions: This study suggests that a polymorphism within the promoter of the TGF{beta}1 gene is associated with increased radiation sensitivity (defined objectively by dose-dependent changes in SPECT lung perfusion).« less

Impact of CT perfusion imaging on the assessment of peripheral chronic pulmonary thromboembolism: clinical experience in 62 patients.

PubMed

Le Faivre, Julien; Duhamel, Alain; Khung, Suonita; Faivre, Jean-Baptiste; Lamblin, Nicolas; Remy, Jacques; Remy-Jardin, Martine

2016-11-01

To evaluate the impact of CT perfusion imaging on the detection of peripheral chronic pulmonary embolisms (CPE). 62 patients underwent a dual-energy chest CT angiographic examination with (a) reconstruction of diagnostic and perfusion images; (b) enabling depiction of vascular features of peripheral CPE on diagnostic images and perfusion defects (20 segments/patient; total: 1240 segments examined). The interpretation of diagnostic images was of two types: (a) standard (i.e., based on cross-sectional images alone) or (b) detailed (i.e., based on cross-sectional images and MIPs). The segment-based analysis showed (a) 1179 segments analyzable on both imaging modalities and 61 segments rated as nonanalyzable on perfusion images; (b) the percentage of diseased segments was increased by 7.2 % when perfusion imaging was compared to the detailed reading of diagnostic images, and by 26.6 % when compared to the standard reading of images. At a patient level, the extent of peripheral CPE was higher on perfusion imaging, with a greater impact when compared to the standard reading of diagnostic images (number of patients with a greater number of diseased segments: n = 45; 72.6 % of the study population). Perfusion imaging allows recognition of a greater extent of peripheral CPE compared to diagnostic imaging. • Dual-energy computed tomography generates standard diagnostic imaging and lung perfusion analysis. • Depiction of CPE on central arteries relies on standard diagnostic imaging. • Detection of peripheral CPE is improved by perfusion imaging.

Direct Exposure of Monolayers of Mammalian Cells to Airborne Pollutants in a Unique Culture System.

DTIC Science & Technology

1981-02-01

of growth medium through the filter from the side opposite the cells so that they are nourished and kept moist. Growth medium perfusing through the...planting dispersed cells (Line V79, Chinese hamster lung fibroblasts) on the membrane filters and exposing to the test gas. The toxic effect was... Medium which perfuses through the filters is drawn off through the tubes at the rear wall of the chamber. The test gas enters at the left end of the

Fate of angiotensin I in the toad Bufo melanostictus

PubMed Central

Ng, K. K. F.

1973-01-01

1. The effects of angiotensin I and II on the blood pressure of pithed toads and the disappearance of angiotensin I and II in the perfused organs of the toad were studied. 2. Angiotensin I was relatively inactive on the blood pressure of pithed toads; it exhibited less than 3% of the pressor activity of angiotensin II. 3. Angiotensin I was not converted to angiotensin II during passage through the lungs. There was also no evidence of net conversion during passage through the kidney and hind quarters. 4. During passage through the lungs, 33-50% of angiotensin I was removed and 25-50% was removed during passage through the hind quarters. No loss of activity was detected when angiotensin II passed through the kidneys. 5. Angiotensin II passed through the lungs and kidneys without loss but 25-50% disappeared during passage through the hind quarters. 6. The relatively low pressor activity of angiotensin I together with its lack of conversion to angiotensin II in isolated perfused organs suggest that the converting enzyme is absent in the toad, Bufo melanostictus. PMID:4357961

Pulmonary physiology during pulmonary embolism.

PubMed

Elliott, C G

1992-04-01

Acute pulmonary thromboembolism produces a number of pathophysiologic derangements of pulmonary function. Foremost among these alterations is increased pulmonary vascular resistance. For patients without preexistent cardiopulmonary disease, increased pulmonary vascular resistance is directly related to the degree of vascular obstruction demonstrated on the pulmonary arteriogram. Vasoconstriction, either reflexly or biochemically mediated, may contribute to increased pulmonary vascular resistance. Acute pulmonary thromboembolism also disturbs matching of ventilation and blood flow. Consequently, some lung units are overventilated relative to perfusion (increased dead space), while other lung units are underventilated relative to perfusion (venous admixture). True right-to-left shunting of mixed venous blood can occur through the lungs (intrapulmonary shunt) or across the atrial septum (intracardiac shunt). In addition, abnormalities of pulmonary gas exchange (carbon monoxide transfer), pulmonary compliance and airway resistance, and ventilatory control may accompany pulmonary embolism. Thrombolytic therapy can reverse the hemodynamic derangements of acute pulmonary thromboembolism more rapidly than anticoagulant therapy. Limited data suggest a sustained benefit of thrombolytic treatment on the pathophysiologic alterations of pulmonary vascular resistance and pulmonary gas exchange produced by acute pulmonary emboli.

[Horseshoe lung with normal pulmonary venous return].

PubMed

Gondra Sangroniz, A; Elorz Lambarri, J; Villar Alvarez, M A; Lecumberri Cortes, I; Ayala Curiel, J

2010-09-01

Horseshoe lung is a rare congenital anomaly characterised by a midline isthmus of pulmonary parenchyma connecting the posterior basal segments of the lungs behind the heart in conjunction with unilateral pulmonary hypoplasia. Of all cases, 80% are associated with scimitar syndrome, consisting of right anomalous pulmonary venous drainage, pulmonary hypoplasia of the right lung and systemic arterial perfusion to some lung areas. A six year old girl who had recurrent lower respiratory infections since birth. Chest Rx, angioCT and MR showed: hypoplasia of the right lung, dextrocardia and pulmonary isthmus bridging both lungs behind the pericardium. The right hypoplastic lung had little systemic supply coming from the abdominal aorta. The right pulmonary artery was hypoplastic. The right pulmonary venous drainage was normal. We present a case of horseshoe lung without abnormal venous drainage. 2010 Asociación Española de Pediatría. Published by Elsevier Espana. All rights reserved.

Applications of imaging technology in radiation research.

PubMed

Lin, MingDe; Jackson, Edward F

2012-04-01

Imaging research and advances in systems engineering have enabled the transition of medical imaging from a means for accomplishing traditional anatomic visualization (i.e., orthopedic planar film X ray) to a means for noninvasively assessing a variety of functional measures. Perfusion imaging is one of the major highlights in functional imaging. In this work, various methods for measuring perfusion using widely-available commercial imaging modalities and contrast agents, specifically X ray and MR (magnetic resonance), will be described. The first section reviews general methods used for perfusion imaging, and the second section provides modality-specific information, focusing on the contrast mechanisms used to calculate perfusion-related parameters. The goal of these descriptions is to illustrate how perfusion imaging can be applied to radiation biology research.

New Avenues for Nanoparticle-Related Therapies

NASA Astrophysics Data System (ADS)

Zhao, Michael; Liu, Mingyao

2018-05-01

Development of nanoparticle-based drug delivery systems has been attempted for the treatment of cancer over the past decade. The enhanced permeability and retention (EPR) effect is the major mechanism to passively deliver nanodrugs to tumor tissue. However, a recent systematic review demonstrated limited success of these studies, with the clearance of nanoparticles by the mononuclear phagocytic system (MPS) being a major hurdle. Herein, we propose that nanotechnologists should reconsider their research focuses, aiming for therapeutic targets other than cancer. Treatments for diseases that do not (or less) rely on EPR should be considered, such as active targeting or MPS evasion systems. For example, systemic delivery of drugs through intravenous injection can be used to treat sepsis, multi-organ failure, metabolic disorders, blood diseases, immune and autoimmune diseases, etc. Local delivery of nanodrugs to organs such as the lung, rectum, or bladder may enhance the local drug concentration with less clearance via MPS. In transplant settings, ex vivo organ perfusion provides a new route to repair injury of isolated organs in the absence of MPS. Based on a similar concept, chemotherapy with in vivo lung perfusion techniques and other isolated organ perfusion provides opportunities for cancer therapy.

beta(2)-adrenoceptor antagonist ICI 118,551 decreases pulmonary vascular tone in mice via a G(i/o) protein/nitric oxide-coupled pathway.

PubMed

Wenzel, Daniela; Knies, Ralf; Matthey, Michaela; Klein, Alexandra M; Welschoff, Julia; Stolle, Vanessa; Sasse, Philipp; Röll, Wilhelm; Breuer, Johannes; Fleischmann, Bernd K

2009-07-01

beta(2)-adrenoceptors are important modulators of vascular tone, particularly in the pulmonary circulation. Because neurohormonal activation occurs in pulmonary arterial hypertension, we have investigated the effect of different adrenergic vasoactive substances on tone regulation in large and small pulmonary arteries, as well as in systemic vessels of mice. We found that the beta(2)-adrenoceptor antagonist ICI 118,551 (ICI) evoked a decrease of vascular tone in large pulmonary arteries and reduced the sensitivity of pulmonary arteries toward different contracting agents, eg, norepinephrine, serotonin, or endothelin. ICI proved to act specifically on pulmonary vessels, because it shifted the dose-response curve of norepinephrine to the right in pulmonary arteries, whereas there was no effect in the aorta. Pharmacological experiments proved that the right shift of the norepinephrine dose-response curve by ICI was mediated via a beta(2)-adrenoceptor/G(i/o) protein-dependent pathway enhancing NO production in the endothelium; these results were corroborated in beta-adrenoceptor and endothelial NO synthase knockout mice where ICI had no effect. ICI increased vascular lumen diameter in lung sections and reduced pulmonary arterial pressure under normoxia and under hypoxia in the isolated perfused lung model. These effects were found to be physiologically relevant, because ICI specifically decreased pulmonary but not systemic blood pressure in vivo. Thus, the beta(2)-adrenoceptor antagonist ICI is a pulmonary arterial-specific vasorelaxant and, therefore, a potentially interesting novel therapeutic agent for the treatment of pulmonary arterial hypertension.

Comparative Effects of Volutrauma and Atelectrauma on Lung Inflammation in Experimental Acute Respiratory Distress Syndrome

PubMed Central

Güldner, Andreas; Braune, Anja; Ball, Lorenzo; Silva, Pedro L.; Samary, Cynthia; Insorsi, Angelo; Huhle, Robert; Rentzsch, Ines; Becker, Claudia; Oehme, Liane; Andreeff, Michael; Vidal Melo, Marcos F.; Winkler, Tilo; Pelosi, Paolo; Rocco, Patricia R. M.; Kotzerke, Jörg; de Abreu, Marcelo Gama

2016-01-01

Objective Volutrauma and atelectrauma promote ventilator-induced lung injury, but their relative contribution to inflammation in ventilator-induced lung injury is not well established. The aim of this study was to determine the impact of volutrauma and atelectrauma on the distribution of lung inflammation in experimental acute respiratory distress syndrome. Design Laboratory investigation. Setting University-hospital research facility. Subjects Ten pigs (five per group; 34.7–49.9 kg) Interventions Animals were anesthetized and intubated, and saline lung lavage was performed. Lungs were separated with a double-lumen tube. Following lung recruitment and decremental positive end-expiratory pressure trial, animals were randomly assigned to 4 hours of ventilation of the left (ventilator-induced lung injury) lung with tidal volume of approximately 3 mL/kg and 1) high positive end-expiratory pressure set above the level where dynamic compliance increased more than 5% during positive end-expiratory pressure trial (volutrauma); or 2) low positive end-expiratory pressure to achieve driving pressure comparable with volutrauma (atelectrauma). The right (control) lung was kept on continuous positive airway pressure of 20 cm H2O, and Co2 was partially removed extracorporeally. Measurements and Main Results Regional lung aeration, specific [18F]fluorodeoxyglucose uptake rate, and perfusion were assessed using computed and positron emission tomography. Volutrauma yielded higher [18F]fluorodeoxyglucose uptake rate in the ventilated lung compared with atelectrauma (median [interquartile range], 0.017 [0.014–0.025] vs 0.013 min−1 [0.010–0.014min−1]; p < 0.01), mainly in central lung regions. Volutrauma yielded higher [18F]fluorodeoxyglucose uptake rate in ventilator-induced lung injury versus control lung (0.017 [0.014–0.025] vs 0.011 min−1 [0.010–0.016min−1]; p < 0.05), whereas atelectrauma did not. Volutrauma decreased blood fraction at similar perfusion and increased normally as well as hyper-aerated lung compartments and tidal hyperaeration. Atelectrauma yielded higher poorly and nonaerated lung compartments, and tidal recruitment. Driving pressure increased in atelectrauma. Conclusions In this model of acute respiratory distress syndrome, volutrauma promoted higher lung inflammation than atelectrauma at comparable low tidal volume and lower driving pressure, suggesting that static stress and strain are major determinants of ventilator-induced lung injury. PMID:27035236

Occult pulmonary embolism: a common occurrence in deep venous thrombosis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dorfman, G.S.; Cronan, J.J.; Tupper, T.B.

1987-02-01

Ventilation-perfusion scans were used in a prospective study to determine the prevalence of occult pulmonary embolus in proven deep venous thrombosis. Fifty-eight patients without symptoms of pulmonary embolism, but with venographically proven deep venous thrombosis, were subjected to chest radiographs, /sup 99m/Tc macroaggregated-albumin perfusion scans, and /sup 133/Xe ventilation scans. Of the 49 patients with deep venous thrombosis proximal to the calf veins, 17 (35%) had high-probability scans. Of all 58 patients, only 12 (21%) had normal scans. When the study population was compared with a group of 430 patients described in reports of pulmonary perfusion in asymptomatic persons, amore » significantly higher percentage of high-probability scans was found in the study population with deep venous thrombosis. Baseline ventilation-perfusion lung scanning is valuable for patients with proven above-knee deep venous thrombosis.« less

Ventilation/perfusion SPECT or SPECT/CT for lung function imaging in patients with pulmonary emphysema?

PubMed

Froeling, Vera; Heimann, Uwe; Huebner, Ralf-Harto; Kroencke, Thomas J; Maurer, Martin H; Doellinger, Felix; Geisel, Dominik; Hamm, Bernd; Brenner, Winfried; Schreiter, Nils F

2015-07-01

To evaluate the utility of attenuation correction (AC) of V/P SPECT images for patients with pulmonary emphysema. Twenty-one patients (mean age 67.6 years) with pulmonary emphysema who underwent V/P SPECT/CT were included. AC/non-AC V/P SPECT images were compared visually and semiquantitatively. Visual comparison of AC/non-AC images was based on a 5-point likert scale. Semiquantitative comparison assessed absolute counts per lung (aCpLu) and lung lobe (aCpLo) for AC/non-AC images using software-based analysis; percentage counts (PC = (aCpLo/aCpLu) × 100) were calculated. Correlation between AC/non-AC V/P SPECT images was analyzed using Spearman's rho correlation coefficient; differences were tested for significance with the Wilcoxon rank sum test. Visual analysis revealed high conformity for AC and non-AC V/P SPECT images. Semiquantitative analysis of PC in AC/non-AC images had an excellent correlation and showed no significant differences in perfusion (ρ = 0.986) or ventilation (ρ = 0.979, p = 0.809) SPECT/CT images. AC of V/P SPECT images for lung lobe-based function imaging in patients with pulmonary emphysema do not improve visual or semiquantitative image analysis.

Dynamic Measurement of Tumor Vascular Permeability and Perfusion using a Hybrid System for Simultaneous Magnetic Resonance and Fluorescence Imaging.

PubMed

Ren, Wuwei; Elmer, Andreas; Buehlmann, David; Augath, Mark-Aurel; Vats, Divya; Ripoll, Jorge; Rudin, Markus

2016-04-01

Assessing tumor vascular features including permeability and perfusion is essential for diagnostic and therapeutic purposes. The aim of this study was to compare fluorescence and magnetic resonance imaging (MRI)-based vascular readouts in subcutaneously implanted tumors in mice by simultaneous dynamic measurement of tracer uptake using a hybrid fluorescence molecular tomography (FMT)/MRI system. Vascular permeability was measured using a mixture of extravascular imaging agents, GdDOTA and the dye Cy5.5, and perfusion using a mixture of intravascular agents, Endorem and a fluorescent probe (Angiosense). Dynamic fluorescence reflectance imaging (dFRI) was integrated into the hybrid system for high temporal resolution. Excellent correspondence between uptake curves of Cy5.5/GdDOTA and Endorem/Angiosense has been found with correlation coefficients R > 0.98. The two modalities revealed good agreement regarding permeability coefficients and centers-of-gravity of the imaging agent distribution. The FMT/dFRI protocol presented is able to accurately map physiological processes and poses an attractive alternative to MRI for characterizing tumor neoangiogenesis.

Lyophilized Kit for the Preparation of the PET Perfusion Agent [(68)Ga]-MAA.

PubMed

Amor-Coarasa, Alejandro; Milera, Andrew; Carvajal, Denny; Gulec, Seza; McGoron, Anthony J

2014-01-01

Rapid developments in the field of medical imaging have opened new avenues for the use of positron emitting labeled microparticles. The radioisotope used in our research was (68)Ga, which is easy to obtain from a generator and has good nuclear properties for PET imaging. Methods. Commercially available macroaggregated albumin (MAA) microparticles were suspended in sterile saline, centrifuged to remove the free albumin and stannous chloride, relyophilized, and stored for later labeling with (68)Ga. Labeling was performed at different temperatures and times. (68)Ga purification settings were also tested and optimized. Labeling yield and purity of relyophilized MAA microparticles were compared with those that were not relyophilized. Results. MAA particles kept their original size distribution after relyophilization. Labeling yield was 98% at 75°C when a (68)Ga purification system was used, compared to 80% with unpurified (68)Ga. Radiochemical purity was over 97% up to 4 hours after the labeling. The relyophilized MAA and labeling method eliminate the need for centrifugation purification of the final product and simplify the labeling process. Animal experiments demonstrated the high in vivo stability of the obtained PET agent with more than 95% of the activity remaining in the lungs after 4 hours.

Factors affecting the lung perfused blood volume in patients with intrapulmonary clots after anti-coagulation therapy.

PubMed

Okada, Munemasa; Masuda, Yu; Nakashima, Yoshiteru; Nomura, Takafumi; Nakao, Sei; Suga, Kazuyoshi; Kido, Shoji; Matsunaga, Naofumi

2015-08-01

Factors affecting the improvement in the lung perfused blood volume (LPBV) were evaluated based on the presence of intrapulmonary clots (IPCs) after anti-coagulation therapy using 64-slice dual-energy CT. 96 patients exhibiting venous thromboembolism underwent initial and repeated LPBV examinations between December 2008 and July 2014. Fifteen patients were excluded due to pulmonary comorbidities, and a total of 81 patients were included in this study. Acute pulmonary embolism (PE) was diagnosed in 46 of the patients (56.7%). LPBV images were three-dimensionally reconstructed with two threshold ranges: 1-120 HU (V120) and 1-5 HU (V5), and the relative value of V5 per V120 expressed as %V5. These values were subsequently compared with indicators of the severity of PE, such as the D-dimer level, heart rate and CT measurements. This study was approved by the local ethics committee. In patients with IPCs, the D-dimer, V5 and %V5values were significantly larger (p≤0.01) in the initial LPBV, although these differences disappeared in subsequent LPBV after treatment. The right ventricular (RV) diameter, RV/left ventricular (RV/LV) diameter ratio and %V5 values were also significantly reduced, whereas the V5 value did not significantly decrease (p=0.07), but V120 value significantly increased (p<0.001) after treatment. However, in patients with IPCs the change rate in %V5 [(subsequent-initial)/initial %V5] showed a better correlation with that in V5 (r=0.94, p<0.001) rate than that in V120 (r=0.19, p=0.19) after treatment. Increased whole lung perfusion (V120) and a decreased low perfusion volume (V5) affect the improvement in the %V5 values after treatment. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

The influence of intraoperative pleural perfusion with matrine-cisplatin or cisplatin on stromal cell-derived factor-1 in non-small cell lung cancer patients with subclinical pleural metastasis.

PubMed

Yang, Cheng-Liang; Liu, Shun-Shou; Ma, Ye-Gang; Liu, Yong-Yu; Xue, Yi-Xue; Huang, Bo

2012-06-01

The early diagnosis and treatment of non-small cell lung cancer (NSCLC) in patients with subclinical pleural metastasis is currently a challenge. In an effort to establish a method for the diagnosis and treatment of these patients, we conducted a single-blind study during which intraoperative pleural lavage cytology (PLC) was performed in 164 patients with NSCLC without obvious pleural effusion. Stromal cell-derived factor-1 (SDF-1) serum concentrations were analyzed using enzyme-linked immunoassay on day 1 prior to tumor resection and on day 7 postoperatively. Western blot analysis was used for the detection of CXCR4 protein expression in resected tumors. Intraoperative pleural perfusion chemotherapy, with either cisplatin or cisplatin plus matrine, was given to patients with positive PLC. A group of 30 patients with NSCLC that did not undergo intraoperative PLC were used as a control group. Of the 164 study patients, 41 (25%) patients had positive PLC. Serum SDF-1 concentrations were higher in PLC-positive patients compared with patients negative for PLC and control patients. Serum SDF-1 concentrations were also lower at postoperative day 7 in patients treated with cisplatin plus matrine compared with control patients and those perfused with cisplatin alone. A lower incidence of chemotherapy-related adverse events was observed in patients treated with cisplatin plus matrine versus those treated with cisplatin alone during the first postoperative month. Patients with positive PLC showed a higher CXCR4 protein expression than patients with negative PLC. Based on the results of this study, PLC combined with serum SDF-1 concentration measurements may be considered as an effective index to determine the risk of subclinical pleural metastasis in patients with lung cancer. In addition, cisplatin plus matrine was confirmed as an initial approach for pleural perfusion and was superior to cisplatin alone.

Comparison of adaptive optics scanning light ophthalmoscopic fluorescein angiography and offset pinhole imaging

PubMed Central

Chui, Toco Y. P.; Dubow, Michael; Pinhas, Alexander; Shah, Nishit; Gan, Alexander; Weitz, Rishard; Sulai, Yusufu N.; Dubra, Alfredo; Rosen, Richard B.

2014-01-01

Recent advances to the adaptive optics scanning light ophthalmoscope (AOSLO) have enabled finer in vivo assessment of the human retinal microvasculature. AOSLO confocal reflectance imaging has been coupled with oral fluorescein angiography (FA), enabling simultaneous acquisition of structural and perfusion images. AOSLO offset pinhole (OP) imaging combined with motion contrast post-processing techniques, are able to create a similar set of structural and perfusion images without the use of exogenous contrast agent. In this study, we evaluate the similarities and differences of the structural and perfusion images obtained by either method, in healthy control subjects and in patients with retinal vasculopathy including hypertensive retinopathy, diabetic retinopathy, and retinal vein occlusion. Our results show that AOSLO OP motion contrast provides perfusion maps comparable to those obtained with AOSLO FA, while AOSLO OP reflectance images provide additional information such as vessel wall fine structure not as readily visible in AOSLO confocal reflectance images. AOSLO OP offers a non-invasive alternative to AOSLO FA without the need for any exogenous contrast agent. PMID:24761299

Histamine release, formation of prostaglandin-like activity (SRS-C) and mast cell degranulation by the direct lytic factor (DLF) and phospholipase A of cobra venom.

PubMed

Damerau, B; Lege, L; Oldigs, H D; Vogt, W

1975-01-01

Cobra venom, alone and in combination, on mast cell degranulation, histamine release and formation of prostaglandin-like activity (SRS-C) was studied in perfused guinea-pig lungs and in mast cell-containing rat peritoneal cell suspensions. For comparison, the effect of equivalent doses of whole cobra venom was investigated. 1. Cobra venom caused mast cell degranulation, histamine release and SRS-C formation in both systems. For comparable effects much higher doses had to be used in guine-pig lungs than in rat peritoneal cell suspensions. 2. Phase A showed little degranulation of mast cells in both systems, a limited histamine release in rat peritoneal cell suspensions and none in perfused guinea-pig lungs. It caused a considerable SRS-C formation in both, lung tissue and peritoneal cell suspensions. 3. DLF caused histamine release, SRS-C formation and mast cell degranulation in both systems; in rat peritoneal cell suspensions it acted almost as strong as equivalent doses of cobra venom, in guinea pig lungs it was much less active. 4. In rat peritoneal cell suspensions the effects of DLF and phase A in combination did not exceed the sum of their single effects. In guinea-pig lungs these two substances interacted in a potentiating synergism. It is concluded that DLF is the main cytotoxic principle of cobra venom, whereas ph-ase A alone is not cytotoxic. The difference in the synergism of DLF and ph-ase A between rat peritoneal cells and guinea-pig lungs may be due to two different actions of DLF and species differences as regards sensitivity against these actions.

Effects of vasoactive intestinal polypeptide on antigen-induced bronchoconstriction and thromboxane release in guinea-pig lung.

PubMed Central

Ciabattoni, G.; Montuschi, P.; Currò, D.; Togna, G.; Preziosi, P.

1993-01-01

1. Exogenous vasoactive intestinal polypeptide (VIP) infused into the pulmonary artery of isolated and ventilated lungs of guinea-pigs decreased, in a dose-dependent fashion (1.0-10.0 nmol), airway resistance and thromboxane B2 (TXB2, the stable hydrolysis product of TXA2) release in the perfusion medium. Prostacyclin (PGI2) synthesis, as reflected by the release of its stable hydrolysis product 6-oxo-PGF1 alpha, was unaffected. Pretreatment with the 5-lipoxygenase inhibitor BWA4c (3.5 x 10(-5) M) did not modify the bronchodilatory effect of VIP or its inhibitory action on TXB2 release. 2. Basal release of immunoreactive VIP from perfused lungs decreased from an initial value of 0.96 +/- 0.10 ng min-1 (mean +/- s.e.mean) in the first 2 min to an average of 0.58 +/- 0.10 ng min-1 in the following 15-20 min. 3. Antigen challenge with ovalbumin (0.1%) in sensitized lungs caused an anaphylactic reaction in 45% of tested lungs, concomitant with a 5 fold increase in both VIP and TXB2 release. Tetrodotoxin pretreatment (10(-6) M) reduced basal VIP release by > 80% and abolished the VIP increase observed during anaphylaxis, without modifying TXB2 release or the bronchoconstrictor response. 4. Indomethacin (10(-6) M) inhibited TXB2 synthesis and release by > 90%, delayed the bronchoconstrictor response and blunted the increased VIP release during lung anaphylaxis, without influencing basal VIP release. 5. The 5-lipoxygenase inhibitor BWA4c (3.5 x 10(-5) M) blunted the increase of TXB2 and VIP release from guinea-pig lung and attenuated the bronchoconstrictor response following ovalbumin challenge.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8495242

Isolated Lung Perfusion as an Adjuvant Treatment of Colorectal Cancer Lung Metastases: A Preclinical Study in a Pig Model

PubMed Central

Pagès, Pierre-Benoit; Facy, Olivier; Mordant, Pierre; Ladoire, Sylvain; Magnin, Guy; Lokiec, Francois; Ghiringhelli, Francois; Bernard, Alain

2013-01-01

Background The lung is a frequent site of colorectal cancer (CRC) metastases. After surgical resection, lung metastases recurrences have been related to the presence of micrometastases, potentially accessible to a high dose chemotherapy administered via adjuvant isolated lung perfusion (ILP). We sought to determine in vitro the most efficient drug when administered to CRC cell lines during a short exposure and in vivo its immediate and delayed tolerance when administered via ILP. Methods First, efficacy of various cytotoxic molecules against a panel of human CRC cell lines was tested in vitro using cytotoxic assay after a 30-minute exposure. Then, early (operative) and delayed (1 month) tolerance of two concentrations of the molecule administered via ILP was tested on 19 adult pigs using hemodynamic, biological and histological criteria. Results In vitro, gemcitabine (GEM) was the most efficient drug against selected CRC cell lines. In vivo, GEM was administered via ILP at regular (20 µg/ml) or high (100 µg/ml) concentrations. GEM administration was associated with transient and dose-dependant pulmonary vasoconstriction, leading to a voluntary decrease in pump inflow in order to maintain a stable pulmonary artery pressure. After this modulation, ILP using GEM was not associated with any systemic leak, systemic damage, and acute or delayed histological pulmonary toxicity. Pharmacokinetics studies revealed dose-dependant uptake associated with heterogenous distribution of the molecule into the lung parenchyma, and persistent cytotoxicity of venous effluent. Conclusions GEM is effective against CRC cells even after a short exposure. ILP with GEM is a safe and reproducible technique. PMID:23527205

Excitotoxicity in the Lung: N-Methyl-D-Aspartate-Induced, Nitric Oxide-Dependent, Pulmonary Edema is Attenuated by Vasoactive Intestinal Peptide and by Inhibitors of Poly(ADP-Ribose) Polymerase

NASA Astrophysics Data System (ADS)

Said, Sami I.; Berisha, Hasan I.; Pakbaz, Hedayatollah

1996-05-01

Excitatory amino acid toxicity, resulting from overactivation of N-methyl-D-aspartate (NMDA) glutamate receptors, is a major mechanism of neuronal cell death in acute and chronic neurological diseases. We have investigated whether excitotoxicity may occur in peripheral organs, causing tissue injury, and report that NMDA receptor activation in perfused, ventilated rat lungs triggered acute injury, marked by increased pressures needed to ventilate and perfuse the lung, and by high-permeability edema. The injury was prevented by competitive NMDA receptor antagonists or by channel-blocker MK-801, and was reduced in the presence of Mg2+. As with NMDA toxicity to central neurons, the lung injury was nitric oxide (NO) dependent: it required L-arginine, was associated with increased production of NO, and was attenuated by either of two NO synthase inhibitors. The neuropeptide vasoactive intestinal peptide and inhibitors of poly(ADP-ribose) polymerase also prevented this injury, but without inhibiting NO synthesis, both acting by inhibiting a toxic action of NO that is critical to tissue injury. The findings indicate that: (i) NMDA receptors exist in the lung (and probably elsewhere outside the central nervous system), (ii) excessive activation of these receptors may provoke acute edematous lung injury as seen in the ``adult respiratory distress syndrome,'' and (iii) this injury can be modulated by blockade of one of three critical steps: NMDA receptor binding, inhibition of NO synthesis, or activation of poly(ADP-ribose) polymerase.

Inhibition of Acid-induced Lung Injury by Hyperosmolar Sucrose in Rats

PubMed Central

Safdar, Zeenat; Yiming, Maimiti; Grunig, Gabriele; Bhattacharya, Jahar

2005-01-01

Rationale: Acid aspiration causes acute lung injury (ALI). Recently, we showed that a brief intravascular infusion of hyperosmolar sucrose, given concurrently with airway acid instillation, effectively blocks the ensuing ALI. Objectives: The objective of the present study was to determine the extent to which intravascular infusion of hyperosmolar sucrose might protect against acid-induced ALI when given either before or after acid instillation. Methods: Our studies were conducted in anesthetized rats and in isolated, blood-perfused rat lungs. We instilled HCl through the airway, and we quantified lung injury in terms of the extravascular lung water (EVLW) content, filtration coefficient (Kfc), and cell counts and protein concentration in the bronchoalveolar lavage. We infused hyperosmolar sucrose via the femoral vein. Results: In anesthetized rats, airway HCl instillation induced ALI as indicated by a 52% increase of EVLW and a threefold increase in Kfc. However, a 15-min intravenous infusion of hyperosmolar sucrose given up to 1 h before or 30 min after acid instillation markedly blunted the increases in EVLW, as well as the increases in cell count, and in protein concentration in the bronchoalveolar lavage. Hyperosmolar pretreatment also blocked the acid-induced increase of Kfc. Studies in isolated perfused lungs indicated that the protective effect of hyperosmolar sucrose was leukocyte independent. Conclusions: We conclude that a brief period of vascular hyperosmolarity protects against acid-induced ALI when the infusion is administered shortly before, or shortly after, acid instillation in the airway. The potential applicability of hyperosmolar sucrose in therapy for ALI requires consideration. PMID:16109982

TU-CD-BRA-08: Single-Energy Computed Tomography-Based Pulmonary Perfusion Imaging: Proof-Of-Principle in a Canine Model

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yamamoto, T; Boone, J; Kent, M

Purpose: Pulmonary perfusion imaging has provided significant insights into pulmonary diseases, and can be useful in radiotherapy. The purpose of this study was to prospectively establish proof-of-principle in a canine model for single-energy CT-based perfusion imaging, which has the potential for widespread clinical implementation. Methods: Single-energy CT perfusion imaging is based on: (1) acquisition of inspiratory breath-hold CT scans before and after intravenous injection of iodinated contrast medium, (2) deformable image registration (DIR) of the two CT image data sets, and (3) subtraction of the pre-contrast image from post-contrast image, yielding a map of Hounsfield unit (HU) enhancement. These subtractionmore » image data sets hypothetically represent perfused blood volume, a surrogate for perfusion. In an IACUC-approved clinical trial, we acquired pre- and post-contrast CT scans in the prone posture for six anesthetized, mechanically-ventilated dogs. The elastix algorithm was used for DIR. The registration accuracy was quantified using the target registration errors (TREs) for 50 pulmonary landmarks in each dog. The gradient of HU enhancement between gravity-dependent (ventral) and non-dependent (dorsal) regions was evaluated to quantify the known effect of gravity, i.e., greater perfusion in ventral regions. Results: The lung volume difference between the two scans was 4.3±3.5% on average (range 0.3%–10.1%). DIR demonstrated an average TRE of 0.7±1.0 mm. HU enhancement in lung parenchyma was 34±10 HU on average and varied considerably between individual dogs, indicating the need for improvement of the contrast injection protocol. HU enhancement in ventral (gravity-dependent) regions was found to be greater than in dorsal regions. A population average ventral-to-dorsal gradient of HU enhancement was strong (R{sup 2}=0.94) and statistically significant (p<0.01). Conclusion: This canine study demonstrated relatively accurate DIR and a strong ventral-to-dorsal gradient of HU enhancement, providing proof-of-principle for single-energy CT pulmonary perfusion imaging. This ongoing study will enroll more dogs and investigate the physiological significance. This study was supported by a Philips Healthcare/Radiological Society of North America (RSNA) Research Seed Grant (RSD1458)« less

Transient right-to-left shunt in massive pulmonary embolism.

PubMed

Panoutsopoulos, G; Ilias, L; Christakopoulou, I

2000-06-01

A 56-yr-old man, two months after an operation for an acoustic neurinoma, gradually developed dyspnea. Massive pulmonary embolism (MPE), with a significant right-to-left (R-L) shunt, was seen in a perfusion scan of the lungs with Tc-99m MAA. Radioactivity was noted in the thyroid, spleen, kidneys and brain. A cardiac ultrasound study did not reveal intracardiac shunting. A few days later, when the patient's condition improved, another perfusion scan of the lungs did not show the shunt, whereas a subsequent digital subtraction angiographic study confirmed the diagnosis of MPE but failed to reveal the cause of the shunt. In the absence of any possible pathophysiological mechanism, to explain the observed R-L shunt, we deduce that the particles of Tc-99m MAA might have passed through the precapillary pulmonary arteriovenous anastomoses and/or through dilated pulmonary capillaries, as a result of highly increased pulmonary vascular pressure due to MPE.

Imaging angiogenesis.

PubMed

Charnley, Natalie; Donaldson, Stephanie; Price, Pat

2009-01-01

There is a need for direct imaging of effects on tumor vasculature in assessment of response to antiangiogenic drugs and vascular disrupting agents. Imaging tumor vasculature depends on differences in permeability of vasculature of tumor and normal tissue, which cause changes in penetration of contrast agents. Angiogenesis imaging may be defined in terms of measurement of tumor perfusion and direct imaging of the molecules involved in angiogenesis. In addition, assessment of tumor hypoxia will give an indication of tumor vasculature. The range of imaging techniques available for these processes includes positron emission tomography (PET), dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), perfusion computed tomography (CT), and ultrasound (US).

Hypoxia-preconditioned mesenchymal stem cells ameliorate ischemia/reperfusion-induced lung injury.

PubMed

Liu, Yung-Yang; Chiang, Chi-Huei; Hung, Shih-Chieh; Chian, Chih-Feng; Tsai, Chen-Liang; Chen, Wei-Chih; Zhang, Haibo

2017-01-01

Hypoxia preconditioning has been proven to be an effective method to enhance the therapeutic action of mesenchymal stem cells (MSCs). However, the beneficial effects of hypoxic MSCs in ischemia/reperfusion (I/R) lung injury have yet to be investigated. In this study, we hypothesized that the administration of hypoxic MSCs would have a positive therapeutic impact on I/R lung injury at molecular, cellular, and functional levels. I/R lung injury was induced in isolated and perfused rat lungs. Hypoxic MSCs were administered in perfusate at a low (2.5×105 cells) and high (1×106 cells) dose. Rats ventilated with a low tidal volume of 6 ml/kg served as controls. Hemodynamics, lung injury indices, inflammatory responses and activation of apoptotic pathways were determined. I/R induced permeability pulmonary edema with capillary leakage and increased levels of reactive oxygen species (ROS), pro-inflammatory cytokines, adhesion molecules, cytosolic cytochrome C, and activated MAPK, NF-κB, and apoptotic pathways. The administration of a low dose of hypoxic MSCs effectively attenuated I/R pathologic lung injury score by inhibiting inflammatory responses associated with the generation of ROS and anti-apoptosis effect, however this effect was not observed with a high dose of hypoxic MSCs. Mechanistically, a low dose of hypoxic MSCs down-regulated P38 MAPK and NF-κB signaling but upregulated glutathione, prostaglandin E2, IL-10, mitochondrial cytochrome C and Bcl-2. MSCs infused at a low dose migrated into interstitial and alveolar spaces and bronchial trees, while MSCs infused at a high dose aggregated in the microcirculation and induced pulmonary embolism. Hypoxic MSCs can quickly migrate into extravascular lung tissue and adhere to other inflammatory or structure cells and attenuate I/R lung injury through anti-oxidant, anti-inflammatory and anti-apoptotic mechanisms. However, the dose of MSCs needs to be optimized to prevent pulmonary embolism and thrombosis.

Hypoxia-preconditioned mesenchymal stem cells ameliorate ischemia/reperfusion-induced lung injury

PubMed Central

Chiang, Chi-Huei; Hung, Shih-Chieh; Chian, Chih-Feng; Tsai, Chen-Liang; Chen, Wei-Chih; Zhang, Haibo

2017-01-01

Background Hypoxia preconditioning has been proven to be an effective method to enhance the therapeutic action of mesenchymal stem cells (MSCs). However, the beneficial effects of hypoxic MSCs in ischemia/reperfusion (I/R) lung injury have yet to be investigated. In this study, we hypothesized that the administration of hypoxic MSCs would have a positive therapeutic impact on I/R lung injury at molecular, cellular, and functional levels. Methods I/R lung injury was induced in isolated and perfused rat lungs. Hypoxic MSCs were administered in perfusate at a low (2.5×105 cells) and high (1×106 cells) dose. Rats ventilated with a low tidal volume of 6 ml/kg served as controls. Hemodynamics, lung injury indices, inflammatory responses and activation of apoptotic pathways were determined. Results I/R induced permeability pulmonary edema with capillary leakage and increased levels of reactive oxygen species (ROS), pro-inflammatory cytokines, adhesion molecules, cytosolic cytochrome C, and activated MAPK, NF-κB, and apoptotic pathways. The administration of a low dose of hypoxic MSCs effectively attenuated I/R pathologic lung injury score by inhibiting inflammatory responses associated with the generation of ROS and anti-apoptosis effect, however this effect was not observed with a high dose of hypoxic MSCs. Mechanistically, a low dose of hypoxic MSCs down-regulated P38 MAPK and NF-κB signaling but upregulated glutathione, prostaglandin E2, IL-10, mitochondrial cytochrome C and Bcl-2. MSCs infused at a low dose migrated into interstitial and alveolar spaces and bronchial trees, while MSCs infused at a high dose aggregated in the microcirculation and induced pulmonary embolism. Conclusions Hypoxic MSCs can quickly migrate into extravascular lung tissue and adhere to other inflammatory or structure cells and attenuate I/R lung injury through anti-oxidant, anti-inflammatory and anti-apoptotic mechanisms. However, the dose of MSCs needs to be optimized to prevent pulmonary embolism and thrombosis. PMID:29117205

Early results in transplantation of initially rejected donor lungs after ex vivo lung perfusion: a case-control study.

PubMed

Wallinder, Andreas; Ricksten, Sven-Erik; Silverborn, Martin; Hansson, Christoffer; Riise, Gerdt C; Liden, Hans; Jeppsson, Anders; Dellgren, Göran

2014-01-01

An increasing number of studies have shown that ex vivo lung perfusion (EVLP) is safe and that rejected donor lungs can be resuscitated and used for lung transplantation (LTx). Early clinical outcomes in patients transplanted with reconditioned lungs at our centre were reviewed and compared with those of contemporary non-EVLP controls. During 18 months starting January 2011, 11 pairs of donor lungs initially deemed unsuitable for transplantation underwent EVLP. Haemodynamic (pulmonary flow, vascular resistance and artery pressure) and respiratory (peak airway pressure and compliance) parameters were analysed during evaluation. Lungs that improved (n = 11) to meet International Society of Heart and Lung Transplantation criteria were transplanted and compared with patients transplanted with non-EVLP lungs (n = 47) during the same time period. Donor lungs were initially rejected due to either inferior PaO2/FiO2 ratio (n = 9), bilateral infiltrate on chest X-ray (n = 1) or ongoing extra corporeal membrane oxygenation (n = 1). The donor lungs improved from a mean PaO2/FiO2 ratio of 27.9 kPa in the donor to a mean of 59.6 kPa at the end of the EVLP (median improvement 28.4 kPa, range 21.0-50.7 kPa). Two single lungs were deemed unsuitable and not used for LTx. Eleven recipients from the regular waiting list underwent either single (n = 3) LTx or double (n = 8) LTx with EVLP-treated lungs. The median time to extubation (12 (range, 3-912) vs 6 (range, 2-1296) h) and median intensive care unit (ICU) stay (152 (range, 40-625) vs 48 (range, 22-1632) h) were longer in the EVLP group (P = 0.05 and P = 0.01, respectively). There were no differences in length of hospital stay (median 28 (range 25-93) vs 28 (18-209), P = 0.21). Two patients in the EVLP group and 6 in the control group had primary graft dysfunction >Grade 1 at 72 h postoperatively. Three patients in the control group died before discharge. All recipients of EVLP lungs were discharged alive from hospital. The use of EVLP seems safe and indicates that lungs otherwise refused for LTx can be recovered and subsequently used for transplantation, although time to extubation and ICU stay were longer for the EVLP group.

Pediatric Lung Transplantation.

PubMed

Sweet, Stuart C

2017-06-01

Pediatric lung transplant is a viable option for treatment of end-stage lung disease in children, with > 100 pediatric lung transplants reported to the Registry of the International Society of Heart and Lung Transplantation each year. Long-term success is limited by availability of donor organs, debilitation as a result of chronic disease, impaired mucus clearance resulting from both surgical and pharmacologic interventions, increased risk for infection resulting from immunosuppression, and most importantly late complications, such as chronic lung allograft dysfunction. Opportunities for investigation and innovation remain in all of these domains: (1) Ex vivo lung perfusion is a promising technology with the potential for increasing the lung donor pool, (2) evolving extracorporeal support strategies coupled with effective rehabilitation will effectively bridge critically ill patients to transplant, and most importantly, (3) research efforts intended to increase our understanding of the underlying mechanisms of chronic lung allograft dysfunction will ultimately lead to the development of effective therapies to prevent or treat the variety of chronic lung allograft dysfunction presentations. Copyright © 2017 by Daedalus Enterprises.

An in vitro Comparison of Microdialysis Relative Recovery of Met- and Leu-Enkephalin Using Cyclodextrins and Antibodies as Affinity Agents

PubMed Central

Fletcher, Heidi J.; Stenken, Julie A.

2008-01-01

Cyclodextrins and antibodies have been used as affinity agents to improve relative recovery during microdialysis sampling. Two neuropeptides, methionine-enkephalin (ME) and leucine-enkephalin (LE), were chosen to compare the use of cyclodextrins and antibodies as possible affinity agents for improving their relative recovery across polycarbonate and polyethersulfone membranes during in vitro sampling. Cyclodextrins (CD) including β-CD, 2-hydroxypropyl-β-cyclodextrin (2HPβ-CD), and γ-CD gave improvements of relative recovery for both peptides of less than 2-fold as compared to controls. Comparisons of relative recovery between tyrosine-glycine-glycine, tyrosine, and phenylalanine using different cyclodextrins in the perfusion fluid were also obtained. Inclusion of an antibody against met-enkephalin in the microdialysis perfusion fluid resulted in relative recovery increases of up to 2.5-fold. These results show that using antibodies as affinity agents during microdialysis sampling may be more effective agents to improve the relative recovery of these opioid neuropeptides. PMID:18558138

A Novel Growth Factor and Anti-Apoptotic Agent for Promoting Lung Development and Treating Lung Disease | NCI Technology Transfer Center | TTC

Cancer.gov

Researchers at the NCI have developed a new therapeutic strategy for lung cancer using secretoglobin family 3A member 2 (SCGB3A2), as a cell proliferative and anti-apoptotic agent. SCGB3A2 can be used to inhibit lung damage that results from treatment with anti-cancer agents. NCI seeks parties to license or co-develop this technology.

Synthesis of fluorine-18 labeled rhodamine B: A potential PET myocardial perfusion imaging agent

PubMed Central

Heinrich, Tobias K.; Gottumukkala, Vijay; Snay, Erin; Dunning, Patricia; Fahey, Frederic H; Treves, S. Ted; Packard, Alan B.

2009-01-01

There is considerable interest in developing an 18F-labeled PET myocardial perfusion agent. Rhodamine dyes share several properties with 99mTc-MIBI, the most commonly used single-photon myocardial perfusion agent, suggesting that an 18F-labeled rhodamine dye might prove useful for this application. In addition to being lipophilic cations, like 99mTc-MIBI, rhodamine dyes are known to accumulate in the myocardium and are substrates for Pgp, the protein implicated in MDR1 multidrug resistance. As the first step in determining whether 18F-labeled rhodamines might be useful as myocardial perfusion agents for PET, our objective was to develop synthetic methods for preparing the 18F-labeled compounds so that they could be evaluated in vivo. Rhodamine B was chosen as the prototype compound for development of the synthesis because the ethyl substituents on the amine moieties of rhodamine B protect them from side reactions, thus eliminating the need to include (and subsequently remove) protecting groups. The 2′-[18F]fluoroethyl ester of rhodamine B was synthesized by heating rhodamine B lactone with [18F]fluoroethyltosylate in acetonitrile at 165°C for 30 min.using [18F]fluoroethyl tosylate, which was prepared by the reaction of ethyleneglycol ditosylate with Kryptofix 2.2.2, K2CO3, and [18F]NaF in acetonitrile for 10 min. at 90°C. The product was purified by semi-preparative HPLC to produce the 2′-[18F]-fluoroethylester in >97% radiochemical purity with a specific activity of 1.3 GBq/μmol, an isolated decay corrected yield of 35%, and a total synthesis time of 90 min. PMID:19783150

Partial liquid ventilation reduces fluid filtration of isolated rabbit lungs with acute hydrochloric acid-induced edema.

PubMed

Loer, S A; Tarnow, J

2001-06-01

Hydrochloric acid aspiration increases pulmonary microvascular permeability. The authors tested the hypothesis that partial liquid ventilation has a beneficial effect on filtration coefficients in acute acid-induced lung injury. Isolated blood-perfused rabbit lungs were assigned randomly to one of four groups. Group 1 (n = 6) served as a control group without edema. In group 2 (n = 6), group 3 (n = 6), and group 4 (n = 6), pulmonary edema was induced by intratracheal instillation of hydrochloric acid (0.1 N, 2 ml/kg body weight). Filtration coefficients were determined 30 min after this injury (by measuring loss of perfusate after increase of left atrial pressure). Group 2 lungs were gas ventilated, and group 3 lungs received partial liquid ventilation (15 ml perfluorocarbon/kg body weight). In group 4 lungs, the authors studied the immediate effects of bronchial perfluorocarbon instillation on ongoing filtration. Intratracheal instillation of hydrochloric acid markedly increased filtration coefficients when compared with non-injured control lungs (2.3 +/- 0.7 vs. 0.31 +/- 0.08 ml.min(-1). mmHg(-1).100 g(-1) wet lung weight, P < 0.01). Partial liquid ventilation reduced filtration coefficients of the injured lungs (to 0.9 +/- 0.3 ml.min(-1).mmHg(-1).100 g(-1) wet lung weight, P = 0.022). Neither pulmonary artery nor capillary pressures (determined by simultaneous occlusion of inflow and outflow of the pulmonary circulation) were changed by hydrochloric acid instillation or by partial liquid ventilation. During ongoing filtration, bronchial perfluorocarbon instillation (5 ml/kg body weight) immediately reduced the amount of filtered fluid by approximately 50% (P = 0.027). In the acute phase after acid injury, partial liquid ventilation reduced pathologic fluid filtration. This effect started immediately after bronchial perfluorocarbon instillation and was not associated with changes in mean pulmonary artery, capillary, or airway pressures. The authors suggest that in the early phase of acid injury, reduction of fluid filtration contributes to the beneficial effects of partial liquid ventilation on gas exchange and lung mechanics.

A novel anticancer agent SNG1153 inhibits growth of lung cancer stem/progenitor cells

PubMed Central

Wang, Jing; Zhu, Hai; Han, Yuqing; Jin, Mingji; Wang, Jun; Zhou, Congya; Ma, Junfeng; Lin, Qingcong; Wang, Zhaoyi; Meng, Kun; Fu, Xueqi

2016-01-01

Lung cancer is the leading cause of cancer-related death in both men and women. Lung cancer contains a small population of cancer cells with stem-like features known as cancer stem cells (CSCs). CSCs are often more resistant to current therapeutic treatments. Thus, it is urgent to develop a novel agent that is able to inhibit CSCs growth. In this study, we examined the ability of SNG1153, a novel chemical agent to inhibit the growth of lung CSCs. We found that SNG1153 inhibited growth and induced apoptosis in established lung cancer cells. We also found that SNG1153 inhibited the tumorsphere formation and decreased CD133-positive (lung CSC marker) cancer cells. SNG1153 was able to attenuate tumor formation in NOD/SCID (non-obese diabetic/severe combined immunodeficient) mice injected with lung tumorsphere cells. We further demonstrated that SNG1153 induced β-catenin phosphorylation and down-regulated β-catenin. Our results thus demonstrate that SNG1153 effectively inhibits the growth of lung CSCs and suggest that SNG1153 may be a novel therapeutic agent to treat human lung cancer. PMID:27281614

RADIOAUTOGRAPHIC DEMONSTRATION OF 5-HYDROXYTRYPTAMINE-3H UPTAKE BY PULMONARY ENDOTHELIAL CELLS

PubMed Central

Strum, Judy M.; Junod, Alain F.

1972-01-01

The lung is able to rapidly remove 5-hydroxytryptamme (5-HT) from the circulation by a Na+-dependent transport mechanism. In order to identify the sites of uptake, radioautographic studies were done on rat lungs which had been isolated and perfused with 5-HT-3H and 0 5 mM iproniazid, a monoamine oxidase inhibitor. In control experiments 10-4 M imipramine was added to the perfusate to inhibit the membrane transport of 5-HT At the light microscope level, silver grains were seen concentrated near capillaries and in the endothelium of large vessels From electron microscope radioautographs a semiquantitative grain count was made and 90% of the silver grains were observed over capillary endothelial cells. The grains were found over the nucleus and cytoplasm of the cell and shewed no preferential association with any particular cytoplasmic inclusion bodies, organelles, or vesicles Other cell types were unlabeled except for a few mast cells, certain vascular smooth muscle cells, and one nerve ending. This radioautographic demonstration of the cell type responsible for the rapid removal of 5-HT from the lung circulation clearly establishes the existence of a new metabolic role for pulmonary endothelial cells. PMID:5044755

Effect of stratified inequality of blood flow on gas exchange in liquid-filled lungs.

NASA Technical Reports Server (NTRS)

West, J. B.; Maloney, J. E.; Castle, B. L.

1972-01-01

This investigation set out to answer two questions: (1) are the distal alveoli in the terminal lung units less well perfused than the proximal alveoli, i.e., is there stratification of blood flow; and (2) if so, does this enhance gas exchange in the presence of stratified inequality of ventilation. Excised dog lungs were ventilated with saline and perfused with blood. Following single inspirations of xenon 133 in saline and various periods of breath holding, the expired xenon concentration against volume was measured and it confirmed marked stratified inequality of ventilation under these conditions. By measuring the rate of depletion of xenon from alveoli during a period of blood flow, we showed that the alveoli which emptied at the end of expiration had 16% less blood flow than those exhaling earlier. However, by measuring the xenon concentration in pulmonary venous blood, we found that about 10% less tracer was transferred from the alveoli into the blood when the inspired xenon was stratified within the respiratory zone. Thus while stratification of blood flow was confirmed, it was shown to impair rather than enhance the efficiency of gas transfer.

Validation of measurements of ventilation-to-perfusion ratio inequality in the lung from expired gas

NASA Technical Reports Server (NTRS)

Prisk, G. Kim; Guy, Harold J B.; West, John B.; Reed, James W.

2003-01-01

The analysis of the gas in a single expirate has long been used to estimate the degree of ventilation-perfusion (Va/Q) inequality in the lung. To further validate this estimate, we examined three measures of Va/Q inhomogeneity calculated from a single full exhalation in nine anesthetized mongrel dogs under control conditions and after exposure to aerosolized methacholine. These measurements were then compared with arterial blood gases and with measurements of Va/Q inhomogeneity obtained using the multiple inert gas elimination technique. The slope of the instantaneous respiratory exchange ratio (R slope) vs. expired volume was poorly correlated with independent measures, probably because of the curvilinear nature of the relationship due to continuing gas exchange. When R was converted to the intrabreath Va/Q (iV/Q), the best index was the slope of iV/Q vs. volume over phase III (iV/Q slope). This was strongly correlated with independent measures, especially those relating to inhomogeneity of perfusion. The correlations for iV/Q slope and R slope considerably improved when only the first half of phase III was considered. We conclude that a useful noninvasive measurement of Va/Q inhomogeneity can be derived from the intrabreath respiratory exchange ratio.

Effects of redox and sulfhydryl reagents on the bioelectric properties of the giant axon of the squid.

PubMed

Huneeus-Cox, F; Fernandez, H L; Smith, B H

1966-09-01

The effects of internally and externally applied sulfhydryl reagents on the bioelectric properties of the giant axon of the squid Loligo pealeii and Dosidicus gigas were studied. Cysteine-HCl (400 mM, pH 7.3) was used to remove axoplasm from the perfusion channel. Oxidizing agents (1 to 60 mM) tended to increase the duration of the action potential and had a slow, irreversible blocking effect when perfused internally; the membrane potential was little affected. Reducing agents applied internally caused a decrease in the spike duration without affecting its height or the membrane potential, although at high concentrations there was reversible deterioration of the action potential. Both external and internal perfusion of mercaptide-forming reagents caused deterioration in the action and membrane potentials with conduction block occurring in 5 to 45 min. 2-mercaptoethanol reversed the effects. Thiol alkylating reagents, iodoacetate and iodoacetamide, were without effect. N-ethylmaleimide did, however, block. Tests with chelating agents for nonheme iron in the membrane brought about no change in the electrical parameters. The implications of the present findings with regard to the macromolecular mechanism of excitation are discussed.

Effects of Redox and Sulfhydryl Reagents on the Bioelectric Properties of the Giant Axon of the Squid

PubMed Central

Huneeus-Cox, F.; Fernandez, H. L.; Smith, B. H.

1966-01-01

The effects of internally and externally applied sulfhydryl reagents on the bioelectric properties of the giant axon of the squid Loligo pealeii and Dosidicus gigas were studied. Cysteine-HCl (400 mM, pH 7.3) was used to remove axoplasm from the perfusion channel. Oxidizing agents (1 to 60 mM) tended to increase the duration of the action potential and had a slow, irreversible blocking effect when perfused internally; the membrane potential was little affected. Reducing agents applied internally caused a decrease in the spike duration without affecting its height or the membrane potential, although at high concentrations there was reversible deterioration of the action potential. Both external and internal perfusion of mercaptide-forming reagents caused deterioration in the action and membrane potentials with conduction block occurring in 5 to 45 min. 2-mercaptoethanol reversed the effects. Thiol alkylating reagents, iodoacetate and iodoacetamide, were without effect. N-ethylmaleimide did, however, block. Tests with chelating agents for nonheme iron in the membrane brought about no change in the electrical parameters. The implications of the present findings with regard to the macromolecular mechanism of excitation are discussed. ImagesFigure 1 PMID:5970570

Chronic hypoxia decreases arterial and venous compliance in isolated perfused rat lungs: an effect that is reversed by exogenous l-arginine

PubMed Central

Jin, Yi; Chen, Bernadette; Calvert, Thomas J.; Chicoine, Louis G.; Liu, Yusen

2013-01-01

Chronic hypoxia (CH)-induced pulmonary hypertension is characterized by vasoconstriction and vascular remodeling, leading to right ventricular dysfunction. Given the role of arterial compliance (Ca) in right ventricular work, a decrease in Ca would add to right ventricular work. Nitric oxide (NO) is a potent vasodilator made by NO synthases from l-arginine (l-Arg). However, little is known of the effect of l-Arg on vascular compliance (Cv) in the lung. We hypothesized that exposure to CH would decrease Ca and that this effect would be reversed by exogenous l-Arg. Sprague-Dawley rats were exposed to either normoxia or CH for 14 days; the lungs were then isolated and perfused. Vascular occlusions were performed and modeled using a three-compliance, two-resistor model. Pressure-flow curves were generated, and a distensible vessel model was used to estimate distensibility and a vascular resistance parameter (R0). Hypoxia resulted in the expected increase in arterial resistance (Ra) as well as a decrease in both Ca and Cv. l-Arg had little effect on Ra, Ca, or Cv in isolated lungs from normoxic animals. l-Arg decreased Ra in lungs from CH rats and redistributed compliance to approximately that found in normoxic lungs. CH increased R0, and l-Arg reversed this increase in R0. l-Arg increased exhaled NO, and inhibition of l-Arg uptake attenuated the l-Arg-induced increase in exhaled NO. These data demonstrate that the CH-induced decrease in Ca was reversed by l-Arg, suggesting that l-Arg may improve CH-induced right ventricular dysfunction. PMID:23103497

Cryopreservation of Viable Human Lung Tissue for Versatile Post-thaw Analyses and Culture

PubMed Central

Baatz, John E.; Newton, Danforth A.; Riemer, Ellen C.; Denlinger, Chadrick E.; Jones, E. Ellen; Drake, Richard R.; Spyropoulos, Demetri D.

2018-01-01

Clinical trials are currently used to test therapeutic efficacies for lung cancer, infections and diseases. Animal models are also used as surrogates for human disease. Both approaches are expensive and time-consuming. The utility of human biospecimens as models is limited by specialized tissue processing methods that preserve subclasses of analytes (e.g. RNA, protein, morphology) at the expense of others. We present a rapid and reproducible method for the cryopreservation of viable lung tissue from patients undergoing lobectomy or transplant. This method involves the pseudo-diaphragmatic expansion of pieces of fresh lung tissue with cryoprotectant formulation (pseudo-diaphragmatic expansion-cryoprotectant perfusion or PDX-CP) followed by controlled-rate freezing in cryovials. Expansion-perfusion rates, volumes and cryoprotectant formulation were optimized to maintain tissue architecture, decrease crystal formation and increase long-term cell viability. Rates of expansion of 4 cc/min or less and volumes ranging from 0.8–1.2 × tissue volume were well-tolerated by lung tissue obtained from patients with chronic obstructive pulmonary disease or idiopathic pulmonary fibrosis, showing minimal differences compared to standard histopathology. Morphology was greatly improved by the PDX-CP procedure compared to simple fixation. Fresh versus post-thawed lung tissue showed minimal differences in histology, RNA integrity numbers and post-translational modified protein integrity (2-dimensional differential gel electrophoresis). It was possible to derive numerous cell types, including alveolar epithelial cells, fibroblasts and stem cells, from the tissue for at least three months after cryopreservation. This new method should provide a uniform, cost-effective approach to the banking of biospecimens, with versatility to be amenable to any post-acquisition process applicable to fresh tissue samples. PMID:24982205

Inhomogeneity of pulmonary perfusion during sustained microgravity

NASA Technical Reports Server (NTRS)

Prisk, G. Kim; Guy, Harold J. B.; Elliott, Ann R.; West, John B.

1994-01-01

The effects of gravity on the inhomogeneity of pulmonary perfusion in man were studied by performing hyperventilation-breathhold single-breath measurements before, during and after 9 days of continuous exposure to microgravity. In microgravity the indicators of inhomogeneity of perfusion, especially the size of cardiogenic oscillations in expired CO2 and the height of phase 4, were both markedly reduced. Cardiogenic oscillations were reduced to approximately 60 of their preflight standing size, while the height of phase 4 was between 0 and -8% (a terminal fall became a small terminal rise) of preflights standing. The terminal change in CO2 was nearly abolished in microgravity indicating more uniformity of blood flow between lung units that close at the end of expiration and units that remain open. This may result from the disappearance of gravity-dependent topographical inequality of blood flow. The residual cardiographic oscillations in expired CO2 imply a persisting inhomogeneity of perfusion in the absence of gravity at a level larger than acinar.

Experimental Study on the Efficacy of Site-Specific PEGylated Human Serum Albumins in Resuscitation From Hemorrhagic Shock.

PubMed

Song, Xinlei; Zhang, Shu; Cheng, Yanna; Zhao, Ting; Lian, Qianqian; Lu, Lu; Wang, Fengshan

2016-11-01

To evaluate the resuscitative efficacy and the effect on reperfusion injury of two site-specific PEGylated human serum albumins modified with linear or branched PEG20kDa, compared with saline, 8% human serum albumin and 25% human serum albumin, in a hemorrhagic shock model. Laboratory. Male Wistar rats. Prospective study. Rats were bled to hemorrhagic hypovolemic shock and resuscitated with different resuscitation fluids. The mean arterial pressure and blood gas variables were measured. Hemorheology analysis was performed to evaluate the influence of resuscitation on RBCs and blood viscosity. The microvascular state was indirectly characterized in terms of monocyte chemotactic protein-1 and endothelial nitric oxide synthase that related to shear stress and vasodilation, respectively. The levels of inflammation-related factors and apoptosis-related proteins were used to evaluate the reperfusion injury in lungs. The results showed that PEGylated human serum albumin could improve the level of mean arterial pressure and blood gas variables more effectively at the end of resuscitation. poly(ethylene glycol) modification was able to increase the viscosity of human serum albumin to the level of effectively enhancing the expression of monocyte chemotactic protein-1 and endothelial nitric oxide synthase, which could promote microvascular perfusion. The hyperosmotic resuscitative agents including both 25% human serum albumin and PEGylated human serum albumins could greatly attenuate lung injury. No significant therapeutic advantages but some disadvantages were found for Y shaped poly(ethylene glycol) modification over linear poly(ethylene glycol) modification, such as causing the decrease of erythrocyte deformability. Linear high molecular weight site-specific PEGylated human serum albumin is recommended to be used as a hyperosmotic resuscitative agent.

Absolute quantification of regional renal blood flow in swine by dynamic contrast-enhanced magnetic resonance imaging using a blood pool contrast agent.

PubMed

Lüdemann, Lutz; Nafz, Benno; Elsner, Franz; Grosse-Siestrup, Christian; Meissler, Michael; Kaufels, Nicola; Rehbein, Hagen; Persson, Pontus B; Michaely, Henrik J; Lengsfeld, Philipp; Voth, Matthias; Gutberlet, Matthias

2009-03-01

To evaluate for the first time in an animal model the possibility of absolute regional quantification of renal medullary and cortical perfusion by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) using a blood pool contrast agent. A total of 18 adult female pigs (age, 16-22 weeks; body weight, 45-65 kg; no dietary restrictions) were investigated by DCE-MRI. Absolute renal blood flow (RBF) measured by an ultrasound transit time flow probe around the renal vein was used as the standard of reference. An inflatable stainless cuff placed around the renal artery near its origin from the abdominal aorta was used to reduce RBF to 60%, 40%, and 20% of the baseline flow. The last measurement was performed with the cuff fully reopened. Absolute RBF values during these 4 perfusion states were compared with the results of DCE-MRI performed on a 1.5-T scanner with an 8-channel phased-array surface coil. All scans were acquired in breath-hold technique in the coronal plane using a field of view of 460 mm.Each dynamic scan commenced with a set of five 3D T1-weighted gradient echo sequences with different flip angles (alpha = 2 degrees, 5 degrees, 10 degrees, 20 degrees, 30 degrees): TE, 0.88 milliseconds; TR, 2.65 milliseconds; slice thickness, 8.8 mm for 4 slices; acquisition matrix, 128 x 128; and acquisitions, 4. These data served to calculate 3D intrinsic longitudinal relaxation rate maps (R10) and magnetization (M0). Immediately after these images, the dynamic 3D T1-weighted gradient echo images were acquired with the same parameters and a constant alpha = 30 degrees, half Fourier, 1 acquisition, 64 frames, a time interval of 1.65 seconds between each frame, and a total duration of 105.6. Three milliliters of an albumin-binding blood pool contrast agent (0.25 mmol/mL gadofosveset trisodium, Vasovist, Bayer Schering Pharma AG, Berlin, Germany) was injected at a rate of 3 mL/s. Perfusion was calculated using the arterial input function from the aorta, which was extracted from the dynamic relaxation rate change maps and perfusion images were calculated on a voxel-by-voxel basis using a singular value decomposition. In 11 pigs, 4 different perfusion states were investigated sequentially. The reduced kidney perfusion measured by ultrasound highly correlated with total renal blood flow determined by DCE-MRI, P < 0.001. The correlation coefficient between both measurements was 0.843. Regional cortical and medullary renal flow was also highly correlated (r = 0.77/0.78, P < 0.001) with the degree of flow reduction. Perfusion values smaller than 50 mL/min/100 cm were overestimated by MRI, high perfusion values slightly underestimated. DCE-MRI using a blood pool contrast agent allows absolute quantification of total kidney perfusion as well as separate determination of cortical and medullary flow. The results show that our technique has sufficient accuracy and reproducibility to be transferred to the clinical setting.

Theoretical considerations in measurement of time discrepancies between input and myocardial time-signal intensity curves in estimates of regional myocardial perfusion with first-pass contrast-enhanced MRI.

PubMed

Natsume, Takahiro; Ishida, Masaki; Kitagawa, Kakuya; Nagata, Motonori; Sakuma, Hajime; Ichihara, Takashi

2015-11-01

The purpose of this study was to develop a method to determine time discrepancies between input and myocardial time-signal intensity (TSI) curves for accurate estimation of myocardial perfusion with first-pass contrast-enhanced MRI. Estimation of myocardial perfusion with contrast-enhanced MRI using kinetic models requires faithful recording of contrast content in the blood and myocardium. Typically, the arterial input function (AIF) is obtained by setting a region of interest in the left ventricular cavity. However, there is a small delay between the AIF and the myocardial curves, and such time discrepancies can lead to errors in flow estimation using Patlak plot analysis. In this study, the time discrepancies between the arterial TSI curve and the myocardial tissue TSI curve were estimated based on the compartment model. In the early phase after the arrival of the contrast agent in the myocardium, the relationship between rate constant K1 and the concentrations of Gd-DTPA contrast agent in the myocardium and arterial blood (LV blood) can be described by the equation K1={dCmyo(tpeak)/dt}/Ca(tpeak), where Cmyo(t) and Ca(t) are the relative concentrations of Gd-DTPA contrast agent in the myocardium and in the LV blood, respectively, and tpeak is the time corresponding to the peak of Ca(t). In the ideal case, the time corresponding to the maximum upslope of Cmyo(t), tmax, is equal to tpeak. In practice, however, there is a small difference in the arrival times of the contrast agent into the LV and into the myocardium. This difference was estimated to correspond to the difference between tpeak and tmax. The magnitudes of such time discrepancies and the effectiveness of the correction for these time discrepancies were measured in 18 subjects who underwent myocardial perfusion MRI under rest and stress conditions. The effects of the time discrepancies could be corrected effectively in the myocardial perfusion estimates. Copyright © 2015 Elsevier Inc. All rights reserved.

RNA-Sequencing studies identify genes differentially regulated during inflammation-driven lung tumorigenesis and targeted by chemopreventive agents

PubMed Central

Qian, Xuemin; Khammanivong, Ali; Song, Jung Min; Teferi, Fitsum; Upadhyaya, Pramod; Dickerson, Erin; Kassie, Fekadu

2016-01-01

Chronic pulmonary inflammation has been consistently shown to increase the risk of lung cancer. Therefore, assessing the molecular links between the two diseases and identification of chemopreventive agents that inhibit inflammation-driven lung tumorigenesis is indispensable. Recently, we found that 4-(methylnitro-samino)-1-(3-pyridyl)-1-butanone (NNK)-induced mouse lung tumorigenesis was significantly enhanced by chronic treatment with the inflammatory agents lipopolysaccharide (LPS) and combinatory treatment with the chemoprevenitve agents silibinin (Sil) and indole-3-carbinol (I3C) significantly inhibited the burden of inflammation-driven lung tumors. In this report, we described gene expression profiling of lung tissues derived from these studies to determine the gene expression signature in inflammation-driven lung tumors and modulation of this signature by the chemopreventive agents Sil and I3C. We found that 330, 2,957, and 1,143 genes were differentially regulated in mice treated with NNK, LPS, and NNK + LPS, respectively. The inflammatory response of lung tumors to LPS, as determined by the number of proinflammatory genes with altered gene expression or the level of alteration, was markedly less than that of normal lungs. Among 1,143 genes differentially regulated in the NNK + LPS group, the expression of 162 genes and associated signaling pathways were significantly modulated by I3C and/or Sil + I3C. These genes include cytokines, chemokines, putative oncogenes and tumor suppressor genes and Ros1, AREG, EREG, Cyp1a1, Arntl, and Npas2. To our knowledge, this is the first report that provides insight into genes that are differentially expressed during inflammation-driven lung tumorigenesis and the modulation of these genes by chemopreventive agents. PMID:25795230

Rapid 3D in vivo 1H human lung respiratory imaging at 1.5 T using ultra-fast balanced steady-state free precession.

PubMed

Pusterla, Orso; Bauman, Grzegorz; Wielpütz, Mark O; Nyilas, Sylvia; Latzin, Philipp; Heussel, Claus P; Bieri, Oliver

2017-09-01

To introduce a reproducible, nonenhanced 1H MRI method for rapid in vivo functional assessment of the whole lung at 1.5 Tesla (T). At different respiratory volumes, the pulmonary signal of ultra-fast steady-state free precession (ufSSFP) follows an adapted sponge model, characterized by a respiratory index α. From the model, α reflects local ventilation-related information, is virtually independent from the lung density and thus from the inspiratory phase and breathing amplitude. Respiratory α-mapping is evaluated for healthy volunteers and patients with obstructive lung disease from a set of five consecutive 3D ultra-fast steady-state free precession (ufSSFP) scans performed in breath-hold and at different inspiratory volumes. For the patients, α-maps were compared with CT, dynamic contrast-enhanced MRI (DCE-MRI), and Fourier decomposition (FD). In healthy volunteers, respiratory α-maps showed good reproducibility and were homogeneous on iso-gravitational planes, but showed a gravity-dependent respiratory gradient. In patients with obstructive pulmonary disease, the functional impairment observed in respiratory α-maps was associated with emphysematous regions present on CT images, perfusion defects observable on DCE-MRI, and impairments visualized on FD ventilation and perfusion maps. Respiratory α-mapping derived from multivolumetric ufSSFP provides insights into functional lung impairment and may serve as a reproducible and normative measure for clinical studies. Magn Reson Med 78:1059-1069, 2017. © 2016 International Society for Magnetic Resonance in Medicine. © 2016 International Society for Magnetic Resonance in Medicine.

Pharmacokinetic evaluation of intrapleural perfusion with hyperthermic chemotherapy using cisplatin in patients with malignant pleural effusion.

PubMed

Sakaguchi, Hirozo; Ishida, H; Nitanda, H; Yamazaki, N; Kaneko, K; Kobayashi, Kunihiko

2017-02-01

Malignant pleural effusion (MPE) has a poor prognosis. Most patients are treated with tube thoracostomy and sclerotherapy, although its success rate is around 64%. We have investigated intrapleural perfusion with hyperthermic chemotherapy (IPHC) using cisplatin in a study with a pharmacokinetic evaluation. Patients with MPE, performance status of 0-1, possibility of good lung expansion and Cr<1.2mg/dL were treated with IPHC. The circuit was filled with 2000mL of normal saline containing cisplatin at a dose of 80mg/m 2 . Under video-assisted thoracoscopic surgery, the thoracic cavity was filled and perfused at a speed of approximately 1L/min at a temperature of 43°C for 1h. Perfusion solution and plasma samples were periodically collected, and concentrations of protein-unbound (free) platinum, which was the active derivative of cisplatin, and total platinum were determined by flameless atomic absorption spectrometry. Twenty patients with MPE (8 lung cancers, 7 mesotheliomas, and 5 others) were enrolled in this study. Rate of free platinum concentration relative to total platinum concentration in perfusion solution after 1hr IPHC at 43°C was 61.1±12.9%. Area under curve (AUC) of free platinum in the pleural space was calculated to be 26.3μg/mLxh, resulting in complete control of pleural effusion for 3 months after IHPC in all cases (95% confidence interval: 83-100%). While, absorption rate of total platinum from the pleural space was 33.8±17.0% (27.4±13.6mg/m 2 ), and the maximum concentration of total platinum in serum was low, 0.66±0.31μg/mL, resulting in controllable side effects; grade 1 renal toxicity: 6 patients, grade 1 emesis: 7 patients. IPHC with cisplatin showed favorable pharmacokinetic profiles for an optional treatment to control malignant pleural effusion. Copyright © 2016 The Author(s). Published by Elsevier B.V. All rights reserved.

[The perfusion technologist: extracorporeal circulation and hemodialysis].

PubMed

Degani, Antonella

2013-01-01

In 1812, the French physiologist Le Gallois hypothesized a device for obtaining extracorporeal circulation (ECC), although it wasn't until 1939 that Gibbon described in detail a machine that could substitute both heart and lungs. In 1954, the US Cardiac Surgeon Lillhei invented 'cross circulation', and the era of open heart surgery began. The development of ECC has created a new profession in medicine, the 'Perfusion Technologist' who is not only responsible for ECC, but also for hemodialysis equipment when this is also required. The present review aims to summarize all issues related to this medical profession.

PDGF-BB regulates the pulmonary vascular tone: impact of prostaglandins, calcium, MAPK- and PI3K/AKT/mTOR signalling and actin polymerisation in pulmonary veins of guinea pigs.

PubMed

Rieg, Annette D; Suleiman, Said; Anker, Carolin; Verjans, Eva; Rossaint, Rolf; Uhlig, Stefan; Martin, Christian

2018-06-19

Platelet-derived growth factor (PDGF)-BB and its receptor PDGFR are highly expressed in pulmonary hypertension (PH) and mediate proliferation. Recently, we showed that PDGF-BB contracts pulmonary veins (PVs) and that this contraction is prevented by inhibition of PDGFR-β (imatinib/SU6668). Here, we studied PDGF-BB-induced contraction and downstream-signalling in isolated perfused lungs (IPL) and precision-cut lung slices (PCLS) of guinea pigs (GPs). In IPLs, PDGF-BB was perfused after or without pre-treatment with imatinib (perfused/nebulised), the effects on the pulmonary arterial pressure (P PA ), the left atrial pressure (P LA ) and the capillary pressure (P cap ) were studied and the precapillary (R pre ) and postcapillary resistance (R post ) were calculated. Perfusate samples were analysed (ELISA) to detect the PDGF-BB-induced release of prostaglandin metabolites (TXA 2 /PGI 2 ). In PCLS, the contractile effect of PDGF-BB was evaluated in pulmonary arteries (PAs) and PVs. In PVs, PDGF-BB-induced contraction was studied after inhibition of PDGFR-α/β, L-Type Ca 2+ -channels, ROCK/PKC, prostaglandin receptors, MAP2K, p38-MAPK, PI3K-α/γ, AKT/PKB, actin polymerisation, adenyl cyclase and NO. Changes of the vascular tone were measured by videomicroscopy. In PVs, intracellular cAMP was measured by ELISA. In IPLs, PDGF-BB increased P PA , P cap and R post . In contrast, PDGF-BB had no effect if lungs were pre-treated with imatinib (perfused/nebulised). In PCLS, PDGF-BB significantly contracted PVs/PAs which was blocked by the PDGFR-β antagonist SU6668. In PVs, inhibition of actin polymerisation and inhibition of L-Type Ca 2+ -channels reduced PDGF-BB-induced contraction, whereas inhibition of ROCK/PKC had no effect. Blocking of EP 1/3 - and TP-receptors or inhibition of MAP2K-, p38-MAPK-, PI3K-α/γ- and AKT/PKB-signalling prevented PDGF-BB-induced contraction, whereas inhibition of EP 4 only slightly reduced it. Accordingly, PDGF-BB increased TXA 2 in the perfusate, whereas PGI 2 was increased in all groups after 120 min and inhibition of IP-receptors did not enhance PDGF-BB-induced contraction. Moreover, PDGF-BB increased cAMP in PVs and inhibition of adenyl cyclase enhanced PDGF-BB-induced contraction, whereas inhibition of NO-formation only slightly increased it. PDGF-BB/PDGFR regulates the pulmonary vascular tone by the generation of prostaglandins, the increase of calcium, the activation of MAPK- or PI3K/AKT/mTOR signalling and actin remodelling. More insights in PDGF-BB downstream-signalling may contribute to develop new therapeutics for PH.

Antioxidants as Potential Therapeutics for Lung Fibrosis

PubMed Central

DAY, BRIAN J.

2009-01-01

Interstitial lung disease encompasses a large group of chronic lung disorders associated with excessive tissue remodeling, scarring, and fibrosis. The evidence of a redox imbalance in lung fibrosis is substantial, and the rationale for testing antioxidants as potential new therapeutics for lung fibrosis is appealing. Current animal models of lung fibrosis have clear involvement of ROS in their pathogenesis. New classes of antioxidant agents divided into catalytic antioxidant mimetics and antioxidant scavengers are being developed. The catalytic antioxidant class is based on endogenous antioxidant enzymes and includes the manganese-containing macrocyclics, porphyrins, salens, and the non–metal-containing nitroxides. The antioxidant scavenging class is based on endogenous antioxidant molecules and includes the vitamin E analogues, thiols, lazaroids, and polyphenolic agents. Numerous studies have shown oxidative stress to be associated with many interstitial lung diseases and that these agents are effective in attenuating fibroproliferative responses in the lung of animals and humans. PMID:17999627

Effect of fenspiride on pulmonary function in the rat and guinea pig.

PubMed

Bee, D; Laude, E A; Emery, C J; Howard, P

1995-03-01

1. Fenspiride is an anti-inflammatory agent that may have a role in reversible obstructive airways disease. Small, but significant, improvements have been seen in airways function and arterial oxygen tension in patients with mild chronic obstructive pulmonary disease. These changes have been attributed to the anti-inflammatory properties of the drug. However, airways function can be improved by other means, e.g. improved ventilation/perfusion ratio or reduced airways resistance. The possibility that fenspiride may have actions other than anti-inflammatory was investigated in two animal species. 2. In the rat, actions on the pulmonary circulation were investigated in the isolated perfused lung, but fenspiride proved to be a poor pulmonary vasodilator, showing only a small reversal of the raised pulmonary artery pressure induced by hypoxia. 3. Ventilation was measured in the anaesthetized rat using whole-body plethysmography. Fenspiride caused no increase in ventilation or changes in arterial blood gases. However, a profound hypotensive action was observed with high doses. 4. The possibility that a decrease in airways resistance (R(aw)) might occur with fenspiride was investigated in anaesthetized guinea pigs. Capsaicin (30 mumol/l) was used to increase baseline R(aw) through bronchoconstriction. Fenspiride gave a dose-dependent partial reversal of the raised R(aw), and its administration by aerosol proved as efficacious as the intravenous route. In addition, the hypotensive side-effect found with intravenous injection was alleviated by aerosolized fenspiride.(ABSTRACT TRUNCATED AT 250 WORDS)

A diagnostic model for chronic hypersensitivity pneumonitis

PubMed Central

Johannson, Kerri A; Elicker, Brett M; Vittinghoff, Eric; Assayag, Deborah; de Boer, Kaïssa; Golden, Jeffrey A; Jones, Kirk D; King, Talmadge E; Koth, Laura L; Lee, Joyce S; Ley, Brett; Wolters, Paul J; Collard, Harold R

2017-01-01

The objective of this study was to develop a diagnostic model that allows for a highly specific diagnosis of chronic hypersensitivity pneumonitis using clinical and radiological variables alone. Chronic hypersensitivity pneumonitis and other interstitial lung disease cases were retrospectively identified from a longitudinal database. High-resolution CT scans were blindly scored for radiographic features (eg, ground-glass opacity, mosaic perfusion) as well as the radiologist’s diagnostic impression. Candidate models were developed then evaluated using clinical and radiographic variables and assessed by the cross-validated C-statistic. Forty-four chronic hypersensitivity pneumonitis and eighty other interstitial lung disease cases were identified. Two models were selected based on their statistical performance, clinical applicability and face validity. Key model variables included age, down feather and/or bird exposure, radiographic presence of ground-glass opacity and mosaic perfusion and moderate or high confidence in the radiographic impression of chronic hypersensitivity pneumonitis. Models were internally validated with good performance, and cut-off values were established that resulted in high specificity for a diagnosis of chronic hypersensitivity pneumonitis. PMID:27245779

Lyophilized Kit for the Preparation of the PET Perfusion Agent [68Ga]-MAA

PubMed Central

Amor-Coarasa, Alejandro; Milera, Andrew; Gulec, Seza; McGoron, Anthony J.

2014-01-01

Rapid developments in the field of medical imaging have opened new avenues for the use of positron emitting labeled microparticles. The radioisotope used in our research was 68Ga, which is easy to obtain from a generator and has good nuclear properties for PET imaging. Methods. Commercially available macroaggregated albumin (MAA) microparticles were suspended in sterile saline, centrifuged to remove the free albumin and stannous chloride, relyophilized, and stored for later labeling with 68Ga. Labeling was performed at different temperatures and times. 68Ga purification settings were also tested and optimized. Labeling yield and purity of relyophilized MAA microparticles were compared with those that were not relyophilized. Results. MAA particles kept their original size distribution after relyophilization. Labeling yield was 98% at 75°C when a 68Ga purification system was used, compared to 80% with unpurified 68Ga. Radiochemical purity was over 97% up to 4 hours after the labeling. The relyophilized MAA and labeling method eliminate the need for centrifugation purification of the final product and simplify the labeling process. Animal experiments demonstrated the high in vivo stability of the obtained PET agent with more than 95% of the activity remaining in the lungs after 4 hours. PMID:24800071

Graphene Oxide/Ag Nanoparticles Cooperated with Simvastatin as a High Sensitive X-Ray Computed Tomography Imaging Agent for Diagnosis of Renal Dysfunctions.

PubMed

Li, Zhan; Tian, Longlong; Liu, Jianli; Qi, Wei; Wu, Qiang; Wang, Haijing; Ali, Mohammad Chand; Wu, Wangsuo; Qiu, Hongdeng

2017-09-01

Graphene oxides (GO) are attracting much attention in the diagnosis and therapy of the subcutaneous tumor as a novel biomaterial, but its diagnosis to tissue dysfunction is yet to be found. Here, a novel application of GO for diagnosis of renal dysfunction via contrast-enhanced computed tomography (CT) is proposed. In order to serve as contrast-enhanced agent, Ag nanoparticles (AgNPs) are composited on the surface of GO to promote its X-ray absorption, and then simvastatin is coinjected for eliminating in vivo toxicity induced by AgNPs. It is found that GO/AgNPs can enhance the imaging of CT into the lung, liver, and kidney of mice for a long circulation time (≈24 h) and a safety profile in vivo in the presence of simvastatin. Interestingly, the lower dose of GO/AgNPs (≈0.5 mg per kg bw) shows an excellent performance for CT imaging of renal perfusion, and visually exhibits the right renal dysfunction in model mice. Hence, this work suggests that graphene nanoparticles will play a vital role for the future medical translational development including drug carrier, biosensing, and disease therapy. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

An observational study of Donor Ex Vivo Lung Perfusion in UK lung transplantation: DEVELOP-UK.

PubMed

Fisher, Andrew; Andreasson, Anders; Chrysos, Alexandros; Lally, Joanne; Mamasoula, Chrysovalanto; Exley, Catherine; Wilkinson, Jennifer; Qian, Jessica; Watson, Gillian; Lewington, Oli; Chadwick, Thomas; McColl, Elaine; Pearce, Mark; Mann, Kay; McMeekin, Nicola; Vale, Luke; Tsui, Steven; Yonan, Nizar; Simon, Andre; Marczin, Nandor; Mascaro, Jorge; Dark, John

2016-11-01

Many patients awaiting lung transplantation die before a donor organ becomes available. Ex vivo lung perfusion (EVLP) allows initially unusable donor lungs to be assessed and reconditioned for clinical use. The objective of the Donor Ex Vivo Lung Perfusion in UK lung transplantation study was to evaluate the clinical effectiveness and cost-effectiveness of EVLP in increasing UK lung transplant activity. A multicentre, unblinded, non-randomised, non-inferiority observational study to compare transplant outcomes between EVLP-assessed and standard donor lungs. Multicentre study involving all five UK officially designated NHS adult lung transplant centres. Patients aged ≥ 18 years with advanced lung disease accepted onto the lung transplant waiting list. The study intervention was EVLP assessment of donor lungs before determining suitability for transplantation. The primary outcome measure was survival during the first 12 months following lung transplantation. Secondary outcome measures were patient-centred outcomes that are influenced by the effectiveness of lung transplantation and that contribute to the health-care costs. Lungs from 53 donors unsuitable for standard transplant were assessed with EVLP, of which 18 (34%) were subsequently transplanted. A total of 184 participants received standard donor lungs. Owing to the early closure of the study, a non-inferiority analysis was not conducted. The Kaplan-Meier estimate of survival at 12 months was 0.67 [95% confidence interval (CI) 0.40 to 0.83] for the EVLP arm and 0.80 (95% CI 0.74 to 0.85) for the standard arm. The hazard ratio for overall 12-month survival in the EVLP arm relative to the standard arm was 1.96 (95% CI 0.83 to 4.67). Patients in the EVLP arm required ventilation for a longer period and stayed longer in an intensive therapy unit (ITU) than patients in the standard arm, but duration of overall hospital stay was similar in both groups. There was a higher rate of very early grade 3 primary graft dysfunction (PGD) in the EVLP arm, but rates of PGD did not differ between groups after 72 hours. The requirement for extracorporeal membrane oxygenation (ECMO) support was higher in the EVLP arm (7/18, 38.8%) than in the standard arm (6/184, 3.2%). There were no major differences in rates of chest radiograph abnormalities, infection, lung function or rejection by 12 months. The cost of EVLP transplants is approximately £35,000 higher than the cost of standard transplants, as a result of the cost of the EVLP procedure, and the increased ECMO use and ITU stay. Predictors of cost were quality of life on joining the waiting list, type of transplant and number of lungs transplanted. An exploratory model comparing a NHS lung transplant service that includes EVLP and standard lung transplants with one including only standard lung transplants resulted in an incremental cost-effectiveness ratio of £73,000. Interviews showed that patients had a good understanding of the need for, and the processes of, EVLP. If EVLP can increase the number of usable donor lungs and reduce waiting, it is likely to be acceptable to those waiting for lung transplantation. Study limitations include small numbers in the EVLP arm, limiting analysis to descriptive statistics and the EVLP protocol change during the study. Overall, one-third of donor lungs subjected to EVLP were deemed suitable for transplant. Estimated survival over 12 months was lower than in the standard group, but the data were also consistent with no difference in survival between groups. Patients receiving these additional transplants experience a higher rate of early graft injury and need for unplanned ECMO support, at increased cost. The small number of participants in the EVLP arm because of early study termination limits the robustness of these conclusions. The reason for the increased PGD rates, high ECMO requirement and possible differences in lung injury between EVLP protocols needs evaluation. Current Controlled Trials ISRCTN44922411. This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol. 20, No. 85. See the NIHR Journals Library website for further project information.

Dynamic contrast-enhanced perfusion area-detector CT assessed with various mathematical models: Its capability for therapeutic outcome prediction for non-small cell lung cancer patients with chemoradiotherapy as compared with that of FDG-PET/CT.

PubMed

Ohno, Yoshiharu; Fujisawa, Yasuko; Koyama, Hisanobu; Kishida, Yuji; Seki, Shinichiro; Sugihara, Naoki; Yoshikawa, Takeshi

2017-01-01

To directly compare the capability of dynamic first-pass contrast-enhanced (CE-) perfusion area-detector CT (ADCT) and PET/CT for early prediction of treatment response, disease progression and overall survival of non-small cell carcinoma (NSCLC) patients treated with chemoradiotherapy. Fifty-three consecutive Stage IIIB NSCLC patients who had undergone PET/CT, dynamic first-pass CE-perfusion ADCT, chemoradiotherapy, and follow-up examination were enrolled in this study. They were divided into two groups: 1) complete or partial response (CR+PR) and 2) stable or progressive disease (SD+PD). Pulmonary arterial and systemic arterial perfusions and total perfusion were assessed at targeted lesions with the dual-input maximum slope method, permeability surface and distribution volume with the Patlak plot method, tumor perfusion with the single-input maximum slope method, and SUV max , and results were averaged to determine final values for each patient. Next, step-wise regression analysis was used to determine which indices were the most useful for predicting therapeutic effect. Finally, overall survival of responders and non-responders assessed by using the indices that had a significant effect on prediction of therapeutic outcome was statistically compared. The step-wise regression test showed that therapeutic effect (r 2 =0.63, p=0.01) was significantly affected by the following three factors in order of magnitude of impact: systemic arterial perfusion, total perfusion, and SUV max . Mean overall survival showed a significant difference for total perfusion (p=0.003) and systemic arterial perfusion (p=0.04). Dynamic first-pass CE-perfusion ADCT as well as PET/CT are useful for treatment response prediction in NSCLC patients treated with chemoradiotherapy. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Assessment of the effects of different sample perfusion procedures on phase-contrast tomographic images of mouse spinal cord

NASA Astrophysics Data System (ADS)

Stefanutti, E.; Sierra, A.; Miocchi, P.; Massimi, L.; Brun, F.; Maugeri, L.; Bukreeva, I.; Nurmi, A.; Begani Provinciali, G.; Tromba, G.; Gröhn, O.; Giove, F.; Cedola, A.; Fratini, M.

2018-03-01

Synchrotron X-ray Phase Contrast micro-Tomography (SXrPCμT) is a powerful tool in the investigation of biological tissues, including the central nervous system (CNS), and it allows to simultaneously detect the vascular and neuronal network avoiding contrast agents or destructive sample preparations. However, specific sample preparation procedures aimed to optimize the achievable contrast- and signal-to-noise ratio (CNR and SNR, respectively) are required. Here we report and discuss the effects of perfusion with two different fixative agents (ethanol and paraformaldehyde) and with a widely used contrast medium (MICROFIL®) on mouse spinal cord. As a main result, we found that ethanol enhances contrast at the grey/white matter interface and increases the contrast in correspondence of vascular features and fibres, thus providing an adequate spatial resolution to visualise the vascular network at the microscale. On the other hand, ethanol is known to induce tissue dehydration, likely reducing cell dimensions below the spatial resolution limit imposed by the experimental technique. Nonetheless, neurons remain well visible using either perfused paraformaldehyde or MICROFIL® compound, as these latter media do not affect tissues with dehydration effects. Paraformaldehyde appears as the best compromise: it is not a contrast agent, like MICROFIL®, but it is less invasive than ethanol and permits to visualise well both cells and blood vessels. However, a quantitative estimation of the relative grey matter volume of each sample has led us to conclude that no significant alterations in the grey matter extension compared to the white matter occur as a consequence of the perfusion procedures tested in this study.

Intrathecal chemotherapy for refractory disseminated medulloblastoma.

PubMed

Yoshimura, Junichi; Nishiyama, Kenichi; Mori, Hiroshi; Takahashi, Hideaki; Fujii, Yukihiko

2008-05-01

To analyze the effect of intrathecal (IT) chemotherapy for disseminated medulloblastoma. Twenty-one patients received IT chemotherapy using the chemotherapeutic agents of methotrexate (MTX) and nitrosoureas (ACNU, MCNU) including nine patients for residual leptomeningeal lesions after initial surgery and radiation, and 12 for a recurrence with leptomeningeal dissemination. Of these 21 patients, 12 received a lumbar and/or ventricular bolus injection of the chemotherapeutic agents, one received the ventriculolumbar perfusion of the agents, and eight received both the perfusion and bolus injection. The doses ranged from 6-7 mg/m(2) of ACNU for perfusion and 3-3.5 mg/m(2) of ACNU, MCNU, or MTX for the bolus injection, and the cycles were administered from 3 to 12 times for perfusion and from 5 to 54 times for the bolus injection. The effects of chemotherapy were assessed by both radiological and cytological examinations, and the clinical symptoms were also assessed. Radiological and/or cytological responses were observed in 10 of 21 patients (47.6%), including seven cases demonstrating a complete remission. The 5-year overall survival rate and 5-year survival rate after dissemination were 61.5 and 46.4%, respectively. Five patients who received a lumbar bolus injection of nitrosoureas experienced paraplegia and double incontinence. One patient who received a ventricular injection of nitrosoureas experienced truncal ataxia. IT chemotherapy was found to be effective in some cases with refractory disseminated medulloblastoma and it seems to be an appropriate treatment choice for leptomeningeal recurrence. However, the frequent bolus injections of nitrosoureas should be avoided to prevent the side effects.

Ultrasonic contrast agents in transcranial perfusion sonography (TPS) for follow-up of patients with high grade gliomas.

PubMed

Ickenstein, G W; Valaikiene, J; Koch, H; Hau, P; Erban, P; Schlachetzki, F

2008-04-01

The aim of this study was to evaluate brain perfusion differences in patients with high grade gliomas after partial tumor resection and irradiation/chemotherapy between tumor and non-tumor hemisphere by transcranial perfusion sonography (TPS) employing a contrast burst imaging (CBI) technique. Six patients with glioblastoma (WHO Grade IV) in the temporoparietal region within the defined axial diencephalic scanning plane were examined by TPS during follow-up. All subjects had an adequate acoustic temporal bone window. Transtemporal insonation on brain tumor and non-tumor hemisphere was performed with a bolus-injection of sulphur hexafluoride-based contrast agent (10 mg i.v., 5mg/ml--SonoVue, Bracco, Altana, Switzerland). Recorded images were analysed off-line by Quanticon Software (3D-Echotech, Munich, Germany) and time intensity curve parameters [area under the curve (AUC, dB s), peak intensity (PI, dB), time to peak (TTP, s)] in five regions of interest (ROI) [thalamus anterior, thalamus posterior, nucleus lentiformis, white matter, whole hemisphere] were evaluated. Statistical analyses were performed. Perfusion differences between brain tumor and non-tumor hemispheres were detected with contrast burst imaging (CBI) technique with a significantly greater mean AUC (5343.69 dB s vs. 4625.04 dB s, p<0.028) and a significantly prolonged TTP (32.72 s vs. 28.91 s, p<0.046) in the tumor hemisphere. Within our study population, TTP and AUC seem to be the most robust parameters for the evaluation of cerebral perfusion differences assessed by transcranial perfusion sonography with CBI technique. We hypothesize that these results correlate with microvascular changes due to treatment regimens, such as microvessel necrosis after irradiation and chemotherapy. Above that, TPS may be of value for the long-term follow-up of brain tumor therapy concept.

[Assessment of myocardial perfusion and left ventricular function with 99mTc-PPN 1011].

PubMed

Kumita, S; Mizumura, S; Oishi, T; Kumazaki, T; Sano, J; Yamazaki, Y; Munakata, K

1993-04-01

First-pass radionuclide angiography (FPRNA) was performed with the new myocardial perfusion agent 99mTc-1,2,bis[bis(2-ethoxyethyl)phosphino] ethane (99mTc-PPN 1011) on stress and at rest. One hour after that, myocardial perfusion was counted by 99mTc-PPN 1011 SPECT. Left ventricular ejection fraction (LVEF) obtained by FPRNA correlated with that by multigated image with 99mTc-HSAD (r = 0.94, n = 11). The reduction of left ventricular function under the exercise (delta LVEF) and the increase of severity score (delta Severity score) have a good relation (r = 0.88) in 7 patients with prior myocardial infarction. Thus 99mTc-PPN 1011 appears to be an ideal radiopharmaceutical for evaluation of ventricular function and myocardial perfusion.

Role of pulmonary diseases and physical condition in the regulation of vasoactive hormones.

PubMed

Hietanen, E; Marniemi, J; Liippo, K; Seppänen, A; Hartiala, J; Viinamäki, O

1988-12-01

Lungs have many non-respiratory metabolic functions, of which some take place in the capillary endothelium, while others are in parenchymal lung tissue. We have studied the role of the lungs in the metabolism of vasoactive and some other hormones by comparing patients who have undergone lung resection to those having various obstructive or fibrotic lung diseases. We have also compared these groups with persons in good physical health. The data suggested that lung resection patients had low angiotensin II levels in plasma but the response of angiotensin II to exercise was normal. Also adrenalin concentration was low in the lung resection group while dopamine did not show any significant difference between the groups. When hormone levels were correlated to the exercise data, renin levels were especially related to physical condition. Serum post-exercise renin values were inversely related to the uneven distribution of lung perfusion, possibly thus reflecting the diminished pulmonary vascularization. A negative association was found between angiotensin II and diffusion capacity. Thus, the angiotensin II levels may preferably be controlled by the non-circulatory functions of the lungs.

Cyclooxygenase-2-dependent bronchoconstriction in perfused rat lungs exposed to endotoxin.

PubMed

Uhlig, S; Nüsing, R; von Bethmann, A; Featherstone, R L; Klein, T; Brasch, F; Müller, K M; Ullrich, V; Wendel, A

1996-05-01

Lipopolysaccharides (LPS), widely used to study the mechanisms of gram-negative sepsis, increase airway resistance by constriction of terminal bronchioles. The role of the cyclooxygenase (COX) isoenzymes and their prostanoid metabolites in this process was studied. Pulmonary resistance, the release of thromboxane (TX) and the expression of COX-2 mRNA were measured in isolated blood-free perfused rat lungs exposed to LPS. LPS induced the release of TX and caused increased airway resistance after about 30 min. Both TX formation and LPS-induced bronchoconstriction were prevented by treatment with the unspecific COX inhibitor acetyl salicylic acid, the specific COX-2 inhibitor CGP-28238, dexamethasone, actinomycin D, or cycloheximide. LPS-induced bronchoconstriction was also inhibited by the TX receptor antagonist BM-13177. The TX-mimetic compound, U-46619, increased airway resistance predominantly by constricting terminal bronchioles. COX-2-specific mRNA in lung tissue was elevated after LPS exposure, and this increase was attenuated by addition of dexamethasone or of actinomycin D. In contrast to LPS, platelet-activating factor (PAF) induced immediate TX release and bronchoconstriction that was prevented by acetyl salicylic acid, but not by CGP-28238. LPS elicits the following biochemical and functional changes in rat lungs: (i) induction of COX-2; (ii) formation of prostaglandins and TX; (iii) activation of the TX receptor on airway smooth muscle cells; (iv) constriction of terminal bronchioles; and (v) increased airway resistance. In contrast to LPS, the PAF-induced TX release is likely to depend on COX-1.

[MRI methods for pulmonary ventilation and perfusion imaging].

PubMed

Sommer, G; Bauman, G

2016-02-01

Separate assessment of respiratory mechanics, gas exchange and pulmonary circulation is essential for the diagnosis and therapy of pulmonary diseases. Due to the global character of the information obtained clinical lung function tests are often not sufficiently specific in the differential diagnosis or have a limited sensitivity in the detection of early pathological changes. The standard procedures of pulmonary imaging are computed tomography (CT) for depiction of the morphology as well as perfusion/ventilation scintigraphy and single photon emission computed tomography (SPECT) for functional assessment. Magnetic resonance imaging (MRI) with hyperpolarized gases, O2-enhanced MRI, MRI with fluorinated gases and Fourier decomposition MRI (FD-MRI) are available for assessment of pulmonary ventilation. For assessment of pulmonary perfusion dynamic contrast-enhanced MRI (DCE-MRI), arterial spin labeling (ASL) and FD-MRI can be used. Imaging provides a more precise insight into the pathophysiology of pulmonary function on a regional level. The advantages of MRI are a lack of ionizing radiation, which allows a protective acquisition of dynamic data as well as the high number of available contrasts and therefore accessible lung function parameters. Sufficient clinical data exist only for certain applications of DCE-MRI. For the other techniques, only feasibility studies and case series of different sizes are available. The clinical applicability of hyperpolarized gases is limited for technical reasons. The clinical application of the techniques described, except for DCE-MRI, should be restricted to scientific studies.

A Case of Pulmonary Hypertension Due to Fistulas Between Multiple Systemic Arteries and the Right Pulmonary Artery in an Adult Discovered for Occulted Dyspnoea.

PubMed

Li, Ji-Feng; Zhai, Zhen-Guo; Kuang, Tu-Guang; Liu, Min; Ma, Zhan-Hong; Li, Yi-Dan; Yang, Yuan-Hua

2017-08-01

Pulmonary hypertension (PH) can be caused by a fistula between the systemic and pulmonary arteries. Here, we report a case of PH due to multiple fistulas between systemic arteries and the right pulmonary artery where the ventilation/perfusion scan showed no perfusion in the right lung. A 32-year-old male patient was hospitalised for community-acquired pneumonia. After treatment with antibiotics, the pneumonia was alleviated but dyspnoea persisted. Pulmonary hypertension was diagnosed using right heart catheterisation, which detected the mean pulmonary artery pressure as 37mmHg. The anomalies were confirmed by contrast-enhanced CT scan (CT pulmonary angiography), systemic arterial angiography and pulmonary angiography. Following embolisation of the largest fistula, the haemodynamics and oxygen dynamics did not improve, and even worsened to some extent. After supportive therapy including diuretics and oxygen, the patient's dyspnoea, WHO function class and right heart function by transthoracic echocardiography all improved during follow-up. Pulmonary hypertension can be present even when the right lung perfusion is lost. Closure of fistulas by embolisation, when those fistulas act as the proliferating vessels, may be harmful. Copyright © 2017 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.

High lung volume increases stress failure in pulmonary capillaries

NASA Technical Reports Server (NTRS)

Fu, Z.; Costello, M. L.; Tsukimoto, K.; Prediletto, R.; Elliott, A. R.; Mathieu-Costello, O.; West, J. B.

1992-01-01

We previously showed that when pulmonary capillaries in anesthetized rabbits are exposed to a transmural pressure (Ptm) of approximately 40 mmHg, stress failure of the walls occurs with disruption of the capillary endothelium, alveolar epithelium, or sometimes all layers. The present study was designed to test whether stress failure occurred more frequently at high than at low lung volumes for the same Ptm. Lungs of anesthetized rabbits were inflated to a transpulmonary pressure of 20 cmH2O, perfused with autologous blood at 32.5 or 2.5 cmH2O Ptm, and fixed by intravascular perfusion. Samples were examined by both transmission and scanning electron microscopy. The results were compared with those of a previous study in which the lung was inflated to a transpulmonary pressure of 5 cmH2O. There was a large increase in the frequency of stress failure of the capillary walls at the higher lung volume. For example, at 32.5 cmH2O Ptm, the number of endothelial breaks per millimeter cell lining was 7.1 +/- 2.2 at the high lung volume compared with 0.7 +/- 0.4 at the low lung volume. The corresponding values for epithelium were 8.5 +/- 1.6 and 0.9 +/- 0.6. Both differences were significant (P less than 0.05). At 52.5 cmH2O Ptm, the results for endothelium were 20.7 +/- 7.6 (high volume) and 7.1 +/- 2.1 (low volume), and the corresponding results for epithelium were 32.8 +/- 11.9 and 11.4 +/- 3.7. At 32.5 cmH2O Ptm, the thickness of the blood-gas barrier was greater at the higher lung volume, consistent with the development of more interstitial edema. Ballooning of the epithelium caused by accumulation of edema fluid between the epithelial cell and its basement membrane was seen at 32.5 and 52.5 cmH2O Ptm. At high lung volume, the breaks tended to be narrower and fewer were oriented perpendicular to the axis of the pulmonary capillaries than at low lung volumes. Transmission and scanning electron microscopy measurements agreed well. Our findings provide a physiological mechanism for other studies showing increased capillary permeability at high states of lung inflation.

In vivo imaging of the pathophysiological changes and neutrophil dynamics in influenza virus-infected mouse lungs.

PubMed

Ueki, Hiroshi; Wang, I-Hsuan; Fukuyama, Satoshi; Katsura, Hiroaki; da Silva Lopes, Tiago Jose; Neumann, Gabriele; Kawaoka, Yoshihiro

2018-06-25

The pathophysiological changes that occur in lungs infected with influenza viruses are poorly understood. Here we established an in vivo imaging system that combines two-photon excitation microscopy and fluorescent influenza viruses of different pathogenicity. This approach allowed us to monitor and correlate several parameters and physiological changes including the spread of infection, pulmonary permeability, pulmonary perfusion speed, number of recruited neutrophils in infected lungs, and neutrophil motion in the lungs of live mice. Several physiological changes were larger and occurred earlier in mice infected with a highly pathogenic H5N1 influenza virus compared with those infected with a mouse-adapted human strain. These findings demonstrate the potential of our in vivo imaging system to provide novel information about the pathophysiological consequences of virus infections.

Automatic delineation of functional lung volumes with 68Ga-ventilation/perfusion PET/CT.

PubMed

Le Roux, Pierre-Yves; Siva, Shankar; Callahan, Jason; Claudic, Yannis; Bourhis, David; Steinfort, Daniel P; Hicks, Rodney J; Hofman, Michael S

2017-10-10

Functional volumes computed from 68 Ga-ventilation/perfusion (V/Q) PET/CT, which we have shown to correlate with pulmonary function test parameters (PFTs), have potential diagnostic utility in a variety of clinical applications, including radiotherapy planning. An automatic segmentation method would facilitate delineation of such volumes. The aim of this study was to develop an automated threshold-based approach to delineate functional volumes that best correlates with manual delineation. Thirty lung cancer patients undergoing both V/Q PET/CT and PFTs were analyzed. Images were acquired following inhalation of Galligas and, subsequently, intravenous administration of 68 Ga-macroaggreted-albumin (MAA). Using visually defined manual contours as the reference standard, various cutoff values, expressed as a percentage of the maximal pixel value, were applied. The average volume difference and Dice similarity coefficient (DSC) were calculated, measuring the similarity of the automatic segmentation and the reference standard. Pearson's correlation was also calculated to compare automated volumes with manual volumes, and automated volumes optimized to PFT indices. For ventilation volumes, mean volume difference was lowest (- 0.4%) using a 15%max threshold with Pearson's coefficient of 0.71. Applying this cutoff, median DSC was 0.93 (0.87-0.95). Nevertheless, limits of agreement in volume differences were large (- 31.0 and 30.2%) with differences ranging from - 40.4 to + 33.0%. For perfusion volumes, mean volume difference was lowest and Pearson's coefficient was highest using a 15%max threshold (3.3% and 0.81, respectively). Applying this cutoff, median DSC was 0.93 (0.88-0.93). Nevertheless, limits of agreement were again large (- 21.1 and 27.8%) with volume differences ranging from - 18.6 to + 35.5%. Using the 15%max threshold, moderate correlation was demonstrated with FEV1/FVC (r = 0.48 and r = 0.46 for ventilation and perfusion images, respectively). No correlation was found between other PFT indices. To automatically delineate functional volumes with 68 Ga-V/Q PET/CT, the most appropriate cutoff was 15%max for both ventilation and perfusion images. However, using this unique threshold systematically provided unacceptable variability compared to the reference volume and relatively poor correlation with PFT parameters. Accordingly, a visually adapted semi-automatic method is favored, enabling rapid and quantitative delineation of lung functional volumes with 68 Ga-V/Q PET/CT.

Evaluation of pharmacokinetic models for perfusion imaging with dynamic contrast-enhanced magnetic resonance imaging in porcine skeletal muscle using low-molecular-weight contrast agents.

PubMed

Hindel, Stefan; Papanastasiou, Giorgos; Wust, Peter; Maaß, Marc; Söhner, Anika; Lüdemann, Lutz

2018-06-01

Pharmacokinetic models for perfusion quantification with a low-molecular-weight contrast agent (LMCA) in skeletal muscle using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) were evaluated. Tissue perfusion was measured in seven regions of interest (ROIs) placed in the total hind leg supplied by the femoral artery in seven female pigs. DCE-MRI was performed using a 3D gradient echo sequence with k-space sharing. The sequence was acquired twice, first after LMCA and then after blood pool contrast agent injection. Blood flow was augmented by continuous infusion of the vasodilator adenosine into the femoral artery, resulting in up to four times increased blood flow. The results obtained with several LMCA models were compared with those of a two-compartment blood pool model (2CBPM) consisting of a capillary and an arteriolar compartment. Measurements performed with a Doppler flow probe placed at the femoral artery served as ground truth. The two-compartment exchange model extended by an arteriolar compartment (E2CXM) showed the highest fit quality of all LMCA models and the most significant correlation with the Doppler measurements, r = 0.78 (P < 0.001). The best correspondence between the capillary perfusion measurements of the LMCA models and those of the 2CBPM was found with the E2CXM (slope of the regression line equal to 1, r = 0.85, P < 0.001). The results for the clinical patient data corresponded very well with the results obtained in the animal experiments. Double-contrast agent DCE-MRI in combination with the E2CXM yields the most reliable results and can be used in clinical routine. Magn Reson Med 79:3154-3162, 2018. © 2017 International Society for Magnetic Resonance in Medicine. © 2017 International Society for Magnetic Resonance in Medicine.

Cerebral perfusion alterations in epileptic patients during peri-ictal and post-ictal phase: PASL vs DSC-MRI.

PubMed

Pizzini, Francesca B; Farace, Paolo; Manganotti, Paolo; Zoccatelli, Giada; Bongiovanni, Luigi G; Golay, Xavier; Beltramello, Alberto; Osculati, Antonio; Bertini, Giuseppe; Fabene, Paolo F

2013-07-01

Non-invasive pulsed arterial spin labeling (PASL) MRI is a method to study brain perfusion that does not require the administration of a contrast agent, which makes it a valuable diagnostic tool as it reduces cost and side effects. The purpose of the present study was to establish the viability of PASL as an alternative to dynamic susceptibility contrast (DSC-MRI) and other perfusion imaging methods in characterizing changes in perfusion patterns caused by seizures in epileptic patients. We evaluated 19 patients with PASL. Of these, the 9 affected by high-frequency seizures were observed during the peri-ictal period (within 5hours since the last seizure), while the 10 patients affected by low-frequency seizures were observed in the post-ictal period. For comparison, 17/19 patients were also evaluated with DSC-MRI and CBF/CBV. PASL imaging showed focal vascular changes, which allowed the classification of patients in three categories: 8 patients characterized by increased perfusion, 4 patients with normal perfusion and 7 patients with decreased perfusion. PASL perfusion imaging findings were comparable to those obtained by DSC-MRI. Since PASL is a) sensitive to vascular alterations induced by epileptic seizures, b) comparable to DSC-MRI for detecting perfusion asymmetries, c) potentially capable of detecting time-related perfusion changes, it can be recommended for repeated evaluations, to identify the epileptic focus, and in follow-up and/or therapy-response assessment. Copyright © 2013 Elsevier Inc. All rights reserved.

Hyperoxia and hypergravity are independent risk factors of atelectasis in healthy sitting humans: a pulmonary ultrasound and SPECT/CT study.

PubMed

Dussault, C; Gontier, E; Verret, C; Soret, M; Boussuges, A; Hedenstierna, G; Montmerle-Borgdorff, S

2016-07-01

Aeroatelectasis has developed in aircrew flying routine peacetime flights on the latest generation high-performance aircraft, when undergoing excessive oxygen supply. To single out the effects of hyperoxia and hypergravity on lung tissue compression, and on ventilation and perfusion, eight subjects were studied before and after 1 h 15 min exposure to +1 to +3.5 Gz in a human centrifuge. They performed the protocol three times, breathing air, 44.5% O2, or 100% O2 and underwent functional and topographical imaging of the whole lung by ultrasound and single-photon emission computed tomography combined with computed tomography (SPECT/CT). Ultrasound lung comets (ULC) and atelectasis both increased after exposure. The number of ULC was <1 pre protocol (i.e., normal lung) and larger post 100% O2 (22 ± 3, mean ± SD) than in all other conditions (P < 0.001). Post 44.5% O2 differed from air (P < 0.05). Seven subjects showed low- to medium-grade atelectasis post 100% O2 There was an effect on grade of gas mixture and hypergravity, with interaction (P < 0.001, respectively); 100% O2, 44.5% O2, and air differed from each other (P < 0.05). SPECT ventilation and perfusion were always normal. Ultrasound concurred with CT in showing normal lung in the upper third and ULC/atelectasis in posterior and inferior areas, not for other localizations. In conclusion, hyperoxia and hypergravity are independent risk factors of reversible atelectasis formation. Ultrasound is a useful screening tool. Together with electrical impedance tomography measurements (reported separately), these findings show that zones with decreased ventilation prone to transient airway closure are present above atelectatic areas. Copyright © 2016 the American Physiological Society.

Magnetic resonance imaging of pediatric lung parenchyma, airways, vasculature, ventilation, and perfusion: state of the art.

PubMed

Liszewski, Mark C; Hersman, F William; Altes, Talissa A; Ohno, Yoshiharu; Ciet, Pierluigi; Warfield, Simon K; Lee, Edward Y

2013-07-01

Magnetic resonance (MR) imaging is a noninvasive imaging modality, particularly attractive for pediatric patients given its lack of ionizing radiation. Despite many advantages, the physical properties of the lung (inherent low signal-to-noise ratio, magnetic susceptibility differences at lung-air interfaces, and respiratory and cardiac motion) have posed technical challenges that have limited the use of MR imaging in the evaluation of thoracic disease in the past. However, recent advances in MR imaging techniques have overcome many of these challenges. This article discusses these advances in MR imaging techniques and their potential role in the evaluation of thoracic disorders in pediatric patients. Copyright © 2013 Elsevier Inc. All rights reserved.

Teaching Pulmonary Gas Exchange Physiology Using Computer Modeling

ERIC Educational Resources Information Center

Kapitan, Kent S.

2008-01-01

Students often have difficulty understanding the relationship of O[subscript 2] consumption, CO[subscript 2] production, cardiac output, and distribution of ventilation-perfusion ratios in the lung to the final arterial blood gas composition. To overcome this difficulty, I have developed an interactive computer simulation of pulmonary gas exchange…

Design and validation of a clinical-scale bioreactor for long-term isolated lung culture.

PubMed

Charest, Jonathan M; Okamoto, Tatsuya; Kitano, Kentaro; Yasuda, Atsushi; Gilpin, Sarah E; Mathisen, Douglas J; Ott, Harald C

2015-06-01

The primary treatment for end-stage lung disease is lung transplantation. However, donor organ shortage remains a major barrier for many patients. In recent years, techniques for maintaining lungs ex vivo for evaluation and short-term (<12 h) resuscitation have come into more widespread use in an attempt to expand the donor pool. In parallel, progress in whole organ engineering has provided the potential perspective of patient derived grafts grown on demand. As both of these strategies advance to more complex interventions for lung repair and regeneration, the need for a long-term organ culture system becomes apparent. Herein we describe a novel clinical scale bioreactor capable of maintaining functional porcine and human lungs for at least 72 h in isolated lung culture (ILC). The fully automated, computer controlled, sterile, closed circuit system enables physiologic pulsatile perfusion and negative pressure ventilation, while gas exchange function, and metabolism can be evaluated. Creation of this stable, biomimetic long-term culture environment will enable advanced interventions in both donor lungs and engineered grafts of human scale. Copyright © 2015 Elsevier Ltd. All rights reserved.

Comparison of transducers with different frequencies in breast contrast-enhanced ultrasound (CEUS) using SonoVue as contrast agent.

PubMed

Wang, Yong-Mei; Fan, Wei; Zhang, Kai; Zhang, Li; Tan, Zhen; Ma, Rong

2016-07-01

To explore the effectiveness of different transducers in breast contrast-enhanced ultrasound (CEUS) using SonoVue(®) (Bracco, Plan-Les-Ouates, Switzerland) as the contrast agent. Breast CEUS was performed in 51 patients with 51 breast lesions using a low-frequency transducer (probe C5-1) and a high-frequency transducer (probe L12-5) separately. All image processes were reviewed for the presence of local blood perfusion defects and surrounding vessels. McNemar's test was conducted to compare the detection effectiveness between these two transducers. Pathological results revealed 38 malignant and 13 benign lesions. The two transducers showed no difference in detecting benign lesions. Among malignant lesions, CEUS conducted by probe C5-1 (frequency range from 1 to 5 MHz) presented 23 (60.5%) lesions with local blood perfusion defects and 26 (68.4%) lesions with surrounding vessels. Meanwhile, probe L12-5 (frequency range from 5 to 12 MHz) showed only 12 (31.6%) lesions with local blood perfusion defects and 12 (31.6%) lesions with surrounding vessel. Probe C5-1 was more sensitive than probe L12-5 in detecting malignant CEUS characteristics (p-value < 0.05). The low-frequency transducer was more sensitive than the high-frequency transducer in breast CEUS using SonoVue as the contrast agent. A new contrast agent with a higher resonance frequency, specially designed for high-frequency transducers, may be helpful in improving the clinical value of breast CEUS. The first study comparing different frequency transducers in breast CEUS of the same patient lesions. We brought out the requirement for CEUS contrast agents which are more suitable for high-frequency examinations.

Distribution of pulmonary ventilation and perfusion during short periods of weightlessness

NASA Technical Reports Server (NTRS)

Michels, D. B.; West, J. B.

1978-01-01

Airborne experiments were conducted on four trained normal male subjects (28-40 yr) to study pulmonary function during short periods (22-27 sec) of zero gravity obtained by flying a jet aircraft through appropriate parabolic trajectories. The cabin was always pressurized to a sea-level altitude. The discussion is limited to pulmonary ventilation and perfusion. The results clearly demonstrate that gravity is the major factor causing nonuniformity in the topographical distribution of pulmonary ventilation. More importantly, the results suggest that virtually all the topographical nonuniformity of ventilation, blood flow, and lung volume observed under 1-G conditions are eliminated during short periods of zero gravity.

Comparison of 4-Dimensional Computed Tomography Ventilation With Nuclear Medicine Ventilation-Perfusion Imaging: A Clinical Validation Study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Vinogradskiy, Yevgeniy, E-mail: yevgeniy.vinogradskiy@ucdenver.edu; Koo, Phillip J.; Castillo, Richard

Purpose: Four-dimensional computed tomography (4DCT) ventilation imaging provides lung function information for lung cancer patients undergoing radiation therapy. Before 4DCT-ventilation can be implemented clinically it needs to be validated against an established imaging modality. The purpose of this work was to compare 4DCT-ventilation to nuclear medicine ventilation, using clinically relevant global metrics and radiologist observations. Methods and Materials: Fifteen lung cancer patients with 16 sets of 4DCT and nuclear medicine ventilation-perfusion (VQ) images were used for the study. The VQ-ventilation images were acquired in planar mode using Tc-99m-labeled diethylenetriamine-pentaacetic acid aerosol inhalation. 4DCT data, spatial registration, and a density-change-based modelmore » were used to compute a 4DCT-based ventilation map for each patient. The percent ventilation was calculated in each lung and each lung third for both the 4DCT and VQ-ventilation scans. A nuclear medicine radiologist assessed the VQ and 4DCT scans for the presence of ventilation defects. The VQ and 4DCT-based images were compared using regional percent ventilation and radiologist clinical observations. Results: Individual patient examples demonstrate good qualitative agreement between the 4DCT and VQ-ventilation scans. The correlation coefficients were 0.68 and 0.45, using the percent ventilation in each individual lung and lung third, respectively. Using radiologist-noted presence of ventilation defects and receiver operating characteristic analysis, the sensitivity, specificity, and accuracy of the 4DCT-ventilation were 90%, 64%, and 81%, respectively. Conclusions: The current work compared 4DCT with VQ-based ventilation using clinically relevant global metrics and radiologist observations. We found good agreement between the radiologist's assessment of the 4DCT and VQ-ventilation images as well as the percent ventilation in each lung. The agreement lessened when the data were analyzed on a regional level. Our study presents an important step for the integration of 4DCT-ventilation into thoracic clinical practice.« less

A Pilot Study of Peritoneal Perfusion with a Novel Hemoglobin Based Oxygen Carrier in Swine (Sus scrofa)

DTIC Science & Technology

2016-10-12

has a high rate of complications, obliges systemic anticoagulation, and requires a significant level of logistics support as well as expertise. In...the endotracheal tube was clamped, ceasing gas exchange in the lung. Arterial blood gases and time to death were then recorded. No differences were...observed between treatment and control animals in terms of C02, 02 and time to death . Peritoneal gas exchange did not improve oxygenation, ventilation or time to death in this severe model of lung injury.

Reduction of vascular leakage by imatinib is associated with preserved microcirculatory perfusion and reduced renal injury markers in a rat model of cardiopulmonary bypass.

PubMed

Koning, N J; de Lange, F; van Meurs, M; Jongman, R M; Ahmed, Y; Schwarte, L A; van Nieuw Amerongen, G P; Vonk, A B A; Niessen, H W; Baufreton, C; Boer, C

2018-06-01

Cardiopulmonary bypass during cardiac surgery leads to impaired microcirculatory perfusion. We hypothesized that vascular leakage is an important contributor to microcirculatory dysfunction. Imatinib, a tyrosine kinase inhibitor, has been shown to reduce vascular leakage in septic mice. We investigated whether prevention of vascular leakage using imatinib preserves microcirculatory perfusion and reduces organ injury markers in a rat model of cardiopulmonary bypass. Male Wistar rats underwent cardiopulmonary bypass after treatment with imatinib or vehicle (n=8 per group). Cremaster muscle microcirculatory perfusion and quadriceps microvascular oxygen saturation were measured using intravital microscopy and reflectance spectroscopy. Evans Blue extravasation was determined in separate experiments. Organ injury markers were determined in plasma, intestine, kidney, and lungs. The onset of cardiopulmonary bypass decreased the number of perfused microvessels by 40% in the control group [9.4 (8.6-10.6) to 5.7 (4.8-6.2) per microscope field; P<0.001 vs baseline], whereas this reduction was not seen in the imatinib group. In the control group, the number of perfused capillaries remained low throughout the experiment, whilst perfusion remained normal after imatinib administration. Microvascular oxygen saturation was less impaired after imatinib treatment compared with controls. Imatinib reduced vascular leakage and decreased fluid resuscitation compared with control [3 (3-6) vs 12 ml (7-16); P=0.024]. Plasma neutrophil-gelatinase-associated-lipocalin concentrations were reduced by imatinib. Prevention of endothelial barrier dysfunction using imatinib preserved microcirculatory perfusion and oxygenation during and after cardiopulmonary bypass. Moreover, imatinib-induced protection of endothelial barrier integrity reduced fluid-resuscitation requirements and attenuated renal and pulmonary injury markers. Copyright © 2017 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.

Nuclear cardiology: Myocardial perfusion and function

DOE Office of Scientific and Technical Information (OSTI.GOV)

Seldin, D.W.

1991-08-01

Myocardial perfusion studies continue to be a major focus of research, with new investigations of the relationship of exercise-redistribution thallium imaging to diagnosis, prognosis, and case management. The redistribution phenomenon, which seemed to be fairly well understood a few years ago, is now recognized to be much more complex than originally thought, and various strategies have been proposed to clarify the meaning of persistent defects. Pharmacologic intervention with dipyridamole and adenosine has become available as an alternative to exercise, and comparisons with exercise imaging and catheterization results have been described. Thallium itself is no longer the sole single-photon perfusion radiopharmaceutical;more » two new technetium agents are now widely available. In addition to perfusion studies, advances in the study of ventricular function have been made, including reports of studies performed in conjunction with technetium perfusion studies, new insights into cardiac physiology, and the prognostic and case-management information that function studies provide. Finally, work has continued with monoclonal antibodies for the identification of areas of myocyte necrosis. 41 references.« less

Real-time contrast ultrasound muscle perfusion imaging with intermediate-power imaging coupled with acoustically durable microbubbles.

PubMed

Seol, Sang-Hoon; Davidson, Brian P; Belcik, J Todd; Mott, Brian H; Goodman, Reid M; Ammi, Azzdine; Lindner, Jonathan R

2015-06-01

There is growing interest in limb contrast-enhanced ultrasound (CEU) perfusion imaging for the evaluation of peripheral artery disease. Because of low resting microvascular blood flow in skeletal muscle, signal enhancement during limb CEU is prohibitively low for real-time imaging. The aim of this study was to test the hypothesis that this obstacle can be overcome by intermediate- rather than low-power CEU when performed with an acoustically resilient microbubble agent. Viscoelastic properties of Definity and Sonazoid were assessed by measuring bulk modulus during incremental increases in ambient pressure to 200 mm Hg. Comparison of in vivo microbubble destruction and signal enhancement at a mechanical index (MI) of 0.1 to 0.4 was performed by sequential reduction in pulsing interval from 10 to 0.05 sec during limb CEU at 7 MHz in mice and 1.8 MHz in dogs. Destruction was also assessed by broadband signal generation during passive cavitation detection. Real-time CEU perfusion imaging with destruction-replenishment was then performed at 1.8 MHz in dogs using an MI of 0.1, 0.2, or 0.3. Sonazoid had a higher bulk modulus than Definity (66 ± 12 vs 29 ± 2 kPa, P = .02) and exhibited less inertial cavitation (destruction) at MIs ≥ 0.2. On in vivo CEU, maximal signal intensity increased incrementally with MI for both agents and was equivalent between agents except at an MI of 0.1 (60% and 85% lower for Sonazoid at 7 and 1.8 MHz, respectively, P < .05). However, on progressive shortening of the pulsing interval, Definity was nearly completely destroyed at MIs ≥ 0.2 at 1.8 and 7 MHz, whereas Sonazoid was destroyed only at 1.8 MHz at MIs ≥ 0.3. As a result, real-time CEU perfusion imaging demonstrated approximately fourfold greater enhancement for Sonazoid at an MI of 0.3 to 0.4. Robust signal enhancement during real-time CEU perfusion imaging of the limb is possible when using intermediate-power imaging coupled with a durable microbubble contrast agent. Copyright © 2015 American Society of Echocardiography. All rights reserved.

Endocytic Uptake, Transport and Macromolecular Interactions of Anionic PAMAM Dendrimers within Lung Tissue.

PubMed

Morris, Christopher J; Aljayyoussi, Ghaith; Mansour, Omar; Griffiths, Peter; Gumbleton, Mark

2017-12-01

Polyamidoamine (PAMAM) dendrimers are a promising class of nanocarrier with applications in both small and large molecule drug delivery. Here we report a comprehensive evaluation of the uptake and transport pathways that contribute to the lung disposition of dendrimers. Anionic PAMAM dendrimers and control dextran probes were applied to an isolated perfused rat lung (IPRL) model and lung epithelial monolayers. Endocytosis pathways were examined in primary alveolar epithelial cultures by confocal microscopy. Molecular interactions of dendrimers with protein and lipid lung fluid components were studied using small angle neutron scattering (SANS). Dendrimers were absorbed across the intact lung via a passive, size-dependent transport pathway at rates slower than dextrans of similar molecular sizes. SANS investigations of concentration-dependent PAMAM transport in the IPRL confirmed no aggregation of PAMAMs with either albumin or dipalmitoylphosphatidylcholine lung lining fluid components. Distinct endocytic compartments were identified within primary alveolar epithelial cells and their functionality in the rapid uptake of fluorescent dendrimers and model macromolecular probes was confirmed by co-localisation studies. PAMAM dendrimers display favourable lung biocompatibility but modest lung to blood absorption kinetics. These data support the investigation of dendrimer-based carriers for controlled-release drug delivery to the deep lung.

Computational Modeling of Airway and Pulmonary Vascular Structure and Function: Development of a “Lung Physiome”

PubMed Central

Tawhai, M. H.; Clark, A. R.; Donovan, G. M.; Burrowes, K. S.

2011-01-01

Computational models of lung structure and function necessarily span multiple spatial and temporal scales, i.e., dynamic molecular interactions give rise to whole organ function, and the link between these scales cannot be fully understood if only molecular or organ-level function is considered. Here, we review progress in constructing multiscale finite element models of lung structure and function that are aimed at providing a computational framework for bridging the spatial scales from molecular to whole organ. These include structural models of the intact lung, embedded models of the pulmonary airways that couple to model lung tissue, and models of the pulmonary vasculature that account for distinct structural differences at the extra- and intra-acinar levels. Biophysically based functional models for tissue deformation, pulmonary blood flow, and airway bronchoconstriction are also described. The development of these advanced multiscale models has led to a better understanding of complex physiological mechanisms that govern regional lung perfusion and emergent heterogeneity during bronchoconstriction. PMID:22011236

Computed Tomography Assessment of Ablation Zone Enhancement in Patients With Early-Stage Lung Cancer After Stereotactic Ablative Radiotherapy.

PubMed

Moore, William; Chaya, Yair; Chaudhry, Ammar; Depasquale, Britney; Glass, Samantha; Lee, Susan; Shin, James; Mikhail, George; Bhattacharji, Priya; Kim, Bong; Bilfinger, Thomas

2015-01-01

Stereotactic ablative radiotherapy (SABR) offers a curative treatment for lung cancer in patients who are marginal surgical candidates. However, unlike traditional surgery the lung cancer remains in place after treatment. Thus, imaging follow-up for evaluation of recurrence is of paramount importance. In this retrospective designed Institutional Review Board-approved study, follow-up contrast-enhanced computed tomography (CT) exams were performed on sixty one patients to evaluate enhancement pattern in the ablation zone at 1, 3, 6, and 12 months after SABR. Eleven patients had recurrence within the ablation zone after SABR. The postcontrast enhancement in the recurrence group showed a washin and washout phenomenon, whereas the radiation-induced lung injury group showed continuous enhancement suggesting an inflammatory process. The textural feature of the ablation zone of enhancement and perfusion as demonstrated in computed tomography nodule enhancement may allow early differentiation of recurrence from radiation-induced lung injury in patients' status after SABR or primary lung cancer.

The Effect of Polyhexanide, Octenidine Dihydrochloride, and Tea Tree Oil as Topical Antiseptic Agents on In Vivo Microcirculation of the Human Skin: A Noninvasive Quantitative Analysis.

PubMed

Rothenberger, Jens; Krauss, Sabrina; Tschumi, Christian; Rahmanian-Schwarz, Afshin; Schaller, Hans-Eberhard; Held, Manuel

2016-10-01

Antiseptics are indispensable for wound management and should focus not only on the efficacy in reducing the bacterial burden but also on how much they interfere in wound healing. In this study, the authors analyzed the direct effect of topical antiseptic agents on the microcirculation of intact human skin. The perfusion dynamics were assessed before, and 10 minutes after, the volunteers' fingers of the right hand (n = 20) were immersed in the following solutions - octenidine dihydrochloride, polyhexanide, tea tree oil, and saline solution. The authors used the Oxygen to See (LEA Medizintechnik GmbH, Giessen, Germany) diagnostic device for noninvasive determination of oxygen supply in microcirculation of blood perfused tissues, which combines a laser light to determine blood flow, as well as white light to determine hemoglobin oxygenation and the relative amount of hemoglobin. Tea tree oil (÷19.0%) (B. Braun Melsungen AG, Melsungen, Germany) and polyhexanide (÷12.4%) (Lavanid, Serag Wiessner GmbH, Naila, Germany) caused a significant increase in blood flow compared to the negative control (-25.6%). Octenidine (Octenisept, Schülke & Mayr GmbH, Norderstedt, Germany) showed a nonsignificant trend towards an increase in blood flow (÷7.2%). There were alterations in the values of hemoglobin oxygenation and the relative amount of hemoglobin, but these were not significant. Perfusion is an important factor for wound healing. Therefore, it might be advantageous if antiseptic agents would increase blood flow. Tea tree oil and polyhexanide have a positive effect on skin blood flow and can therefore be used especially in critically perfused wounds, provided the adverse reactions and the antimicrobial efficacy are comparable.

Technical considerations in percutaneous hepatic perfusion--a multi-center experience.

PubMed

Antoine, Radcliffe A

2011-03-01

Patients diagnosed with primary or metastatic liver cancer face a daunting future that is complicated by limited treatment options. Percutaneous hepatic perfusion is a novel approach to chemotherapy delivery that offers significant benefits over contemporary modalities. Percutaneous hepatic perfusion is a procedure in which a chemotherapeutic agent is administered at high doses via the hepatic artery where it perfuses the liver, is extracted and filtered using a veno-veno bypass circuit, a fenestrated multi-lumen double-balloon catheter, and two biocompatible hemoperfusion filters. Venous access is gained at the groin through the femoral vein after which the catheter is advanced and positioned in the inferior vena cava just below the right atrium.The catheter's proximal and distal balloons are inflated to occlude the inferior vena cava above and below the hepatic veins. The occlusion isolated the chemo-rich venous outflow of the liver from the systemic venous circulation. This maneuver also diverts venous blood returning to the heart from lower extremities of the azygos vein. Once the patient is on bypass, the agent is infused through the hepatic artery where it saturates the liver. The chemo-rich venous outflow is extracted through the double-balloon catheter by the bypass circuit. The blood is continuously filtered and cleared of the agent as it passes through the filters and returned to the patient through a catheter placed in the right internal jugular vein. A phase I study demonstrated efficacy with an overall radiographic response rate of 30% observed in treated patients. In 10 patients with ocular melanoma, a 50% overall response rate was observed, including two complete responses. The technique is minimally invasive and can be performed safely by a well-trained multi-disciplinary team. It offers significant benefits including multiple procedures without risks commonly associated with open abdominal surgery.

Novel synthesis and initial preclinical evaluation of (18)F-[FDG] labeled rhodamine: a potential PET myocardial perfusion imaging agent.

PubMed

AlJammaz, Ibrahim; Al-Otaibi, Basim; AlHindas, Hussein; Okarvi, Subhani M

2015-10-01

Myocardial perfusion imaging is one of the most commonly performed investigations in nuclear medicine studies. Due to the clinical importance of [(18)F]-fluoro-2-deoxy-D-glucose ([(18)F]-FDG) and its availability in almost every PET center, a new radiofluorinated [(18)F]-FDG-rhodamine conjugate was synthesized using [(18)F]-FDG as a prosthetic group. In a convenient and simple one-step radiosynthesis, [(18)F]-FDG-rhodamine conjugate was prepared in quantitative radiochemical yields, with total synthesis time of nearly 20 min and radiochemical purity of greater than 98%, without the need for HPLC purification, which make these approaches amenable for automation. Biodistribution studies in normal rats at 60 min post-injection demonstrated a high uptake in the heart (>11% ID/g) and favorable pharmacokinetics. Additionally, [(18)F]-FDG-rhodamine showed an extraction value of 27.63%±5.12% in rat hearts. These results demonstrate that [(18)F]-FDG-rhodamine conjugate may be useful as an imaging agent for the positron emission tomography evaluation of myocardial perfusion. Copyright © 2015 Elsevier Inc. All rights reserved.

Effect of dimethylaminoethanol, an inhibitor of betaine production, on the disposition of choline in the rat kidney

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lohr, J.; Acara, M.

1990-01-01

The choline metabolite betaine has been shown to be an important organic osmoregulatory solute in the kidney. The isolated perfused rat kidney and kidney slice incubations were used to investigate the effect of 2-dimethylaminoethanol (DMAE), a choline oxidase inhibitor, on the renal excretion and metabolism of choline. In the isolated perfused kidney, ({sup 14}C)choline, at an initial perfusate concentration of 300 microM, was effectively removed from the perfusate over 25 min, with nearly all the {sup 14}C in the perfusate accounted for by betaine during the remainder of the 90-min perfusion. DMAE at concentrations of 3.0 or 5.0 mM significantlymore » decreased the rate of removal of ({sup 14}C)choline from the perfusate and the rate of addition of ({sup 14}C)betaine to the perfusate, yet (14C)betaine remained the only metabolite of choline in perfusate and urine. In kidney tissue slice experiments, conversion of ({sup 14}C)choline to ({sup 14}C)betaine was found in cortical, outer medullary and inner medullary regions of rat kidney. DMAE at 5.0 mM significantly inhibited ({sup 14}C)betaine production in each of the three regions studied. These data show that DMAE is an effective inhibitor of betaine production by the kidney and, as such, may be an important agent for the study of osmoregulation by the kidney.« less

Airway disease: anatomopathologic patterns and functional correlations.

PubMed

Mormile, F; Ciappi, G

1997-01-01

Airways represent a serial and parallel branched system, through which the alveoli are connected with the external air. They participate in the mechanical and immune defense against noxious agents, regional flow regulation to optimize the perfusion/ventilation ratio and provide lung mechanical support. Functional exploration of central airways is based on resistance measurement, flow-volume curve or spirometry, while peripheral airways influence parameters as the upstream resistance, the slope of phase III nitrogen washout and the residual volume. Bronchodynamic tests supply important information on airway reversibility and nonspecific reactivity. Anatomopathologic alterations of obstructive chronic bronchitis, pulmonary emphysema and bronchial asthma account for their specific functional and bronchodynamic alterations. There is a growing interest for bronchiolitis in the clinical, radiologic and functional field. This type of lesion, always present in COPD, asthma and interstitial disease, becomes relevant when isolated or predominant. The most useful anatomofunctional classification separates the "constrictive" forms, the cause of obstruction and hyperinflation, from "proliferative" forms where an intraluminal proliferation more or less extended to alveolar air spaces as in BOOP (bronchiolitis obliterans organizing pneumonia) results in restrictive dysfunction. Constrictive bronchiolitis obliterans represents a severe and frequent complication of lung and bone marrow transplantation. Idiopathic BOOP may occur with cough or flue-like symptoms. In other cases, constrictive and proliferative forms may have a toxic (gases or drugs), postinfective or immune etiology (rheumatoid arthritis, LES, etc). Respiratory bronchiolitis or smokers' bronchiolitis, an often asymptomatic lesion, rarely associated to an interstitial lung disease, should be considered separately. The relationships between respiratory bronchiolitis, COPD and initial centriacinar emphysema is still to be elucidated. The diagnostic combination of the more sensitive functional tests with HRCT will allow a better understanding of the natural history of the various forms of bronchiolitis.

Assessment of cardiac function using myocardial perfusion imaging technique on SPECT with 99mTc sestamibi

NASA Astrophysics Data System (ADS)

Gani, M. R. A.; Nazir, F.; Pawiro, S. A.; Soejoko, D. S.

2016-03-01

Suspicion on coronary heart disease can be confirmed by observing the function of left ventricle cardiac muscle with Myocardial Perfusion Imaging techniques. The function perfusion itself is indicated by the uptake of radiopharmaceutical tracer. The 31 patients were studied undergoing the MPI examination on Gatot Soebroto Hospital using 99mTc-sestamibi radiopharmaceutical with stress and rest conditions. Stress was stimulated by physical exercise or pharmacological agent. After two hours, the patient did rest condition on the same day. The difference of uptake percentage between stress and rest conditions will be used to determine the malfunction of perfusion due to ischemic or infarct. Degradation of cardiac function was determined based on the image-based assessment of five segments of left ventricle cardiac. As a result, 8 (25.8%) patients had normal myocardial perfusion and 11 (35.5%) patients suspected for having partial ischemia. Total ischemia occurred to 8 (25.8%) patients with reversible and irreversible ischemia and the remaining 4 (12.9%) patients for partial infarct with characteristic the percentage of perfusion ≤50%. It is concluded that MPI technique of image-based assessment on uptake percentage difference between stress and rest conditions can be employed to predict abnormal perfusion as complementary information to diagnose the cardiac function.

Potential Role of Lung Ventilation Scintigraphy in the Assessment of COPD

PubMed Central

Cukic, Vesna; Begic, Amela

2014-01-01

Objective: To highlight the importance of the lung ventilation scintigraphy (LVS) to study the regional distribution of lung ventilation and to describe most frequent abnormal patterns of lung ventilation distribution obtained by this technique in COPD and to compare the information obtained by LVS with the that obtained by traditional lung function tests. Material and methods: The research was done in 20 patients with previously diagnosed COPD who were treated in Intensive care unit of Clinic for pulmonary diseases and TB “Podhrastovi” Clinical Center, University of Sarajevo in exacerbation of COPD during first three months of 2014. Each patient was undergone to testing of pulmonary function by body plethysmography and ventilation/perfusion lung scintigraphy with radio pharmaceutics Technegas, 111 MBq Tc -99m-MAA. We compared the results obtained by these two methods. Results: All patients with COPD have a damaged lung function tests examined by body plethysmography implying airflow obstruction, but LVS indicates not only airflow obstruction and reduced ventilation, but also indicates the disorders in distribution in lung ventilation. Conclusion: LVS may add further information to the functional evaluation of COPD to that provided by traditional lung function tests and may contribute to characterizing the different phenotypes of COPD. PMID:25132709

Research on rat's pulmonary acute injury induced by lunar soil simulant.

PubMed

Sun, Yan; Liu, Jin-Guo; Zheng, Yong-Chun; Xiao, Chun-Ling; Wan, Bing; Guo, Li; Wang, Xu-Guang; Bo, Wei

2018-02-01

The steps to the moon never stopped after the Apollo Project. Lessons from manned landings on the moon have shown that lunar dust has great influence on the health of astronauts. In this paper, comparative studies between the lunar soil simulant (LSS) and PM2.5 were performed to discover their harm to human biological systems and explore the methods of prevention and treatment of dust poisoning for future lunar manned landings. Rats were randomly divided into the control group, two CAS-1 lunar soil simulant groups (tracheal perfusion with 7 mg and 0.7 mg, respectively, in a 1-mL volume) and the PM2.5 group (tracheal perfusion with 0.7 mg in a 1-mL volume). The biochemical indicators in the bronchoalveolar lavage fluid (BALF), MPO activity in the lung tissue, pathologic changes, and inflammatory cells in the BALF were measured after 4 h and 24 h. The LSS group showed cytotoxicity that was closely related to the concentration. The figures of the two LSS groups (4 and 24 h) show that the alveolar septa were thickened. Additionally, it was observed that neutrophils had infiltrated, and various levels of inflammation occurred around the vascular and bronchial structures. The overall results of the acute effects of the lungs caused by dust showed that the lung toxicity of LSS was greater than that of PM2.5. LSS could induce lung damage and inflammatory lesions. The biomarkers in BALF caused by acute injury were consistent with histopathologic observations. Copyright © 2017. Published by Elsevier Taiwan LLC.

[Effect of dexmedetomidine on perfusion of free flaps transferred to head and neck].

PubMed

Dobrodeev, A S; Rabinovich, S A; Malykhina, I F

The paper presents the impact of perioperative care on feasibility of free fibula flap transfer for facial reconstruction. Flaps vitality was measured by means of somatic oximetry in 85 patients aged 20-74 years receiving reconstruction procedures in midfacial and lower facial areas. The patients were divided in three groups according to sedation agent used postoperatively. It has been demonstrated that dexmedetomidine postoperative sedation significantly improved free fibula flaps perfusion compared to propofol sedation.

Pharmacotherapy of Acute Lung Injury and Acute Respiratory Distress Syndrome

PubMed Central

Raghavendran, Krishnan; Pryhuber, Gloria S.; Chess, Patricia R.; Davidson, Bruce A.; Knight, Paul R.; Notter, Robert H.

2009-01-01

Acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS) are characterized by rapid-onset respiratory failure following a variety of direct and indirect insults to the parenchyma or vasculature of the lungs. Mortality from ALI/ARDS is substantial, and current therapy primarily emphasizes mechanical ventilation and judicial fluid management plus standard treatment of the initiating insult and any known underlying disease. Current pharmacotherapy for ALI/ARDS is not optimal, and there is a significant need for more effective medicinal chemical agents for use in these severe and lethal lung injury syndromes. To facilitate future chemical-based drug discovery research on new agent development, this paper reviews present pharmacotherapy for ALI/ARDS in the context of biological and biochemical drug activities. The complex lung injury pathophysiology of ALI/ARDS offers an array of possible targets for drug therapy, including inflammation, cell and tissue injury, vascular dysfunction, surfactant dysfunction, and oxidant injury. Added targets for pharmacotherapy outside the lungs may also be present, since multiorgan or systemic pathology is common in ALI/ARDS. The biological and physiological complexity of ALI/ARDS requires the consideration of combined-agent treatments in addition to single-agent therapies. A number of pharmacologic agents have been studied individually in ALI/ARDS, with limited or minimal success in improving survival. However, many of these agents have complementary biological/biochemical activities with the potential for synergy or additivity in combination therapy as discussed in this article. PMID:18691048

Hepatic Blood Perfusion Estimated by Dynamic Contrast-Enhanced Computed Tomography in Pigs Limitations of the Slope Method

PubMed Central

Winterdahl, Michael; Sørensen, Michael; Keiding, Susanne; Mortensen, Frank V.; Alstrup, Aage K. O.; Hansen, Søren B.; Munk, Ole L.

2012-01-01

Objective To determine whether dynamic contrast-enhanced computed tomography (DCE-CT) and the slope method can provide absolute measures of hepatic blood perfusion from hepatic artery (HA) and portal vein (PV) at experimentally varied blood flow rates. Materials and Methods Ten anesthetized 40-kg pigs underwent DCE-CT during periods of normocapnia (normal flow), hypocapnia (decreased flow), and hypercapnia (increased flow), which was induced by adjusting the ventilation. Reference blood flows in HA and PV were measured continuously by surgically-placed ultrasound transit-time flowmeters. For each capnic condition, the DCE-CT estimated absolute hepatic blood perfusion from HA and PV were calculated using the slope method and compared with flowmeter based absolute measurements of hepatic perfusions and relative errors were analyzed. Results The relative errors (mean±SEM) of the DCE-CT based perfusion estimates were −21±23% for HA and 81±31% for PV (normocapnia), 9±23% for HA and 92±42% for PV (hypocapnia), and 64±28% for HA and −2±20% for PV (hypercapnia). The mean relative errors for HA were not significantly different from zero during hypo- and normocapnia, and the DCE-CT slope method could detect relative changes in HA perfusion between scans. Infusion of contrast agent led to significantly increased hepatic blood perfusion, which biased the PV perfusion estimates. Conclusions Using the DCE-CT slope method, HA perfusion estimates were accurate at low and normal flow rates whereas PV perfusion estimates were inaccurate and imprecise. At high flow rate, both HA perfusion estimates were significantly biased. PMID:22836307

Decellularized Rat Lung Scaffolds Using Sodium Lauryl Ether Sulfate for Tissue Engineering.

PubMed

Ma, Jinhui; Ju, Zhihai; Yu, Jie; Qiao, Yeru; Hou, Chenwei; Wang, Chen; Hei, Feilong

Perfusion decellularization with detergents is effective to maintain the architecture and proteins of extracellular matrix (ECM) for use in the field of lung tissue engineering (LTE). However, it is unclear which detergent is ideal to produce an acellular lung scaffold. In this study, we obtained two decellularized rat lung scaffolds using a novel detergent sodium lauryl ether sulfate (SLES) and a conventional detergent sodium dodecyl sulfate (SDS). Both decellularized lung scaffolds were assessed by histology, immunohistochemistry, scanning electron microscopy, DNA quantification, sulfated glycosaminoglycans (GAGs) quantification and western blot. Subsequently, the scaffolds were implanted subcutaneously in rats for 6 weeks and were evaluated via hematoxylin and eosin staining and Masson staining. Results indicated that SLES was effective to remove cells; moreover, lungs decellularized with SLES showed better preservation of sulfated GAGs, lung architecture, and ECM proteins than SDS. After 6 weeks, SLES scaffolds demonstrated a significantly greater potential for cell infiltration and blood vessel formation compared with SDS scaffolds. Taken together, we conclude that SLES is a promising detergent to produce an acellular scaffold using LTE for eventual transplantation.

Contrast-enhanced ultrasound evaluation of pancreatic cancer xenografts in nude mice after irradiation with sub-threshold focused ultrasound for tumor ablation

PubMed Central

Wang, Rui; Guo, Qian; Chen, Yi Ni; Hu, Bing; Jiang, Li Xin

2017-01-01

We evaluated the efficacy of contrast-enhanced ultrasound for assessing tumors after irradiation with sub-threshold focused ultrasound (FUS) ablation in pancreatic cancer xenografts in nude mice. Thirty tumor-bearing nude mice were divided into three groups: Group A received sham irradiation, Group B received a moderate-acoustic energy dose (sub-threshold), and Group C received a high-acoustic energy dose. In Group B, B-mode ultrasound (US), color Doppler US, and dynamic contrast-enhanced ultrasound (DCE-US) studies were conducted before and after irradiation. After irradiation, tumor growth was inhibited in Group B, and the tumors shrank in Group C. In Group A, the tumor sizes were unchanged. In Group B, contrast-enhanced ultrasound (CEUS) images showed a rapid rush of contrast agent into and out of tumors before irradiation. After irradiation, CEUS revealed contrast agent perfusion only at the tumor periphery and irregular, un-perfused volumes of contrast agent within the tumors. DCE-US perfusion parameters, including peak intensity (PI) and area under the curve (AUC), had decreased 24 hours after irradiation. PI and AUC were increased 48 hours and 2weeks after irradiation. Time to peak (TP) and sharpness were increased 24 hours after irradiation. TP decreased at 48 hours and 2 weeks after irradiation. CEUS is thus an effective method for early evaluation after irradiation with sub-threshold FUS. PMID:28402267

Thoracic magnetic resonance imaging: pulmonary thromboembolism.

PubMed

Fink, Christian; Henzler, Thomas; Shirinova, Aysel; Apfaltrer, Paul; Wasser, Klaus

2013-05-01

Ongoing technical developments have substantially improved the potential of magnetic resonance imaging (MRI) in the assessment of the pulmonary circulation. These developments includes improved magnet and hardware design, new k-space sampling techniques (ie, parallel imaging), and alternative contrast materials. With these techniques, not only can pulmonary vessels be visualized by MR angiography with high spatial resolution but also the perfusion of the lungs and its changes in relation to pulmonary thromboembolism (PE) can be assessed. Considering venous thromboembolism as a systemic disease, MR venography might be added for the diagnosis of underlying deep venous thrombosis. A unique advantage of MRI over other imaging tests is its potential to evaluate changes in cardiac function as a result of obstruction of the pulmonary circulation, which may have a significant impact on patient monitoring and treatment. Finally, MRI does not involve radiation, which is advantageous, especially in young patients. Over the years, a number of studies have shown promising results not only for MR angiography but also for MRI of lung perfusion and for MR venography. This review article summarizes and discusses the current evidence on pulmonary MRI for patients with suspected PE.

Thoracoscopic pneumonectomy for severe bronchiectasis in a 9-year-old female.

PubMed

Anselmo, Dean M; Perez, Iris A; Shaul, Donald B

2008-10-01

Thoracoscopic total pneumonectomy has not been previously described in the pediatric surgical literature. In this paper, we describe a case of pneumonectomy performed through a minimally invasive approach in a 9-year-old female with Down's syndrome and gastroesophageal reflux disease. The patient suffered from multiple recurrent aspiration pneumonias, which progressed to bronchiectasis of the entire left lung. As a result, the patient was hypoxemic and required continuous supplemental oxygen. Preoperative perfusion scans showed diminished perfusion of the left lung. Thoracoscopy was performed by using 3-5 mm trocars and one 12-mm trocar. Insufflation pressure was maintained at 5 mm Hg. Dissection was performed at the hilum by using hook electrocautery and the LigaSure device (ValleyLab, Boulder, CO). The pulmonary artery, veins, and left mainstem bronchus were sequentially divided by using a 35-mm ENDO GIA vascular stapler (Ethicon Endo-Surgery, Cincinnati, OH). There were no intraoperative complications. Eight months following surgery, her health is improved and she no longer requires supplemental oxygen. Thoracoscopic pneumonectomy is a safe, technically feasible approach for severe bronchiectasis in children.

Microcapillary imaging of lamina cribrosa in porcine eyes using photoacoustic microscopy

NASA Astrophysics Data System (ADS)

Moothanchery, Mohesh; Chuangsuwanich, Thanadet; Yan, Alvan Tsz Chung; Schmetterer, Leopold; Girard, Michael J. A.; Pramanik, Manojit

2018-02-01

In order to understand the pathophysiology of glaucoma, Lamina cribrosa (LC) perfusion needs to be the subject of thorough investigation. It is currently difficult to obtain high resolution images of the embedded microcapillary network of the LC using conventional imaging techniques. In this study, an optical resolution photoacoustic microscopy (OR-PAM) system was used for imaging lamina cribrosa of an ex vivo porcine eye. Extrinsic contrast agent was used to perfuse the eye via its ciliary arteries. The OR-PAM system have a lateral resolution of 4 μm and an axial resolution of 30 μm. The high resolution system could able resolve a perfused LC microcapillary network to show vascular structure within the LC thickness. OR-PAM could be a promising imaging modality to study the LC perfusion and hence could be used to elucidate the hemodynamic aspect of glaucoma.

Uncontrolled Donation After Circulatory Determination of Death Donors (uDCDDs) as a Source of Lungs for Transplant

PubMed Central

Egan, T. M.; Requard, J. J.

2017-01-01

In April 2014, the American Journal of Transplantation published a report on the first lung transplant in the United States recovered from an uncontrolled donation after circulatory determination of death donor (uDCDD), assessed by ex vivo lung perfusion (EVLP). The article identified logistical and ethical issues related to introduction of lung transplant from uDCDDs. In an open clinical trial, we have Food and Drug Administration and Institutional Review Board approval to transplant lungs recovered from uDCDDs judged suitable after EVLP. Through this project and other experiences with lung recovery from uDCDDs, we have identified solutions to many logistical challenges and have addressed ethical issues surrounding lung transplant from uDCDDs that were mentioned in this case report. Here, we discuss those challenges, including issues related to recovery of other solid organs from uDCDDs. Despite logistical challenges, uDCDDs could solve the critical shortage of lungs for transplant. Furthermore, by avoiding the deleterious impact of brain death and days of positive pressure ventilation, and by using opportunities to treat lungs in the decedent or during EVLP, lungs recovered from uDCDDs may ultimately prove to be better than lungs currently being transplanted from conventional brain-dead organ donors. PMID:25873272

Estimation of contrast agent bolus arrival delays for improved reproducibility of liver DCE MRI

NASA Astrophysics Data System (ADS)

Chouhan, Manil D.; Bainbridge, Alan; Atkinson, David; Punwani, Shonit; Mookerjee, Rajeshwar P.; Lythgoe, Mark F.; Taylor, Stuart A.

2016-10-01

Delays between contrast agent (CA) arrival at the site of vascular input function (VIF) sampling and the tissue of interest affect dynamic contrast enhanced (DCE) MRI pharmacokinetic modelling. We investigate effects of altering VIF CA bolus arrival delays on liver DCE MRI perfusion parameters, propose an alternative approach to estimating delays and evaluate reproducibility. Thirteen healthy volunteers (28.7  ±  1.9 years, seven males) underwent liver DCE MRI using dual-input single compartment modelling, with reproducibility (n  =  9) measured at 7 days. Effects of VIF CA bolus arrival delays were assessed for arterial and portal venous input functions. Delays were pre-estimated using linear regression, with restricted free modelling around the pre-estimated delay. Perfusion parameters and 7 days reproducibility were compared using this method, freely modelled delays and no delays using one-way ANOVA. Reproducibility was assessed using Bland-Altman analysis of agreement. Maximum percent change relative to parameters obtained using zero delays, were  -31% for portal venous (PV) perfusion, +43% for total liver blood flow (TLBF), +3247% for hepatic arterial (HA) fraction, +150% for mean transit time and  -10% for distribution volume. Differences were demonstrated between the 3 methods for PV perfusion (p  =  0.0085) and HA fraction (p  <  0.0001), but not other parameters. Improved mean differences and Bland-Altman 95% Limits-of-Agreement for reproducibility of PV perfusion (9.3 ml/min/100 g, ±506.1 ml/min/100 g) and TLBF (43.8 ml/min/100 g, ±586.7 ml/min/100 g) were demonstrated using pre-estimated delays with constrained free modelling. CA bolus arrival delays cause profound differences in liver DCE MRI quantification. Pre-estimation of delays with constrained free modelling improved 7 days reproducibility of perfusion parameters in volunteers.

Chemoprevention of Lung Cancer

PubMed Central

Szabo, Eva; Mao, Jenny T.; Lam, Stephen; Reid, Mary E.

2013-01-01

Background: Lung cancer is the most common cause of cancer death in men and women in the United States. Cigarette smoking is the main risk factor. Former smokers are at a substantially increased risk of developing lung cancer compared with lifetime never smokers. Chemoprevention refers to the use of specific agents to reverse, suppress, or prevent the process of carcinogenesis. This article reviews the major agents that have been studied for chemoprevention. Methods: Articles of primary, secondary, and tertiary prevention trials were reviewed and summarized to obtain recommendations. Results: None of the phase 3 trials with the agents β-carotene, retinol, 13-cis-retinoic acid, α-tocopherol, N-acetylcysteine, acetylsalicylic acid, or selenium has demonstrated beneficial and reproducible results. To facilitate the evaluation of promising agents and to lessen the need for a large sample size, extensive time commitment, and expense, surrogate end point biomarker trials are being conducted to assist in identifying the most promising agents for later-stage chemoprevention trials. With the understanding of important cellular signaling pathways and the expansion of potentially important targets, agents (many of which target inflammation and the arachidonic acid pathway) are being developed and tested which may prevent or reverse lung carcinogenesis. Conclusions: By integrating biologic knowledge, additional early-phase trials can be performed in a reasonable time frame. The future of lung cancer chemoprevention should entail the evaluation of single agents or combinations that target various pathways while working toward identification and validation of intermediate end points. PMID:23649449

Standard donor lung procurement with normothermic ex vivo lung perfusion: A prospective randomized clinical trial.

PubMed

Slama, Alexis; Schillab, Lukas; Barta, Maximilian; Benedek, Aris; Mitterbauer, Andreas; Hoetzenecker, Konrad; Taghavi, Shahrokh; Lang, Gyoergy; Matilla, Jose; Ankersmit, Hendrik; Hager, Helmut; Roth, Georg; Klepetko, Walter; Aigner, Clemens

2017-07-01

Ex vivo lung perfusion (EVLP) was primarily developed for evaluation of impaired donor lungs. The good clinical results raise the question for its possible impact on lungs meeting standard criteria. Before application of EVLP on such lungs enters routine clinical practice, it must be demonstrated whether EVLP would affect or improve outcome when used in standard donor lungs. We performed a prospective randomized trial to investigate the role of EVLP in standard lung transplantation (Tx). This prospective randomized clinical trial compared patients who underwent Tx with ex vivo evaluated donor lungs with an equivalent patient population without previous EVLP. From October 2013 to May 2015, 193 lung Tx were performed at the Medical University of Vienna. During this period, 80 recipient/donor pairs that met the inclusion criteria were included in this trial, 41 pairs in the control group, and 39 in the EVLP group. In the EVLP group, 4 lungs (10.2%) ultimately did not qualify for Tx and were rejected for lung Tx owing to technical reasons (n = 2) and quality criteria (n = 2). Donor and recipient characteristics were comparable in both groups. Total cold ischemic time in the EVLP group was significantly longer for both implanted lungs (first side, 372 minutes vs 291 minutes, p < 0.001; second side, 437 minutes vs 370 minutes, p = 0.001); median duration of surgery showed no differences (277 minutes vs 275 minutes). Median oxygen partial pressure/fraction of inspired oxygen ratio at 24 hours after Tx was 516 (range, 280-557) in the EVLP group and 491 (range, 352-575) in the control group (p = 0.63). Incidence of primary graft dysfunction >1 was lower in the EVLP group at all time points compared with the control group (24 hours, 5.7% vs 19.5%, p = 0.10), and need for post-operative prolonged extracorporeal membrane oxygenation was lower in the EVLP group (5.7% vs 12.2%, p = 0.44). Short-term clinical outcomes did not differ between recipients in the 2 groups. Patients remained intubated (1.6 days vs 1.6 days, p = 0.67), in the intensive care unit (6 days vs 6 days, p = 0.76), and in the hospital (23 days vs 19 days, p = 0.42) for a comparable period of time. The 30-day survival was 97.1% vs 100% (p = 0.46). This study provides evidence that EVLP can safely be used in standard donor lungs. Functional results and perioperative outcome are comparable to those achieved with standard donor lung preservation techniques. As an evaluation tool, EVLP allows clinicians to identify and to possibly exclude lungs with functional impairment. Finally, EVLP can safely extend total preservation time. Copyright © 2017 International Society for the Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

Phosphotyrosine phosphatase and tyrosine kinase inhibition modulate airway pressure-induced lung injury.

PubMed

Parker, J C; Ivey, C L; Tucker, A

1998-11-01

We determined whether drugs which modulate the state of protein tyrosine phosphorylation could alter the threshold for high airway pressure-induced microvascular injury in isolated perfused rat lungs. Lungs were ventilated for successive 30-min periods with peak inflation pressures (PIP) of 7, 20, 30, and 35 cmH2O followed by measurement of the capillary filtration coefficient (Kfc), a sensitive index of hydraulic conductance. In untreated control lungs, Kfc increased by 1.3- and 3.3-fold relative to baseline (7 cmH2O PIP) after ventilation with 30 and 35 cmH2O PIP. However, in lungs treated with 100 microM phenylarsine oxide (a phosphotyrosine phosphatase inhibitor), Kfc increased by 4.7- and 16.4-fold relative to baseline at these PIP values. In lungs treated with 50 microM genistein (a tyrosine kinase inhibitor), Kfc increased significantly only at 35 cmH2O PIP, and the three groups were significantly different from each other. Thus phosphotyrosine phosphatase inhibition increased the susceptibility of rat lungs to high-PIP injury, and tyrosine kinase inhibition attenuated the injury relative to the high-PIP control lungs.

Lung mechanical and vascular changes during positive- and negative-pressure lung inflations: importance of reference pressures in the pulmonary vasculature.

PubMed

Peták, Ferenc; Albu, Gergely; Lele, Enikö; Hantos, Zoltán; Morel, Denis R; Fontao, Fabienne; Habre, Walid

2009-03-01

The continuous changes in lung mechanics were related to those in pulmonary vascular resistance (Rv) during lung inflations to clarify the mechanical changes in the bronchoalveolar system and the pulmonary vasculature. Rv and low-frequency lung impedance data (Zl) were measured continuously in isolated, perfused rat lungs during 2-min inflation-deflation maneuvers between transpulmonary pressures of 2.5 and 22 cmH(2)O, both by applying positive pressure at the trachea and by generating negative pressure around the lungs in a closed box. ZL was averaged and evaluated for 2-s time windows; airway resistance (Raw), parenchymal damping and elastance (H) were determined in each window. Lung inflation with positive and negative pressures led to very similar changes in lung mechanics, with maximum decreases in Raw [-68 +/- 4 (SE) vs. -64 +/- 18%] and maximum increases in H (379 +/- 36 vs. 348 +/- 37%). Rv, however, increased with positive inflation pressure (15 +/- 1%), whereas it exhibited mild decreases during negative-pressure expansions (-3 +/- 0.3%). These results demonstrate that pulmonary mechanical changes are not affected by the opposing modes of lung inflations and confirm the importance of relating the pulmonary vascular pressures in interpreting changes in Rv.

Iodine-122-labeled amphetamine derivative with potential for PET brain blood-flow studies

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mathis, C.A.; Sargent, T. 3d.; Shulgin, A.T.

1985-11-01

The positron emitter SSI (t1/2 3.6 min) was collected from a xenon- SS/iodine- SS ( SSXe/ SSI) generator and incorporated into an amphetamine analog, 2,4-dimethoxy-N,N-dimethyl-5-( SSI)iodophenylisopropylamine (5-( SSI)-2,4-DNNA). The remote synthesis was achieved in 3 min with a 50% radioincorporation yield and a product radiopurity of greater than 98%. 5-( SSI)-2,4-DNNA was injected into a beagle dog and a brain section imaged with positron emission tomography (PET). The uptake and retention of 5-( SSI)-2,4-DNNA was compared to that of YSRb in the same animal. Dynamic PET activity data were obtained 0-20 min postinjection of 5-( SSI)-2,4-DNNA and showed rapid uptakemore » by brain and good cerebral/extracerebral tissue distinction. A whole-body scan of a dog was also obtained with 5-123I-2,4-DNNA showing uptake in brain, lung, and other body organs. The feasibility of incorporating SSI into an extracted brain perfusion agent for use with PET is demonstrated.« less

Common-path Fourier domain optical coherence tomography of irradiated human skin and ventilated isolated rabbit lungs

NASA Astrophysics Data System (ADS)

Popp, A.; Wendel, M.; Knels, L.; Knuschke, P.; Mehner, M.; Koch, T.; Boller, D.; Koch, P.; Koch, E.

2005-08-01

A compact common path Fourier domain optical coherence tomography (FD-OCT) system based on a broadband superluminescence diode is used for biomedical imaging. The epidermal thickening of human skin after exposure to ultraviolet radiation is measured to proof the feasibility of FD-OCT for future substitution of invasive biopsies in a long term study on natural UV skin protection. The FD-OCT system is also used for imaging lung parenchyma. FD-OCT images of a formalin fixated lung show the same alveolar structure as scanning electron microscopy images. In the ventilated and blood-free perfused isolated rabbit lung FD-OCT is used for real-time cross-sectional image capture of alveolar mechanics throughout tidal ventilation. The alveolar mechanics changing from alternating recruitment-derecruitment at zero positive end-expiratory pressure (PEEP) to persistent recruitment after applying a PEEP of 5 cm H2O is observed in the OCT images.

Correlation between acoustic radiation force impulse (ARFI)-based tissue elasticity measurements and perfusion parameters acquired by perfusion CT in cirrhotic livers: a proof of principle.

PubMed

Esser, Michael; Bitzer, Michael; Kolb, Manuel; Fritz, Jan; Kurucay, Mustafa; Ruff, Christer; Horger, Marius

2018-06-13

To investigate whether liver stiffness measured by acoustic radiation force impulse (ARFI) sonoelastography always correlates with the liver perfusion parameters quantified by perfusion CT in patients with known liver cirrhosis. Sonoelastography and perfusion CT were performed in 50 patients (mean age 65.5; range 45-87 years) with liver cirrhosis, who were classified according to Child-Pugh into class A (30/50, 60%), B (17/50, 34%), and C (3/50, 6%). For standardized ARFI measurements in the left liver lobe at a depth of 4 cm, a convex 6-MHz probe was used. CT examinations were performed using 80 kV, 100 mAs, and 50 ml of iodinated contrast agent injected at 5 ml/s. Using standardized region-of-interest measurements, we quantified arterial, portal venous, and total liver perfusion. There was a significant linear correlation between tissue stiffness and arterial liver perfusion (p = 0.015), and also when limiting the analysis to patients with histology (p = 0.019). In addition, there was a positive correlation between the total blood supply (arterial + portal-venous liver perfusion) to the liver and tissue stiffness (p = 0.001; with histology, p = 0.027). Shear wave velocity increased with higher Child-Pugh stages (p = 0.013). The degree of tissue stiffness in cirrhotic livers correlates expectedly-even if only moderately-with the magnitude of arterial liver perfusion and total liver perfusion. As such, liver elastography remains the leading imaging tool in assessing liver fibrosis.

Chemopreventive and Anti-cancer Efficacy of Silibinin against Growth and Progression of Lung Cancer

PubMed Central

Mateen, Samiha; Raina, Komal; Agarwal, Rajesh

2014-01-01

The use of systemic chemotherapeutic drugs and molecular-targeted therapies in the treatment of patients with locally advanced or metastatic lung cancer has its limitations due to the associated acute and cumulative dose limiting toxicities and acquisition of drug resistance. Prevention and therapeutic intervention by dietary agents including nutraceuticals which are non-toxic, cost-effective, and physiologically bioavailable, are emerging approaches in lung cancer management. In this regard, silibinin, a natural flavonolignan, has been rigorously evaluated for the prevention and growth control of lung cancer through extensive in vitro and in vivo studies. Successful studies conducted so far, have established that silibinin is effective both alone and in combination with other agents (e.g. chemotherapeutic and epigenetic agents) in significantly inhibiting the growth of lung cancer cells. In vivo, its effects have been shown to be mediated through inhibition of proliferation, angiogenesis and epigenetic-related events. Therefore, the present review focuses on encompassing the efficacy and mechanisms of silibinin against lung cancer. PMID:23682778

Evaluation of optimized magnetic resonance perfusion imaging scanning time window after contrast agent injection for differentiating benign and malignant breast lesions

PubMed Central

Dong, Jie; Wang, Dawei; Ma, Zhenshen; Deng, Guodong; Wang, Lanhua; Zhang, Jiandong

2017-01-01

The aim of the study was evaluate the 3.0 T magnetic resonance (MR) perfusion imaging scanning time window following contrast injection for differentiating benign and malignant breast lesions and to determine the optimum scanning time window for increased scanner usage efficiency and reduced diagnostic adverse risk factors. A total of 52 women with breast abnormalities were selected for conventional MR imaging and T1 dynamic-enhanced imaging. Quantitative parameters [volume transfer constant (Ktrans), rate constant (Kep) and extravascular extracellular volume fraction (Ve)] were calculated at phases 10, 20, 30, 40 and 50, which represented time windows at 5, 10, 15, 20 and 25 min, respectively, following injection of contrast agent. The association of the parameters at different phases with benign and malignant tumor diagnosis was analyzed. MR perfusion imaging was verified as an effective modality in the diagnosis of breast malignancies and the best scanning time window was identified: i) Values of Ktrans and Kep at all phases were statistically significant in differentiating benign and malignant tumors (P<0.05), while the value of Ve had statistical significance only at stage 10, but not at any other stages (P>0.05); ii) values of Ve in benign tumors increased with phase number, but achieved no obvious changes at different phases in malignant tumors; iii) the optimum scanning time window of breast perfusion imaging with 3.0 T MR was between phases 10 and 30 (i.e., between 5 and 15 min after contrast agent injection). The variation trend of Ve values at different phases may serve as a diagnostic reference for differentiating benign and malignant breast abnormalities. The most efficient scanning time window was indicated to be 5 min after contrast injection, based on the observation that the Ve value only had statistical significance in diagnosis at stage 10. However, the optimal scanning time window is from 5 to 15 min following the injection of contrast agent, since that the variation trend of Ve is able to serve as a diagnostic reference. PMID:28450944

Evaluation of optimized magnetic resonance perfusion imaging scanning time window after contrast agent injection for differentiating benign and malignant breast lesions.

PubMed

Dong, Jie; Wang, Dawei; Ma, Zhenshen; Deng, Guodong; Wang, Lanhua; Zhang, Jiandong

2017-03-01

The aim of the study was evaluate the 3.0 T magnetic resonance (MR) perfusion imaging scanning time window following contrast injection for differentiating benign and malignant breast lesions and to determine the optimum scanning time window for increased scanner usage efficiency and reduced diagnostic adverse risk factors. A total of 52 women with breast abnormalities were selected for conventional MR imaging and T1 dynamic-enhanced imaging. Quantitative parameters [volume transfer constant (K trans ), rate constant (K ep ) and extravascular extracellular volume fraction (V e )] were calculated at phases 10, 20, 30, 40 and 50, which represented time windows at 5, 10, 15, 20 and 25 min, respectively, following injection of contrast agent. The association of the parameters at different phases with benign and malignant tumor diagnosis was analyzed. MR perfusion imaging was verified as an effective modality in the diagnosis of breast malignancies and the best scanning time window was identified: i) Values of K trans and K ep at all phases were statistically significant in differentiating benign and malignant tumors (P<0.05), while the value of V e had statistical significance only at stage 10, but not at any other stages (P>0.05); ii) values of V e in benign tumors increased with phase number, but achieved no obvious changes at different phases in malignant tumors; iii) the optimum scanning time window of breast perfusion imaging with 3.0 T MR was between phases 10 and 30 (i.e., between 5 and 15 min after contrast agent injection). The variation trend of V e values at different phases may serve as a diagnostic reference for differentiating benign and malignant breast abnormalities. The most efficient scanning time window was indicated to be 5 min after contrast injection, based on the observation that the V e value only had statistical significance in diagnosis at stage 10. However, the optimal scanning time window is from 5 to 15 min following the injection of contrast agent, since that the variation trend of V e is able to serve as a diagnostic reference.

Comparison of a single indicator and gravimetric technique for estimation of extravascular lung water in endotoxemic pigs.

PubMed

Rossi, Patrik; Wanecek, Michael; Rudehill, Anders; Konrad, David; Weitzberg, Eddie; Oldner, Anders

2006-05-01

To compare the single thermal indicator dilution (STID) technique for measurement of extravascular lung water (EVLW(STID)) with gravimetrically determined EVLW (EVLW(GRAV)) in anesthetized pigs under sham and endotoxemic conditions. Open experimental comparative animal study. University animal research laboratory. Fifteen anesthetized landrace pigs. Endotoxin infusion during 5 hrs in five pigs. Six animals were only anesthetized and rested for 5 hrs. In four additional animals, the impact on EVLW(STID) measurements by changes in pulmonary perfusion, ventilation, and the combination of the two was studied. The alterations in ventilation and perfusion were induced by caval balloon inflation, inflation of the pulmonary artery catheter balloon, and bronchial plugging respectively. The STID technique, with default settings of the intrathoracic blood volume (ITBV) to global end-diastolic volume (GEDV) (i.e., the extrapulmonary intravascular volume between the point of injection of the indicator, and the point of detection) relationship (ITBV = 1.25GEDV), systematically overestimated the EVLW index compared with the gravimetrical method (mean bias of 5.4 mL/kg). By adapting the ITBV to GEDV relationship to the current model (ITBV = 1.52GEDV + 49.7), the accuracy of the STID technique improved. Moreover, the measurement of EVLW(STID) proved to be reduced by manipulation of pulmonary perfusion and ventilation. However, the STID technique could detect an increase in EVLW during endotoxemia independent of the ITBV/GEDV relationship used. Despite technological improvement, the dilution techniques for the measurement of EVLW might still be influenced by changes in perfusion and ventilation. The STID technique, in addition, might demand adjustment of the ITBV/GEDV relationship to the particular condition and species subjected to measurement. The STID technique may, however, be a useful tool for monitoring changes of EVLW over time, but further studies are warranted to confirm this.

Heterogeneity of pulmonary perfusion as a mechanistic image-based phenotype in emphysema susceptible smokers.

PubMed

Alford, Sara K; van Beek, Edwin J R; McLennan, Geoffrey; Hoffman, Eric A

2010-04-20

Recent evidence suggests that endothelial dysfunction and pathology of pulmonary vascular responses may serve as a precursor to smoking-associated emphysema. Although it is known that emphysematous destruction leads to vasculature changes, less is known about early regional vascular dysfunction which may contribute to and precede emphysematous changes. We sought to test the hypothesis, via multidetector row CT (MDCT) perfusion imaging, that smokers showing early signs of emphysema susceptibility have a greater heterogeneity in regional perfusion parameters than emphysema-free smokers and persons who had never smoked (NS). Assuming that all smokers have a consistent inflammatory response, increased perfusion heterogeneity in emphysema-susceptible smokers would be consistent with the notion that these subjects may have the inability to block hypoxic vasoconstriction in patchy, small regions of inflammation. Dynamic ECG-gated MDCT perfusion scans with a central bolus injection of contrast were acquired in 17 NS, 12 smokers with normal CT imaging studies (SNI), and 12 smokers with subtle CT findings of centrilobular emphysema (SCE). All subjects had normal spirometry. Quantitative image analysis determined regional perfusion parameters, pulmonary blood flow (PBF), and mean transit time (MTT). Mean and coefficient of variation were calculated, and statistical differences were assessed with one-way ANOVA. MDCT-based MTT and PBF measurements demonstrate globally increased heterogeneity in SCE subjects compared with NS and SNI subjects but demonstrate similarity between NS and SNI subjects. These findings demonstrate a functional lung-imaging measure that provides a more mechanistically oriented phenotype that differentiates smokers with and without evidence of emphysema susceptibility.

Prognostic and Pathogenic Role of Angiopoietin-1 and -2 in Pneumonia.

PubMed

Gutbier, Birgitt; Neuhauß, Anne-Kathrin; Reppe, Katrin; Ehrler, Carolin; Santel, Ansgar; Kaufmann, Jörg; Scholz, Markus; Weissmann, Norbert; Morawietz, Lars; Mitchell, Timothy J; Aliberti, Stefano; Hippenstiel, Stefan; Suttorp, Norbert; Witzenrath, Martin

2018-02-15

During pneumonia, pathogen-host interaction evokes inflammation and lung barrier dysfunction. Tie2-activation by Angiopoietin-1 reduces, while Tie2-blockade by Angiopoietin-2 increases inflammation and permeability during sepsis. The role of Angiopoietin-1/-2 in pneumonia remains unidentified. To investigate the prognostic and pathogenetic impact of Angiopoietins in regulating pulmonary vascular barrier function and inflammation in bacterial pneumonia. Serum Angiopoietin levels were quantified in pneumonia patients of two independent cohorts (n=148, n=395). Human post mortem lung tissue, pneumolysin- or Angiopoietin-2-stimulated endothelial cells, isolated perfused and ventilated mouse lungs, and mice with pneumococcal pneumonia were investigated. In pneumonia patients, decreased serum Angiopoietin-1 and increased Angiopoietin-2 levels were observed as compared to healthy subjects. Higher Angiopoietin-2 serum levels were found in community-acquired pneumonia patients who died within 28 days after diagnosis compared to survivors. ROC analysis revealed improved prognostic accuracy of CURB-65 for 28-day survival, intensive care treatment and length of hospital stay if combined with Angiopoietin-2 serum levels. In vitro, pneumolysin enhanced endothelial Angiopoietin-2 release, Angiopoietin-2 increased endothelial permeability, and Angiopoietin-1 reduced pneumolysin-evoked endothelial permeability. Ventilated and perfused lungs of mice with Angiopoietin-2-knockdown showed reduced permeability upon pneumolysin stimulation. Increased pulmonary Angiopoietin-2 and reduced Angiopoietin-1 mRNA expression were observed in S. pneumoniae infected mice. Finally, Angiopoietin-1 therapy reduced inflammation and permeability in murine pneumonia. These data suggest a central role of Angiopoietin-1/-2 in pneumonia-evoked inflammation and permeability. Increased Angiopoietin-2 serum levels predicted mortality and length of hospital stay, and Angiopoietin-1 may provide a therapeutic target for severe pneumonia.

Prostaglandins induce vascular endothelial growth factor in a human monocytic cell line and rat lungs via cAMP.

PubMed

Höper, M M; Voelkel, N F; Bates, T O; Allard, J D; Horan, M; Shepherd, D; Tuder, R M

1997-12-01

Prostaglandins have emerged as a therapeutic option for patients with peripheral vascular disease as well as pulmonary hypertension as a means to increase blood flow. We tested the hypothesis that prostaglandins regulate vascular endothelial growth factor (VEGF) expression in the human monocytic THP-1 cell line and in isolated perfused rat lungs. Our data show that the stable PGI2-analogue iloprost induces VEGF gene expression (predominantly VEGF121, but also VEGF165 isoforms) and VEGF protein synthesis in THP-1 cells. This effect is abolished by dexamethasone and by Rp-cAMP, a specific inhibitor of cAMP-dependent protein kinase (PKA) activation. The calcium channel blocker diltiazem has no effect on the iloprost-induced VEGF gene expression, and depletion of intracellular Ca2+ stores by long-term exposure (16 h) of THP-1 cells to thapsigargin does not inhibit iloprost-induced VEGF gene expression, suggesting that an increase in intracellular Ca2+ is not essential for VEGF gene induction by iloprost. However, an increase of intracellular Ca2+ by a short-term (2 h) exposure of THP-1 cells to thapsigargin or to the calcium-ionophore A23187 increases VEGF mRNA levels, indicating that a change in intracellular Ca2+ by itself can alter VEGF gene expression. The effects of thapsigargin or A23187 on VEGF gene expression are also mediated via cAMP-PKA since they are inhibited by Rp-cAMP. In isolated perfused rat lungs, PGI2 and PGE2 increases VEGF mRNA abundance whereas Rp-cAMP inhibits the prostaglandin-induced VEGF gene activation. Thus, our data suggest that prostaglandins stimulate VEGF gene expression in monocytic cells and in rat lungs via a cAMP-dependent mechanism.

Lung ventilation injures areas with discrete alveolar flooding, in a surface tension-dependent fashion.

PubMed

Wu, You; Kharge, Angana Banerjee; Perlman, Carrie E

2014-10-01

With proteinaceous-liquid flooding of discrete alveoli, a model of the edema pattern in the acute respiratory distress syndrome, lung inflation over expands aerated alveoli adjacent to flooded alveoli. Theoretical considerations suggest that the overexpansion may be proportional to surface tension, T. Yet recent evidence indicates proteinaceous edema liquid may not elevate T. Thus whether the overexpansion is injurious is not known. Here, working in the isolated, perfused rat lung, we quantify fluorescence movement from the vasculature to the alveolar liquid phase as a measure of overdistension injury to the alveolar-capillary barrier. We label the perfusate with fluorescence; micropuncture a surface alveolus and instill a controlled volume of nonfluorescent liquid to obtain a micropunctured-but-aerated region (control group) or a region with discrete alveolar flooding; image the region at a constant transpulmonary pressure of 5 cmH2O; apply five ventilation cycles with a positive end-expiratory pressure of 0-20 cmH2O and tidal volume of 6 or 12 ml/kg; return the lung to a constant transpulmonary pressure of 5 cmH2O; and image for an additional 10 min. In aerated areas, ventilation is not injurious. With discrete alveolar flooding, all ventilation protocols cause sustained injury. Greater positive end-expiratory pressure or tidal volume increases injury. Furthermore, we determine T and find injury increases with T. Inclusion of either plasma proteins or Survanta in the flooding liquid does not alter T or injury. Inclusion of 2.7-10% albumin and 1% Survanta together, however, lowers T and injury. Contrary to expectation, albumin inclusion in our model facilitates exogenous surfactant activity. Copyright © 2014 the American Physiological Society.

Lung ventilation injures areas with discrete alveolar flooding, in a surface tension-dependent fashion

PubMed Central

Wu (吴右), You; Kharge, Angana Banerjee

2014-01-01

With proteinaceous-liquid flooding of discrete alveoli, a model of the edema pattern in the acute respiratory distress syndrome, lung inflation over expands aerated alveoli adjacent to flooded alveoli. Theoretical considerations suggest that the overexpansion may be proportional to surface tension, T. Yet recent evidence indicates proteinaceous edema liquid may not elevate T. Thus whether the overexpansion is injurious is not known. Here, working in the isolated, perfused rat lung, we quantify fluorescence movement from the vasculature to the alveolar liquid phase as a measure of overdistension injury to the alveolar-capillary barrier. We label the perfusate with fluorescence; micropuncture a surface alveolus and instill a controlled volume of nonfluorescent liquid to obtain a micropunctured-but-aerated region (control group) or a region with discrete alveolar flooding; image the region at a constant transpulmonary pressure of 5 cmH2O; apply five ventilation cycles with a positive end-expiratory pressure of 0–20 cmH2O and tidal volume of 6 or 12 ml/kg; return the lung to a constant transpulmonary pressure of 5 cmH2O; and image for an additional 10 min. In aerated areas, ventilation is not injurious. With discrete alveolar flooding, all ventilation protocols cause sustained injury. Greater positive end-expiratory pressure or tidal volume increases injury. Furthermore, we determine T and find injury increases with T. Inclusion of either plasma proteins or Survanta in the flooding liquid does not alter T or injury. Inclusion of 2.7–10% albumin and 1% Survanta together, however, lowers T and injury. Contrary to expectation, albumin inclusion in our model facilitates exogenous surfactant activity. PMID:25080924

Assessment of bronchial and pulmonary blood supply in non-small cell lung cancer subtypes using computed tomography perfusion.

PubMed

Nguyen-Kim, Thi Dan Linh; Frauenfelder, Thomas; Strobel, Klaus; Veit-Haibach, Patrick; Huellner, Martin W

2015-03-01

The aim of this study was to investigate the dual blood supply of non-small cell lung cancer (NSCLC) and its association with tumor subtype, size, and stage, using computed tomography perfusion (CTP). A total of 54 patients (median age, 65 years; range, 42-79 years; 15 women, 39 men) with suspected lung cancer underwent a CTP scan of the lung tumor. Pulmonary and bronchial vasculature regions of interest were used to calculate independently CTP parameters (blood flow [BF], blood volume [BV], and mean transit time [MTT]) of the tumor tissue. The mean and maximum pulmonary and bronchial perfusion indexes (PImean and PImax) were calculated. The tumoral volume and the largest tumoral diameter were assessed. Differences in CTP parameters and indexes among NSCLC subtypes, tumor stages and tumor dimensions were analyzed using non-parametric tests. According to biopsy, 37 patients had NSCLC (22 adenocarcinomas [ACs], 8 squamous cell carcinomas [SCCs], 7 large-cell carcinomas [LCC]). The mean bronchial BF/pulmonary BF, bronchial BV/pulmonary BV, and bronchial MTT/pulmonary MTT was 41.2 ± 30.0/36.9 ± 24.2 mL/100 mL/min, 11.4 ± 9.7/10.4 ± 9.4 mL/100 mL, and 11.4 ± 4.3/14.9 ± 4.4 seconds, respectively. In general, higher bronchial BF than pulmonary BF was observed in NSCLC (P = 0.014). Using a tumoral volume cutoff of 3.5 cm, a significant difference in pulmonary PImax was found (P = 0.028). There was a significantly higher mean pulmonary BF in LCCs and SCCs compared with ACs (P = 0.018 and P = 0.044, respectively), whereas the mean bronchial BF was only significantly higher in LCCs compared with ACs (P = 0.024). Correspondingly, the PImax was significantly higher in LCCs and SCCs than in ACs (P = 0.001 for both). Differences between bronchial and pulmonary PImean and PImax among T stages and Union Internationale Contre le Cancer stages were not statistically significant (P values ranging from 0.691 to 0.753). The known dual blood supply of NSCLC, which depends on tumor size and histological subtype, is reflected in CTP parameters, with parameters depending both on tumor size and histological subtype. This has to be accounted for when analyzing NSCLC with CTP.

Uncontrolled Donation After Circulatory Determination of Death Donors (uDCDDs) as a Source of Lungs for Transplant.

PubMed

Egan, T M; Requard, J J

2015-08-01

In April 2014, the American Journal of Transplantation published a report on the first lung transplant in the United States recovered from an uncontrolled donation after circulatory determination of death donor (uDCDD), assessed by ex vivo lung perfusion (EVLP). The article identified logistical and ethical issues related to introduction of lung transplant from uDCDDs. In an open clinical trial, we have Food and Drug Administration and Institutional Review Board approval to transplant lungs recovered from uDCDDs judged suitable after EVLP. Through this project and other experiences with lung recovery from uDCDDs, we have identified solutions to many logistical challenges and have addressed ethical issues surrounding lung transplant from uDCDDs that were mentioned in this case report. Here, we discuss those challenges, including issues related to recovery of other solid organs from uDCDDs. Despite logistical challenges, uDCDDs could solve the critical shortage of lungs for transplant. Furthermore, by avoiding the deleterious impact of brain death and days of positive pressure ventilation, and by using opportunities to treat lungs in the decedent or during EVLP, lungs recovered from uDCDDs may ultimately prove to be better than lungs currently being transplanted from conventional brain-dead organ donors. © Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.

Comparison of microdialysis sampling perfusion fluid components on the foreign body reaction in rat subcutaneous tissue.

PubMed

Keeler, Geoffrey D; Durdik, Jeannine M; Stenken, Julie A

2014-06-16

Microdialysis sampling is a commonly used technique for collecting solutes from the extracellular space of tissues in laboratory animals and humans. Large molecular weight solutes can be collected using high molecular weight cutoff (MWCO) membranes (100kDa or greater). High MWCO membranes require addition of high molecular weight dextrans or albumin to the perfusion fluid to prevent fluid loss via ultrafiltration. While these perfusion fluid additives are commonly used during microdialysis sampling, the tissue response to the loss of these compounds across the membrane is poorly understood. Tissue reactions to implanted microdialysis sampling probes containing different microdialysis perfusion fluids were compared over a 7-day time period in rats. The base perfusion fluid was Ringer's solution supplemented with either bovine serum albumin (BSA), rat serum albumin (RSA), Dextran-70, or Dextran-500. A significant inflammatory response to Dextran-70 was observed. No differences in the tissue response between BSA and RSA were observed. Among these agents, the BSA, RSA, and Dextran-500 produced a significantly reduced inflammatory response compared to the Dextran-70. This work demonstrates that use of Dextran-70 in microdialysis sampling perfusion fluids should be eliminated and replaced with Dextran-500 or other alternatives. Copyright © 2013 Elsevier B.V. All rights reserved.

Whole-body PET/CT evaluation of tumor perfusion using generator-based 62Cu-ethylglyoxal bis(thiosemicarbazonato)copper(II): validation by direct comparison to 15O-water in metastatic renal cell carcinoma.

PubMed

Fletcher, James W; Logan, Theodore F; Eitel, Jacob A; Mathias, Carla J; Ng, Yen; Lacy, Jeffrey L; Hutchins, Gary D; Green, Mark A

2015-01-01

This study was undertaken to demonstrate the feasibility of whole-body (62)Cu-ethylglyoxal bis(thiosemicarbazonato)copper(II) ((62)Cu-ETS) PET/CT tumor perfusion imaging in patients with metastatic renal carcinoma and to validate (62)Cu-ETS as a quantitative marker of tumor perfusion by direct comparison with (15)O-water perfusion imaging. PET/CT imaging of 10 subjects with stage IV renal cell cancer was performed after intravenous administration of (15)O-water (10-min dynamic list-mode study) with the heart and at least 1 tumor in the PET field of view, followed 10 min later by intravenous (62)Cu-ETS (6-min list-mode study). Whole-body (62)Cu imaging was then performed from 6 to 20 min at 2-3 min/bed position. Blood flow (K1) was quantified with both agents for normal and malignant tissues in the 21.7-cm dynamic field of view. The required arterial input functions were derived from the left atrium and, in the case of (62)Cu-ETS, corrected for partial decomposition of the agent by blood with data from an in vitro analysis using a sample of each patient's blood. This imaging protocol was repeated at an interval of 3-4 wk after initiation of a standard clinical treatment course of the antiangiogenic agent sunitinib. All subjects received the scheduled (62)Cu-ETS doses for the dynamic and subsequent whole-body PET/CT scans, but technical issues resulted in no baseline (15)O-water data for 2 subjects. Direct comparisons of the perfusion estimates for normal tissues and tumor metastases were made in 18 paired baseline and treatment studies (10 subjects; 8 baseline studies, 10 repeated studies during treatment). There was an excellent correlation between the blood flow estimates made with (62)Cu-ETS and (15)O-water for normal tissues (muscle, thyroid, myocardium) and malignant lesions (pulmonary nodules, bone lesions); the regression line was y = 0.85x + 0.15, R(2) = 0.83, for the 88 regions analyzed. (62)Cu-ETS provided high-quality whole-body PET/CT images, and (62)Cu-ETS measures of blood flow were highly and linearly correlated with (15)O-water-derived K1 values (mL(-1) ⋅ min(-1) ⋅ g). This tracer is suitable for use as a PET tracer of tumor perfusion in patients with metastatic renal cell carcinoma. © 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

Screening for Hepatopulmonary Syndrome in Cirrhotic Patients Using Technetium 99m-macroaggregated Albumin Perfusion Lung Scan (Tc-MAA): Diagnostic Approach and Clinical Correlations.

PubMed

Fragaki, Maria; Sifaki-Pistolla, Dimitra; Samonakis, Dimitrios N; Koulentaki, Mairi; Koukouraki, Sofia; Stathaki, Maria; Kouroumalis, Elias

2017-09-28

The aims of this study were to prospectively screen cirrhotic patients with arterial blood gas test and albumin perfusion scan, identify those fulfilling the classic hepatopulmonary syndrome (HPS) criteria, correlate with clinical parameters, and evaluate the survival of patients with HPS compared with those without HPS in a genetically homogenous Cretan cirrhotic population. Data on consecutive 102 patients within 1 year were collected and analyzed. All patients underwent a technetium 99m-macroaggregated albumin perfusion lung scan (Tc-MAA). Diagnosis of HPS was based on the presence of the quantitative index Tc-MAA≥6% and a [P(A-a)O2]≥15 mm Hg (≥20 mm Hg for patients over >64 y). In 94/102 patients, complete scintigraphic data were available. In total, 24 (26%) patients fulfilled the diagnostic criteria of HPS; 95.8% of them had mild-to-moderate HPS. In 8 patients the Tc-MAA scintigraphy could not be interpreted. There was no difference in HPS between decompensated (24.6%) and compensated cirrhosis (27.3%). In the multivariate analysis only the quantitative index was significant for the diagnosis of HPS (P=0.001, odds ratio; 95% confidence interval, 7.05; 2.27-21.87). Kaplan- Meier survival curves indicated a similar overall prognosis for patients diagnosed with HPS (P=0.105). HPS is a frequent complication of cirrhosis. Mild-to-moderate HPS has no significant effect on survival of cirrhotic patients. The quantitative Tc-MAA test is a reliable tool for diagnosis.

Computed Tomography and Optical Imaging of Osteogenesis-angiogenesis Coupling to Assess Integration of Cranial Bone Autografts and Allografts.

PubMed

Cohn Yakubovich, Doron; Tawackoli, Wafa; Sheyn, Dmitriy; Kallai, Ilan; Da, Xiaoyu; Pelled, Gadi; Gazit, Dan; Gazit, Zulma

2015-12-22

A major parameter determining the success of a bone-grafting procedure is vascularization of the area surrounding the graft. We hypothesized that implantation of a bone autograft would induce greater bone regeneration by abundant blood vessel formation. To investigate the effect of the graft on neovascularization at the defect site, we developed a micro-computed tomography (µCT) approach to characterize newly forming blood vessels, which involves systemic perfusion of the animal with a polymerizing contrast agent. This method enables detailed vascular analysis of an organ in its entirety. Additionally, blood perfusion was assessed using fluorescence imaging (FLI) of a blood-borne fluorescent agent. Bone formation was quantified by FLI using a hydroxyapatite-targeted probe and µCT analysis. Stem cell recruitment was monitored by bioluminescence imaging (BLI) of transgenic mice that express luciferase under the control of the osteocalcin promoter. Here we describe and demonstrate preparation of the allograft, calvarial defect surgery, µCT scanning protocols for the neovascularization study and bone formation analysis (including the in vivo perfusion of contrast agent), and the protocol for data analysis. The 3D high-resolution analysis of vasculature demonstrated significantly greater angiogenesis in animals with implanted autografts, especially with respect to arteriole formation. Accordingly, blood perfusion was significantly higher in the autograft group by the 7(th) day after surgery. We observed superior bone mineralization and measured greater bone formation in animals that received autografts. Autograft implantation induced resident stem cell recruitment to the graft-host bone suture, where the cells differentiated into bone-forming cells between the 7(th) and 10(th) postoperative day. This finding means that enhanced bone formation may be attributed to the augmented vascular feeding that characterizes autograft implantation. The methods depicted may serve as an optimal tool to study bone regeneration in terms of tightly bounded bone formation and neovascularization.

Vertebral osteoporosis: perfused animal cadaver model for testing new vertebroplastic agents.

PubMed

Hoell, Thomas; Huschak, Gerald; Beier, Andre; Holzhausen, Hans-Juergen; Meisel, Hans-Joerg; Emmrich, Frank

2010-12-01

Experimental study. It was aimed to establish a cadaver model to imitate osteoporotic perfused vertebral bone and to allow for transpedicular transfer of bone cement and various new materials into vertebrae. The model was perfused to simulate vertebroplasty in the presence of transvertebral blood flow. The injection of bone cement into vertebrae bears the risk of irreversible discharge of material into the venous system of the spinal canal. The bovine cadaver model studied allows visual studies of material distribution in a vertebral bone, the potential spill-out of material, and quantification of washout and disintegration phenomena. Thoracic and lumbar vertebrae from 1-year-old calves were cut transversally into 5 mm slices, macerated, and decalcified. The softened bone slices were compressed between 2 transparent plastic discs. A standard vertebroplasty cannula (outer diameter 3.5 mm, inner diameter 2.5 mm) was inserted into the vertebral body via the pedicle to transfer the different vertebroplasty materials. Arterial blood flow was simulated by means of liquid irrigation via 2 needles in the ventral part of the vertebral body slice. Metal powder was mixed with the solution to indicate the blood flow in the bone. The model was evaluated with the vertebroplasty cement polymethylmethacrylate. The model permitted visualization of the insertion and distribution of vertebroplasty materials. Liquid bone cement was effused into the spinal canal as in the clinical situation. Higher modulus cement acted in the same way as in clinical vertebroplasty. Rigid vertebroplasty agents led to trabecular fractures and stable mechanical interactions with the bone and eventually moved dorsal bone fragments into the spinal canal. Sedimentation of the metal powder indicated regions of perfusion. The model simulated the clinical behavior of liquid and higher modulus vertebroplasty agents in the presence of blood flow. It enabled safe ex vivo testing of the mechanical and physical properties of alternative vertebroplasty materials under flow conditions.

UK nuclear medicine survey, 1992-93.

PubMed

Elliott, A T; Elliott, F M; Shields, R A

1996-01-01

A postal survey of UK nuclear medicine departments was undertaken to collate information on equipment, numbers of procedures and staffing levels for the years 1992 and 1993. It was estimated that there are 235 sites undertaking nuclear medicine, the total number of procedures performed being some 490,000 in 1993 compared with 430,000 in 1989. Informal investigation suggests that the increase is due to greater usage of myocardial perfusion and lung ventilation/perfusion studies. Wide variations were noted in staffing levels, with only 22% of departments having medical cover of half-time equivalent or better: over 30% of departments have less than one consultant session per week. Approximately 20% of departments claimed to have no physics input, with a further 20% having less than one session per week.

Ventilation-perfusion relationships in the lung during head-out water immersion

NASA Technical Reports Server (NTRS)

Derion, Toniann; Guy, Harold J. B.; Tsukimoto, Koichi; Schaffartzik, Walter; Prediletto, Renato; Poole, David C.; Knight, Douglas R.; Wagner, Peter D.

1992-01-01

Mechanisms of altered pulmonary gas exchange during water immersion were studied in 12 normal males: 6 young (aged 20-29) and 6 older (aged 40-45). It is concluded that, in young subjects with closing volume (CV) less than expiratory reserve volume (ERV), gas exchange was enhanced during immersion, because normal ventilation-perfusion relations were preserved, and by mass balance, the ventilation/O2 uptake changes elevated arterial P(O2). In older males with CV greater than ERV and 52 percent of tidal volume below CV, immersion-induced airways closure during tidal breathing was associated with minimally increased shunt that did not significantly impair gas exchange. It is suggested that airways closure of this degree is of little importance to gas exchange.

Arsenic, asbestos and radon: emerging players in lung tumorigenesis

PubMed Central

2012-01-01

The cause of lung cancer is generally attributed to tobacco smoking. However lung cancer in never smokers accounts for 10 to 25% of all lung cancer cases. Arsenic, asbestos and radon are three prominent non-tobacco carcinogens strongly associated with lung cancer. Exposure to these agents can lead to genetic and epigenetic alterations in tumor genomes, impacting genes and pathways involved in lung cancer development. Moreover, these agents not only exhibit unique mechanisms in causing genomic alterations, but also exert deleterious effects through common mechanisms, such as oxidative stress, commonly associated with carcinogenesis. This article provides a comprehensive review of arsenic, asbestos, and radon induced molecular mechanisms responsible for the generation of genetic and epigenetic alterations in lung cancer. A better understanding of the mode of action of these carcinogens will facilitate the prevention and management of lung cancer related to such environmental hazards. PMID:23173984

Tc-99m macro aggregated albumin scintigraphy – indications other than pulmonary embolism: A pictorial essay

PubMed Central

Gandhi, Sunny J; Babu, Sanjay; Subramanyam, Padma; Shanmuga Sundaram, Palaniswamy

2013-01-01

Introduction: Tc-99m macro aggregated albumin (MAA) is synonymous for lung perfusion scintigraphy and is part of the study in the evaluation of pulmonary thromboembolism. We wanted to highlight the utilities of Tc-99m MAA other than pulmonary embolism as a pictorial assay. Materials and Methods: Patients referred for Tc-99m MAA scintigraphy under various indications were included in this pictorial essay. Commercially available TechneScan LyoMAA cold kit from Mallinckrodt Medical B.V., Holland was used. Acquisition protocols for different indications are described in this article. Different clinical indications (e.g., pulmonary artery stenosis, hepatopulmonary syndrome, FEV1 calculation in lung surgery planning, selective internal radiation therapy planning, venography for deep venous thrombosis, left to right cardiac shunts, etc.) where Tc-99m MAA scintigraphy was asked for; how it helped in different clinical scenarios and how it can be used clinically is explained with unique and interesting case examples and images. We also reviewed the literature to look for certain remote indications of MAA imaging for the sake of completion like – (shunt scintigraphy, peritoneopleural communication, etc.) Conclusion: Tc-99m MAA is a very useful radiopharmaceutical, which can be used for many other indications apart from the commonly used indication of lung perfusion scan in pulmonary embolism. It can provide useful clinical information in other indications, which we try to highlight in this article. PMID:24250023

To Find a Better Dosimetric Parameter in the Predicting of Radiation-Induced Lung Toxicity Individually: Ventilation, Perfusion or CT based.

PubMed

Xiao, Lin-Lin; Yang, Guoren; Chen, Jinhu; Wang, Xiaohui; Wu, Qingwei; Huo, Zongwei; Yu, Qingxi; Yu, Jinming; Yuan, Shuanghu

2017-03-15

This study aimed to find a better dosimetric parameter in predicting of radiation-induced lung toxicity (RILT) in patients with non-small cell lung cancer (NSCLC) individually: ventilation(V), perfusion (Q) or computerized tomography (CT) based. V/Q single-photon emission computerized tomography (SPECT) was performed within 1 week prior to radiotherapy (RT). All V/Q imaging data was integrated into RT planning system, generating functional parameters based on V/Q SPECT. Fifty-seven NSCLC patients were enrolled in this prospective study. Fifteen (26.3%) patients underwent grade ≥2 RILT, the remaining forty-two (73.7%) patients didn't. Q-MLD, Q-V20, V-MLD, V-V20 of functional parameters correlated more significantly with the occurrence of RILT compared to V20, MLD of anatomical parameters (r = 0.630; r = 0.644; r = 0.617; r = 0.651 vs. r = 0.424; r = 0.520 p < 0.05, respectively). In patients with chronic obstructive pulmonary diseases (COPD), V functional parameters reflected significant advantage in predicting RILT; while in patients without COPD, Q functional parameters reflected significant advantage. Analogous results were existed in fractimal analysis of global pulmonary function test (PFT). In patients with central-type NSCLC, V parameters were better than Q parameters; while in patients with peripheral-type NSCLC, the results were inverse. Therefore, this study demonstrated that choosing a suitable dosimetric parameter individually can help us predict RILT accurately.

SU-E-QI-06: Design and Initial Validation of a Precise Capillary Phantom to Test Perfusion Systems

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wood, R; Iacobucci, G; Khobragade, P

2014-06-15

Purpose: To design a precise perfusion phantom mimicking capillaries of the brain vasculature which could be used to test various perfusion protocols and algorithms which generate perfusion maps. Methods: A perfusion phantom was designed in Solidworks and built using additive manufacturing. The phantom was an overall cylindrical shape of diameter and height 20mm and containing capillaries of 200μm or 300μm which were parallel and in contact making up the inside volume where flow was allowed. We created a flow loop using a peristaltic pump and contrast agent was injected manually. Digital Subtraction Angiographic images and low contrast images with conemore » beam CT were acquired after the contrast was injected. These images were analyzed by our own code in LabVIEW software and Time-Density Curve, MTT and TTP was calculated. Results: Perfused area was visible in the cone beam CT images; however, individual capillaries were not distinguishable. The Time-Density Curve acquired was accurate, sensitive and repeatable. The parameters MTT, and TTP offered by the phantom were very sensitive to slight changes in the TDC shape. Conclusion: We have created a robust calibrating model for evaluation of existing perfusion data analysis systems. This approach is extremely sensitive to changes in the flow due to the high temporal resolution and could be used as a golden standard to assist developers in calibrating and testing of imaging perfusion systems and software algorithms. Supported by NIH Grant: 2R01EB002873 and an equipment grant from Toshiba Medical Systems Corporation.« less

Regional ventilation-perfusion distribution is more uniform in the prone position

NASA Technical Reports Server (NTRS)

Mure, M.; Domino, K. B.; Lindahl, S. G.; Hlastala, M. P.; Altemeier, W. A.; Glenny, R. W.

2000-01-01

The arterial blood PO(2) is increased in the prone position in animals and humans because of an improvement in ventilation (VA) and perfusion (Q) matching. However, the mechanism of improved VA/Q is unknown. This experiment measured regional VA/Q heterogeneity and the correlation between VA and Q in supine and prone positions in pigs. Eight ketamine-diazepam-anesthetized, mechanically ventilated pigs were studied in supine and prone positions in random order. Regional VA and Q were measured using fluorescent-labeled aerosols and radioactive-labeled microspheres, respectively. The lungs were dried at total lung capacity and cubed into 603-967 small ( approximately 1.7-cm(3)) pieces. In the prone position the homogeneity of the ventilation distribution increased (P = 0.030) and the correlation between VA and Q increased (correlation coefficient = 0.72 +/- 0.08 and 0.82 +/- 0.06 in supine and prone positions, respectively, P = 0.03). The homogeneity of the VA/Q distribution increased in the prone position (P = 0.028). We conclude that the improvement in VA/Q matching in the prone position is secondary to increased homogeneity of the VA distribution and increased correlation of regional VA and Q.

Adenovirus-mediated HIF-1α gene transfer promotes repair of mouse airway allograft microvasculature and attenuates chronic rejection

PubMed Central

Jiang, Xinguo; Khan, Mohammad A.; Tian, Wen; Beilke, Joshua; Natarajan, Ramesh; Kosek, Jon; Yoder, Mervin C.; Semenza, Gregg L.; Nicolls, Mark R.

2011-01-01

Chronic rejection, manifested as small airway fibrosis (obliterative bronchiolitis [OB]), is the main obstacle to long-term survival in lung transplantation. Recent studies demonstrate that the airways involved in a lung transplant are relatively hypoxic at baseline and that OB pathogenesis may be linked to ischemia induced by a transient loss of airway microvasculature. Here, we show that HIF-1α mediates airway microvascular repair in a model of orthotopic tracheal transplantation. Grafts with a conditional knockout of Hif1a demonstrated diminished recruitment of recipient-derived Tie2+ angiogenic cells to the allograft, impaired repair of damaged microvasculature, accelerated loss of microvascular perfusion, and hastened denudation of epithelial cells. In contrast, graft HIF-1α overexpression induced via an adenoviral vector prolonged airway microvascular perfusion, preserved epithelial integrity, extended the time window for the graft to be rescued from chronic rejection, and attenuated airway fibrotic remodeling. HIF-1α overexpression induced the expression of proangiogenic factors such as Sdf1, Plgf, and Vegf, and promoted the recruitment of vasoreparative Tie2+ cells. This study demonstrates that a therapy that enhances vascular integrity during acute rejection may promote graft health and prevent chronic rejection. PMID:21606594

A diagnostic model for chronic hypersensitivity pneumonitis.

PubMed

Johannson, Kerri A; Elicker, Brett M; Vittinghoff, Eric; Assayag, Deborah; de Boer, Kaïssa; Golden, Jeffrey A; Jones, Kirk D; King, Talmadge E; Koth, Laura L; Lee, Joyce S; Ley, Brett; Wolters, Paul J; Collard, Harold R

2016-10-01

The objective of this study was to develop a diagnostic model that allows for a highly specific diagnosis of chronic hypersensitivity pneumonitis using clinical and radiological variables alone. Chronic hypersensitivity pneumonitis and other interstitial lung disease cases were retrospectively identified from a longitudinal database. High-resolution CT scans were blindly scored for radiographic features (eg, ground-glass opacity, mosaic perfusion) as well as the radiologist's diagnostic impression. Candidate models were developed then evaluated using clinical and radiographic variables and assessed by the cross-validated C-statistic. Forty-four chronic hypersensitivity pneumonitis and eighty other interstitial lung disease cases were identified. Two models were selected based on their statistical performance, clinical applicability and face validity. Key model variables included age, down feather and/or bird exposure, radiographic presence of ground-glass opacity and mosaic perfusion and moderate or high confidence in the radiographic impression of chronic hypersensitivity pneumonitis. Models were internally validated with good performance, and cut-off values were established that resulted in high specificity for a diagnosis of chronic hypersensitivity pneumonitis. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Infusion of freshly isolated autologous bone marrow derived mononuclear cells prevents endotoxin-induced lung injury in an ex-vivo perfused swine model

PubMed Central

2013-01-01

Introduction The acute respiratory distress syndrome (ARDS), affects up to 150,000 patients per year in the United States. We and other groups have demonstrated that bone marrow derived mesenchymal stromal stem cells prevent ARDS induced by systemic and local administration of endotoxin (lipopolysaccharide (LPS)) in mice. Methods A study was undertaken to determine the effects of the diverse populations of bone marrow derived cells on the pathophysiology of ARDS, using a unique ex-vivo swine preparation, in which only the ventilated lung and the liver are perfused with autologous blood. Six experimental groups were designated as: 1) endotoxin alone, 2) endotoxin + total fresh whole bone marrow nuclear cells (BMC), 3) endotoxin + non-hematopoietic bone marrow cells (CD45 neg), 4) endotoxin + hematopoietic bone marrow cells (CD45 positive), 5) endotoxin + buffy coat and 6) endotoxin + in vitro expanded swine CD45 negative adherent allogeneic bone marrow cells (cultured CD45neg). We measured at different levels the biological consequences of the infusion of the different subsets of cells. The measured parameters were: pulmonary vascular resistance (PVR), gas exchange (PO2), lung edema (lung wet/dry weight), gene expression and serum concentrations of the pro-inflammatory cytokines IL-1β, TNF-α and IL-6. Results Infusion of freshly purified autologous total BMCs, as well as non-hematopoietic CD45(-) bone marrow cells significantly reduced endotoxin-induced pulmonary hypertension and hypoxemia and reduced the lung edema. Also, in the groups that received BMCs and cultured CD45neg we observed a decrease in the levels of IL-1β and TNF-α in plasma. Infusion of hematopoietic CD45(+) bone marrow cells or peripheral blood buffy coat cells did not protect against LPS-induced lung injury. Conclusions We conclude that infusion of freshly isolated autologous whole bone marrow cells and the subset of non-hematopoietic cells can suppress the acute humoral and physiologic responses induced by endotoxemia by modulating the inflammatory response, mechanisms that do not involve engraftment or trans-differentiation of the cells. These observations may have important implications for the design of future cell therapies for ARDS. PMID:23497755

Spontaneous Effort During Mechanical Ventilation: Maximal Injury With Less Positive End-Expiratory Pressure.

PubMed

Yoshida, Takeshi; Roldan, Rollin; Beraldo, Marcelo A; Torsani, Vinicius; Gomes, Susimeire; De Santis, Roberta R; Costa, Eduardo L V; Tucci, Mauro R; Lima, Raul G; Kavanagh, Brian P; Amato, Marcelo B P

2016-08-01

We recently described how spontaneous effort during mechanical ventilation can cause "pendelluft," that is, displacement of gas from nondependent (more recruited) lung to dependent (less recruited) lung during early inspiration. Such transfer depends on the coexistence of more recruited (source) liquid-like lung regions together with less recruited (target) solid-like lung regions. Pendelluft may improve gas exchange, but because of tidal recruitment, it may also contribute to injury. We hypothesize that higher positive end-expiratory pressure levels decrease the propensity to pendelluft and that with lower positive end-expiratory pressure levels, pendelluft is associated with improved gas exchange but increased tidal recruitment. Crossover design. University animal research laboratory. Anesthetized landrace pigs. Surfactant depletion was achieved by saline lavage in anesthetized pigs, and ventilator-induced lung injury was produced by ventilation with high tidal volume and low positive end-expiratory pressure. Ventilation was continued in each of four conditions: positive end-expiratory pressure (low or optimized positive end-expiratory pressure after recruitment) and spontaneous breathing (present or absent). Tidal recruitment was assessed using dynamic CT and regional ventilation/perfusion using electric impedance tomography. Esophageal pressure was measured using an esophageal balloon manometer. Among the four conditions, spontaneous breathing at low positive end-expiratory pressure not only caused the largest degree of pendelluft, which was associated with improved ventilation/perfusion matching and oxygenation, but also generated the greatest tidal recruitment. At low positive end-expiratory pressure, paralysis worsened oxygenation but reduced tidal recruitment. Optimized positive end-expiratory pressure decreased the magnitude of spontaneous efforts (measured by esophageal pressure) despite using less sedation, from -5.6 ± 1.3 to -2.0 ± 0.7 cm H2O, while concomitantly reducing pendelluft and tidal recruitment. No pendelluft was observed in the absence of spontaneous effort. Spontaneous effort at low positive end-expiratory pressure improved oxygenation but promoted tidal recruitment associated with pendelluft. Optimized positive end-expiratory pressure (set after lung recruitment) may reverse the harmful effects of spontaneous breathing by reducing inspiratory effort, pendelluft, and tidal recruitment.

Acute and delayed toxicity of gemcitabine administered during isolated lung perfusion: a preclinical dose-escalation study in pigs.

PubMed

Pagès, Pierre-Benoit; Derangere, Valentin; Bouchot, Olivier; Magnin, Guy; Charon-Barra, Céline; Lokiec, François; Ghiringhelli, François; Bernard, Alain

2015-08-01

Colorectal cancer is the third most commonly diagnosed cancer worldwide, with up to 25% of patients presenting with metastases at the time of diagnosis. Despite pulmonary metastasectomy many patients go on to develop pulmonary recurrence, which might be linked to the presence of lung micrometastases. In this setting, the adjuvant administration of high-dose chemotherapy by isolated lung perfusion (ILP) has shown encouraging results. However, the tolerance to and efficacy of modern gemcitabine (GEM)-based chemotherapy regimens during adjuvant ILP remain unknown. We conducted a dose-escalating preclinical study to evaluate the immediate and delayed toxicity of GEM in a pig model to define dose-limiting toxicity (DLT) and maximum tolerated concentration. Twenty-three pigs were given increasing concentrations of GEM during ILP, and were awakened at the end of the procedure. The concentrations of GEM were 40, 80, 160, 320, 640 and 1280 µg/ml. Serum and lung samples were taken to measure GEM concentrations. Pulmonary damage was evaluated by histological examination and cleaved caspase-3 detection. Immediate and delayed (1 month) toxicity were recorded. All of the animals underwent successful ILP with GEM. No systemic leak was observed. The three pigs that received a concentration of GEM of 1280 µg/ml died of hypoxia after lung recirculation at the end of the procedure. Eleven pigs survived for 1 month. Major lung toxicity was observed for the concentration of GEM of 640 µg/ml, both at the end of the procedure and after 1 month. DLT was defined at the concentration of 640 µg/ml and the maximum tolerated dose (MTD) was defined at the concentration of 320 µg/ml. ILP with GEM is a safe and reproducible technique in this large-animal model, which includes 1 month of survival. The MTD in this pig model was a concentration of GEM of 320 µg/ml. © The Author 2014. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

Vertebral Uptake of Tc-99m Macroaggregated Albumin (MAA) with SPECT/CT Occurring in Superior Vena Cava Obstruction.

PubMed

Karls, Shawn; Hassoun, Hani; Derbekyan, Vilma

2016-09-01

A 67-year-old male presented with dyspnea for which lung scintigraphy was ordered to rule out pulmonary embolus. Planar images demonstrated abnormal midline uptake of Tc-99m macroaggregated albumin, which SPECT/CT localized to several thoracic vertebrae. Thoracic vertebral uptake on perfusion lung scintigraphy was previously described on planar imaging. Radionuclide venography and contrast-enhanced CT subsequently demonstrated superior vena cava (SVC) obstruction with collateralization through the azygous/hemiazygous system and vertebral venous plexus. SPECT/CT differentiated residual esophageal/tracheal ventilation activity, a clinically insignificant finding, from vertebral uptake indicative of SVC obstruction, a potentially life-threatening condition.

Maintenance of cAMP in non-heart-beating donor lungs reduces ischemia-reperfusion injury.

PubMed

Hoffmann, S C; Bleiweis, M S; Jones, D R; Paik, H C; Ciriaco, P; Egan, T M

2001-06-01

Studies suggest that pulmonary vascular ischemia-reperfusion injury (IRI) can be attenuated by increasing intracellular cAMP concentrations. The purpose of this study was to determine the effect of IRI on capillary permeability, assessed by capillary filtration coeficient (Kfc), in lungs retrieved from non-heart-beating donors (NHBDs) and reperfused with the addition of the beta(2)-adrenergic receptor agonist isoproterenol (iso), and rolipram (roli), a phosphodiesterase (type IV) inhibitor. Using an in situ isolated perfused lung model, lungs were retrieved from NHBD rats at varying intervals after death and either ventilated with O(2) or not ventilated. The lungs were reperfused with Earle's solution with or without a combination of iso (10 microM) and roli (2 microM). Kfc, lung viability, and pulmonary hemodynamics were measured. Lung tissue levels of adenine nucleotides and cAMP were measured by HPLC. Combined iso and roli (iso/roli) reperfusion decreased Kfc significantly (p < 0.05) compared with non-iso/roli-reperfused groups after 2 h of postmortem ischemia. Total adenine nucleotide (TAN) levels correlated with Kfc in non-iso/roli-reperfused (r = 0.89) and iso/roli-reperfused (r = 0.97) lungs. cAMP levels correlated with Kfc (r = 0.93) in iso/roli-reperfused lungs. Pharmacologic augmentation of tissue TAN and cAMP levels might ameliorate the increased capillary permeability observed in lungs retrieved from NHBDs.

Delicaflavone induces autophagic cell death in lung cancer via Akt/mTOR/p70S6K signaling pathway.

PubMed

Sui, Yuxia; Yao, Hong; Li, Shaoguang; Jin, Long; Shi, Peiying; Li, Zhijun; Wang, Gang; Lin, Shilan; Wu, Youjia; Li, Yuxiang; Huang, Liying; Liu, Qicai; Lin, Xinhua

2017-03-01

Searching for potential anticancer agents from natural sources is an effective strategy for developing novel chemotherapeutic agents. In this study, data supporting the in vitro and in vivo anticancer effects of delicaflavone, a rarely occurring biflavonoid from Selaginella doederleinii, were reported. Delicaflavone exhibited favorable anticancer properties, as shown by the MTT assay and xenograft model of human non-small cell lung cancer in male BALB/c nude mice without observable adverse effect. By transmission electron microscopy with acridine orange and Cyto-ID®Autophagy detection dyes, Western blot analysis, and RT-PCR assay, we confirmed that delicaflavone induces autophagic cell death by increasing the ratio of LC3-II to LC3-I, which are autophagy-related proteins, and promoting the generation of acidic vesicular organelles and autolysosomes in the cytoplasm of human lung cancer A549 and PC-9 cells in a time- and dose-dependent manner. Delicaflavone downregulated the expression of phospho-Akt, phospho-mTOR, and phospho-p70S6K in a time- and dose-dependent manner, suggesting that it induced autophagy by inhibiting the Akt/mTOR/p70S6K pathway in A549 and PC-9 cells. Delicaflavone is a potential anticancer agent that can induce autophagic cell death in human non-small cell lung cancer via the Akt/mTOR/p70S6K signaling pathway. Delicaflavone showed anti-lung cancer effects in vitro and in vivo. Delicaflavone induced autophagic cell death via Akt/mTOR/p70S6K signaling pathway. Delicaflavone did not show observable side effects in a xenograft mouse model. Delicaflavone may represent a potential therapeutic agent for lung cancer. Delicaflavone showed anti-lung cancer effects in vitro and in vivo. Delicaflavone induced autophagic cell death via Akt/mTOR/p70S6K signaling pathway. Delicaflavone did not show observable side effects in a xenograft mouse model. Delicaflavone may represent a potential therapeutic agent for lung cancer.

Towards a virtual lung: multi-scale, multi-physics modelling of the pulmonary system.

PubMed

Burrowes, K S; Swan, A J; Warren, N J; Tawhai, M H

2008-09-28

The essential function of the lung, gas exchange, is dependent on adequate matching of ventilation and perfusion, where air and blood are delivered through complex branching systems exposed to regionally varying transpulmonary and transmural pressures. Structure and function in the lung are intimately related, yet computational models in pulmonary physiology usually simplify or neglect structure. The geometries of the airway and vascular systems and their interaction with parenchymal tissue have an important bearing on regional distributions of air and blood, and therefore on whole lung gas exchange, but this has not yet been addressed by modelling studies. Models for gas exchange have typically incorporated considerable detail at the level of chemical reactions, with little thought for the influence of structure. To date, relatively little attention has been paid to modelling at the cellular or subcellular level in the lung, or to linking information from the protein structure/interaction and cellular levels to the operation of the whole lung. We review previous work in developing anatomically based models of the lung, airways, parenchyma and pulmonary vasculature, and some functional studies in which these models have been used. Models for gas exchange at several spatial scales are briefly reviewed, and the challenges and benefits from modelling cellular function in the lung are discussed.

MRI using hyperpolarized noble gases.

PubMed

Kauczor, H; Surkau, R; Roberts, T

1998-01-01

The aim of this study was to review the physical basis of MRI using hyperpolarized noble gases as well as the present status of preclinical and clinical applications. Non-radioactive noble gases with a nuclear spin 1/2 (He-3, Xe-129) can be hyperpolarized by optical pumping. Polarization is transferred from circularly polarized laser light to the noble-gas atoms via alkali-metal vapors (spin exchange) or metastable atoms (metastability exchange). Hyperpolarization results in a non-equilibrium polarization five orders of magnitude higher than the Boltzmann equilibrium compensating for the several 1000 times lower density of noble gases as compared with liquid state hydrogen concentrations in tissue and allows for short imaging times. Hyperpolarization can be stored sufficiently long (3 h to 6 days) to allow for transport and application. Magnetic resonance systems require a broadband radio-frequency system - which is generally available for MR spectroscopy - and dedicated coils. The hyperpolarized gases are administered as inhalative "contrast agents" allowing for imaging of the airways and airspaces. Besides the known anesthetic effect of xenon, no adverse effects are observed in volunteers or patients. Pulse sequences are optimized to effectively use the non-renewable hyperpolarization before it decays or is destroyed, using fast low-flip-angles strategies to allow for dynamic/breath-hold imaging of highly diffusible (He) or soluble (Xe) gases with in vivo T1-times well below 1 min. Since helium is not absorbed in considerable amounts, its application is restricted to the lung. Xe-129 is also under investigation for imaging of white matter disease and functional studies of cerebral perfusion. Magnetic resonance imaging using hyperpolarized gases is emerging as a technical challenge and opportunity for the MR community. Preliminary experience suggests potential for functional imaging of pulmonary ventilation and cerebral perfusion.

Evaluation of carrier agents for hyperpolarized xenon MRI

NASA Technical Reports Server (NTRS)

Venkatesh, A. K.; Zhao, L.; Balamore, D.; Jolesz, F. A.; Albert, M. S.

2000-01-01

Several biocompatible carrier agents, in which xenon is highly soluble and has a long T(1), were tested, and injected in living rats. These included saline, Intralipid suspension, perfluorocarbon emulsion and (129)Xe gas-filled liposomes. The T(1) of (129)Xe in these compounds ranged from 47 to 116 s. Vascular injection of these carrier agents was tolerated well, encouraging their use for further experiments in live animals. In vivo spectra, obtained from gas-filled liposomes and perfluorocarbon solutions, suggest that these carrier agents have potential for use in angiography and perfusion imaging. Copyright 2000 John Wiley & Sons, Ltd.

Myocardial contrast echocardiography in mice: technical and physiological aspects.

PubMed

Verkaik, Melissa; van Poelgeest, Erik M; Kwekkeboom, Rick F J; Ter Wee, Piet M; van den Brom, Charissa E; Vervloet, Marc G; Eringa, Etto C

2018-03-01

Myocardial contrast echocardiography (MCE) offers the opportunity to study myocardial perfusion defects in mice in detail. The value of MCE compared with single-photon emission computed tomography, positron emission tomography, and computed tomography consists of high spatial resolution, the possibility of quantification of blood volume, and relatively low costs. Nevertheless, a number of technical and physiological aspects should be considered to ensure reproducibility among research groups. The aim of this overview is to describe technical aspects of MCE and the physiological parameters that influence myocardial perfusion data obtained with this technique. First, technical aspects of MCE discussed in this technical review are logarithmic compression of ultrasound data by ultrasound systems, saturation of the contrast signal, and acquisition of images during different phases of the cardiac cycle. Second, physiological aspects of myocardial perfusion that are affected by the experimental design are discussed, including the anesthesia regimen, systemic cardiovascular effects of vasoactive agents used, and fluctuations in body temperature that alter myocardial perfusion. When these technical and physiological aspects of MCE are taken into account and adequately standardized, MCE is an easily accessible technique for mice that can be used to study the control of myocardial perfusion by a wide range of factors.

Toward a clinical application of ex situ boron neutron capture therapy for lung tumors at the RA-3 reactor in Argentina

DOE Office of Scientific and Technical Information (OSTI.GOV)

Farías, R. O.; Trivillin, V. A.; Portu, A. M.

Purpose: Many types of lung tumors have a very poor prognosis due to their spread in the whole organ volume. The fact that boron neutron capture therapy (BNCT) would allow for selective targeting of all the nodules regardless of their position, prompted a preclinical feasibility study of ex situ BNCT at the thermal neutron facility of RA-3 reactor in the province of Buenos Aires, Argentina. (L)-4p-dihydroxy-borylphenylalanine fructose complex (BPA-F) biodistribution studies in an adult sheep model and computational dosimetry for a human explanted lung were performed to evaluate the feasibility and the therapeutic potential of ex situ BNCT. Methods: Twomore » kinds of boron biodistribution studies were carried out in the healthy sheep: a set of pharmacokinetic studies without lung excision, and a set that consisted of evaluation of boron concentration in the explanted and perfused lung. In order to assess the feasibility of the clinical application of ex situ BNCT at RA-3, a case of multiple lung metastases was analyzed. A detailed computational representation of the geometry of the lung was built based on a real collapsed human lung. Dosimetric calculations and dose limiting considerations were based on the experimental results from the adult sheep, and on the most suitable information published in the literature. In addition, a workable treatment plan was considered to assess the clinical application in a realistic scenario. Results: Concentration-time profiles for the normal sheep showed that the boron kinetics in blood, lung, and skin would adequately represent the boron behavior and absolute uptake expected in human tissues. Results strongly suggest that the distribution of the boron compound is spatially homogeneous in the lung. A constant lung-to-blood ratio of 1.3 ± 0.1 was observed from 80 min after the end of BPA-F infusion. The fact that this ratio remains constant during time would allow the blood boron concentration to be used as a surrogate and indirect quantification of the estimated value in the explanted healthy lung. The proposed preclinical animal model allowed for the study of the explanted lung. As expected, the boron concentration values fell as a result of the application of the preservation protocol required to preserve the lung function. The distribution of the boron concentration retention factor was obtained for healthy lung, with a mean value of 0.46 ± 0.14 consistent with that reported for metastatic colon carcinoma model in rat perfused lung. Considering the human lung model and suitable tumor control probability for lung cancer, a promising average fraction of controlled lesions higher than 85% was obtained even for a low tumor-to-normal boron concentration ratio of 2. Conclusions: This work reports for the first time data supporting the validity of the ovine model as an adequate human surrogate in terms of boron kinetics and uptake in clinically relevant tissues. Collectively, the results and analysis presented would strongly suggest that ex situ whole lung BNCT irradiation is a feasible and highly promising technique that could greatly contribute to the treatment of metastatic lung disease in those patients without extrapulmonary spread, increasing not only the expected overall survival but also the resulting quality of life.« less

Toward a clinical application of ex situ boron neutron capture therapy for lung tumors at the RA-3 reactor in Argentina.

PubMed

Farías, R O; Garabalino, M A; Ferraris, S; Santa María, J; Rovati, O; Lange, F; Trivillin, V A; Monti Hughes, A; Pozzi, E C C; Thorp, S I; Curotto, P; Miller, M E; Santa Cruz, G A; Bortolussi, S; Altieri, S; Portu, A M; Saint Martin, G; Schwint, A E; González, S J

2015-07-01

Many types of lung tumors have a very poor prognosis due to their spread in the whole organ volume. The fact that boron neutron capture therapy (BNCT) would allow for selective targeting of all the nodules regardless of their position, prompted a preclinical feasibility study of ex situ BNCT at the thermal neutron facility of RA-3 reactor in the province of Buenos Aires, Argentina. (l)-4p-dihydroxy-borylphenylalanine fructose complex (BPA-F) biodistribution studies in an adult sheep model and computational dosimetry for a human explanted lung were performed to evaluate the feasibility and the therapeutic potential of ex situ BNCT. Two kinds of boron biodistribution studies were carried out in the healthy sheep: a set of pharmacokinetic studies without lung excision, and a set that consisted of evaluation of boron concentration in the explanted and perfused lung. In order to assess the feasibility of the clinical application of ex situ BNCT at RA-3, a case of multiple lung metastases was analyzed. A detailed computational representation of the geometry of the lung was built based on a real collapsed human lung. Dosimetric calculations and dose limiting considerations were based on the experimental results from the adult sheep, and on the most suitable information published in the literature. In addition, a workable treatment plan was considered to assess the clinical application in a realistic scenario. Concentration-time profiles for the normal sheep showed that the boron kinetics in blood, lung, and skin would adequately represent the boron behavior and absolute uptake expected in human tissues. Results strongly suggest that the distribution of the boron compound is spatially homogeneous in the lung. A constant lung-to-blood ratio of 1.3 ± 0.1 was observed from 80 min after the end of BPA-F infusion. The fact that this ratio remains constant during time would allow the blood boron concentration to be used as a surrogate and indirect quantification of the estimated value in the explanted healthy lung. The proposed preclinical animal model allowed for the study of the explanted lung. As expected, the boron concentration values fell as a result of the application of the preservation protocol required to preserve the lung function. The distribution of the boron concentration retention factor was obtained for healthy lung, with a mean value of 0.46 ± 0.14 consistent with that reported for metastatic colon carcinoma model in rat perfused lung. Considering the human lung model and suitable tumor control probability for lung cancer, a promising average fraction of controlled lesions higher than 85% was obtained even for a low tumor-to-normal boron concentration ratio of 2. This work reports for the first time data supporting the validity of the ovine model as an adequate human surrogate in terms of boron kinetics and uptake in clinically relevant tissues. Collectively, the results and analysis presented would strongly suggest that ex situ whole lung BNCT irradiation is a feasible and highly promising technique that could greatly contribute to the treatment of metastatic lung disease in those patients without extrapulmonary spread, increasing not only the expected overall survival but also the resulting quality of life.

Hepatorenal syndrome.

PubMed

Papper, S

1980-01-01

Renal failure without apparent cause (the hepatorenal syndrome) may develop in the course of cirrhosis of the liver. While the development of renal failure bears a poor prognosis, spontaneous recovery can occur. The data suggest that for the most part patients die in rather than of renal failure. The latter seems to be only part of a broader more fundamental disturbance. The pathogenesis of HRS is unknown, but the evidence supports an impairment of effective renal perfusion. The two major hypotheses concerning the nature of the impaired perfusion are that it is a physiologic response to alterations in the extrarenal circulation, and that there is an unidentified humoral agent(s) produced by or inadequately inactivated by or bypassing the diseased liver and causing circulatory changes in the kidney as well as in other organs. It is possible that both mechanisms are operative. Treatment is unsatisfactory and emphasis is presently best placed upon searching for more treatable causes of renal functional impairment in individual patients.

Validation of Perfusion Quantification with 3D Gradient Echo Dynamic Contrast-Enhanced Magnetic Resonance Imaging Using a Blood Pool Contrast Agent in Skeletal Swine Muscle

PubMed Central

Hindel, Stefan; Sauerbrey, Anika; Maaß, Marc; Maderwald, Stefan; Schlamann, Marc; Lüdemann, Lutz

2015-01-01

The purpose of our study was to validate perfusion quantification in a low-perfused tissue by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) with shared k-space sampling using a blood pool contrast agent. Perfusion measurements were performed in a total of seven female pigs. An ultrasonic Doppler probe was attached to the right femoral artery to determine total flow in the hind leg musculature. The femoral artery was catheterized for continuous local administration of adenosine to increase blood flow up to four times the baseline level. Three different stable perfusion levels were induced. The MR protocol included a 3D gradient-echo sequence with a temporal resolution of approximately 1.5 seconds. Before each dynamic sequence, static MR images were acquired with flip angles of 5°, 10°, 20°, and 30°. Both static and dynamic images were used to generate relaxation rate and baseline magnetization maps with a flip angle method. 0.1 mL/kg body weight of blood pool contrast medium was injected via a central venous catheter at a flow rate of 5 mL/s. The right hind leg was segmented in 3D into medial, cranial, lateral, and pelvic thigh muscles, lower leg, bones, skin, and fat. The arterial input function (AIF) was measured in the aorta. Perfusion of the different anatomic regions was calculated using a one- and a two-compartment model with delay- and dispersion-corrected AIFs. The F-test for model comparison was used to decide whether to use the results of the one- or two-compartment model fit. Total flow was calculated by integrating volume-weighted perfusion values over the whole measured region. The resulting values of delay, dispersion, blood volume, mean transit time, and flow were all in physiologically and physically reasonable ranges. In 107 of 160 ROIs, the blood signal was separated, using a two-compartment model, into a capillary and an arteriolar signal contribution, decided by the F-test. Overall flow in hind leg muscles, as measured by the ultrasound probe, highly correlated with total flow determined by MRI, R = 0.89 and P = 10−7. Linear regression yielded a slope of 1.2 and a y-axis intercept of 259 mL/min. The mean total volume of the investigated muscle tissue corresponds to an offset perfusion of 4.7mL/(min ⋅ 100cm3). The DCE-MRI technique presented here uses a blood pool contrast medium in combination with a two-compartment tracer kinetic model and allows absolute quantification of low-perfused non-cerebral organs such as muscles. PMID:26061498

Dynamic iterative beam hardening correction (DIBHC) in myocardial perfusion imaging using contrast-enhanced computed tomography.

PubMed

Stenner, Philip; Schmidt, Bernhard; Allmendinger, Thomas; Flohr, Thomas; Kachelrie, Marc

2010-06-01

In cardiac perfusion examinations with computed tomography (CT) large concentrations of iodine in the ventricle and in the descending aorta cause beam hardening artifacts that can lead to incorrect perfusion parameters. The aim of this study is to reduce these artifacts by performing an iterative correction and by accounting for the 3 materials soft tissue, bone, and iodine. Beam hardening corrections are either implemented as simple precorrections which cannot account for higher order beam hardening effects, or as iterative approaches that are based on segmenting the original image into material distribution images. Conventional segmentation algorithms fail to clearly distinguish between iodine and bone. Our new algorithm, DIBHC, calculates the time-dependent iodine distribution by analyzing the voxel changes of a cardiac perfusion examination (typically N approximately 15 electrocardiogram-correlated scans distributed over a total scan time up to T approximately 30 s). These voxel dynamics are due to changes in contrast agent. This prior information allows to precisely distinguish between bone and iodine and is key to DIBHC where each iteration consists of a multimaterial (soft tissue, bone, iodine) polychromatic forward projection, a raw data comparison and a filtered backprojection. Simulations with a semi-anthropomorphic dynamic phantom and clinical scans using a dual source CT scanner with 2 x 128 slices, a tube voltage of 100 kV, a tube current of 180 mAs, and a rotation time of 0.28 seconds have been carried out. The uncorrected images suffer from beam hardening artifacts that appear as dark bands connecting large concentrations of iodine in the ventricle, aorta, and bony structures. The CT-values of the affected tissue are usually underestimated by roughly 20 HU although deviations of up to 61 HU have been observed. For a quantitative evaluation circular regions of interest have been analyzed. After application of DIBHC the mean values obtained deviate by only 1 HU for the simulations and the corrected values show an increase of up to 61 HU for the measurements. One iteration of DIBHC greatly reduces the beam hardening artifacts induced by the contrast agent dynamics (and those due to bone) now allowing for an improved assessment of contrast agent uptake in the myocardium which is essential for determining myocardial perfusion.

Comparative analysis of renal flow using contrast power Doppler and gray-scale ultrasound

NASA Astrophysics Data System (ADS)

Sehgal, Chandra M.; Arger, Peter H.; Bovee, Kenneth C.; Pugh, Charles; Kirchhofer, Justin I.

1997-05-01

Our previous studies have shown that renal perfusion can be visualized by imaging the transit of a contrast agent through the parenchyma of the organ using gray scale (GS) and power Doppler (PD) ultrasound.However, the relative merits and the sensitivities of the two imaging methods are not known. This study compares the effectiveness of the two modes in visualizing kidney perfusion at the clinical dose of contrast agents. GS and PD images of the dog kidneys were recorded using a clinical ultrasound scanner at 4-7 MHz. A fixed longitudinal plane of the kidney was imaged by mounting the transducer on the animal with a specially designed holder. A dose of 0.1 m1/kg of Echogen was injected intravenously and GS and PD images were recorded simultaneously on two separate time-encoded video tapes during the passage of the contrast agent through the kidneys. The enhancement of GS and PD images was assessed qualitatively by three radiologists. The quantitative assessment was made by measuring the regional and global enhancements of digitized B-scan and PS images. Regional measurements were made by comparing brightness of the post contrast images with that of a pre-contrast reference image pixel by pixel. Student t-test was used to determine the statistical significance of the change. The regions representing statistically significant differences were encoded on the image in color with brightness proportional to the magnitude of change. The regions with no significant change were represented in GS. This generated a series of new images, referred to as StatMap, with color representing regions of perfusion. Changes in power Doppler images were visually detectable with high confidence in all five dogs by al three radiologists. There was no perceptible changes in B-scans. Computer analysis of PD images yielded characteristic indicator dilution curves in all five dogs with an initial rise time of 2-5 sec and a peak at 7-20 sec. The enhancement in PD lasted for 97-400 seconds. The peak to pre-injection Doppler power ratio was 2.41 +/- 0.85. There were not detectable changes in gray scale images except in one dog which exhibited a small change. The StatMap images of PD exhibited perfusion over the entire kidney, whereas the GS images showed perfusion to be sparsely distributed.

Polydeoxyribonucleotides and nitric oxide release from guinea-pig hearts during ischaemia and reperfusion.

PubMed Central

Masini, E.; Lupini, M.; Mugnai, L.; Raspanti, S.; Mannaioni, P. F.

1995-01-01

1. Two polydeoxyribonucleotides, produced by the controlled hydrolysis of DNA of mammalian lung (defibrotide and its lower molecular weight fraction, P.O. 085 DV), were studied for their ability to modify the release of nitrite and the coronary flow in perfusates collected from isolated, normally perfused hearts of guinea-pigs and from hearts subjected to regional ischaemia and reperfusion. 2. In guinea-pig normally perfused hearts, both defibrotide (DFT) and its fraction, P.O. 085 DV, increase the amount of nitrite appearing in perfusates in a concentration-dependent fashion. At the highest concentration studied (10(-6) M), P.O. 085 DV was more effective than DFT. A concomitant increase in the coronary flow was observed. 3. The increase in nitrite in perfusates and the increase in coronary flow induced by both DFT and P.O. 085 DV were significantly reduced by NG-monomethyl-L-arginine (L-NMMA, 10(-4) M), an inhibitor of nitric oxide synthase (NOS). 4. The endothelium-dependent vasodilator, acetylcholine (ACh), enhances the formation of nitrite and the coronary flow. Both the increase in coronary flow and in the formation of nitrite were significantly reduced by L-NMMA (10(-4) M). 5. In guinea-pig hearts subjected to ischaemia and reperfusion, the effect of both compounds in increasing the amount of nitrite in perfusates was more evident and more pronounced with P.O. 085 DV. 6. Reperfusion-induced arrhythmias were significantly reduced by both compounds to the extent of complete protection afforded by compound P.O. 085 DV. 7. The cardioprotective and antiarrhythmic effects of DFT and P.O. 085 DV are discussed. PMID:7582482

WE-G-18C-02: Estimation of Optimal B-Value Set for Obtaining Apparent Diffusion Coefficient Free From Perfusion in Non-Small Cell Lung Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Karki, K; Hugo, G; Ford, J

2014-06-15

Purpose: Diffusion-weighted MRI (DW-MRI) is increasingly being investigated for radiotherapy planning and response assessment. Selection of a limited number of b-values in DW-MRI is important to keep geometrical variations low and imaging time short. We investigated various b-value sets to determine an optimal set for obtaining monoexponential apparent diffusion coefficient (ADC) close to perfusion-insensitive intravoxel incoherent motion (IVIM) model ADC (ADC IVIM) in nonsmall cell lung cancer. Methods: Seven patients had 27 DW-MRI scans before and during radiotherapy in a 1.5T scanner. Respiratory triggering was applied to the echo-planar DW-MRI with TR=4500ms approximately, TE=74ms, pixel size=1.98X1.98mm{sub 2}, slice thickness=4–6mm andmore » 7 axial slices. Diffusion gradients were applied to all three axes producing traceweighted images with eight b-values of 0–1000μs/μm{sup 2}. Monoexponential model ADC values using various b-value sets were compared to ADC IVIM using all b-values. To compare the relative noise in ADC maps, intra-scan coefficient of variation (CV) of active tumor volumes was computed. Results: ADC IVIM, perfusion coefficient and perfusion fraction for tumor volumes were in the range of 880-1622 μm{sup 2}/s, 8119-33834 μm{sup 2}/s and 0.104–0.349, respectively. ADC values using sets of 250, 800 and 1000; 250, 650 and 1000; and 250–1000μs/μm{sup 2} only were not significantly different from ADC IVIM(p>0.05, paired t-test). Error in ADC values for 0–1000, 50–1000, 100–1000, 250–1000, 500–1000, and three b-value sets- 250, 500 and 1000; 250, 650 and 1000; and 250, 800 and 1000μs/μm{sup 2} were 15.0, 9.4, 5.6, 1.4, 11.7, 3.7, 2.0 and 0.2% relative to the reference-standard ADC IVIM, respectively. Mean intrascan CV was 20.2, 20.9, 21.9, 24.9, 32.6, 25.8, 25.4 and 24.8%, respectively, whereas that for ADC IVIM was 23.3%. Conclusion: ADC values of two 3 b-value sets (250, 650 and 1000; and 250, 800 and 1000μs/μm{sup 2}) approached ADC IVIM, with relative noise comparable to that of ADC IVIM. These sets may be used to obtain perfusion-insensitive ADC values in lung tumors. E. Weiss: Funding through Varian Medical Systems and Philips Oncology Systems, UpToDate royalties. G. Hugo: NIH R01CA166119, P01 CA116602, NHMRC Project Grant.« less

Non-invasive ventilation in prone position for refractory hypoxemia after bilateral lung transplantation.

PubMed

Feltracco, Paolo; Serra, Eugenio; Barbieri, Stefania; Persona, Paolo; Rea, Federico; Loy, Monica; Ori, Carlo

2009-01-01

Temporary graft dysfunction with gas exchange abnormalities is a common finding during the postoperative course of a lung transplant and is often determined by the post-reimplantation syndrome. Supportive measures including oxygen by mask, inotropes, diuretics, and pulmonary vasodilators are usually effective in non-severe post-reimplantation syndromes. However, in less-responsive clinical pictures, tracheal intubation with positive pressure ventilation, or non-invasive positive pressure ventilation (NIV), is necessary. We report on the clinical course of two patients suffering from refractory hypoxemia due to post-reimplantation syndrome treated with NIV in the prone and Trendelenburg positions. NIV was well tolerated and led to resolution of atelectactic areas and dishomogeneous lung infiltrates. Repeated turning from supine to prone under non invasive ventilation determined a stable improvement of gas exchange and prevented a more invasive approach. Even though NIV in the prone position has not yet entered into clinical practice, it could be an interesting option to achieve a better match between ventilation and perfusion. This technique, which we successfully applied in lung transplantation, can be easily extended to other lung diseases with non-recruitable dorso-basal areas.

Trauma of lung due to impact load.

PubMed

Yen, R T; Fung, Y C; Liu, S Q

1988-01-01

A quantitative evaluation of lung injury due to impact loading is of general interest. Hemorrhage and edema are the usual sequelae to traumatic pulmonary impact. To gain some quantitative understanding of the phenomena, we perfused excised rabbit lung with Macrodex at isogravimetric condition and monitored lung weight continuously after impact. It is shown that a factor of importance is the rigidity of the surface on which the lung rests. The rate of lung weight increase is smaller if the lung was 'freely' supported on a soft cloth, more if it was supported on a rigid plate. This suggests the influence of stress wave reflection. The critical condition correlates with the initial velocity of impact at the surface of the lung, or with the maximum deflection. For a freely supported lung, the rate of lung weight increase was 22% of the initial total lung weight per h after impact when the impact velocity was 11.5 ms-1, 30% when the velocity was 13.2 ms-1, several 100% at 13.5 ms-1, signaling massive lung injury. Since the velocity of sound in rabbit lung is 33.3 ms-1 when the inflation (transpulmonary) pressure is 10 cm H2O, the critical velocity of 13.5 ms-1 corresponds to a Mach number of 0.4. The maximum surface displacement of the lung is almost linearly proportional to the initial velocity of impact. The exact cause of edema and hemorrhage is unknown; we hypothesize that it is due to tensile stress in the alveolar wall caused by the impact.

Transbronchial drainage using endobronchial ultrasonography with guide sheath for lung abscess: A case report.

PubMed

Yaguchi, Daizo; Ichikawa, Motoshi; Inoue, Noriko; Kobayashi, Daisuke; Shizu, Masato; Imai, Naoyuki

2018-05-01

Lung abscess was previously treated surgically, but is now mainly treated with antibiotics and ideally with direct drainage, although postural drainage canalso be used. A chest abnormal shadow was detected in an 82-year-old man and he was referred to our department in November 2017. On chest computed tomography (CT), a low-density mass shadow was present in the left S8 segment. Lung abscess and lung cancer were considered as differential diagnoses, and treatment with sulbactam sodium/ampicillin sodium (SBT/ABPC) was first initiated for lung abscess. The etiologic agent could not be identified by sputum examination, and the abscess shadow remained. Lung abscess. Endobronchial ultrasonography with a guide sheath (EBUS-GS)-guided bronchoscopy was performed on hospital day 21 to diagnose the lesion, identify the etiologic agent if the lesion was a lung abscess, and attempt drainage. Vacuum aspiration performed in the guide sheath after the probe was placed within the lesion produced 4-5 ml of gray turbid pus, and the abscess was judged to have been drained. A subsequent pathological examination did not detect malignant cells. Klebsiella pneumoniae, Prevotella spp. was identified as the etiologic agent in bacteriological tests. Antibiotics were changed based on sensitivity test results, and drainage was similarly performed on hospital day 28. The shadow gradually improved and disappeared. Therefore, this procedure and treatment led to identification of the etiologic agent and helped with cure of the disease. Based on the basic principle of treatment for abscess using as much drainage as possible, EBUS-GS-guided transbronchial drainage may be considered to be a "new procedure" for lung abscess.

Transbronchial drainage using endobronchial ultrasonography with guide sheath for lung abscess

PubMed Central

Yaguchi, Daizo; Ichikawa, Motoshi; Inoue, Noriko; Kobayashi, Daisuke; Shizu, Masato; Imai, Naoyuki

2018-01-01

Abstract Rationale: Lung abscess was previously treated surgically, but is now mainly treated with antibiotics and ideally with direct drainage, although postural drainage canalso be used. Patient concerns: A chest abnormal shadow was detected in an 82-year-old man and he was referred to our department in November 2017. On chest computed tomography (CT), a low-density mass shadow was present in the left S8 segment. Lung abscess and lung cancer were considered as differential diagnoses, and treatment with sulbactam sodium/ampicillin sodium (SBT/ABPC) was first initiated for lung abscess. The etiologic agent could not be identified by sputum examination, and the abscess shadow remained. Diagnoses: Lung abscess. Interventions: Endobronchial ultrasonography with a guide sheath (EBUS-GS)-guided bronchoscopy was performed on hospital day 21 to diagnose the lesion, identify the etiologic agent if the lesion was a lung abscess, and attempt drainage. Vacuum aspiration performed in the guide sheath after the probe was placed within the lesion produced 4-5 ml of gray turbid pus, and the abscess was judged to have been drained. Outcomes: A subsequent pathological examination did not detect malignant cells. Klebsiella pneumoniae, Prevotella spp. was identified as the etiologic agent in bacteriological tests. Antibiotics were changed based on sensitivity test results, and drainage was similarly performed on hospital day 28. The shadow gradually improved and disappeared. Therefore, this procedure and treatment led to identification of the etiologic agent and helped with cure of the disease. Lessons: Based on the basic principle of treatment for abscess using as much drainage as possible, EBUS-GS-guided transbronchial drainage may be considered to be a “new procedure” for lung abscess. PMID:29768382

Analysis of tracer transit in rat brain after carotid artery and femoral vein administrations using linear system theory.

PubMed

Rudin, M; Beckmann, N; Sauter, A

1997-01-01

Determination of tissue perfusion rates by MRI bolus tracking methods relies on the central volume principle which states that tissue blood flow is given by the tissue blood volume divided by the mean tracer transit time (MTT). Accurate determination of the MTT requires knowledge of the arterial input function which in MRI experiments is usually not known, especially when using small animals. The problem of unknown arterial input can be circumvented in animal experiments by directly injecting the contrast agent into a feeding artery of the tissue of interest. In the present article the passage of magnetite nanoparticles through the rat cerebral cortex is analyzed after injection into the internal carotid artery. The results are discussed in the framework of linear system theory using a one-compartment model for brain tissue and by using the well characterized gamma-variate function to describe the tissue concentration profile of the contrast agent. The results obtained from the intra-arterial tracer administration experiments are then compared with the commonly used intra-venous injection of the contrast agent in order to estimate the contribution of the peripheral circulation to the MTT values in the latter case. The experiments were analyzed using a two-compartment model and the gamma-variate function. As an application perfusion rates in normal and ischemic cerebral cortex of hypertensive rats were estimated in a model of focal cerebral ischemia. The results indicate that peripheral circulation has a significant influence on the MTT values and thus on the perfusion rates, which cannot be neglected.

State of the Art: Response Assessment in Lung Cancer in the Era of Genomic Medicine

PubMed Central

Hatabu, Hiroto; Johnson, Bruce E.; McLoud, Theresa C.

2014-01-01

Tumor response assessment has been a foundation for advances in cancer therapy. Recent discoveries of effective targeted therapy for specific genomic abnormalities in lung cancer and their clinical application have brought revolutionary advances in lung cancer therapy and transformed the oncologist’s approach to patients with lung cancer. Because imaging is a major method of response assessment in lung cancer both in clinical trials and practice, radiologists must understand the genomic alterations in lung cancer and the rapidly evolving therapeutic approaches to effectively communicate with oncology colleagues and maintain the key role in lung cancer care. This article describes the origin and importance of tumor response assessment, presents the recent genomic discoveries in lung cancer and therapies directed against these genomic changes, and describes how these discoveries affect the radiology community. The authors then summarize the conventional Response Evaluation Criteria in Solid Tumors and World Health Organization guidelines, which continue to be the major determinants of trial endpoints, and describe their limitations particularly in an era of genomic-based therapy. More advanced imaging techniques for lung cancer response assessment are presented, including computed tomography tumor volume and perfusion, dynamic contrast material–enhanced and diffusion-weighted magnetic resonance imaging, and positron emission tomography with fluorine 18 fluorodeoxyglucose and novel tracers. State-of-art knowledge of lung cancer biology, treatment, and imaging will help the radiology community to remain effective contributors to the personalized care of lung cancer patients. © RSNA, 2014 PMID:24661292

Intermedin Stabilized Endothelial Barrier Function and Attenuated Ventilator-induced Lung Injury in Mice

PubMed Central

Müller-Redetzky, Holger Christian; Kummer, Wolfgang; Pfeil, Uwe; Hellwig, Katharina; Will, Daniel; Paddenberg, Renate; Tabeling, Christoph; Hippenstiel, Stefan; Suttorp, Norbert; Witzenrath, Martin

2012-01-01

Background Even protective ventilation may aggravate or induce lung failure, particularly in preinjured lungs. Thus, new adjuvant pharmacologic strategies are needed to minimize ventilator-induced lung injury (VILI). Intermedin/Adrenomedullin-2 (IMD) stabilized pulmonary endothelial barrier function in vitro. We hypothesized that IMD may attenuate VILI-associated lung permeability in vivo. Methodology/Principal Findings Human pulmonary microvascular endothelial cell (HPMVEC) monolayers were incubated with IMD, and transcellular electrical resistance was measured to quantify endothelial barrier function. Expression and localization of endogenous pulmonary IMD, and its receptor complexes composed of calcitonin receptor-like receptor (CRLR) and receptor activity-modifying proteins (RAMPs) 1–3 were analyzed by qRT-PCR and immunofluorescence in non ventilated mouse lungs and in lungs ventilated for 6 h. In untreated and IMD treated mice, lung permeability, pulmonary leukocyte recruitment and cytokine levels were assessed after mechanical ventilation. Further, the impact of IMD on pulmonary vasoconstriction was investigated in precision cut lung slices (PCLS) and in isolated perfused and ventilated mouse lungs. IMD stabilized endothelial barrier function in HPMVECs. Mechanical ventilation reduced the expression of RAMP3, but not of IMD, CRLR, and RAMP1 and 2. Mechanical ventilation induced lung hyperpermeability, which was ameliorated by IMD treatment. Oxygenation was not improved by IMD, which may be attributed to impaired hypoxic vasoconstriction due to IMD treatment. IMD had minor impact on pulmonary leukocyte recruitment and did not reduce cytokine levels in VILI. Conclusions/Significance IMD may possibly provide a new approach to attenuate VILI. PMID:22563471

A preclinical rodent model of acute radiation-induced lung injury after ablative focal irradiation reflecting clinical stereotactic body radiotherapy.

PubMed

Hong, Zhen-Yu; Lee, Hae-June; Choi, Won Hoon; Lee, Yoon-Jin; Eun, Sung Ho; Lee, Jung Il; Park, Kwangwoo; Lee, Ji Min; Cho, Jaeho

2014-07-01

In a previous study, we established an image-guided small-animal micro-irradiation system mimicking clinical stereotactic body radiotherapy (SBRT). The goal of this study was to develop a rodent model of acute phase lung injury after ablative irradiation. A radiation dose of 90 Gy was focally delivered to the left lung of C57BL/6 mice using a small animal stereotactic irradiator. At days 1, 3, 5, 7, 9, 11 and 14 after irradiation, the lungs were perfused with formalin for fixation and paraffin sections were stained with hematoxylin and eosin (H&E) and Masson's trichrome. At days 7 and 14 after irradiation, micro-computed tomography (CT) images of the lung were taken and lung functional measurements were performed with a flexiVent™ system. Gross morphological injury was evident 9 days after irradiation of normal lung tissues and dynamic sequential events occurring during the acute phase were validated by histopathological analysis. CT images of the mouse lungs indicated partial obstruction located in the peripheral area of the left lung. Significant alteration in inspiratory capacity and tissue damping were detected on day 14 after irradiation. An animal model of radiation-induced lung injury (RILI) in the acute phase reflecting clinical stereotactic body radiotherapy was established and validated with histopathological and functional analysis. This model enhances our understanding of the dynamic sequential events occurring in the acute phase of radiation-induced lung injury induced by ablative dose focal volume irradiation.

Evaluation of heart perfusion in patients with acute myocardial infarction using dynamic contrast-enhanced magnetic resonance imaging.

PubMed

Nielsen, Gitte; Fritz-Hansen, Thomas; Dirks, Christina G; Jensen, Gorm B; Larsson, Henrik B W

2004-09-01

To investigate the diagnostic ability of quantitative magnetic resonance imaging (MRI) heart perfusion in acute heart patients, a fast, multislice dynamic contrast-enhanced MRI sequence was applied to patients with acute myocardial infarction. Seven patients with acute transmural myocardial infarction were studied using a Turbo-fast low angle shot (FLASH) MRI sequence to monitor the first pass of an extravascular contrast agent (CA), gadolinium diethylene triamine pentaacetic acid (Gd-DTPA). Quantitation of perfusion, expressed as Ki (mL/100 g/minute), in five slices, each having 60 sectors, provided an estimation of the severity and extent of the perfusion deficiency. Reperfusion was assessed both by noninvasive criteria and by coronary angiography (CAG). The Ki maps clearly delineated the infarction in all patients. Thrombolytic treatment was clearly beneficial in one case, but had no effect in the two other cases. Over the time-course of the study, normal perfusion values were not reestablished following thrombolytic treatment in all cases investigated. This study shows that quantitative MRI perfusion values can be obtained from acutely ill patients following acute myocardial infarction. The technique provides information on both the volume and severity of affected myocardial tissue, enabling the power of treatment regimes to be assessed objectively, and this approach should aid individual patient stratification and prognosis. Copyright 2004 Wiley-Liss, Inc.

Human Lung Homotransplantation

PubMed Central

White, J. J.; Tanser, P. H.; Anthonisen, N. R.; Wynands, J. E.; Pare, J. A. P.; Becklake, M. R.; Munro, D. D.; MacLean, L. D.

1966-01-01

Left lung homotransplantation was performed in a 31-year-old man in terminal irreversible respiratory failure due to advanced silicosis. Within 10 minutes of completion of transplantation, arterial pO2 rose from 52 to 211 mm. Hg, pCO2 dropped from 90 to 43 mm. Hg, and pH rose from 7.15 to 7.42. On assisted ventilation, arterial O2 tension was maintained within normal limits for the first four days. Thereafter, arterio-alveolar difference for O2 increased to 300 mm. and that for CO2 to 25 mm. Xenon-133 ventilation perfusion ratios confirmed differences between the two lungs. Terminally, bronchopneumonia and hypoxemia were present. Surfactant content of the lung was within normal limits. Postmortem examination revealed bronchopneumonia, bronchial infarction, lymphatic engorgement and mild rejection. Future efforts should emphasize selection of non-infected donors, minimal reliance on steroids for immunosuppression, cardiopulmonary bypass during transplantation, and more definite criteria for rejection. ImagesFig. 2Fig. 3Fig. 4Fig. 8Fig. 9Fig. 11Fig. 12Fig. 13Fig. 14 PMID:5328358

Peptidase modulation of the pulmonary effects of tachykinins in tracheal superfused guinea pig lungs.

PubMed Central

Martins, M A; Shore, S A; Gerard, N P; Gerard, C; Drazen, J M

1990-01-01

The effects of the angiotensin converting enzyme (ACE) inhibitor captopril and the neutral endopeptidase (NEP) inhibitors thiorphan and SCH 32615 on the changes in airway opening pressure (PaO) and the recovery of offered peptide were studied after intratracheal administration of substance P (SP) and neurokinin A (NKA) in isolated guinea pig lungs superfused through the trachea. Pao changes and the recovery of offered peptide were significantly greater in NEP inhibitor-treated lungs than in control lungs. Captopril did not cause a significant change in the physiological effects or the recovery of SP and NKA. HPLC analysis of [3H]Pro2,4-SP and 125I-Histidyl1-NKA perfused through the airways showed major cleavage products consistent with NEP action. We conclude that there is significant degradation of both SP and NKA after tracheal infusion of peptides by NEP-like but not by ACE activity; this effect significantly influences the physiological effects of these peptides. Images PMID:1688568

Peptidase modulation of the pulmonary effects of tachykinins in tracheal superfused guinea pig lungs.

PubMed

Martins, M A; Shore, S A; Gerard, N P; Gerard, C; Drazen, J M

1990-01-01

The effects of the angiotensin converting enzyme (ACE) inhibitor captopril and the neutral endopeptidase (NEP) inhibitors thiorphan and SCH 32615 on the changes in airway opening pressure (PaO) and the recovery of offered peptide were studied after intratracheal administration of substance P (SP) and neurokinin A (NKA) in isolated guinea pig lungs superfused through the trachea. Pao changes and the recovery of offered peptide were significantly greater in NEP inhibitor-treated lungs than in control lungs. Captopril did not cause a significant change in the physiological effects or the recovery of SP and NKA. HPLC analysis of [3H]Pro2,4-SP and 125I-Histidyl1-NKA perfused through the airways showed major cleavage products consistent with NEP action. We conclude that there is significant degradation of both SP and NKA after tracheal infusion of peptides by NEP-like but not by ACE activity; this effect significantly influences the physiological effects of these peptides.

Effect of antioxidants on vanadate-induced toxicity towards isolated perfused rat livers.

PubMed

Younes, M; Kayser, E; Strubelt, O

1991-01-01

The effect of trolox C, a water soluble vitamin E analogue, propyl gallate and ascorbate on vanadate hepatotoxicity was investigated in vitro. In isolated perfused livers from fasted rats, sodium orthovanadate (2 mmol/l) led to toxic responses including reduction of oxygen consumption, release of cytosolic (glutamate-pyruvate-transaminase (GPT) and lactate dehydrogenase (LDH)) and mitochondrial (glutamate-dehydrogenase (GLDH)) enzymes, intracellular accumulation of calcium, a marked depletion of glutathione (GSH) and an enhanced formation and release of thiobarbituric acid- (TBA) reactive material. Trolox C and propyl gallate inhibited the release of GPT and LDH partially and that of GLDH totally, but had no influence on vanadate-induced calcium accumulation or on the reduction of oxygen consumption. Both agents suppressed vanadate-induced lipid peroxidation (LPO) and partially prevented GSH depletion. Ascorbate failed to provide any protection probably due to the interference of its pro-oxidant potential with its antioxidant activity. The protection, mainly of mitochondria, afforded by those agents which also inhibited LPO substantiates our previous findings that the pro-oxidant activity of vanadate is mainly responsible for its direct hepatotoxic actions [2]. Besides, reduction of organ perfusion rate due to vasoconstriction also contributes to vanadate toxicity, but oxidative stress is not involved in this indirect toxic activity.

Tranilast-induced stress alleviation in solid tumors improves the efficacy of chemo- and nanotherapeutics in a size-independent manner

NASA Astrophysics Data System (ADS)

Papageorgis, Panagiotis; Polydorou, Christiana; Mpekris, Fotios; Voutouri, Chrysovalantis; Agathokleous, Eliana; Kapnissi-Christodoulou, Constantina P.; Stylianopoulos, Triantafyllos

2017-04-01

Accumulation of mechanical stresses during cancer progression can induce blood and lymphatic vessel compression, creating hypo-perfusion, hypoxia and interstitial hypertension which decrease the efficacy of chemo- and nanotherapies. Stress alleviation treatment has been recently proposed to reduce mechanical stresses in order to decompress tumor vessels and improve perfusion and chemotherapy. However, it remains unclear if it improves the efficacy of nanomedicines, which present numerous advantages over traditional chemotherapeutic drugs. Furthermore, we need to identify safe and well-tolerated pharmaceutical agents that reduce stress levels and may be added to cancer patients’ treatment regimen. Here, we show mathematically and with a series of in vivo experiments that stress alleviation improves the delivery of drugs in a size-independent manner. Importantly, we propose the repurposing of tranilast, a clinically approved anti-fibrotic drug as stress-alleviating agent. Using two orthotopic mammary tumor models, we demonstrate that tranilast reduces mechanical stresses, decreases interstitial fluid pressure (IFP), improves tumor perfusion and significantly enhances the efficacy of different-sized drugs, doxorubicin, Abraxane and Doxil, by suppressing TGFβ signaling and expression of extracellular matrix components. Our findings strongly suggest that repurposing tranilast could be directly used as a promising strategy to enhance, not only chemotherapy, but also the efficacy of cancer nanomedicine.

Prediction of radiation-induced normal tissue complications in radiotherapy using functional image data

NASA Astrophysics Data System (ADS)

Nioutsikou, Elena; Partridge, Mike; Bedford, James L.; Webb, Steve

2005-03-01

The aim of this study has been to explicitly include the functional heterogeneity of an organ as a factor that contributes to the probability of complication of normal tissues following radiotherapy. Situations for which the inclusion of this information can be advantageous to the design of treatment plans are then investigated. A Java program has been implemented for this purpose. This makes use of a voxelated model of a patient, which is based on registered anatomical and functional data in order to enable functional voxel weighting. Using this model, the functional dose-volume histogram (fDVH) and the functional normal tissue complication probability (fNTCP) are then introduced as extensions to the conventional dose-volume histogram (DVH) and normal tissue complication probability (NTCP). In the presence of functional heterogeneity, these tools are physically more meaningful for plan evaluation than the traditional indices, as they incorporate additional information and are anticipated to show a better correlation with outcome. New parameters mf, nf and TD50f are required to replace the m, n and TD50 parameters. A range of plausible values was investigated, awaiting fitting of these new parameters to patient outcomes where functional data have been measured. As an example, the model is applied to two lung datasets utilizing accurately registered computed tomography (CT) and single photon emission computed tomography (SPECT) perfusion scans. Assuming a linear perfusion-function relationship, the biological index mean perfusion weighted lung dose (MPWLD) has been extracted from integration over outlined regions of interest. In agreement with the MPWLD ranking, the fNTCP predictions reveal that incorporation of functional imaging in radiotherapy treatment planning is most beneficial for organs with a large volume effect and large focal areas of dysfunction. There is, however, no additional advantage in cases presenting with homogeneous function. Although presented for lung radiotherapy, this model is general. It can also be applied to positron emission tomography (PET)-CT or functional magnetic resonance imaging (fMRI)-CT registered data and extended to the functional description of tumour control probability.

The pulmonary pharmacology of [4-methoxy-N1-(4-trans-nitrooxycyclohexyl)-N3-(3-pyridinylmethyl)-1,3-benzenedicarboxamide] (2NTX-99), an anti-atherotrombotic compound with therapeutic potential in pathological conditions that target lung vasculature.

PubMed

Brivio, I; Buccellati, C; Fumagalli, F; Hodge, J; Casagrande, C; Folco, G C; Sala, A

2012-08-01

The pharmacological activity of 2NTX-99 ([4-methoxy-N1-(4-trans-nitrooxycyclohexyl)-N3-(3-pyridinylmethyl)-1,3-benzenedicarboxamide]) was investigated in vitro in the intact, rat pulmonary vasculature and in guinea pig airways. Rat lungs were perfused at constant flow and changes in vascular tone recorded. Challenge with the TXA₂ analogue 9,11-dideoxy-9α11α-methanoepoxy ProstaglandinF₂ (U46619, 0.5 μM) increased vessel tone (32.48±1.5 vs 13.13±0.56 mmHg; n=12). 2NTX-99 (0.1-100 μM; n=5), caused a concentration-dependent relaxation, prevented by 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one (ODQ, 10 μM, n=4), an inhibitor of soluble guanylate cyclase. Acetylcholine (0.1-10 μM; n=3) and a reference NO-donor, isosorbide-5-mononitrate (5-100 μM; n=4), were ineffective. Intraluminal perfusion of washed human platelets (2 × 10⁸ cells/ml) increased intravascular pressure after challenge with arachidonic acid (AA, 2 μM; n=5), an increase abolished by acetylsalicylic acid and significantly reduced by 2NTX-99 (40 μM; n=5). TXB₂ in the lung perfusate was detected after platelet activation, 2NTX-99 inhibited TXA₂ synthesis (6.45±0.6 and 1.10±0.2 ng/ml, respectively). 2NTX-99 did not alter central or peripheral airway responsiveness to Histamine (0.001-300 μM; n=6), U46619 (0.001-3 μM, n=3) or LTD₄ (1 pM-1 μM; n=6). 2NTX-99 vasodilates the pulmonary vasculature via the release of nitric oxide (NO) and reduces intraluminal, AA-induced, TXA₂ formation. The combined activity of 2NTX-99 as an NO-donor and a TXA₂-synthesis inhibitor provides strong support for its potential therapeutic use in pathologies of the pulmonary vascular bed (e.g. pulmonary hypertension). Copyright © 2012 Elsevier Inc. All rights reserved.

Pyridostigmine bromide modulates topical irritant-induced cytokine release from human epidermal keratinocytes and isolated perfused porcine skin.

PubMed

Monteiro-Riviere, Nancy A; Baynes, Ronald E; Riviere, Jim E

2003-02-01

Gulf War personnel were given pyridostigmine bromide (PB) as a prophylactic treatment against organophosphate nerve agent exposure, and were exposed to the insecticide permethrin and the insect repellent N,N-diethyl-m-toluamide (DEET). The purpose of this study was to assess the effects of PB to modulate release of inflammatory biomarkers after topical chemical exposure to chemical mixtures containing permethrin and DEET applied in ethanol or water vehicles. Treatments were topically applied to isolated perfused porcine skin flaps (IPPSFs). Concentrations of interleukin-8 (IL-8), tumor necrosis factor-alpha (TNF-alpha) and prostaglandin E(2) (PGE(2)) were assayed in perfusate to probe for potential inflammatory effects after complex mixture application. IPPSFs (n=4/treatment) were topically dosed with mixtures of permethrin, DEET, and permethrin/DEET, in ethanol. Each treatment was repeated with perfusate spiked with 50 ng/ml of PB. Perfusate was also spiked with 30 ng/ml diisopropylfluorophosphate to simulate low level organophosphate nerve agent exposure. Timed IPPSF venous effluent samples (0.5,1,2,4, and 8 h) were assayed by ELISA for IL-8 and TNF-alpha and by EIA for PGE(2). Overall, PB infusion caused a decrease or IL-8 and PGE(2) release. Effects on TNF-alpha were vehicle dependent. To probe the potential mechanism of this PB effect, human epidermal keratinocyte HEK cell cultures were exposed to permethrin DEET permethrin/DEET, with and without PB in DMSO. IL-8 was assayed at 1, 2, 4, 8, 12 and 24 h. PB suppressed IL-8 in permethrin and ethanol treatment from 4 to 24 h confirming the IPPSF results. In conclusion, these studies suggest that systemic exposure to PB suppressed IL-8 release at multiple time points in two skin model systems. This interaction merits further study.

Influence of amplitude-related perfusion parameters in the parotid glands by non-fat-saturated dynamic contrast-enhanced magnetic resonance imaging.

PubMed

Chiu, Su-Chin; Cheng, Cheng-Chieh; Chang, Hing-Chiu; Chung, Hsiao-Wen; Chiu, Hui-Chu; Liu, Yi-Jui; Hsu, Hsian-He; Juan, Chun-Jung

2016-04-01

To verify whether quantification of parotid perfusion is affected by fat signals on non-fat-saturated (NFS) dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and whether the influence of fat is reduced with fat saturation (FS). This study consisted of three parts. First, a retrospective study analyzed DCE-MRI data previously acquired on different patients using NFS (n = 18) or FS (n = 18) scans. Second, a phantom study simulated the signal enhancements in the presence of gadolinium contrast agent at six concentrations and three fat contents. Finally, a prospective study recruited nine healthy volunteers to investigate the influence of fat suppression on perfusion quantification on the same subjects. Parotid perfusion parameters were derived from NFS and FS DCE-MRI data using both pharmacokinetic model analysis and semiquantitative parametric analysis. T tests and linear regression analysis were used for statistical analysis with correction for multiple comparisons. NFS scans showed lower amplitude-related parameters, including parameter A, peak enhancement (PE), and slope than FS scans in the patients (all with P < 0.0167). The relative signal enhancement in the phantoms was proportional to the dose of contrast agent and was lower in NFS scans than in FS scans. The volunteer study showed lower parameter A (6.75 ± 2.38 a.u.), PE (42.12% ± 14.87%), and slope (1.43% ± 0.54% s(-1)) in NFS scans as compared to 17.63 ± 8.56 a.u., 104.22% ± 25.15%, and 9.68% ± 1.67% s(-1), respectively, in FS scans (all with P < 0.005). These amplitude-related parameters were negatively associated with the fat content in NFS scans only (all with P < 0.05). On NFS DCE-MRI, quantification of parotid perfusion is adversely affected by the presence of fat signals for all amplitude-related parameters. The influence could be reduced on FS scans.

Development of a perfusion reversed-phase high performance liquid chromatography method for the characterisation of maize products using multivariate analysis.

PubMed

Rodriguez-Nogales, J M; Garcia, M C; Marina, M L

2006-02-03

A perfusion reversed-phase high performance liquid chromatography (RP-HPLC) method has been designed to allow rapid (3.4 min) separations of maize proteins with high resolution. Several factors, such as extraction conditions, temperature, detection wavelength and type and concentration of ion-pairing agent were optimised. A fine optimisation of the gradient elution was also performed by applying experimental design. Commercial maize products for human consumption (flours, precocked flours, fried snacks and extruded snacks) were characterised for the first time by perfusion RP-HPLC and their chromatographic profiles allowed a differentiation among products relating the different technological process used for their preparation. Furthermore, applying discriminant analysis makes it possible to group the samples according with the technological process suffered by maize products, obtaining a good prediction in 92% of the samples.

Parasympathetic control of Na, K transport in perfused submaxillary duct of the rat.

PubMed

Schneyer, L H

1977-07-01

The effects of stimulating the parasympathetic innervation to rat submaxillary gland on ductal transport of Na, K, water, and transepithelial PD, were tested in the main excretory duct during perfusion through its lumen. During nerve stimulation, transepithelial PD was consistently decreased, usually by about 15 mV, and this decrease could be blocked by atropine but not by adrenergic blocking agents. Net flux of Na, K, or water was not significantly changed during stimulation. One-way flux of Na from the lumen also was unaffected. The decrease in PD during stimulation was not affected by substituting isethionate for Cl or increasing [K] in the luminal perfusion medium. It is concluded that parasympathetic effects are exerted on the ductal cells, but that these probably do not involve conductance changes at the luminal membrane.

Percutaneous Isolated Hepatic Perfusion for the Treatment of Unresectable Liver Malignancies

DOE Office of Scientific and Technical Information (OSTI.GOV)

Burgmans, Mark C., E-mail: m.c.burgmans@lumc.nl; Leede, Eleonora M. de, E-mail: e.m.de-leede@lumc.nl; Martini, Christian H., E-mail: c.h.martini@lumc.nl

2016-06-15

Liver malignancies are a major burden of disease worldwide. The long-term prognosis for patients with unresectable tumors remains poor, despite advances in systemic chemotherapy, targeted agents, and minimally invasive therapies such as ablation, chemoembolization, and radioembolization. Thus, the demand for new and better treatments for malignant liver tumors remains high. Surgical isolated hepatic perfusion (IHP) has been shown to be effective in patients with various hepatic malignancies, but is complex, associated with high complication rates and not repeatable. Percutaneous isolated liver perfusion (PHP) is a novel minimally invasive, repeatable, and safer alternative to IHP. PHP is rapidly gaining interest andmore » the number of procedures performed in Europe now exceeds 200. This review discusses the indications, technique and patient management of PHP and provides an overview of the available data.« less

Imaging lung perfusion

PubMed Central

Wielpütz, Mark O.; Kauczor, Hans-Ulrich

2012-01-01

From the first measurements of the distribution of pulmonary blood flow using radioactive tracers by West and colleagues (J Clin Invest 40: 1–12, 1961) allowing gravitational differences in pulmonary blood flow to be described, the imaging of pulmonary blood flow has made considerable progress. The researcher employing modern imaging techniques now has the choice of several techniques, including magnetic resonance imaging (MRI), computerized tomography (CT), positron emission tomography (PET), and single photon emission computed tomography (SPECT). These techniques differ in several important ways: the resolution of the measurement, the type of contrast or tag used to image flow, and the amount of ionizing radiation associated with each measurement. In addition, the techniques vary in what is actually measured, whether it is capillary perfusion such as with PET and SPECT, or larger vessel information in addition to capillary perfusion such as with MRI and CT. Combined, these issues affect quantification and interpretation of data as well as the type of experiments possible using different techniques. The goal of this review is to give an overview of the techniques most commonly in use for physiological experiments along with the issues unique to each technique. PMID:22604884

Radionuclide evaluation of lung trauma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lull, R.J.; Tatum, J.L.; Sugerman, H.J.

1983-07-01

Nuclear medicine imaging procedures can play a significant role in evaluating the pulmonary complications that are seen in trauma patients. A quantitative method for measuring increased pulmonary capillary permeability that uses Tc-99m HSA allows early diagnosis of acute respiratory distress syndrome (ARDS) and accurately differentiates this condition from pneumonia or cardiogenic pulmonary edema. This technique may be of great value in following the response to therapy. The use of 133Xe to diagnose inhalation injury remains an important diagnostic tool, particularly at hospitals with specialized burn units. Regional decreases in ventilation-perfusion images reliably localize aspirated foreign bodies. Radionuclide techniques that aremore » used to demonstrate gastropulmonary aspiration remain controversial and require further clinical evaluation. Pulmonary perfusion imaging, although nonspecific, may provide the earliest clue for correct diagnosis of fat embolism, air embolism, contusion, or laceration. Furthermore, the possibility of perfusion abnormality due to these uncommon conditions must be remembered whenever trauma patients are evaluated for pulmonary thromboembolism with scintigraphy. Occasionally, liver or spleen scintigraphy may be the most appropriate procedure when penetrating chest trauma also involves these subdiaphragmatic organs.« less

Experimental ex vivo lung perfusion with sevoflurane: effects on damaged donor lung grafts.

PubMed

Wang, Xingyu; Parapanov, Roumen; Francioli, Cyril; Perentes, Jean Yannis; Letovanec, Igor; Gonzalez, Michel; Kern, Christian; Ris, Hans-Beat; Piquilloud, Lise; Marcucci, Carlo; Krueger, Thorsten; Liaudet, Lucas; Gronchi, Fabrizio

2018-06-01

Volatile anaesthetics can provide significant protection against reperfusion injury in various experimental settings. The aim of this study was to assess the potential of sevoflurane treatment, the most commonly used volatile anaesthetic in modern anaesthesia, in rat lungs donated after circulatory death and reconditioned in an ex vivo lung perfusion (EVLP) system. Fifteen rats were sacrificed and divided into 3 groups. In the control and sevoflurane groups, the heart-lung blocks were exposed to 1 h of warm ischaemia and 2 h of cold ischaemia and were mounted on an EVLP circuit for 3 h, in the absence or in the presence of 2% sevoflurane. In the baseline group, heart-lung blocks were harvested immediately after euthanasia. Physiological data, lung nitro-oxidative stress, lactate dehydrogenase (LDH), expression of cytokines, oedema and histopathological findings were assessed during or post-EVLP. The sevoflurane group showed significantly reduced LDH (8.82 ± 3.58 arbitrary unit vs 3.80 ± 3.02 arbitrary unit, P = 0.03), protein carbonyl (1.17 ± 0.44 nmol⋅mg-1 vs 0.55 ± 0.11 nmol⋅mg-1, P = 0.006), 3-nitrotyrosine (197.44 ± 18.47 pg⋅mg-1 vs 151.05 ± 23.54 pg⋅mg-1, P = 0.004), cytokine-induced neutrophil chemoattractant factor 1 (1.17 ± 0.32 ng⋅mg-1 vs 0.66 ± 0.28 ng⋅mg-1, P = 0.03) and tumour necrosis factor alpha (1.50 ± 0.59 vs 0.59 ± 0.38 ng⋅mg-1, P = 0.02) when compared with the control group. In addition, sevoflurane lungs gained significantly less weight (0.72 ± 0.09 g vs 0.72 ± 0.09 g, P = 0.044), had less perivascular oedema (0.58 ± 0.09 vs 0.47 ± 0.07, P = 0.036), and improved static pulmonary compliance (+0.215 ml⋅cmH2O-1, P = 0.003) and peak airways pressure (-1.33 cmH2O, P = 0.04) but similar oxygenation capacity (+1.61 mmHg, P = 0.77) and pulmonary vascular resistances (+0.078 mmHg⋅min⋅ml-1, P = 0.15) when compared with the control group. These findings suggest that the potential of sevoflurane in protecting the lungs donated after cardiac death and reconditioned using EVLP could improve the outcome of these lungs following subsequent transplantation.

Monitoring of Nonsteroidal Immunosuppressive Drugs in Patients With Lung Disease and Lung Transplant Recipients

PubMed Central

Meyer, Keith C; Nathanson, Ian; Angel, Luis; Bhorade, Sangeeta M; Chan, Kevin M; Culver, Daniel; Harrod, Christopher G; Hayney, Mary S; Highland, Kristen B; Limper, Andrew H; Patrick, Herbert; Strange, Charlie; Whelan, Timothy

2012-01-01

Objectives: Immunosuppressive pharmacologic agents prescribed to patients with diffuse interstitial and inflammatory lung disease and lung transplant recipients are associated with potential risks for adverse reactions. Strategies for minimizing such risks include administering these drugs according to established, safe protocols; monitoring to detect manifestations of toxicity; and patient education. Hence, an evidence-based guideline for physicians can improve safety and optimize the likelihood of a successful outcome. To maximize the likelihood that these agents will be used safely, the American College of Chest Physicians established a committee to examine the clinical evidence for the administration and monitoring of immunosuppressive drugs (with the exception of corticosteroids) to identify associated toxicities associated with each drug and appropriate protocols for monitoring these agents. Methods: Committee members developed and refined a series of questions about toxicities of immunosuppressives and current approaches to administration and monitoring. A systematic review was carried out by the American College of Chest Physicians. Committee members were supplied with this information and created this evidence-based guideline. Conclusions: It is hoped that these guidelines will improve patient safety when immunosuppressive drugs are given to lung transplant recipients and to patients with diffuse interstitial lung disease. PMID:23131960

Image-based evaluations of distribution and cytotoxicity of Irinotecan (CPT-11) in a multi-compartment micro-cell coculture device.

PubMed

Nakayama, Hidenari; Kimura, Hiroshi; Fujii, Teruo; Sakai, Yasuyuki

2014-06-01

We recently developed a polydimethylsiloxane (PDMS)-based three-compartment microfluidic cocultivation device enabling real-time interactions of different cell populations as an advanced physiologically-relevant cell-based assay. This device had valves and small magnetic stirrer-based internal pumps for easy and flexible perfusion operations. In this study, we applied this device for the evaluation of Irinotecan (CPT-11) toxicity to the lung, because it is detoxified by the liver and accumulated in the fat in humans. We successfully cultured representative three different tissue model cells in each compartment under the individual culture conditions and also in entire perfusion. Growth inhibition of rat lung epithelial cell line L-2, was measured when administered with 50 μM CPT-11 under various cocultivation conditions with respect to the presences and absence of primary rat hepatocytes (liver tissue model) and adipocyte-like cells (fat tissue model) induced from a mouse fibroblast cell line, 3T3-L1. Although CPT-11 showed moderate toxicity to the pure culture of L-2 cells in the device after 72 h of perfusion culture, this was lowered mainly in the presence of the liver tissue. Inhibition of the L-2 cell growth agreed with the area under curve (AUC) values obtained from fluorescent image-based analyses in each compartment. These results demonstrate that developed simple and flexible microfluidic cocultivation device, with appropriate image-based analyses, can be used in evaluating toxicokinetic behaviors of drug candidates in systemic levels. Copyright © 2013 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.

Effect of dobutamine on extravascular lung water index, ventilator function, and perfusion parameters in acute respiratory distress syndrome associated with septic shock.

PubMed

Zhou, Min; Dai, Ji; Du, Min; Wang, Wei; Guo, Changxing; Wang, Yi; Tang, Rui; Xu, Fengling; Rao, Zhuqing; Sun, Gengyun

2016-08-01

The role of dobutamine in the relief of pulmonary edema during septic shock-induced acute respiratory distress syndrome (ARDS) remains undetermined, due to a lack of controllable and quantitative clinical studies. Our objective was to assess the potential effects of dobutamine on extravascular lung water index (ELWI) in septic shock-induced ARDS, reflecting its importance in pulmonary edema. At the same time, ventilator function and perfusion parameters were evaluated. We designed a prospective, non-randomized, non-blinded, controlled study to compare the differences in PiCCO parameters after 6 h of constant dobutamine infusion (15 μg/kg/min), in the baseline parameters in 26 septic shock-related ARDS patients with cardiac index ≥ 2.5I/min/m(2) and hyperlactatemia. These patients (12 survivors/14 non-survivors) were monitored using the PiCCO catheter system within 48 h of onset of septic shock. The dynamic changes in ELWI, which is typically used for quantifying the extent of pulmonary edema, were evaluated, and the corresponding ventilator function and tissue perfusion parameters were also measured. Decreasing ELWI (p = 0.0376) was accompanied by significantly decreased SVRI (p < 0.0001). Despite a significant increase in cardiac output (p < 0.0001), no differences were found in ITBI or GEDI. Moreover, the required dose of norepinephrine was decreased (p = 0.0389), and urine output was increased (p = 0.0358), accompanied by stabilized lactacidemia and MAP. Additionally, airway pressure was moderately improved. During the early stage of septic shock-induced ARDS, dobutamine treatment demonstrated a beneficial effect by relieving pulmonary edema in patients, without a negative elevation in preload or hemodynamics, which might account for the improvements in ventilator function and tissue hypoperfusion.

Liberal Versus Restrictive Intravenous Fluid Therapy for Early Septic Shock: Rationale for a Randomized Trial.

PubMed

Self, Wesley H; Semler, Matthew W; Bellomo, Rinaldo; Brown, Samuel M; deBoisblanc, Bennett P; Exline, Matthew C; Ginde, Adit A; Grissom, Colin K; Janz, David R; Jones, Alan E; Liu, Kathleen D; Macdonald, Stephen P J; Miller, Chadwick D; Park, Pauline K; Reineck, Lora A; Rice, Todd W; Steingrub, Jay S; Talmor, Daniel; Yealy, Donald M; Douglas, Ivor S; Shapiro, Nathan I

2018-05-09

Prompt intravenous fluid therapy is a fundamental treatment for patients with septic shock. However, the optimal approach for administering intravenous fluid in septic shock resuscitation is unknown. Two competing strategies are emerging: a liberal fluids approach, consisting of a larger volume of initial fluid (50 to 75 mL/kg [4 to 6 L in an 80-kg adult] during the first 6 hours) and later use of vasopressors, versus a restrictive fluids approach, consisting of a smaller volume of initial fluid (≤30 mL/kg [≤2 to 3 L]), with earlier reliance on vasopressor infusions to maintain blood pressure and perfusion. Early fluid therapy may enhance or maintain tissue perfusion by increasing venous return and cardiac output. However, fluid administration may also have deleterious effects by causing edema within vital organs, leading to organ dysfunction and impairment of oxygen delivery. Conversely, a restrictive fluids approach primarily relies on vasopressors to reverse hypotension and maintain perfusion while limiting the administration of fluid. Both strategies have some evidence to support their use but lack robust data to confirm the benefit of one strategy over the other, creating clinical and scientific equipoise. As part of the National Heart, Lung, and Blood Institute Prevention and Early Treatment of Acute Lung Injury Network, we designed a randomized clinical trial to compare the liberal and restrictive fluids strategies, the Crystalloid Liberal or Vasopressor Early Resuscitation in Sepsis trial. The purpose of this article is to review the current literature on approaches to early fluid resuscitation in adults with septic shock and outline the rationale for the upcoming trial. Copyright © 2018 American College of Emergency Physicians. Published by Elsevier Inc. All rights reserved.

Modulatory effect of neuropeptide Y on acetylcholine-induced oedema and vasoconstriction in isolated perfused lungs of rabbit.

PubMed Central

Delaunois, A; Gustin, P; Dessy-Doize, C; Ansay, M

1994-01-01

1. The modulatory role of neuropeptide Y (NPY) on pulmonary oedema induced by acetylcholine and capsaicin was investigated. The effects of NPY on the haemodynamic response to acetylcholine, phenylephrine and substance P were also investigated. 2. Isolated, ventilated, exsanguinated lungs of the rabbit were perfused with a constant flow of recirculating blood-free perfusate. The double/arterial/venous occlusion method was used to partition the total pressure gradient (delta Pt) into four components: the arterial gradient (delta Pa), the pre- and post-capillary gradients (respectively delta Pa' and delta Pv') and the venous pressure gradient (delta Pv). Endothelial permeability was evaluated by measuring the capillary filtration coefficient (Kf,c). 3. Acetylcholine (10(-8) M to 10(-4) M) and substance P (SP, 10(-10) M to 10(-6) M) induced a concentration-dependent increase in the Kf,c. Capsaicin (10(-4) M) and 5-hydroxytryptamine (5-HT) (10(-4) M) also increased this parameter. NPY (10(-8) M) completely inhibited the effects of acetylcholine and capsaicin on the Kf,c, without preventing the effects of substance P and 5-HT. 4. Acetylcholine induced concentration-dependent vasoconstriction in the precapillary segment. The effect was inhibited by NPY and aspirin, an inhibitor of cyclo-oxygenase, while ketanserin, a 5-HT2 receptor antagonist, and SR140333, a new NK1 antagonist, had no protective effect. Phenylephrine increased delta Pa at high concentration, an effect also inhibited by NPY and aspirin. Substance P had no significant haemodynamic effect. When injected together with NPY, substance P (10(-6) M) induced a significant increase in the total pressure gradient.(ABSTRACT TRUNCATED AT 250 WORDS) Images Figure 2 Figure 3 PMID:7532083

Lung cancer risk among workers in the construction industry: results from two case-control studies in Montreal.

PubMed

Lacourt, Aude; Pintos, Javier; Lavoué, Jérôme; Richardson, Lesley; Siemiatycki, Jack

2015-09-22

Given the large number of workers in the construction industry, it is important to derive accurate and valid estimates of cancer risk, and in particular lung cancer risk. In most previous studies, risks among construction workers were compared with general populations including blue and white collar workers. The main objectives of this study were to assess whether construction workers experience excess lung cancer risk, and whether exposure to selected construction industry exposures carries excess risks. We wished to address these objectives within the sub-population of blue collar workers. Two case-control studies were conducted in Montreal. Combined, they included 1593 lung cancer cases and 1427 controls, of whom 1304 cases and 1081 controls had been blue collar workers. Detailed lifetime job histories were obtained and translated by experts into histories of exposure to chemical agents. The two key analyses were to estimate odds ratio (OR) estimates of lung cancer risk: a) for all blue-collar construction workers compared with other blue-collar workers, and b) for construction workers exposed to each of 20 exposure agents found in the construction industry compared with construction workers unexposed to those agents. All analyses were conducted using unconditional logistic regression adjusted for socio-demographic factors and smoking history. The OR for all construction workers combined was 1.11 (95 % CI: 0.90-1.38), based on 381 blue collar construction workers. Analyses of specific exposures were hampered by small numbers and imprecise estimates. While none of 20 occupational agents examined was significantly associated with lung cancer, the following agents manifested non-significantly elevated ORs: asbestos, silica, Portland cement, soil dust, calcium oxide and calcium sulfate. Compared with other blue collar workers, there was only a slight increased risk of lung cancer for subjects who ever held an occupation in the construction industry. The analyses of agents within the construction industry produced imprecise estimates of risk, but nevertheless pointed to some plausible associations. Excess risks for asbestos and silica were in line with previous knowledge. The possible excess risks with the other inorganic dusts require further corroboration.

Multiwell cell culture plate format with integrated microfluidic perfusion system

NASA Astrophysics Data System (ADS)

Domansky, Karel; Inman, Walker; Serdy, Jim; Griffith, Linda G.

2006-01-01

A new cell culture analog has been developed. It is based on the standard multiwell cell culture plate format but it provides perfused three-dimensional cell culture capability. The new capability is achieved by integrating microfluidic valves and pumps into the plate. The system provides a means to conduct high throughput assays for target validation and predictive toxicology in the drug discovery and development process. It can be also used for evaluation of long-term exposure to drugs or environmental agents or as a model to study viral hepatitis, cancer metastasis, and other diseases and pathological conditions.

Butyrylcholinesterase in guinea pig lung lavage: a novel biomarker to assess lung injury following inhalation exposure to nerve agent VX.

PubMed

Graham, Jacob R; Wright, Benjamin S; Rezk, Peter E; Gordon, Richard K; Sciuto, Alfred M; Nambiar, Madhusoodana P

2006-06-01

Respiratory disturbances play a central role in chemical warfare nerve agent (CWNA) induced toxicity; they are the starting point of mass casualty and the major cause of death. We developed a microinstillation technique of inhalation exposure to nerve agent VX and assessed lung injury by biochemical analysis of the bronchoalveolar lavage fluid (BALF). Here we demonstrate that normal guinea pig BALF has a significant amount of cholinesterase activity. Treatment with Huperzine A, a specific inhibitor of acetylcholinesterase (AChE), showed that a minor fraction of BALF cholinesterase is AChE. Furthermore, treatment with tetraisopropyl pyrophosphoramide (iso-OMPA), a specific inhibitor of butyrylcholinesterase (BChE), inhibited more than 90% of BChE activity, indicating the predominance of BChE in BALF. A predominance of BChE expression in the lung lavage was seen in both genders. Substrate specific inhibition indicated that nearly 30% of the cholinesterase in lung tissue homogenate is AChE. BALF and lung tissue AChE and BChE activities were strongly inhibited in guinea pigs exposed for 5 min to 70.4 and 90.4 microg/m3 VX and allowed to recover for 15 min. In contrast, BALF AChE activity was increased 63% and 128% and BChE activity was increased 77% and 88% after 24 h of recovery following 5 min inhalation exposure to 70.4 microg/m3 and 90.4 mg/m3 VX, respectively. The increase in BALF AChE and BChE activity was dose dependent. Since BChE is synthesized in the liver and present in the plasma, an increase in BALF indicates endothelial barrier injury and leakage of plasma into lung interstitium. Therefore, a measure of increased levels of AChE and BChE in the lung lavage can be used to determine the chronology of barrier damage as well as the extent of lung injury following exposure to chemical warfare nerve agents.

Cell-surface marker discovery for lung cancer

PubMed Central

Cohen, Allison S.; Khalil, Farah K.; Welsh, Eric A.; Schabath, Matthew B.; Enkemann, Steven A.; Davis, Andrea; Zhou, Jun-Min; Boulware, David C.; Kim, Jongphil; Haura, Eric B.; Morse, David L.

2017-01-01

Lung cancer is the leading cause of cancer deaths in the United States. Novel lung cancer targeted therapeutic and molecular imaging agents are needed to improve outcomes and enable personalized care. Since these agents typically cannot cross the plasma membrane while carrying cytotoxic payload or imaging contrast, discovery of cell-surface targets is a necessary initial step. Herein, we report the discovery and characterization of lung cancer cell-surface markers for use in development of targeted agents. To identify putative cell-surface markers, existing microarray gene expression data from patient specimens were analyzed to select markers with differential expression in lung cancer compared to normal lung. Greater than 200 putative cell-surface markers were identified as being overexpressed in lung cancers. Ten cell-surface markers (CA9, CA12, CXorf61, DSG3, FAT2, GPR87, KISS1R, LYPD3, SLC7A11 and TMPRSS4) were selected based on differential mRNA expression in lung tumors vs. non-neoplastic lung samples and other normal tissues, and other considerations involving known biology and targeting moieties. Protein expression was confirmed by immunohistochemistry (IHC) staining and scoring of patient tumor and normal tissue samples. As further validation, marker expression was determined in lung cancer cell lines using microarray data and Kaplan–Meier survival analyses were performed for each of the markers using patient clinical data. High expression for six of the markers (CA9, CA12, CXorf61, GPR87, LYPD3, and SLC7A11) was significantly associated with worse survival. These markers should be useful for the development of novel targeted imaging probes or therapeutics for use in personalized care of lung cancer patients. PMID:29371917

Effects of high-fat diet and losartan on renal cortical blood flow using contrast ultrasound imaging.

PubMed

Declèves, Anne-Emilie; Rychak, Joshua J; Smith, Dan J; Sharma, Kumar

2013-11-01

Obesity-related kidney disease occurs as a result of complex interactions between metabolic and hemodynamic effects. Changes in microvascular perfusion may play a major role in kidney disease; however, these changes are difficult to assess in vivo. Here, we used perfusion ultrasound imaging to evaluate cortical blood flow in a mouse model of high-fat diet-induced kidney disease. C57BL/6J mice were randomized to a standard diet (STD) or a high-fat diet (HFD) for 30 wk and then treated either with losartan or a placebo for an additional 6 wk. Noninvasive ultrasound perfusion imaging of the kidney was performed during infusion of a microbubble contrast agent. Blood flow within the microvasculature of the renal cortex and medulla was derived from imaging data. An increase in the time required to achieve full cortical perfusion was observed for HFD mice relative to STD. This was reversed following treatment with losartan. These data were concurrent with an increased glomerular filtration rate in HFD mice compared with STD- or HFD-losartan-treated mice. Losartan treatment also abrogated fibro-inflammatory disease, assessed by markers at the protein and messenger level. Finally, a reduction in capillary density was found in HFD mice, and this was reversed upon losartan treatment. This suggests that alterations in vascular density may be responsible for the elevated perfusion time observed by imaging. These data demonstrate that ultrasound contrast imaging is a robust and sensitive method for evaluating changes in renal microvascular perfusion and that cortical perfusion time may be a useful parameter for evaluating obesity-related renal disease.

Free radicals generated by electrolysis reduces nitro blue tetrazolium in isolated rat heart.

PubMed

Chahine, R; Huet, M P; Oliva, L; Nadeau, R

1997-02-01

Oxygen free radicals (OFR) are highly cytotoxic when produced in the myocardium under certain pathological conditions. In isolated rat hearts perfused retrogradely, OFR were generated by electrolysis of the Krebs-Henseleit buffer (two platinum electrodes, DC current, 10 mA, 1 min). In order to find evidence that OFR are produced, we used nitro blue tetrazolium (NBT) a soluble compound which yields a dark blue formazan pigment in the presence of reducing agents. Hearts were subdivided into: control, electrolysed, NBT (3.3 mg/ml) perfusion during electrolysis in the presence or absence of scavengers. The xanthine-xanthine oxidase (XXO) system known to produce superoxide radical was used as a reference. Specimens were fixed with formaldehyde and stained with eosine or Kernechtrot in preparation for light microscopical examination. Several areas of acute necrosis expressed by hyalinisation and loss of striation were observed in electrolysed hearts which present a pattern of wavy disrupted myofibers and an increase in interstitial spaces. A very faint deposition of formazan was observed in some rare areas of NBT perfused heart. Only the electrolysed group perfused with NBT and the one perfused with XXO plus NBT presented an extensive formazan deposition, mostly in the areas of fibre necrosis. Formazan was barely detectable when superoxide dismutase plus catalase were perfused in the XXO system, while it was still apparent when perfused in electrolysed hearts. These results support the hypothesis that electrolysis can be used to generate different species of OFR and to evaluate the protective action of scavenger and antioxidants against OFR-induced myocardial damage.

TH-CD-202-09: Free-Breathing Proton MRI Functional Lung Avoidance Maps to Guide Radiation Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Capaldi, D; Sheikh, K; Parraga, G

Purpose: Pulmonary functional MRI using inhaled gas contrast agents was previously investigated as a way to identify well-functioning lung in patients with NSCLC who are clinical candidates for radiotherapy. Hyperpolarized noble-gas ({sup 3}He and {sup 129}Xe) MRI has also been optimized to measure functional lung information, but for a number of reasons, the clinical translation of this approach to guide radiotherapy planning has been limited. As an alternative, free-breathing pulmonary 1H MRI using clinically available MRI systems and pulse sequences provides a non-contrast-enhanced method to generate both ventilation and perfusion maps. Free-breathing {sup 1}H MRI exploits non-rigid registration and Fouriermore » decomposition of MRI signal intensity differences (Bauman et al., MRM, 2009) that may be generated during normal tidal breathing. Here, our objective was to generate free-breathing {sup 1}H MRI ventilation and lung function avoidance maps in patients with NSCLC as a way to guide radiation therapy planning. Methods: Stage IIIA/IIIB NSCLC patients (n=8, 68±9yr) provided written informed consent to a randomized controlled clinical trial ( https://clinicaltrials.gov/ct2/show/NCT02002052 ) that aimed to compare outcomes related to image-guided versus conventional radiation therapy planning. Hyperpolarized {sup 3}He/{sup 129}Xe and dynamic free tidal-breathing {sup 1}H MRI were acquired as previously described (Capaldi et al., Acad Radiol, 2015). Non-rigid registration was performed using the modality-independent-neighbourhood-descriptor (MIND) deformable approach (Heinrich et al., Med Image Anal, 2012). Ventilation-defect-percent ({sup 3}He:VDP{sub He}, {sup 129}Xe:VDP{sub Xe}, Free-breathing-{sup 1}H:VDP{sub FB}) and the corresponding ventilation maps were compared using Pearson correlation coefficients (r) and the Dice similarity coefficient (DSC). Results: VDP{sub FB} was significantly related to VDP{sub He} (r=.71; p=.04) and VDP{sub Xe} (r=.80; p=.01) and there were also strong spatial relationships (DSC{sub He}/DSC{sub Xe}=89±3%/77±11%). Conclusion: In this proof of concept study in NSCLC patients, free-breathing {sup 1}H MRI ventilation defects were quantitatively and spatially related to inhaled-noble-gas MRI ventilation defects. Free-breathing {sup 1}H MRI measures lung function/ventilation that can be used to optimize radiotherapy planning in NSCLC patients.« less

Lipopolysaccharide-induced pulmonary endothelial barrier disruption and lung edema: critical role for bicarbonate stimulation of AC10.

PubMed

Nickols, Jordan; Obiako, Boniface; Ramila, K C; Putinta, Kevin; Schilling, Sarah; Sayner, Sarah L

2015-12-15

Bacteria-induced sepsis is a common cause of pulmonary endothelial barrier dysfunction and can progress toward acute respiratory distress syndrome. Elevations in intracellular cAMP tightly regulate pulmonary endothelial barrier integrity; however, cAMP signals are highly compartmentalized: whether cAMP is barrier-protective or -disruptive depends on the compartment (plasma membrane or cytosol, respectively) in which the signal is generated. The mammalian soluble adenylyl cyclase isoform 10 (AC10) is uniquely stimulated by bicarbonate and is expressed in pulmonary microvascular endothelial cells (PMVECs). Elevated extracellular bicarbonate increases cAMP in PMVECs to disrupt the endothelial barrier and increase the filtration coefficient (Kf) in the isolated lung. We tested the hypothesis that sepsis-induced endothelial barrier disruption and increased permeability are dependent on extracellular bicarbonate and activation of AC10. Our findings reveal that LPS-induced endothelial barrier disruption is dependent on extracellular bicarbonate: LPS-induced barrier failure and increased permeability are exacerbated in elevated bicarbonate compared with low extracellular bicarbonate. The AC10 inhibitor KH7 attenuated the bicarbonate-dependent LPS-induced barrier disruption. In the isolated lung, LPS failed to increase Kf in the presence of minimal perfusate bicarbonate. An increase in perfusate bicarbonate to the physiological range (24 mM) revealed the LPS-induced increase in Kf, which was attenuated by KH7. Furthermore, in PMVECs treated with LPS for 6 h, there was a dose-dependent increase in AC10 expression. Thus these findings reveal that LPS-induced pulmonary endothelial barrier failure requires bicarbonate activation of AC10. Copyright © 2015 the American Physiological Society.

Lipopolysaccharide-induced pulmonary endothelial barrier disruption and lung edema: critical role for bicarbonate stimulation of AC10

PubMed Central

Nickols, Jordan; Obiako, Boniface; Ramila, K. C.; Putinta, Kevin; Schilling, Sarah

2015-01-01

Bacteria-induced sepsis is a common cause of pulmonary endothelial barrier dysfunction and can progress toward acute respiratory distress syndrome. Elevations in intracellular cAMP tightly regulate pulmonary endothelial barrier integrity; however, cAMP signals are highly compartmentalized: whether cAMP is barrier-protective or -disruptive depends on the compartment (plasma membrane or cytosol, respectively) in which the signal is generated. The mammalian soluble adenylyl cyclase isoform 10 (AC10) is uniquely stimulated by bicarbonate and is expressed in pulmonary microvascular endothelial cells (PMVECs). Elevated extracellular bicarbonate increases cAMP in PMVECs to disrupt the endothelial barrier and increase the filtration coefficient (Kf) in the isolated lung. We tested the hypothesis that sepsis-induced endothelial barrier disruption and increased permeability are dependent on extracellular bicarbonate and activation of AC10. Our findings reveal that LPS-induced endothelial barrier disruption is dependent on extracellular bicarbonate: LPS-induced barrier failure and increased permeability are exacerbated in elevated bicarbonate compared with low extracellular bicarbonate. The AC10 inhibitor KH7 attenuated the bicarbonate-dependent LPS-induced barrier disruption. In the isolated lung, LPS failed to increase Kf in the presence of minimal perfusate bicarbonate. An increase in perfusate bicarbonate to the physiological range (24 mM) revealed the LPS-induced increase in Kf, which was attenuated by KH7. Furthermore, in PMVECs treated with LPS for 6 h, there was a dose-dependent increase in AC10 expression. Thus these findings reveal that LPS-induced pulmonary endothelial barrier failure requires bicarbonate activation of AC10. PMID:26475732

Detection of early changes in lung cell cytology by flow-systems analysis techniques, July 1--December 31, 1975

DOE Office of Scientific and Technical Information (OSTI.GOV)

Steinkamp, J.A.; Ingram, M.; Hansen, K.M.

1976-03-01

This report summarizes results of preliminary experiments to demonstrate the feasibility of using automated flow-systems analysis in detecting early changes of respiratory epithelium exposed to physical and chemical agents associated with the by-products of nonnuclear energy production. The Syrian hamster was selected as the experimental test animal to begin investigation of the effects of toxic agents to cells of the respiratory tract. Since initiation of the program approximately six months ago, the goals have been acquisition of adequate numbers of exfoliated cells from the lung; adaptation of cytological techniques developed on human exfoliated gynecological samples to hamster lung epithelium formore » obtaining single-cell suspensions; utilization of existing cell staining methods to measure DNA content in lung cells; and analysis of DNA content and cell size. As the flow-system cell analysis technology is adapted to the measurement of exfoliated lung cells, rapid and quantitative determination of early changes in the physical and biochemical cellular properties will be attempted as a function of exposure to the toxic agents. (auth)« less

Popcorn worker's lung: in vitro exposure to diacetyl, an ingredient in microwave popcorn butter flavoring, increases reactivity to methacholine.

PubMed

Fedan, J S; Dowdy, J A; Fedan, K B; Hubbs, A F

2006-08-15

Workers who inhale microwave popcorn butter flavorings experience decrements in lung function and can develop clinical bronchiolitis obliterans, i.e., "popcorn worker's lung" (Kreiss, K., Gomaa, A., Kullman, G., Fedan, K., Simoes, E.J., Enright, P.L., 2002. Clinical bronchiolitis obliterans in workers at a microwave-popcorn plant. N. Engl. J. Med. 347, 330-338.). In a rat inhalation model, vapors of an artificial butter flavoring damaged the epithelium of the upper and lower airways (Hubbs, A.F., Battelli, L.A., Goldsmith, W.T., Porter, D.W., Frazer, D., Friend, S., Schwegler-Berry, D., Mercer, R.R., Reynolds, J.S., Grote, A., Castranova, V., Kullman, G., Fedan, J.S., Dowdy, J., Jones, W.G., 2002. Necrosis of nasal and airway epithelium in rats inhaling vapors of artificial butter flavoring. Toxicol. Appl. Pharmacol. 185, 128-135.). Diacetyl, a butter flavoring component, is a major volatile ketone in the popcorn-processing workplace. We investigated the effects of diacetyl on epithelium of guinea pig isolated airway preparations and the effects of diacetyl in vitro on reactivity to bronchoactive agents. In the isolated, perfused trachea preparation, diacetyl added to the intraluminal (mucosal) bath elicited responses that began with contraction (threshold ca. 3 mM) and ended with relaxation. After a 4-h incubation with intraluminal diacetyl (3 mM), contractions to extraluminal (serosal) methacholine (MCh) were slightly increased; however, sensitivity to intraluminally (mucosally) applied MCh was increased by 10-fold. Relaxation responses of MCh (3 x 10(-7) M)-contracted tracheas to extraluminally applied terbutaline and intraluminally applied 120 mM KCl, to evoke epithelium-derived relaxing factor release, were unaffected by diacetyl. Exposure of the tracheal epithelium in Ussing chambers to diacetyl decreased transepithelial potential difference and resistance. These findings suggest that diacetyl exposure compromised epithelial barrier function, leading to hyperreactivity to mucosally applied MCh. The respiratory epithelium appears to serve as an initial target for the toxic effects of diacetyl in the airways.

Aerosolized PGE1, PGI2 and nitroprusside protect against vascular leakage in lung ischaemia-reperfusion.

PubMed

Schütte, H; Löckinger, A; Seeger, W; Grimminger, F

2001-07-01

High permeability oedema is an important feature in lung injury secondary to ischaemia-reperfusion. This study investigated the influence of aerosolized prostaglandin E1 (PGE1), prostaglandin I2 (PCI2) and the nitric oxide (NO)-donor, sodium nitroprusside (SNP) on microvascular barrier function in pulmonary ischaemia-reperfusion. Buffer-perfused rabbit lungs were exposed to 180 or 210 min of warm ischaemia while maintaining anoxic ventilation and a positive intravascular pressure. Reperfusion provoked a transient, mostly precapillary elevation of vascular resistance, followed by a severe increase of the capillary filtration coefficient (Kfc) versus nonischaemic controls (3.17+/-0.34 versus 0.85+/-0.05 cm3 x s(-1) cmH2O(-1) x g(-1) x 10(-4) after 30 min of reperfusion), and progressive oedema formation. Short-term aerosolization of SNP, PGE1 or PGI2 at the beginning of ischaemia largely suppressed the Kfc increase (1.36+/-0.22, 1.32+/-0.23 and 1.32+/-0.22 cm3 x s(-1) x cmH2O(-1) x g(-1) x 10(-4), respectively) and oedema formation. In contrast, application prior to reperfusion was much less effective, with some reduction of Kfc increase by PGI2 and SNP and no effect of PGE, (1.79+/-0.31, 2.2+/-0.53 and 3.2+/-0.05 cm3 x s(-1) x cmH2O(-1) x g(-1) x 10(-4), respectively). Haemodynamics, including microvascular pressure, were only marginally affected by the chosen doses of aerosolized vasodilators. It is concluded that short-term aerosolization of prostaglandin E1, prostaglandin I2 and sodium nitroprusside at the onset of ischaemia is highly effective in maintaining endothelial barrier properties in pulmonary ischaemia-reperfusion. This effect is apparently attributable to nonvasodilatory mechanisms exerted by these agents. Alveolar deposition of prostaglandins and/or nitric oxide donors by the aerosol technique may offer pulmonary protection in ischaemia-reperfusion injury.

Comparison of the Cardiac MicroPET Images Obtained Using [(18)F]FPTP and [(13)N]NH3 in Rat Myocardial Infarction Models.

PubMed

Kim, Dong-Yeon; Kim, Hyeon Sik; Jang, Hwa Youn; Kim, Ju Han; Bom, Hee-Seung; Min, Jung-Joon

2014-10-09

The short half-life of current positron emission tomography (PET) cardiac tracers limits their widespread clinical use. We previously developed a (18)F-labeled phosphonium cation, [(18)F]FPTP, that demonstrated sharply defined myocardial defects in a corresponding infarcted myocardium. The aim of this study was to compare the image properties of PET scans obtained using [(18)F]FPTP with those obtained using [(13)N]NH3 in rat myocardial infarction models. Perfusion abnormality was analyzed in 17 segments of polar map images. The myocardium-to-liver and myocardium-to-lung ratios of [(18)F]FPTP were 10.48 and 2.65 times higher, respectively, than those of [(13)N]NH3 in images acquired 30 min after tracer injection. The myocardial defect size measured by [(18)F]FPTP correlated more closely with the hypoperfused area measured by quantitative 2,3,5-triphenyltetrazolium chloride staining (r = 0.89, P < 0.01) than did [(13)N]NH3 (r = 0.84, P < 0.01). [(18)F]FPTP might be useful as a replacement for the myocardial agent [(13)N]NH3 in cardiac PET/CT applications.

Efficacy and safety of different doses of tirofiban combined with ticagrelor on diabetic patients with AMI receiving in emergency percutaneous coronary intervention (PCI)

PubMed Central

Liu, Yang; Liu, Hengliang; Hao, Zhenxuan; Geng, Guoying; Chen, Qi; Han, Wenjie; Jia, Kailong; Zhou, Yuxin

2015-01-01

Objective: The aim of this study was to investigate the efficacy and safety of dual antiplatelet drugs combined with different doses of tirofiban on diabetic patients with acute myocardial infarction (AMI) receiving emergency percutaneous coronary intervention (PCI). Methods: 158 diabetic patients with AMI undergone emergency PCI were randomly divided into three groups: Group A (53 cases) as the control group-dual anti-platelet agents (aspirin + ticagrelor); Group B (52 cases)-dual anti-platelet agents + conventional dose of tirofiban [10 μg/kg by PCI and 0.15 μg/(kg·min) by continue venous pump for 24 h]; Group C (53 cases)-dual antiplatelet agents + half-dose tirofiban [10 μg/kg by PCI and 0.075 μg/(kg·min) by continue venous pump for 24 h]. Results: Compared with group A, thrombolysis in myocardial infarction 3 (TIMI3) blood flow and TIMI myocardial perfusion grade 3 (TMPG3) myocardial perfusion of patients in group B and group C after PCI was significantly higher (P < 0.05), the average day of hospitalization was significantly shorter (P < 0.05), reinfarction during hospitalization, post-infarction angina, severe arrhythmia, the incidence of cardiac function above KillipIII level was significantly lower (P < 0.05). And the differences between group B and C was not statistically significant (P > 0.05). Severe bleeding and moderate incidence of bleeding in group B was significantly higher than that in group A and group C (P < 0.05). Conclusions: Based on combination of dual the anti-platelet agents and ticagrelor for diabetic patients with AMI receiving PCI, the combination of half-dose tirofiban can effectively improve TIMI flow and TMPG myocardial tissue perfusion, and reduce the incidence of major adverse cardiac events (MACE) and severe bleeding. PMID:26379951

SU-F-R-51: Radiomics in CT Perfusion Maps of Head and Neck Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nesteruk, M; Riesterer, O; Veit-Haibach, P

2016-06-15

Purpose: The aim of this study was to test the predictive value of radiomics features of CT perfusion (CTP) for tumor control, based on a preselection of radiomics features in a robustness study. Methods: 11 patients with head and neck cancer (HNC) and 11 patients with lung cancer were included in the robustness study to preselect stable radiomics parameters. Data from 36 HNC patients treated with definitive radiochemotherapy (median follow-up 30 months) was used to build a predictive model based on these parameters. All patients underwent pre-treatment CTP. 315 texture parameters were computed for three perfusion maps: blood volume, bloodmore » flow and mean transit time. The variability of texture parameters was tested with respect to non-standardizable perfusion computation factors (noise level and artery contouring) using intraclass correlation coefficients (ICC). The parameter with the highest ICC in the correlated group of parameters (inter-parameter Spearman correlations) was tested for its predictive value. The final model to predict tumor control was built using multivariate Cox regression analysis with backward selection of the variables. For comparison, a predictive model based on tumor volume was created. Results: Ten parameters were found to be stable in both HNC and lung cancer regarding potentially non-standardizable factors after the correction for inter-parameter correlations. In the multivariate backward selection of the variables, blood flow entropy showed a highly significant impact on tumor control (p=0.03) with concordance index (CI) of 0.76. Blood flow entropy was significantly lower in the patient group with controlled tumors at 18 months (p<0.1). The new model showed a higher concordance index compared to the tumor volume model (CI=0.68). Conclusion: The preselection of variables in the robustness study allowed building a predictive radiomics-based model of tumor control in HNC despite a small patient cohort. This model was found to be superior to the volume-based model. The project was supported by the KFSP Tumor Oxygenation of the University of Zurich, by a grant of the Center for Clinical Research, University and University Hospital Zurich and by a research grant from Merck (Schweiz) AG.« less

[Anomalous systemic arterial supply to normal basal segments of the left lung (Pryce type I)].

PubMed

Ryu, Chusei; Sawada, Takahiro; Machino, Ryusuke

2013-03-01

Patient 1 was a 54-year-old female diagnosed with anomalous systemic arterial supply to normal basal segments of the left lung discovered as an abnormality on chest X-ray radiography. Patient 2 was a 47-year-old male in whom the disease was diagnosed by close examination of bloody sputum. Division of the abnormal artery and left lower lobectomy were performed in patient 1. Arterial congestion and serpentine distribution were noted in the basal segments of the lung, which was the region perfused by the abnormal artery, on histopathological examination. Arteriosclerotic changes were noted in the vascular wall, but no abnormal vascular wall or alveolar structure was noted in S6, which was not included in theperfused region. Based on the above findings, division of the abnormal artery and left basal segmentectomy were performed in patient 2. Bloody sputum disappeared, and activity of daily living( ADL) were not impaired after surgery.

Electrical impedance tomography

PubMed Central

Lobo, Beatriz; Hermosa, Cecilia; Abella, Ana

2018-01-01

Continuous assessment of respiratory status is one of the cornerstones of modern intensive care unit (ICU) monitoring systems. Electrical impedance tomography (EIT), although with some constraints, may play the lead as a new diagnostic and guiding tool for an adequate optimization of mechanical ventilation in critically ill patients. EIT may assist in defining mechanical ventilation settings, assess distribution of tidal volume and of end-expiratory lung volume (EELV) and contribute to titrate positive end-expiratory pressure (PEEP)/tidal volume combinations. It may also quantify gains (recruitment) and losses (overdistention or derecruitment), granting a more realistic evaluation of different ventilator modes or recruitment maneuvers, and helping in the identification of responders and non-responders to such maneuvers. Moreover, EIT also contributes to the management of life-threatening lung diseases such as pneumothorax, and aids in guiding fluid management in the critical care setting. Lastly, assessment of cardiac function and lung perfusion through electrical impedance is on the way. PMID:29430443

Growing experience with extracorporeal membrane oxygenation as a bridge to lung transplantation.

PubMed

Shafii, Alexis E; Mason, David P; Brown, Chase R; Vakil, Nakul; Johnston, Douglas R; McCurry, Kenneth R; Pettersson, Gosta B; Murthy, Sudish C

2012-01-01

Extracorporeal membrane oxygenation (ECMO) is rarely used as a bridge to lung transplantation (BTT) because of its associated morbidity and mortality. However, recent advancements in perfusion technology and critical care have revived interest in this application of ECMO. We retrospectively reviewed our utilization of ECMO as BTT and evaluated our early and midterm results. Nineteen patients were placed on ECMO with the intent to transplant of which 14 (74%) were successfully transplanted. Early and midterm survival of transplanted patients was 75% (1 year) and 63% (3 years), respectively, with the most favorable results observed in interstitial lung disease patients supported in the venovenous configuration. Extracorporeal membrane oxygenation-bridged transplant survival rates were equivalent to nonbridged recipients, but early morbidity and mortality are high and the failure to bridge to transplant is significant. Overall, successfully bridged patients can derive a tangible benefit, albeit with considerable consumption of resources.

Hyperenteroglucagonaemia and small intestinal mucosal growth after colonic perfusion of glucose in rats.

PubMed Central

Miazza, B M; Al-Mukhtar, M Y; Salmeron, M; Ghatei, M A; Felce-Dachez, M; Filali, A; Villet, R; Wright, N A; Bloom, S R; Crambaud, J C

1985-01-01

Beside intraluminal factors, humoral agents play an important role in intestinal adaptation. Enteroglucagon, the mucosal concentration of which is maximal in the terminal ileum and colon, is the strongest candidate for the role of small intestinal mucosal growth factor. The present experiment was designed to study the role of colonic enteroglucagon in stimulating mucosal growth in rats with a normal small intestine. After eight days of glucose large bowel perfusion, enteroglucagon plasma concentrations were 120.7 +/- SEM 9.2 pmol/l, versus 60.1 +/- 6.8 in mannitol perfused control rats (p less than 0.001). Gastrin, cholecystokinin, neurotensin, pancreatic glucagon, and insulin plasma concentrations were unchanged. Crypt cell proliferation, measured by the vincristine metaphase arrest technique, increased significantly in the small intestine of glucose perfused animals (p less than 0.005-0.001) in comparison with the controls. This resulted in a greater mucosal mass in both proximal and distal small bowel: mucosal wet weight, DNA, protein and alpha D-glucosidase per unit length intestine were all significantly higher (p less than 0.05-0.001) than in mannitol perfused rats. Our data, therefore, support the hypothesis that enteroglucagon is an enterotrophic factor and stress the possible role of the colon in the regulation of small bowel trophicity. PMID:3996942

Exploring Thermoresponsive Affinity Agents to Enhance Microdialysis Sampling Efficiency of Proteins

NASA Astrophysics Data System (ADS)

Vasicek, Thaddeus

Affinity agents increase microdialysis protein relative recovery, yet they have not seen widespread use within the microdialysis community due to their additional instrumentation requirements and prohibitive cost. This dissertation describes new affinity agents for microdialysis that require no additional instrumentation to use, have nearly 100% particle recovery, are 7 times more cost efficient than alternatives, and have low specificity enabling their use for a wide variety of proteins. Initially gold nanoparticles were chosen as an affinity ligand support due to their high surface area/volume ratio and colloidal stability. Poly (N-isopropylacrylamide) was immobilized to the gold nanoparticles, which served to sterically stabilize the particles and to act as a generic, reversible protein capture agent. A method was developed to reproducibly vary and quantify poly (N-isopropylacrylamide) graft density from 0.09 to 0.40 ligands/nm2 on gold nanoparticles. During characterization of the polymer coated gold nanoparticles, irreversible particle agglomeration was observed at low polymer graft density in ionic solutions, which prevented further development as a protein capture agent. Poly (N-isopropylacrylamide) nanogels, which have low nonspecific adsorption, low interparticle attractive forces owing to the low curvature of the particle, and a low Hamaker constant, were synthesized to overcome the agglomeration problem. A generic protein affinity ligand cibacron blue, was immobilized to the nanogels, which enabled rapid determination of particle recovery. The perfusion of the nanogels through a microdialysis probe was optimized yielding 100% particle recovery using a combination of a syringe and peristaltic pump. The microdialysis collection efficiency of CCL2, a physiologically relevant cytokine, was increased 3-fold with addition of the nanogel to the microdialysis perfusion fluid. The reduction in instrumentation requirements, low cost, and low specificity obtained with the new affinity agents will lead to increased affinity agent use for microdiaylsis protein sampling.

Targeting the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway: an emerging treatment strategy for squamous cell lung carcinoma.

PubMed

Beck, Joseph Thaddeus; Ismail, Amen; Tolomeo, Christina

2014-09-01

Squamous cell lung carcinoma accounts for approximately 30% of all non-small cell lung cancers (NSCLCs). Despite progress in the understanding of the biology of cancer, cytotoxic chemotherapy remains the standard of care for patients with squamous cell lung carcinoma, but the prognosis is generally poor. The phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway is one of the most commonly activated signaling pathways in cancer, leading to cell proliferation, survival, and differentiation. It has therefore become a major focus of clinical research. Various alterations in the PI3K/AKT/mTOR pathway have been identified in squamous cell lung carcinoma and a number of agents targeting these alterations are in clinical development for use as single agents and in combination with other targeted and conventional treatments. These include pan-PI3K inhibitors, isoform-specific PI3K inhibitors, AKT inhibitors, mTOR inhibitors, and dual PI3K/mTOR inhibitors. These agents have demonstrated antitumor activity in preclinical models of NSCLC and preliminary clinical evidence is also available for some agents. This review will discuss the role of the PI3K/AKT/mTOR pathway in cancer and how the discovery of genetic alterations in this pathway in patients with squamous cell lung carcinoma can inform the development of targeted therapies for this disease. An overview of ongoing clinical trials investigating PI3K/AKT/mTOR pathway inhibitors in squamous cell lung carcinoma will also be included. Copyright © 2014 Elsevier Ltd. All rights reserved.

Pulmonary Thromboembolism: Evaluation By Intravenous Angiography

NASA Astrophysics Data System (ADS)

Pond, Gerald D.; Cook, Glenn C.; Woolfenden, James M.; Dodge, Russell R.

1981-11-01

Using perfusion lung scans as a guide, digital video subtraction angiography of the pulmonary arteries was performed in human subjects suspected of having pulmonary embolism. Dogs were employed as a pulmonary embolism model and both routine pulmonary angiography and intravenous pulmonary angiograms were obtained for comparison purposes. We have shown by our preliminary results that the technique is extremely promising as a safe and accurate alternative to routine pulmonary angiography in selected patients.

Development of a microinstillation model of inhalation exposure to assess lung injury following exposure to toxic chemicals and nerve agents in Guinea pigs.

PubMed

Nambiar, Madhusoodana P; Wright, Benjamin S; Rezk, Peter E; Smith, Kelvin B; Gordon, Richard K; Moran, Theodore S; Richards, Shannon M; Sciuto, Alfred M

2006-01-01

Respiratory disturbances due to chemical warfare nerve agents (CWNAs) are the starting point of mass casualty and the primary cause of death by these weapons of terror and mass destruction. However, very few studies have been implemented to assess respiratory toxicity and exacerbation induced by CWNAs, especially methylphosphonothioic acid S-(2-(bis(1-methylethyl)amino)ethyl)O-ethyl ester (VX). In this study, we developed a microinstillation technique of inhalation exposure to assess lung injury following exposure to CWNAs and toxic chemicals. Guinea pigs were gently intubated by placing a microcatheter into the trachea 1.5 to 2.0 cm centrally above the bifurcation. This location is crucial to deliver aerosolized agents uniformly to the lung's lobes. The placement of the tube is calculated by measuring the distance from the upper front teeth to the tracheal bifurcation, which is typically 8.5 cm for guinea pigs of equivalent size and a weight range of 250 g to 300 g. The catheter is capable of withstanding 100 psi pressure; the terminus has five peripheral holes to pump air that aerosolizes the nerve agent that is delivered in the central hole. The microcatheter is regulated by a central control system to deliver the aerosolized agent in a volume lower than the tidal volume of the guinea pigs. The average particle size of the nerve agent delivered was 1.48 +/- 0.07 micrometer. The microinstillation technology has been validated by exposing the animals to Coomassie brilliant blue, which showed a uniform distribution of the dye in different lung lobes. In addition, the concentration of the dye in the lungs correlated with the dose/time of exposure. Furthermore, histopathological analysis confirmed the absence of barotraumas following micoinstillation. This novel technique delivers the agent safely, requires less amount of agent, avoids exposure to skin, pelt, and eye, and circumvents the concern of deposition of the particles in the nasal and palette due to the switching of breathing from nasal to oronasal in whole-body dynamic chamber or nose only exposure. Currently, we are using this inhalation exposure technique to investigate lung injuries and respiratory disturbances following direct exposure to VX.

Using synchrotron radiation angiography with a highly sensitive detector to identify impaired peripheral perfusion in rat pulmonary emphysema

PubMed Central

Ito, Hiromichi; Matsushita, Shonosuke; Hyodo, Kazuyuki; Sato, Yukio; Sakakibara, Yuzuru

2013-01-01

Owing to limitations in spatial resolution and sensitivity, it is difficult for conventional angiography to detect minute changes of perfusion in diffuse lung diseases, including pulmonary emphysema (PE). However, a high-gain avalanche rushing amorphous photoconductor (HARP) detector can give high sensitivity to synchrotron radiation (SR) angiography. SR angiography with a HARP detector provides high spatial resolution and sensitivity in addition to time resolution owing to its angiographic nature. The purpose of this study was to investigate whether this SR angiography with a HARP detector could evaluate altered microcirculation in PE. Two groups of rats were used: group PE and group C (control). Transvenous SR angiography with a HARP detector was performed and histopathological findings were compared. Peak density of contrast material in peripheral lung was lower in group PE than group C (p < 0.01). The slope of the linear regression line in scattering diagrams was also lower in group PE than C (p < 0.05). The correlation between the slope and extent of PE in histopathology showed significant negative correlation (p < 0.05, r = 0.61). SR angiography with a HARP detector made it possible to identify impaired microcirculation in PE by means of its high spatial resolution and sensitivity. PMID:23412496

Impact of residual pulmonary obstruction on the long-term outcome of patients with pulmonary embolism.

PubMed

Pesavento, Raffaele; Filippi, Lucia; Palla, Antonio; Visonà, Adriana; Bova, Carlo; Marzolo, Marco; Porro, Fernando; Villalta, Sabina; Ciammaichella, Maurizio; Bucherini, Eugenio; Nante, Giovanni; Battistelli, Sandra; Muiesan, Maria Lorenza; Beltramello, Giampietro; Prisco, Domenico; Casazza, Franco; Ageno, Walter; Palareti, Gualtiero; Quintavalla, Roberto; Monti, Simonetta; Mumoli, Nicola; Zanatta, Nello; Cappelli, Roberto; Cattaneo, Marco; Moretti, Valentino; Corà, Francesco; Bazzan, Mario; Ghirarduzzi, Angelo; Frigo, Anna Chiara; Miniati, Massimo; Prandoni, Paolo

2017-05-01

The impact of residual pulmonary obstruction on the outcome of patients with pulmonary embolism is uncertain.We recruited 647 consecutive symptomatic patients with a first episode of pulmonary embolism, with or without concomitant deep venous thrombosis. They received conventional anticoagulation, were assessed for residual pulmonary obstruction through perfusion lung scanning after 6 months and then were followed up for up to 3 years. Recurrent venous thromboembolism and chronic thromboembolic pulmonary hypertension were assessed according to widely accepted criteria.Residual pulmonary obstruction was detected in 324 patients (50.1%, 95% CI 46.2-54.0%). Patients with residual pulmonary obstruction were more likely to be older and to have an unprovoked episode. After a 3-year follow-up, recurrent venous thromboembolism and/or chronic thromboembolic pulmonary hypertension developed in 34 out of the 324 patients (10.5%) with residual pulmonary obstruction and in 15 out of the 323 patients (4.6%) without residual pulmonary obstruction, leading to an adjusted hazard ratio of 2.26 (95% CI 1.23-4.16).Residual pulmonary obstruction, as detected with perfusion lung scanning at 6 months after a first episode of pulmonary embolism, is an independent predictor of recurrent venous thromboembolism and/or chronic thromboembolic pulmonary hypertension. Copyright ©ERS 2017.

Summary statement novel agents in the treatment of lung cancer: Fifth Cambridge Conference assessing opportunities for combination therapy.

PubMed

Lynch, Thomas J; Blumenschein, George R; Engelman, Jeffrey A; Espinoza-Delgado, Igor; Govindan, Ramaswamy; Hanke, Jeff; Hanna, Nasser H; Heymach, John V; Hirsch, Fred R; Janne, Pasi A; Lilenbaum, Rogerio C; Natale, Ronald B; Riely, Gregory J; Sequist, Lecia V; Shapiro, Geoffrey I; Shaw, Alice; Shepherd, Frances A; Socinski, Mark; Sorensen, A Gregory; Wakelee, Heather A; Weitzman, Aaron

2008-06-01

The promise of effective targeted therapy for lung cancer requires rigorous identification of potential targets combined with intensive discovery and development efforts aimed at developing effective "drugs" for these targets. We now recognize that getting the right drug to the right target in the right patient is more complicated than one could have imagined a decade ago. As knowledge of targets and development of agents have proliferated and advanced, so too have data demonstrating the biologic heterogeneity of tumors. The finding that lung cancers are genetically diverse and can exhibit several pathways of resistance in response to targeted agents makes the prospect for curative therapy more daunting. It is becoming increasingly clear that single-agent treatment will be the exception rather than the rule. This information raises important new questions about the development and assessment of novel agents in lung cancer treatment: (1) How do we identify the most important drug targets for tumor initiation and maintenance? (2) What is the best way to assess drug candidates that may only be relevant in a small fraction of patients? (3) What models do we use to predict clinical response and identify effective combinations? And (4) how do we bring combination regimens to the clinic, particularly when the agents are not yet approved individually and may be under development from different companies? The Fifth Cambridge Conference on Novel Agents in the Treatment of Lung Cancer was held in Cambridge, Massachusetts, on October 1-2, 2007, to discuss these questions by reviewing recent progress in the field and advancing recommendations for research and patient care. New information, conclusions, and recommendations considered significant for the field by the program faculty are summarized here and presented at greater length in the individual articles and accompanying discussions that comprise the full conference proceedings. A CME activity based on this summary is also available at www.informedicalcme.com/cme.

A novel gallium bisaminothiolate complex as a myocardial perfusion imaging agent

PubMed Central

Plössl, Karl; Chandra, Rajesh; Qu, Wenchao; Lieberman, Brian P.; Kung, Mei-Ping; Zhou, Rong; Huang, Bin; Kung, Hank F.

2010-01-01

The development of new myocardial perfusion imaging agents for positron emission tomography (PET) may improve the resolution and quantitation of changes in regional myocardial perfusion measurement. It is known that a 68Ge/68Ga generator can provide a convenient source of PET tracers because of the long physical half-life of 68Ge (271 days). A new ligand, 7,8-dithia-16,24-diaza-trispiro[5.2.5.2.5.3] pentacosa-15,24-diene, which consists of a N2S2-chelating core incorporated into three cyclohexyl rings, was prepared. To test feasibility and potential utility, the N2S2 ligand was successfully labeled and tested with 67Ga (half-life=3.26 day; γ=93.3, 184.6 and 300.2 keV), which showed >92% radiochemical purity. The corresponding “cold” Ga complex was synthesized, and its structure containing a pyramidal N2S2 chloride core was elucidated with X-ray crystallography. In vivo biodistribution of this novel 67Ga complex, evaluated in normal rats, exhibited excellent heart uptake and retention, with 2.1% and 0.9% initial dose/organ at 2 and 60 min, respectively, after an intravenous injection. Autoradiography was performed in normal rats and in rats that had the left anterior descending coronary artery permanently ligated surgically. Autoradiography showed an even uptake of activity in the normal heart, and there was a distinctively lower uptake in the damaged side of the surgically modified heart. In conclusion, the new N2S2 ligand was readily prepared and labeled with radioactive 67Ga. Biodistribution in rats revealed high initial heart uptake and relatively high retention reflecting regional myocardial perfusion. PMID:18158947

Analysis of point-to-point lung motion with full inspiration and expiration CT data using non-linear optimization method: optimal geometric assumption model for the effective registration algorithm

NASA Astrophysics Data System (ADS)

Kim, Namkug; Seo, Joon Beom; Heo, Jeong Nam; Kang, Suk-Ho

2007-03-01

The study was conducted to develop a simple model for more robust lung registration of volumetric CT data, which is essential for various clinical lung analysis applications, including the lung nodule matching in follow up CT studies, semi-quantitative assessment of lung perfusion, and etc. The purpose of this study is to find the most effective reference point and geometric model based on the lung motion analysis from the CT data sets obtained in full inspiration (In.) and expiration (Ex.). Ten pairs of CT data sets in normal subjects obtained in full In. and Ex. were used in this study. Two radiologists were requested to draw 20 points representing the subpleural point of the central axis in each segment. The apex, hilar point, and center of inertia (COI) of each unilateral lung were proposed as the reference point. To evaluate optimal expansion point, non-linear optimization without constraints was employed. The objective function is sum of distances from the line, consist of the corresponding points between In. and Ex. to the optimal point x. By using the nonlinear optimization, the optimal points was evaluated and compared between reference points. The average distance between the optimal point and each line segment revealed that the balloon model was more suitable to explain the lung expansion model. This lung motion analysis based on vector analysis and non-linear optimization shows that balloon model centered on the center of inertia of lung is most effective geometric model to explain lung expansion by breathing.

Estimation of Lung Ventilation

NASA Astrophysics Data System (ADS)

Ding, Kai; Cao, Kunlin; Du, Kaifang; Amelon, Ryan; Christensen, Gary E.; Raghavan, Madhavan; Reinhardt, Joseph M.

Since the primary function of the lung is gas exchange, ventilation can be interpreted as an index of lung function in addition to perfusion. Injury and disease processes can alter lung function on a global and/or a local level. MDCT can be used to acquire multiple static breath-hold CT images of the lung taken at different lung volumes, or with proper respiratory control, 4DCT images of the lung reconstructed at different respiratory phases. Image registration can be applied to this data to estimate a deformation field that transforms the lung from one volume configuration to the other. This deformation field can be analyzed to estimate local lung tissue expansion, calculate voxel-by-voxel intensity change, and make biomechanical measurements. The physiologic significance of the registration-based measures of respiratory function can be established by comparing to more conventional measurements, such as nuclear medicine or contrast wash-in/wash-out studies with CT or MR. An important emerging application of these methods is the detection of pulmonary function change in subjects undergoing radiation therapy (RT) for lung cancer. During RT, treatment is commonly limited to sub-therapeutic doses due to unintended toxicity to normal lung tissue. Measurement of pulmonary function may be useful as a planning tool during RT planning, may be useful for tracking the progression of toxicity to nearby normal tissue during RT, and can be used to evaluate the effectiveness of a treatment post-therapy. This chapter reviews the basic measures to estimate regional ventilation from image registration of CT images, the comparison of them to the existing golden standard and the application in radiation therapy.

Magnetic Particle Imaging for Real-Time Perfusion Imaging in Acute Stroke.

PubMed

Ludewig, Peter; Gdaniec, Nadine; Sedlacik, Jan; Forkert, Nils D; Szwargulski, Patryk; Graeser, Matthias; Adam, Gerhard; Kaul, Michael G; Krishnan, Kannan M; Ferguson, R Matthew; Khandhar, Amit P; Walczak, Piotr; Fiehler, Jens; Thomalla, Götz; Gerloff, Christian; Knopp, Tobias; Magnus, Tim

2017-10-24

The fast and accurate assessment of cerebral perfusion is fundamental for the diagnosis and successful treatment of stroke patients. Magnetic particle imaging (MPI) is a new radiation-free tomographic imaging method with a superior temporal resolution, compared to other conventional imaging methods. In addition, MPI scanners can be built as prehospital mobile devices, which require less complex infrastructure than computed tomography (CT) and magnetic resonance imaging (MRI). With these advantages, MPI could accelerate the stroke diagnosis and treatment, thereby improving outcomes. Our objective was to investigate the capabilities of MPI to detect perfusion deficits in a murine model of ischemic stroke. Cerebral ischemia was induced by inserting of a microfilament in the internal carotid artery in C57BL/6 mice, thereby blocking the blood flow into the medial cerebral artery. After the injection of a contrast agent (superparamagnetic iron oxide nanoparticles) specifically tailored for MPI, cerebral perfusion and vascular anatomy were assessed by the MPI scanner within seconds. To validate and compare our MPI data, we performed perfusion imaging with a small animal MRI scanner. MPI detected the perfusion deficits in the ischemic brain, which were comparable to those with MRI but in real-time. For the first time, we showed that MPI could be used as a diagnostic tool for relevant diseases in vivo, such as an ischemic stroke. Due to its shorter image acquisition times and increased temporal resolution compared to that of MRI or CT, we expect that MPI offers the potential to improve stroke imaging and treatment.

Brain Delivery of Drug and MRI Contrast Agent: Detection and Quantitative Determination of Brain Deposition of CPT-Glu Using LC-MS/MS and Gd-DTPA Using Magnetic Resonance Imaging.

PubMed

Tabanor, Kayann; Lee, Phil; Kiptoo, Paul; Choi, In-Young; Sherry, Erica B; Eagle, Cheyenne Sun; Williams, Todd D; Siahaan, Teruna J

2016-02-01

Successful treatment and diagnosis of neurological diseases depend on reliable delivery of molecules across the blood-brain barrier (BBB), which restricts penetration of pharmaceutical drugs and diagnostic agents into the brain. Thus, developing new noninvasive strategies to improve drug delivery across the BBB is critically needed. This study was aimed at evaluating the activity of HAV6 peptide (Ac-SHAVSS-NH2) in improving brain delivery of camptothecin-glutamate (CPT-Glu) conjugate and gadolinium-diethylenetriaminepentaacetate (Gd-DTPA) contrast agent in Sprague-Dawley rats. Brain delivery of both CPT-Glu and Gd-DTPA was evaluated in an in situ rat brain perfusion model in the presence and absence of HAV6 peptide (1.0 mM). Gd-DTPA (0.6 mmol/kg) was intravenously (iv) administered with and without HAV6 peptide (0.019 mmol/kg) in rats. The detection and quantification of CPT-Glu and Gd-DTPA in the brain were carried out by LC-MS/MS and quantitative magnetic resonance imaging (MRI), respectively. Rats perfused with CPT-Glu in combination with HAV6 had significantly higher deposition of drug in the brain compared to CPT-Glu alone. MRI results also showed that administration of Gd-DTPA in the presence of HAV6 peptide led to significant accumulation of Gd-DTPA in various regions of the brain in both the in situ rat brain perfusion and in vivo studies. All observations taken together indicate that HAV6 peptide can disrupt the BBB and enhance delivery of small molecules into the brain.

Brain Delivery of Drug and MRI Contrast Agent: Detection and Quantitative Determination of Brain Deposition of CPT-Glu Using LC-MS/MS and Gd-DTPA Using Magnetic Resonance Imaging

PubMed Central

Tabanor, Kayann; Lee, Phil; Kiptoo, Paul; Choi, In-Young; Sherry, Erica B.; Eagle, Cheyenne Sun; Williams, Todd D.; Siahaan, Teruna J.

2015-01-01

Successful treatment and diagnosis of neurological diseases depend on reliable delivery of molecules across the blood-brain barrier (BBB), which restricts penetration of pharmaceutical drugs and diagnostic agents into the brain. Thus, developing new non-invasive strategies to improve drug delivery across the BBB is critically needed. This study was aimed at evaluating the activity of HAV6 peptide (Ac-SHAVSS-NH2) in improving brain delivery of camptothecin-glutamate (CPT-Glu) conjugate and gadolinium-diethylenetriaminepentaacetate (Gd-DTPA) contrast agent in Sprague-Dawley rats. Brain delivery of both CPT-Glu and Gd-DTPA was evaluated in an in situ rat brain perfusion model in the presence and absence of HAV6 peptide (1.0 mM). Gd-DTPA (0.6 mmol/kg) was intravenously (i.v.) administered with and without HAV6 peptide (0.019 mmol/kg) in rats. The detection and quantification of CPT-Glu and Gd-DTPA in the brain were carried out by LC-MS/MS and quantitative magnetic resonance imaging (MRI), respectively. Rats perfused with CPT-Glu in combination with HAV6 had significantly higher deposition of drug in the brain compared to CPT-Glu alone. MRI results also showed that administration of Gd-DTPA in the presence of HAV6 peptide led to significant accumulation of Gd-DTPA in various regions of the brain in both the in situ rat brain perfusion and in vivo studies. All observations taken together indicate that HAV6 peptide can disrupt the BBB and enhance delivery of small molecules into the brain. PMID:26705088

Technical Considerations in Percutaneous Hepatic Perfusion—A Multi-Center Experience

PubMed Central

Antoine, Radcliffe A.

2011-01-01

Abstract: Patients diagnosed with primary or metastatic liver cancer face a daunting future that is complicated by limited treatment options. Percutaneous hepatic perfusion is a novel approach to chemotherapy delivery that offers significant benefits over contemporary modalities. Percutaneous hepatic perfusion is a procedure in which a chemotherapeutic agent is administered at high doses via the hepatic artery where it perfuses the liver, is extracted and filtered using a veno-veno bypass circuit, a fenestrated multi-lumen double-balloon catheter, and two biocompatible hemoperfusion filters. Venous access is gained at the groin through the femoral vein after which the catheter is advanced and positioned in the inferior vena cava just below the right atrium. The catheter’s proximal and distal balloons are inflated to occlude the inferior vena cava above and below the hepatic veins. The occlusion isolated the chemo-rich venous outflow of the liver from the systemic venous circulation. This maneuver also diverts venous blood returning to the heart from lower extremities of the azygos vein. Once the patient is on bypass, the agent is infused through the hepatic artery where it saturates the liver. The chemorich venous outflow is extracted through the double-balloon catheter by the bypass circuit. The blood is continuously filtered and cleared of the agent as it passes through the filters and returned to the patient through a catheter placed in the right internal jugular vein. A phase I study demonstrated efficacy with an overall radiographic response rate of 30% observed in treated patients. In 10 patients with ocular melanoma, a 50% overall response rate was observed, including two complete responses. The technique is minimally invasive and can be performed safely by a well-trained multi-disciplinary team. It offers significant benefits including multiple procedures without risks commonly associated with open abdominal surgery. PMID:21449232

Myocardial perfusion cardiovascular magnetic resonance: optimized dual sequence and reconstruction for quantification.

PubMed

Kellman, Peter; Hansen, Michael S; Nielles-Vallespin, Sonia; Nickander, Jannike; Themudo, Raquel; Ugander, Martin; Xue, Hui

2017-04-07

Quantification of myocardial blood flow requires knowledge of the amount of contrast agent in the myocardial tissue and the arterial input function (AIF) driving the delivery of this contrast agent. Accurate quantification is challenged by the lack of linearity between the measured signal and contrast agent concentration. This work characterizes sources of non-linearity and presents a systematic approach to accurate measurements of contrast agent concentration in both blood and myocardium. A dual sequence approach with separate pulse sequences for AIF and myocardial tissue allowed separate optimization of parameters for blood and myocardium. A systems approach to the overall design was taken to achieve linearity between signal and contrast agent concentration. Conversion of signal intensity values to contrast agent concentration was achieved through a combination of surface coil sensitivity correction, Bloch simulation based look-up table correction, and in the case of the AIF measurement, correction of T2* losses. Validation of signal correction was performed in phantoms, and values for peak AIF concentration and myocardial flow are provided for 29 normal subjects for rest and adenosine stress. For phantoms, the measured fits were within 5% for both AIF and myocardium. In healthy volunteers the peak [Gd] was 3.5 ± 1.2 for stress and 4.4 ± 1.2 mmol/L for rest. The T2* in the left ventricle blood pool at peak AIF was approximately 10 ms. The peak-to-valley ratio was 5.6 for the raw signal intensities without correction, and was 8.3 for the look-up-table (LUT) corrected AIF which represents approximately 48% correction. Without T2* correction the myocardial blood flow estimates are overestimated by approximately 10%. The signal-to-noise ratio of the myocardial signal at peak enhancement (1.5 T) was 17.7 ± 6.6 at stress and the peak [Gd] was 0.49 ± 0.15 mmol/L. The estimated perfusion flow was 3.9 ± 0.38 and 1.03 ± 0.19 ml/min/g using the BTEX model and 3.4 ± 0.39 and 0.95 ± 0.16 using a Fermi model, for stress and rest, respectively. A dual sequence for myocardial perfusion cardiovascular magnetic resonance and AIF measurement has been optimized for quantification of myocardial blood flow. A validation in phantoms was performed to confirm that the signal conversion to gadolinium concentration was linear. The proposed sequence was integrated with a fully automatic in-line solution for pixel-wise mapping of myocardial blood flow and evaluated in adenosine stress and rest studies on N = 29 normal healthy subjects. Reliable perfusion mapping was demonstrated and produced estimates with low variability.

Lung lesions and anti-ulcer agents beneficial effect: anti-ulcer agents pentadecapeptide BPC 157, ranitidine, omeprazole and atropine ameliorate lung lesion in rats.

PubMed

Stancic-Rokotov, D; Slobodnjak, Z; Aralica, J; Aralica, G; Perovic, D; Staresinic, M; Gjurasin, M; Anic, T; Zoricic, I; Buljat, G; Prkacin, I; Sikiric, P; Seiwerth, S; Rucman, R; Petek, M; Turkovic, B; Kokic, N; Jagic, V; Boban-Blagaic, A

2001-01-01

Anti-ulcer agents may likely attenuate lesions outside the gastrointestinal tract, since they had protected gastrectomized rats (a "direct cytoprotective effect"). Therefore, their therapeutic potential in lung/stomach lesions were shown. Rats received an intratracheal (i.t.) HCl instillation [1.5 ml/kg HCl (pH 1.75)] (lung lesion), and an intragastric (i.g.) instillation of 96% ethanol (gastric lesion; 1 ml/rat, 24 h after i.t. HCl instillation), then sacrificed 1 h after ethanol. Basically, in lung-injured rats, the subsequent ethanol-gastric lesion was markedly aggravated. This aggravation, however, in turn, did not affect the severity of the lung lesions in the further period, at least for 1 h of observation. Taking intratracheal HCl-instillation as time 0, a gastric pentadecapeptide, GEPPPGKPADDAGLV, M.W.1419, coded BPC 157 (10 microg, 10 ng, 10 pg), ranitidine (10 mg), atropine (10 mg), omeprazole (10 mg), were given [/kg, intraperitoneally (i.p.)] (i) once, only prophylactically [as a pre-treatment (at -1h)], or as a co-treatment [at 0)], or only therapeutically (at +18h or +24 h); (ii) repeatedly, combining prophylactic/therapeutic regimens [(-1 h)+(+24 h)] or [(0)+(+24 h)], or therapeutic/therapeutic regimens [(+18 h)+(+24 h)]. For all agents, combining their prophylactic and salutary regimens (at -1 h/+24 h, or at 0/+24 h) attenuated lung lesions; even if effect had been not seen already with a single application, it became prominent after repeated treatment. In single application studies, relative to controls, a co-treatment (except to omeprazole), a pre-treatment (at -1 h) (pentadecapeptide BPC 157 and atropine, but not ranitidine and omeprazole) regularly attenuated, while therapeutically, atropine (at +18 h), pentadecapeptide BPC 157 highest dose and omeprazole (at +24 h), reversed the otherwise more severe lung lesions.

Correlation-based perfusion mapping using time-resolved MR angiography: A feasibility study for patients with suspicions of steno-occlusive craniocervical arteries.

PubMed

Nam, Yoonho; Jang, Jinhee; Park, Sonya Youngju; Choi, Hyun Seok; Jung, So-Lyung; Ahn, Kook-Jin; Kim, Bum-Soo

2018-05-22

To explore the feasibility of using correlation-based time-delay (CTD) maps produced from time-resolved MR angiography (TRMRA) to diagnose perfusion abnormalities in patients suspected to have steno-occlusive lesions in the craniocervical arteries. Twenty-seven patients who were suspected to have steno-occlusive lesions in the craniocervical arteries underwent both TRMRA and brain single-photon emission computed tomography (SPECT). TRMRA was performed on the supra-aortic area after intravenous injection of a 0.03 mmol/kg gadolinium-based contrast agent. Time-to-peak (TTP) maps and CTD maps of the brain were automatically generated from TRMRA data, and their quality was assessed. Detection of perfusion abnormalities was compared between CTD maps and the time-series maximal intensity projection (MIP) images from TRMRA and TTP maps. Correlation coefficients between quantitative changes in SPECT and parametric maps for the abnormal perfusion areas were calculated. The CTD maps were of significantly superior quality than TTP maps (p < 0.01). For perfusion abnormality detection, CTD maps (kappa 0.84, 95% confidence interval [CI] 0.67-1.00) showed better agreement with SPECT than TTP maps (0.66, 0.46-0.85). For perfusion deficit detection, CTD maps showed higher accuracy (85.2%, 95% CI 66.3-95.8) than MIP images (66.7%, 46-83.5), with marginal significance (p = 0.07). In abnormal perfusion areas, correlation coefficients between SPECT and CTD (r = 0.74, 95% CI 0.34-0.91) were higher than those between SPECT and TTP (r = 0.66, 0.20-0.88). CTD maps generated from TRMRA were of high quality and offered good diagnostic performance for detecting perfusion abnormalities associated with steno-occlusive arterial lesions in the craniocervical area. • Generation of perfusion parametric maps from time-resolved MR angiography is clinically useful. • Correlation-based delay maps can be used to detect perfusion abnormalities associated with steno-occlusive craniocervical arteries. • Estimation of correlation-based delay is robust for low signal-to-noise 4D MR data.

Functional Imaging of the Lungs with Gas Agents

PubMed Central

Kruger, Stanley J.; Nagle, Scott K.; Couch, Marcus J.; Ohno, Yoshiharu; Albert, Mitchell; Fain, Sean B.

2015-01-01

This review focuses on the state-of-the-art of the three major classes of gas contrast agents used in magnetic resonance imaging (MRI) – hyperpolarized (HP) gas, molecular oxygen, and fluorinated gas – and their application to clinical pulmonary research. During the past several years there has been accelerated development of pulmonary MRI. This has been driven in part by concerns regarding ionizing radiation using multi-detector computed tomography (CT). However, MRI also offers capabilities for fast multi-spectral and functional imaging using gas agents that are not technically feasible with CT. Recent improvements in gradient performance and radial acquisition methods using ultra-short echo time (UTE) have contributed to advances in these functional pulmonary MRI techniques. Relative strengths and weaknesses of the main functional imaging methods and gas agents are compared and applications to measures of ventilation, diffusion, and gas exchange are presented. Functional lung MRI methods using these gas agents are improving our understanding of a wide range of chronic lung diseases, including chronic obstructive pulmonary disease (COPD), asthma, and cystic fibrosis (CF) in both adults and children. PMID:26218920

Regional Myocardial Blood Volume and Flow: First-Pass MR Imaging with Polylysine-Gd-DTPA

PubMed Central

Wilke, Norbert; Kroll, Keith; Merkle, Hellmut; Wang, Ying; Ishibashi, Yukata; Xu, Ya; Zhang, Jiani; Jerosch-Herold, Michael; Mühler, Andreas; Stillman, Arthur E.; Bassingthwaighte, James B.; Bache, Robert; Ugurbil, Kamil

2010-01-01

The authors investigated the utility of an intravascular magnetic resonance (MR) contrast agent, poly-L-lysine-gadolinium diethylenetriaminepentaacetic acid (DTPA), for differentiating acutely ischemic from normally perfused myocardium with first-pass MR imaging. Hypoperfused regions, identified with microspheres, on the first-pass images displayed significantly decreased signal intensities compared with normally perfused myocardium (P < .0007). Estimates of regional myocardial blood content, obtained by measuring the ratio of areas under the signal intensity-versus-time curves in tissue regions and the left ventricular chamber, averaged 0.12 mL/g ± 0.04 (n = 35), compared with a value of 0.11 mL/g ± 0.05 measured with radiolabeled albumin in the same tissue regions. To obtain MR estimates of regional myocardial blood flow, in situ calibration curves were used to transform first-pass intensity-time curves into content-time curves for analysis with a multiple-pathway, axially distributed model. Flow estimates, obtained by automated parameter optimization, averaged 1.2 mL/min/g ± 0.5 [n = 29), compared with 1.3 mL/min/g ± 0.3 obtained with tracer microspheres in the same tissue specimens at the same time. The results represent a combination of T1-weighted first-pass imaging, intravascular relaxation agents, and a spatially distributed perfusion model to obtain absolute regional myocardial blood flow and volume. PMID:7766986

Reproducible insulin secretion from isolated rat pancreas preparations using an organ bath.

PubMed

Morita, Asuka; Ouchi, Motoshi; Terada, Misao; Kon, Hiroe; Kishimoto, Satoko; Satoh, Keitaro; Otani, Naoyuki; Hayashi, Keitaro; Fujita, Tomoe; Inoue, Ken-Ichi; Anzai, Naohiko

2018-02-09

Diabetes mellitus is a lifestyle-related disease that is characterized by inappropriate or diminished insulin secretion. Ex vivo pharmacological studies of hypoglycemic agents are often conducted using perfused pancreatic preparations. Pancreas preparations for organ bath experiments do not require cannulation and are therefore less complex than isolated perfused pancreas preparations. However, previous research has generated almost no data on insulin secretion from pancreas preparations using organ bath preparations. The purpose of this study was to investigate the applicability of isolated rat pancreas preparations using the organ bath technique in the quantitative analysis of insulin secretion from β-cells. We found that insulin secretion significantly declined during incubation in the organ bath, whereas it was maintained in the presence of 1 µM GLP-1. Conversely, amylase secretion exhibited a modest increase during incubation and was not altered in the presence of GLP-1. These results demonstrate that the pancreatic organ bath preparation is a sensitive and reproducible method for the ex vivo assessment of the pharmacological properties of hypoglycemic agents.

Cell signaling molecules as drug targets in lung cancer: an overview.

PubMed

Mukherjee, Tapan K; Paul, Karan; Mukhopadhyay, Srirupa

2011-07-01

Lung being one of the vital and essential organs in the body, lung cancer is a major cause of mortality in the modern human society. Lung cancer can be broadly subdivided into nonsmall cell lung cancer (NSCLC) and small cell lung cancer (SCLC). Although NSCLC is sometimes treated with surgery, the advanced and metastatic NSCLC and SCLC usually respond better to chemotherapy and radiation. The most important targets of these chemotherapeutic agents are various intracellular signaling molecules. The primary focus of this review article is to summarize the description of various cell signaling molecules involved in lung cancer development and their regulation by chemotherapeutic agents. Extensive research work in recent years has identified several cellular signaling molecules that may be intricately involved in the complexity of lung cancer. Some of these cell signaling molecules are epidermal growth factor receptors, vascular endothelial growth factor receptors, mammalian target of rapamycin, mitogen-activated protein kinase phosphatase-1, peroxisome proliferator-activated receptor-gamma, matrix metalloproteinases and receptor for advanced glycation end-products. The present review will strengthen our current knowledge regarding the efficacy of the above-mentioned cell signaling molecules as potential beneficial drug targets against lung cancer.

Key Facts about Tularemia

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