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Sample records for pentoxide induces pulmonary

  1. Genetic susceptibility to interstitial pulmonary fibrosis in mice induced by vanadium pentoxide (V2O5)

    PubMed Central

    Walters, Dianne M.; White, Kevin M.; Patel, Ushma; Davis, Martin J.; Veluci-Marlow, Roberta M.; Bhupanapadu Sunkesula, Solomon Raju; Bonner, James C.; Martin, Jessica R.; Gladwell, Wes; Kleeberger, Steven R.

    2014-01-01

    Interstitial lung diseases (ILDs) are characterized by injury, inflammation, and scarring of alveoli, leading to impaired function. The etiology of idiopathic forms of ILD is not understood, making them particularly difficult to study due to the lack of appropriate animal models. Consequently, few effective therapies have emerged. We developed an inbred mouse model of ILD using vanadium pentoxide (V2O5), the most common form of a transition metal found in cigarette smoke, fuel ash, mineral ores, and steel alloys. Pulmonary responses to V2O5, including dose-dependent increases in lung permeability, inflammation, collagen content, and dysfunction, were significantly greater in DBA/2J mice compared to C57BL/6J mice. Inflammatory and fibrotic responses persisted for 4 mo in DBA/2J mice, while limited responses in C57BL/6J mice resolved. We investigated the genetic basis for differential responses through genetic mapping of V2O5-induced lung collagen content in BXD recombinant inbred (RI) strains and identified significant linkage on chromosome 4 with candidate genes that associate with V2O5-induced collagen content across the RI strains. Results suggest that V2O5 may induce pulmonary fibrosis through mechanisms distinct from those in other models of pulmonary fibrosis. These findings should further advance our understanding of mechanisms involved in ILD and thereby aid in identification of new therapeutic targets.—Walters, D. M., White, K. M., Patel, U., Davis, M. J., Veluci-Marlow, R. M., Bhupanapadu Sunkesula, S. R., Bonner, J. C., Martin, J. R., Gladwell, W., Kleeberger, S. R. Genetic susceptibility to interstitial pulmonary fibrosis in mice induced by vanadium pentoxide (V2O5). PMID:24285090

  2. Vanadium pentoxide induces pulmonary inflammation and tumor promotion in a strain-dependent manner

    PubMed Central

    2010-01-01

    Background Elevated levels of air pollution are associated with increased risk of lung cancer. Particulate matter (PM) contains transition metals that may potentiate neoplastic development through the induction of oxidative stress and inflammation, a lung cancer risk factor. Vanadium pentoxide (V2O5) is a component of PM derived from fuel combustion as well as a source of occupational exposure in humans. In the current investigation we examined the influence of genetic background on susceptibility to V2O5-induced inflammation and evaluated whether V2O5 functions as a tumor promoter using a 2-stage (initiation-promotion) model of pulmonary neoplasia in mice. Results A/J, BALB/cJ (BALB), and C57BL/6J (B6) mice were treated either with the initiator 3-methylcholanthrene (MCA; 10 μg/g; i.p.) or corn oil followed by 5 weekly aspirations of V2O5 or PBS and pulmonary tumors were enumerated 20 weeks following MCA treatment. Susceptibility to V2O5-induced pulmonary inflammation was assessed in bronchoalveolar lavage fluid (BALF), and chemokines, transcription factor activity, and MAPK signaling were quantified in lung homogenates. We found that treatment of animals with MCA followed by V2O5 promoted lung tumors in both A/J (10.3 ± 0.9 tumors/mouse) and BALB (2.2 ± 0.36) mice significantly above that observed with MCA/PBS or V2O5 alone (P < 0.05). No tumors were observed in the B6 mice in any of the experimental groups. Mice sensitive to tumor promotion by V2O5 were also found to be more susceptible to V2O5-induced pulmonary inflammation and hyperpermeability (A/J>BALB>B6). Differential strain responses in inflammation were positively associated with elevated levels of the chemokines KC and MCP-1, higher NFκB and c-Fos binding activity, as well as sustained ERK1/2 activation in lung tissue. Conclusions In this study we demonstrate that V2O5, an occupational and environmentally relevant metal oxide, functions as an in vivo lung tumor promoter among different inbred

  3. Cation-Induced Coiling of Vanadium Pentoxide Nanobelts

    PubMed Central

    2010-01-01

    Single-crystalline V2O5·xH2O nanorings and microloops were chemically assembled via an ion-induced chemical spinning route in the designed hydrothermal system. The morphology and structure of products were investigated by means of scanning electron microscopy (SEM) and transmission electron microscopy (TEM). X-ray powder diffraction (XRD) measurement, energy-dispersive X-ray spectroscopy (EDS) microanalysis and thermal gravimetric analysis (TGA) revealed that the composition of nanorings and microloops is V2O5·1·1H2O. For these oxide nanorings and microloops, the cation-induced coiling growth mechanism of vanadium pentoxide nanobelts has been proposed on the basis of crystallographic structure of vanadium pentoxide. Our proposed chemical spinning process and the rational solution-phase synthesis route can also be extended to prepare novel 1D materials with layered or more complex structures. PMID:21076706

  4. Vanadium pentoxide

    Integrated Risk Information System (IRIS)

    Vanadium pentoxide ; CASRN 1314 - 62 - 1 Human health assessment information on a chemical substance is included in the IRIS database only after a comprehensive review of toxicity data , as outlined in the IRIS assessment development process . Sections I ( Health Hazard Assessments for Noncarcinogen

  5. Vanadium pentoxide-coated ultrafine titanium dioxide particles induce cellular damage and micronucleus formation in V79 cells.

    PubMed

    Bhattacharya, K; Cramer, H; Albrecht, C; Schins, R; Rahman, Q; Zimmermann, U; Dopp, E

    2008-01-01

    Surface-treated titanium dioxide (TiO(2)) particles coated with vanadium pentoxide (V(2)O(5)) are used industrially for selective catalytic reactions such as the removal of nitrous oxide from exhaust gases of combustion power plants (SCR process) and in biomaterials for increasing the strength of implants. In the present study, untreated ultrafine TiO(2) particles (anatase, diameter: 30-50 nm) and vanadium pentoxide (V(2)O(5))-treated anatase particles were tested for their cyto- and genotoxic effects in V79 cells (hamster lung fibroblasts). Cytotoxic effects of the particles were assessed by trypan blue exclusion, while genotoxic effects were investigated by micronucleus (MN) assay. In addition, the generation of reactive oxygen species (ROS) was determined by the acellular method of electron spin resonance technique (ESR) and by the cellular technique of determination of thiobarbituric acid-reactive substances (TBARS). Our results demonstrate that V(2)O(5)-treated TiO(2) particles induce more potent cyto- and genotoxic effects than untreated particles. Further, acellular and cellular radical formation was more pronounced with V(2)O(5)-anatase than untreated anatase. Thus, data indicate that V(2)O(5)-treated TiO(2) particles were more reactive than natural anatase and capable of inducing DNA damage in mammalian cells through production of free radicals. PMID:18569605

  6. Drug-induced pulmonary disease

    MedlinePlus

    ... improve. Some drug-induced lung diseases, such as pulmonary fibrosis, may never go away. ... Complications that may develop include: Diffuse interstitial pulmonary fibrosis Hypoxemia (low blood oxygen) Respiratory failure

  7. Hyskon-induced pulmonary edema.

    PubMed

    Mangar, D

    1993-12-01

    Hyskon (32 percent dextran-70) (Hyskon Division, Pharmacia) is used during hysteroscopy to help visualization of the uterine surfaces. Pulmonary edema of an uncertain cause has occurred in many patients. Because this study could not be conducted in humans, we determined if Hyskon caused cardiogenic or non-cardiogenic pulmonary edema in a dog model. Dogs were randomly assigned to receive an infusion of Hyskon or whole blood to sustain left ventricular end-diastolic pressure between 20 and 23 millimeters of mercury for 60 minutes. In dogs receiving blood, there was no protein in the bronchoalveolar lavage before or after blood was given. In the Hyskon group, there was no protein in the bronchoalveolar lavage before Hyskon and 0.6 +/- 1.4 milligrams per deciliter (range of 0.1 to 3.7 milligram per deciliter) after Hyskon. The ratio of bronchoalveolar lavage protein to plasma protein after Hyskon was 8.0 +/- 18.0 percent compared with zero percent in the blood group. Hyskon altered pulmonary microvascular membrane permeability, causing alveolar flooding with plasma proteins and possibly accounting for the deterioration of oxygenation and pulmonary compliance seen in patients. These results suggest a significant noncardiogenic component of Hyskon induced pulmonary edema. PMID:7505487

  8. Drugs induced pulmonary arterial hypertension.

    PubMed

    Seferian, Andrei; Chaumais, Marie-Camille; Savale, Laurent; Günther, Sven; Tubert-Bitter, Pascale; Humbert, Marc; Montani, David

    2013-09-01

    Pulmonary arterial hypertension (PAH) is a rare disorder characterized by progressive obliteration of the pulmonary microvasculature, resulting in elevated pulmonary vascular resistance and premature death. According to the current classification, PAH can be associated with exposure to certain drugs or toxins, particularly appetite suppressant drugs, such as aminorex, fenfluramine derivatives and benfluorex. These drugs have been confirmed to be risk factors for PAH and were withdrawn from the market. The supposed mechanism is an increase in serotonin levels, which was demonstrated to act as a growth factor for the pulmonary arterial smooth muscle cells. Amphetamines, phentermine and mazindol were less frequently used but are also considered as possible risk factors for PAH. Dasatinib, a dual Src/Abl kinase inhibitor, used in the treatment of chronic myelogenous leukaemia was associated with cases of severe PAH, in part reversible after its withdrawal. Recently several studies raised the potential endothelial dysfunction that could be induced by interferon, and few cases of PAH have been reported with interferon therapy. Other possible risk factors for PAH include: nasal decongestants, like phenylpropanolamine, dietary supplement - L-Tryptophan, selective serotonin reuptake inhibitors, pergolide and other drugs that could act on 5HT2B receptors. Interestingly, PAH remains a rare complication of these drugs, suggesting possible individual susceptibility and further studies are needed to identify patients at risk of drugs induced PAH. PMID:23972547

  9. Severe amiodarone induced pulmonary toxicity

    PubMed Central

    Nacca, Nicholas; Yuhico, Luke S; Pinnamaneni, Sowmya; Szombathy, Tamas

    2012-01-01

    A known complication of Amiodarone therapy is Amiodarone induced Pulmonary Toxicity (APT). Several features of this adverse effect make it difficult to diagnosis and treat. The case of a 63-year-old male with classic radiographic and histologic findings of APT is discussed. Clinical presentation, pathophysiology, diagnostic findings, and treatment strategies are reviewed. The patient was successfully managed with pulse high dose steroid therapy. PMID:23205299

  10. Pulmonary Artery Denervation Reduces Pulmonary Artery Pressure and Induces Histological Changes in an Acute Porcine Model of Pulmonary Hypertension

    PubMed Central

    Arnold, Nadine D.; Chang, William; Watson, Oliver; Swift, Andrew J.; Condliffe, Robin; Elliot, Charlie A.; Kiely, David G.; Suvarna, S. Kim; Gunn, Julian; Lawrie, Allan

    2015-01-01

    Background— Pulmonary arterial hypertension is a devastating disease with high morbidity and mortality and limited treatment options. Recent studies have shown that pulmonary artery denervation improves pulmonary hemodynamics in an experimental model and in an early clinical trial. We aimed to evaluate the nerve distribution around the pulmonary artery, to determine the effect of radiofrequency pulmonary artery denervation on acute pulmonary hypertension induced by vasoconstriction, and to demonstrate denervation of the pulmonary artery at a histological level. Methods and Results— Histological evaluation identified a circumferential distribution of nerves around the proximal pulmonary arteries. Nerves were smaller in diameter, greater in number, and located in closer proximity to the luminal aspect of the pulmonary arterial wall beyond the pulmonary artery bifurcation. To determine the effect of pulmonary arterial denervation acute pulmonary hypertension was induced in 8 pigs by intravenous infusion of thromboxane A2 analogue. Animals were assigned to either pulmonary artery denervation, using a prototype radiofrequency catheter and generator, or a sham procedure. Pulmonary artery denervation resulted in reduced mean pulmonary artery pressure and pulmonary vascular resistance and increased cardiac output. Ablation lesions on the luminal surface of the pulmonary artery were accompanied by histological and biochemical alteration in adventitial nerves and correlated with improved hemodynamic parameters. Conclusions— Pulmonary artery denervation offers the possibility of a new treatment option for patients with pulmonary arterial hypertension. Further work is required to determine the long-term efficacy and safety. PMID:26553697

  11. Cocaine-induced pulmonary changes: HRCT findings *

    PubMed Central

    de Almeida, Renata Rocha; Zanetti, Gláucia; Souza, Arthur Soares; de Souza, Luciana Soares; Silva, Jorge Luiz Pereira e; Escuissato, Dante Luiz; Irion, Klaus Loureiro; Mançano, Alexandre Dias; Nobre, Luiz Felipe; Hochhegger, Bruno; Marchiori, Edson

    2015-01-01

    Abstract Objective: To evaluate HRCT scans of the chest in 22 patients with cocaine-induced pulmonary disease. Methods: We included patients between 19 and 52 years of age. The HRCT scans were evaluated by two radiologists independently, discordant results being resolved by consensus. The inclusion criterion was an HRCT scan showing abnormalities that were temporally related to cocaine use, with no other apparent causal factors. Results: In 8 patients (36.4%), the clinical and tomographic findings were consistent with "crack lung", those cases being studied separately. The major HRCT findings in that subgroup of patients included ground-glass opacities, in 100% of the cases; consolidations, in 50%; and the halo sign, in 25%. In 12.5% of the cases, smooth septal thickening, paraseptal emphysema, centrilobular nodules, and the tree-in-bud pattern were identified. Among the remaining 14 patients (63.6%), barotrauma was identified in 3 cases, presenting as pneumomediastinum, pneumothorax, and hemopneumothorax, respectively. Talcosis, characterized as perihilar conglomerate masses, architectural distortion, and emphysema, was diagnosed in 3 patients. Other patterns were found less frequently: organizing pneumonia and bullous emphysema, in 2 patients each; and pulmonary infarction, septic embolism, eosinophilic pneumonia, and cardiogenic pulmonary edema, in 1 patient each. Conclusions: Pulmonary changes induced by cocaine use are varied and nonspecific. The diagnostic suspicion of cocaine-induced pulmonary disease depends, in most of the cases, on a careful drawing of correlations between clinical and radiological findings. PMID:26398752

  12. Naloxone-induced pulmonary edema.

    PubMed

    Schwartz, J A; Koenigsberg, M D

    1987-11-01

    We present the case of a 68-year-old woman with acute pulmonary edema secondary to the administration of naloxone to reverse an inadvertent narcotic overdose. The patient presented following a 12-hour history of increasingly bizarre behavior and confusion. A total IV dose of 1.6 mg naloxone was administered in an attempt to reverse the suspected overconsumption of a codeine-containing cough suppressant. She immediately became agitated, tachycardic, and diaphoretic; a clinical diagnosis of acute pulmonary edema was made. Following treatment with furosemide, nitroglycerin, and morphine sulfate, the patient recovered completely without further incident. Although naloxone is thought to be a safe drug with few complications, it should not be used indiscriminantly, and the smallest doses necessary to elicit the desired response should be used. PMID:3662194

  13. Update on exercise-induced pulmonary hemorrhage.

    PubMed

    Sullivan, Stacey; Hinchcliff, Kenneth

    2015-04-01

    Exercise-induced pulmonary hemorrhage (EIPH) is an important disease of horses that perform high-intensity athletic activity. EIPH is an ongoing concern for the racing industry because of its high prevalence; potential impact on performance; welfare concerns; and use of prophylactic medications, such as furosemide, on race day. During the last 10 years, significant progress has been made in understanding the pathogenesis and risk factors for EIPH and the impact of the disease on performance and career. This article summarizes the most recent advances in EIPH. PMID:25770069

  14. Amiodarone-induced pulmonary toxicity mimicking acute pulmonary edema.

    PubMed

    Fabiani, Iacopo; Tacconi, Danilo; Grotti, Simone; Brandini, Rossella; Salvadori, Claudia; Caremani, Marcello; Bolognese, Leonardo

    2011-05-01

    Amiodarone is a highly effective antiarrhythmic drug. Its long-term use may, however, lead to several adverse effects, with pulmonary toxicity being the most serious. The article presents the case of a 78-year-old woman with a history of cardiac surgery, who after 2 years of amiodarone therapy for prophylactic treatment of atrial fibrillation developed amiodarone pneumonitis mimicking an acute pulmonary edema. The patient failed to respond to diuretic therapy and several courses of anti-infective therapy. Differential diagnosis of different causes of pulmonary infiltrates did not demonstrate any other abnormality. Lung biopsy findings were consistent with the diagnosis of amiodarone pneumonitis. Given the widespread use of amiodarone as an antiarrhythmic agent, pneumologists and cardiologists should consider this important adverse effect as a differential diagnosis of pulmonary distress refractory to therapy in all patients treated with amiodarone who present with respiratory symptoms and pneumonia-like illness. PMID:19924000

  15. Vanadium pentoxide nanotubes by eelectrospinning

    NASA Astrophysics Data System (ADS)

    Lala, Neeta L.; Jose, R.; Yusoff, M. M.

    2012-11-01

    Nanofibers of vanadium pentoxide (V2O5) were synthesized by electrospinning a polymeric solution containing vanadium ion and with subsequent sintering. Conventionally, electrospun TNFs were produced by using a co-axial spinneret; however, TNFs in the present study were obtained by manipulating the concentration ratio of the precursor solution, distance, humidity and flow rate during electrospinning using a single spinneret and sintering with time and temperature change. On the basis of this hypothesis, nanofibers could be altered from elongated 1-D nanofibers to nanowires, nanotubes, spheres and flakes respectively. The surface morphology, structure, roughness and the crystal structure were analyzed using Field Emission Scanning Electron Microscopy (FE-SEM), Transmission Electron Microscopy (TEM), and X-ray diffraction (XRD). The current work has demonstrated a case study for energy storage where V2O5 nanotubes when tested shows the capacitance of 190 Fg-1 in 2M KCl electrolyte indicating an example for the energy storage which may be applicable for other electrochemical devices such as Li-ion batteries, fuel cells, hydrogen storage etc.

  16. Diffuse interstitial pulmonary fibrosis: pulmonary fibrosis in mice induced by treatment with butylated hydroxytoluene and oxygen

    SciTech Connect

    Haschek, W.M.; Brody, A.R.; Klein-Szanto, A.J.P.; Witschi, H.

    1981-12-01

    It is proposed that the pulmonary fibrosis induced in mice by treatment with BHT and oxygen is a good experimental model for human pulmonary fibrosis. The mechanism of synergistic and additive effects of various agents on pulmonary injury and the epithelial mesenchymal interactions occurring during the early and late phases of lung repair could be studied. This model could be used for study of the effects of various concentrations of oxygen on diffusely damaged lung and assessment of the efficacy of drugs in preventing or resolving excessive collagen accumulation in lung. In addition, the relationship between pulmonary fibrosis and emphysema could be studied.

  17. The Curious Question of Exercise-Induced Pulmonary Edema

    PubMed Central

    Bates, Melissa L.; Farrell, Emily T.; Eldridge, Marlowe W.

    2011-01-01

    The question of whether pulmonary edema develops during exercise on land is controversial. Yet, the development of pulmonary edema during swimming and diving is well established. This paper addresses the current controversies that exist in the field of exercise-induced pulmonary edema on land and with water immersion. It also discusses the mechanisms by which pulmonary edema can develop during land exercise, swimming, and diving and the current gaps in knowledge that exist. Finally, this paper discusses how these fields can continue to advance and the areas where clinical knowledge is lacking. PMID:21660232

  18. The effects of oxygen induced pulmonary vasoconstriction on bedside measurement of pulmonary gas exchange.

    PubMed

    Weinreich, Ulla M; Thomsen, Lars P; Rees, Stephen E; Rasmussen, Bodil S

    2016-04-01

    In patients with respiratory failure measurements of pulmonary gas exchange are of importance. The bedside automatic lung parameter estimator (ALPE) of pulmonary gas exchange is based on changes in inspired oxygen (FiO2) assuming that these changes do not affect pulmonary circulation. This assumption is investigated in this study. Forty-two out of 65 patients undergoing coronary artery bypass grafting (CABG) had measurements of mean pulmonary arterial pressure (MPAP), cardiac output and pulmonary capillary wedge pressure thus enabling the calculation of pulmonary vascular resistance (PVR) at each FiO2 level. The research version of ALPE was used and FiO2 was step-wise reduced a median of 0.20 and ultimately returned towards baseline values, allowing 6-8 min' steady state period at each of 4-6 levels before recording the oxygen saturation (SpO2). FiO2 reduction led to median decrease in SpO2 from 99 to 92 %, an increase in MPAP of 4 mmHg and an increase in PVR of 36 dyn s cm(-5). Changes were immediately reversed on returning FiO2 towards baseline. In this study changes in MPAP and PVR are small and immediately reversible consistent with small changes in pulmonary gas exchange. This indicates that mild deoxygenation induced pulmonary vasoconstriction does not have significant influences on the ALPE parameters in patients after CABG. PMID:25962614

  19. Upregulated Copper Transporters in Hypoxia-Induced Pulmonary Hypertension

    PubMed Central

    Zimnicka, Adriana M.; Tang, Haiyang; Guo, Qiang; Kuhr, Frank K.; Oh, Myung-Jin; Wan, Jun; Chen, Jiwang; Smith, Kimberly A.; Fraidenburg, Dustin R.; Choudhury, Moumita S. R.; Levitan, Irena; Machado, Roberto F.; Kaplan, Jack H.; Yuan, Jason X.-J.

    2014-01-01

    Pulmonary vascular remodeling and increased arterial wall stiffness are two major causes for the elevated pulmonary vascular resistance and pulmonary arterial pressure in patients and animals with pulmonary hypertension. Cellular copper (Cu) plays an important role in angiogenesis and extracellular matrix remodeling; increased Cu in vascular smooth muscle cells has been demonstrated to be associated with atherosclerosis and hypertension in animal experiments. In this study, we show that the Cu-uptake transporter 1, CTR1, and the Cu-efflux pump, ATP7A, were both upregulated in the lung tissues and pulmonary arteries of mice with hypoxia-induced pulmonary hypertension. Hypoxia also significantly increased expression and activity of lysyl oxidase (LOX), a Cu-dependent enzyme that causes crosslinks of collagen and elastin in the extracellular matrix. In vitro experiments show that exposure to hypoxia or treatment with cobalt (CoCl2) also increased protein expression of CTR1, ATP7A, and LOX in pulmonary arterial smooth muscle cells (PASMC). In PASMC exposed to hypoxia or treated with CoCl2, we also confirmed that the Cu transport is increased using 64Cu uptake assays. Furthermore, hypoxia increased both cell migration and proliferation in a Cu-dependent manner. Downregulation of hypoxia-inducible factor 1α (HIF-1α) with siRNA significantly attenuated hypoxia-mediated upregulation of CTR1 mRNA. In summary, the data from this study indicate that increased Cu transportation due to upregulated CTR1 and ATP7A in pulmonary arteries and PASMC contributes to the development of hypoxia-induced pulmonary hypertension. The increased Cu uptake and elevated ATP7A also facilitate the increase in LOX activity and thus the increase in crosslink of extracellular matrix, and eventually leading to the increase in pulmonary arterial stiffness. PMID:24614111

  20. Gemcitabine-Induced Pulmonary Toxicity: A Case Report of Pulmonary Veno-Occlusive Disease

    PubMed Central

    Turco, Célia; Jary, Marine; Kim, Stefano; Moltenis, Mélanie; Degano, Bruno; Manzoni, Philippe; Nguyen, Thierry; Genet, Bruno; Rabier, Marie-Blanche Valnet; Heyd, Bruno; Borg, Christophe

    2015-01-01

    INTRODUCTION Gemcitabine is a chemotherapeutic agent frequently used by for the treatment of several malignancies both in the adjuvant and metastatic setting. Although myelosuppression is the most adverse event of this therapy, gemcitabine might induce severe pulmonary toxicities. We describe a case of pulmonary veno-occlusive disease (PVOD) related to gemcitabine. CASE PRESENTATION The patient was an 83-year-old man with a metastatic pancreatic cancer who was treated by gemcitabine as first-line therapy. He was in good health and received no other chemotherapy. A dose of 1000 mg/m2 of gemcitabine was administered over a 30-minute intravenous infusion on days 1, 8, and 15 of a 28-day cycle. After a period of 6 months, a complete response was observed. Nevertheless, the patient developed a severe dyspnea, with arterial hypoxemia and very low lung diffusion for carbon monoxide. A CT scan showed diffuse ground glass opacities with septal lines, bilateral pleural effusion, and lymph node enlargement. On echocardiography, there was a suspicion of pulmonary hypertension with elevated systolic pulmonary artery pressure and normal left ventricular pressures. Right heart catheterization confirmed pulmonary hypertension and normal pulmonary artery occlusion pressure. Diagnosis of PVOD was made, and a gemcitabine-induced toxicity was suspected. A symptomatic treatment was started. At last follow-up, patient was in functional class I with near-normal of CT scan, arterial blood gases, and echocardiography. A gemcitabine-induced PVOD is the more likely diagnosis. PMID:26380562

  1. [Toxic and drug-induced lesions of the pulmonary parenchyma].

    PubMed

    Russi, E

    1992-05-01

    Pulmonary tissue may be damaged by certain toxins or drugs in a dose-dependent way or by a hypersensitivity reaction. Pathological changes consist of a permeability pulmonary edema, an alveolar hemorrhage, an alveolitis and finally the formation of pulmonary fibrosis. Ingestion of the weed killer paraquat may induce a rapidly progressive and lethal form of fibrosing alveolitis, the inhalation of nitrous oxides may elicit lung edema. The most common drugs causing lung damage are cytotoxic agents, often used in combination, and the noncytotoxic drugs amiodarone and nitrofurantoin. PMID:1589677

  2. Dasatinib induces lung vascular toxicity and predisposes to pulmonary hypertension.

    PubMed

    Guignabert, Christophe; Phan, Carole; Seferian, Andrei; Huertas, Alice; Tu, Ly; Thuillet, Raphaël; Sattler, Caroline; Le Hiress, Morane; Tamura, Yuichi; Jutant, Etienne-Marie; Chaumais, Marie-Camille; Bouchet, Stéphane; Manéglier, Benjamin; Molimard, Mathieu; Rousselot, Philippe; Sitbon, Olivier; Simonneau, Gérald; Montani, David; Humbert, Marc

    2016-09-01

    Pulmonary arterial hypertension (PAH) is a life-threatening disease that can be induced by dasatinib, a dual Src and BCR-ABL tyrosine kinase inhibitor that is used to treat chronic myelogenous leukemia (CML). Today, key questions remain regarding the mechanisms involved in the long-term development of dasatinib-induced PAH. Here, we demonstrated that chronic dasatinib therapy causes pulmonary endothelial damage in humans and rodents. We found that dasatinib treatment attenuated hypoxic pulmonary vasoconstriction responses and increased susceptibility to experimental pulmonary hypertension (PH) in rats, but these effects were absent in rats treated with imatinib, another BCR-ABL tyrosine kinase inhibitor. Furthermore, dasatinib treatment induced pulmonary endothelial cell apoptosis in a dose-dependent manner, while imatinib did not. Dasatinib treatment mediated endothelial cell dysfunction via increased production of ROS that was independent of Src family kinases. Consistent with these findings, we observed elevations in markers of endothelial dysfunction and vascular damage in the serum of CML patients who were treated with dasatinib, compared with CML patients treated with imatinib. Taken together, our findings indicate that dasatinib causes pulmonary vascular damage, induction of ER stress, and mitochondrial ROS production, which leads to increased susceptibility to PH development. PMID:27482885

  3. Paraquat induced pulmonary fibrosis in three survivors.

    PubMed Central

    Hudson, M; Patel, S B; Ewen, S W; Smith, C C; Friend, J A

    1991-01-01

    Pulmonary lesions following paraquat poisoning are believed to be almost invariably fatal. The three patients reports here survived despite persistent radiological change. One of the patients died after taking a larger dose of paraquat one year later, and at necropsy histological changes attributable to the two episodes of paraquat poisoning were apparent. Images PMID:2028434

  4. Pulmonary and generalized lysosomal storage induced by amphiphilic drugs.

    PubMed Central

    Hruban, Z

    1984-01-01

    Administration of amphiphilic drugs to experimental animals causes formation of myelinoid bodies in many cell types, accumulation of foamy macrophages in pulmonary alveoli and pulmonary alveolar proteinosis. These changes are the result of an interaction between the drugs and phospholipids which leads to an alteration in physicochemical properties of the phospholipids. Impairment of the digestion of altered pulmonary secretions in phagosomes of macrophages results in accumulation of foam cells in pulmonary alveoli. Impairment of the metabolism of altered phospholipids removed by autophagy induces an accumulation of myelinoid bodies. The administration of amphiphilic compounds thus causes pulmonary intra-alveolar histiocytosis which is a part of a drug-induced lysosomal storage or generalized lipidosis. The accumulation of drug-lipid complexes in myelinoid bodies and in pulmonary foam cells may lead to alteration of cellular functioning and to clinical disease. Currently over 50 amphiphilic drugs are known. Unique pharmacological properties necessitate clinical use of some of these drugs. The occurrence and severity of potential clinical side effects depend on the nature of each drug, dosage and duration of treatment, simultaneous administration of other drugs and foods, individual metabolic pattern of the patient and other factors. Further studies on factors preventing and potentiating adverse effects of amphiphilic drugs are indicated. Images FIGURE 1. FIGURE 2. FIGURE 3. FIGURE 4. FIGURE 5. FIGURE 6. FIGURE 7. FIGURE 8. FIGURE 9. FIGURE 10. PMID:6376111

  5. Chemotherapy-induced pulmonary hypertension: role of alkylating agents.

    PubMed

    Ranchoux, Benoît; Günther, Sven; Quarck, Rozenn; Chaumais, Marie-Camille; Dorfmüller, Peter; Antigny, Fabrice; Dumas, Sébastien J; Raymond, Nicolas; Lau, Edmund; Savale, Laurent; Jaïs, Xavier; Sitbon, Olivier; Simonneau, Gérald; Stenmark, Kurt; Cohen-Kaminsky, Sylvia; Humbert, Marc; Montani, David; Perros, Frédéric

    2015-02-01

    Pulmonary veno-occlusive disease (PVOD) is an uncommon form of pulmonary hypertension (PH) characterized by progressive obstruction of small pulmonary veins and a dismal prognosis. Limited case series have reported a possible association between different chemotherapeutic agents and PVOD. We evaluated the relationship between chemotherapeutic agents and PVOD. Cases of chemotherapy-induced PVOD from the French PH network and literature were reviewed. Consequences of chemotherapy exposure on the pulmonary vasculature and hemodynamics were investigated in three different animal models (mouse, rat, and rabbit). Thirty-seven cases of chemotherapy-associated PVOD were identified in the French PH network and systematic literature analysis. Exposure to alkylating agents was observed in 83.8% of cases, mostly represented by cyclophosphamide (43.2%). In three different animal models, cyclophosphamide was able to induce PH on the basis of hemodynamic, morphological, and biological parameters. In these models, histopathological assessment confirmed significant pulmonary venous involvement highly suggestive of PVOD. Together, clinical data and animal models demonstrated a plausible cause-effect relationship between alkylating agents and PVOD. Clinicians should be aware of this uncommon, but severe, pulmonary vascular complication of alkylating agents. PMID:25497573

  6. The significance of nanoparticles in particle-induced pulmonary fibrosis

    PubMed Central

    Byrne, James D; Baugh, John A

    2008-01-01

    Exposure to airborne nanoparticles contributes to many chronic pulmonary diseases. Nanoparticles, classified as anthropogenic and natural particles, and fibers of diameters less than 100 nm, have unrestricted access to most areas of the lung due to their size. Size relates to the deposition efficiency of the particle, with particles in the nano-range having the highest efficiencies. The deposition of nanoparticles in the lung can lead to chronic inflammation, epithelial injury, and further to pulmonary fibrosis. Cases of particle-induced pulmonary fibrosis, namely pneumoconiosis, are mostly occupationally influenced, and continue to be documented around the world. The tremendous growth of nanotechnology, however, has spurred fears of increased rates of pulmonary diseases, especially fibrosis. The severity of toxicological consequences warrants further examination of the effects of nanoparticles in humans, possible treatments and increased regulatory measures. PMID:18523535

  7. Urantide alleviates monocrotaline induced pulmonary arterial hypertension in Wistar rats.

    PubMed

    Mei, Yifang; Jin, Hong; Tian, Wei; Wang, Hao; Wang, Han; Zhao, Yanping; Zhang, Zhiyi; Meng, Fanchao

    2011-08-01

    Pulmonary arterial hypertension (PAH) is a serious disorder with poor prognosis. Urotensin II (UII) has been confirmed to be powerful vasoconstrictor than endothelin-1, which may play an important role in PAH development. The aim of this study is to observe the effects of urantide, a UII receptor antagonist, on monocrotaline (MCT) induced PAH in rats. 60 male Wistar rats were divided into six groups. For early treatment experiment, rats were divided into normal control group, MCT(4w) model group (MCT + saline × 3 wks from the 8th day of MCT injection) and urantide early treatment group (MCT + urantide 10 μg/kg/d × 3 wks, 1 week after MCT injection once). For late treatment experiment, rats were divided as controls, MCT(6w) model group (MCT + saline × 2 wks, 4 weeks after MCT injection once) and urantide late treatment group (MCT + urantide 10 μg/kg/d × 2 wks, 4 weeks after MCT injection once). At the end of experiments, mean pulmonary arterial pressures (mPAP) and mean blood pressure (MBP) of rats in each group were measured by catheterization. Right ventricular weight ratio was also weighed. Relaxation effects of urantide on intralobar pulmonary arterial rings of normal control and MCT(4w) model rats were investigated. Pulmonary artery remodeling was detected by hematoxylin and eosin (HE) staining and immunohistochemistry analysis. Serum nitric oxide (NO) levels in all six groups were assayed by ELISA kits. Urantide markedly reduced the mPAP levels of MCT induced PAH in both early and late treatment groups. It didn't change the MBP. Urantide dose-dependently relaxed the pulmonary arterial rings of normal control and MCT(4w) model rats. Moreover, N(G)-Nitro-l-arginine Methyl Ester (l-NAME) blocked the dilation response induced by urantide. In addition, urantide inhibited the pulmonary vascular remodeling remarkably. Serum NO level elevated in both early and late treatment rats with urantide infusion. These results suggest that urantide effectively alleviated

  8. Oxidative stress-induced autophagy: Role in pulmonary toxicity

    SciTech Connect

    Malaviya, Rama; Laskin, Jeffrey D.; Laskin, Debra L.

    2014-03-01

    Autophagy is an evolutionarily conserved catabolic process important in regulating the turnover of essential proteins and in elimination of damaged organelles and protein aggregates. Autophagy is observed in the lung in response to oxidative stress generated as a consequence of exposure to environmental toxicants. Whether autophagy plays role in promoting cell survival or cytotoxicity is unclear. In this article recent findings on oxidative stress-induced autophagy in the lung are reviewed; potential mechanisms initiating autophagy are also discussed. A better understanding of autophagy and its role in pulmonary toxicity may lead to the development of new strategies to treat lung injury associated with oxidative stress. - Highlights: • Exposure to pulmonary toxicants is associated with oxidative stress. • Oxidative stress is known to induce autophagy. • Autophagy is upregulated in the lung following exposure to pulmonary toxicants. • Autophagy may be protective or pathogenic.

  9. Development of a tantalum pentoxide Luneberg lens

    NASA Technical Reports Server (NTRS)

    Bryan, D. A.; Chubb, C. R.; Powers, J. K.; Reed, W. R.; Dalke, E. A.; Tomaschke, H. E.

    1982-01-01

    A process has been developed for the fabrication of a tantalum pentoxide waveguide Luneburg lens as the input collimator for an optical signal processing circuit on a silicon substrate, such as an integrated wavelength demultiplexer. The development of such a lens involved improvement of the deposition mask profile, reduction of surface scattering by underlaying the lens, reduction of edge scattering by using shims under the mask, and prediction and measurement of the TE-TM polarization aberration. It is shown that polarization aberration significantly affects the design of a demultiplexer system.

  10. Obaculactone protects against bleomycin-induced pulmonary fibrosis in mice.

    PubMed

    Wang, Xingqi; Ouyang, Zijun; You, Qian; He, Shuai; Meng, Qianqian; Hu, Chunhui; Wu, Xudong; Shen, Yan; Sun, Yang; Wu, Xuefeng; Xu, Qiang

    2016-07-15

    Idiopathic pulmonary fibrosis is a progressive, degenerative and almost irreversible disease. There is hardly an effective cure for lung damage due to pulmonary fibrosis. The purpose of this study was to evaluate the role of obaculactone in an already-assessed model of idiopathic pulmonary fibrosis induced by bleomycin administration. Mice were subjected to intratracheal instillation of bleomycin, and obaculactone was given orally after bleomycin instillation daily for 23days. Treatment with obaculactone ameliorated body weight loss, lung histopathology abnormalities and pulmonary collagen deposition, with a decrease of the inflammatory cell number and the cytokine level in bronchoalveolar lavage fluid. Moreover, obaculactone inhibited the expression of icam1, vcam1, inos and cox2, and attenuated oxidative stress in bleomycin-treated lungs. Importantly, the production of collagen I and α-SMA in lung tissues as well as the levels of TGF-β1, ALK5, p-Smad2 and p-Smad3 in lung homogenates was also reduced after obaculactone treatment. Finally, the TGF-β1-induced epithelial-mesenchymal transition via Smad-dependent and Smad-independent pathways was reversed by obaculactone. Collectively, these data suggest that obaculactone may be a promising drug candidate for the treatment of idiopathic pulmonary fibrosis. PMID:27180239

  11. EXERCISE-INDUCED PULMONARY HEMORRHAGE AFTER RUNNING A MARATHON

    EPA Science Inventory

    We report on a healthy 26-year-old male who had an exercise-induced pulmonary hemorrhage (EIPH) within 24 hours of running a marathon. There were no symptoms, abnormalities on exam, or radiographic infiltrates. He routinely participated in bronchoscopy research and the EIPH was e...

  12. Obstruction-induced pulmonary vascular remodeling.

    PubMed

    Chow, Ming-Jay; Zou, Yu; He, Huamei; McGowan, Francis X; Zurakowski, David; Zhang, Yanhang

    2011-11-01

    Pulmonary obstruction occurs in many common forms of congenital heart disease. In this study, pulmonary artery (PA) banding is used as a model for pulmonary stenosis. Significant remodeling of the vascular bed occurs as a result of a prolonged narrowing of the PAs, and here we quantify the biophysical and molecular changes proximal and distal to the obstruction. Main and branch PAs are harvested from banded and sham rabbits and their mechanical properties are assessed using a biaxial tensile tester. Measurements defined as initial and stiff slopes are taken, assuming a linear region at the start and end of the J-shaped stress-strain curves, along with a transitional knee point. Collagen, elastin assays, Movat's pentachrome staining, and Doppler protocols are used to quantify biochemical, structural, and physiological differences. The banded main PAs have significantly greater initial slopes while banded branch PAs have lower initial slopes; however, this change in mechanical behavior cannot be explained by the assay results as the elastin content in both main and branch PAs is not significantly different. The stiff slopes of the banded main PAs are higher, which is attributed to the significantly greater amounts of insoluble collagen. Shifting of the knee points reveals a decreased toe region in the main PAs but an opposite trend in the branch PAs. The histology results show a loss of integrity of the media, increase in ground substance, and dispersion of collagen in the banded tissue samples. This indicates other structural changes could have led to the mechanical differences in banded and normal tissue. PMID:22168741

  13. Drug-induced pulmonary arterial hypertension: a recent outbreak.

    PubMed

    Montani, David; Seferian, Andrei; Savale, Laurent; Simonneau, Gérald; Humbert, Marc

    2013-09-01

    Pulmonary arterial hypertension (PAH) is a rare disorder characterised by progressive obliteration of the pulmonary microvasculature resulting in elevated pulmonary vascular resistance and premature death. According to the current classification PAH can be associated with exposure to certain drugs or toxins, particularly to appetite suppressant intake drugs, such as aminorex, fenfluramine derivatives and benfluorex. These drugs have been confirmed to be risk factors for PAH and were withdrawn from the market. The supposed mechanism is an increase in serotonin levels, which was demonstrated to act as a growth factor for the pulmonary artery smooth muscle cells. Amphetamines, phentermine and mazindol were less frequently used, but are considered possible risk factors, for PAH. Dasatinib, dual Src/Abl kinase inhibitor, used in the treatment of chronic myelogenous leukaemia was associated with cases of severe PAH, potentially in part reversible after dasatinib withdrawal. Recently, several studies have raised the issue of potential endothelial dysfunction that could be induced by interferon, and a few cases of PAH have been reported with interferon therapy. PAH remains a rare complication of these drugs, suggesting possible individual susceptibility, and further studies are needed to identify patients at risk of drug-induced PAH. PMID:23997051

  14. Intercellular Adhesion Molecule 1 Knockout Abrogates Radiation Induced Pulmonary Inflammation

    NASA Astrophysics Data System (ADS)

    Hallahan, Dennis E.; Virudachalam, Subbulakshmi

    1997-06-01

    Increased expression of intercellular adhesion molecule 1 (ICAM-1; CD54) is induced by exposure to ionizing radiation. The lung was used as a model to study the role of ICAM-1 in the pathogenesis of the radiation-induced inflammation-like response. ICAM-1 expression increased in the pulmonary microvascular endothelium and not in the endothelium of larger pulmonary vessels following treatment of mice with thoracic irradiation. To quantify radiation-induced ICAM-1 expression, we utilized fluorescence-activated cell sorting analysis of anti-ICAM-1 antibody labeling of pulmonary microvascular endothelial cells from human cadaver donors (HMVEC-L cells). Fluorochrome conjugates and UV microscopy were used to quantify the fluorescence intensity of ICAM in the irradiated lung. These studies showed a dose- and time-dependent increase in ICAM-1 expression in the pulmonary microvascular endothelium. Peak expression occurred at 24 h, while threshold dose was as low as 2 Gy. To determine whether ICAM-1 is required for inflammatory cell infiltration into the irradiated lung, the anti-ICAM-1 blocking antibody was administered by tail vein injection to mice following thoracic irradiation. Inflammatory cells were quantified by immunofluorescence for leukocyte common antigen (CD45). Mice treated with the anti-ICAM-1 blocking antibody showed attenuation of inflammatory cell infiltration into the lung in response to ionizing radiation exposure. To verify the requirement of ICAM-1 in the inflammation-like radiation response, we utilized the ICAM-1 knockout mouse. ICAM-1 was not expressed in the lungs of ICAM-1-deficient mice following treatment with thoracic irradiation. ICAM-1 knockout mice had no increase in the inflammatory cell infiltration into the lung in response to thoracic irradiation. These studies demonstrate a radiation dose-dependent increase in ICAM-1 expression in the pulmonary microvascular endothelium, and show that ICAM-1 is required for inflammatory cell infiltration

  15. Intercellular adhesion molecule 1 knockout abrogates radiation induced pulmonary inflammation.

    PubMed

    Hallahan, D E; Virudachalam, S

    1997-06-10

    Increased expression of intercellular adhesion molecule 1 (ICAM-1; CD54) is induced by exposure to ionizing radiation. The lung was used as a model to study the role of ICAM-1 in the pathogenesis of the radiation-induced inflammation-like response. ICAM-1 expression increased in the pulmonary microvascular endothelium and not in the endothelium of larger pulmonary vessels following treatment of mice with thoracic irradiation. To quantify radiation-induced ICAM-1 expression, we utilized fluorescence-activated cell sorting analysis of anti-ICAM-1 antibody labeling of pulmonary microvascular endothelial cells from human cadaver donors (HMVEC-L cells). Fluorochrome conjugates and UV microscopy were used to quantify the fluorescence intensity of ICAM in the irradiated lung. These studies showed a dose- and time-dependent increase in ICAM-1 expression in the pulmonary microvascular endothelium. Peak expression occurred at 24 h, while threshold dose was as low as 2 Gy. To determine whether ICAM-1 is required for inflammatory cell infiltration into the irradiated lung, the anti-ICAM-1 blocking antibody was administered by tail vein injection to mice following thoracic irradiation. Inflammatory cells were quantified by immunofluorescence for leukocyte common antigen (CD45). Mice treated with the anti-ICAM-1 blocking antibody showed attenuation of inflammatory cell infiltration into the lung in response to ionizing radiation exposure. To verify the requirement of ICAM-1 in the inflammation-like radiation response, we utilized the ICAM-1 knockout mouse. ICAM-1 was not expressed in the lungs of ICAM-1-deficient mice following treatment with thoracic irradiation. ICAM-1 knockout mice had no increase in the inflammatory cell infiltration into the lung in response to thoracic irradiation. These studies demonstrate a radiation dose-dependent increase in ICAM-1 expression in the pulmonary microvascular endothelium, and show that ICAM-1 is required for inflammatory cell infiltration

  16. Molecular mechanisms of hypoxia-inducible factor-induced pulmonary arterial smooth muscle cell alterations in pulmonary hypertension.

    PubMed

    Veith, Christine; Schermuly, Ralph T; Brandes, Ralf P; Weissmann, Norbert

    2016-03-01

    Oxygen (O2) is essential for the viability and function of most metazoan organisms and thus is closely monitored at both the organismal and the cellular levels. However, alveoli often encounter decreased O2 levels (hypoxia), leading to activation of physiological or pathophysiological responses in the pulmonary arteries. Such changes are achieved by activation of transcription factors. The hypoxia-inducible factors (HIFs) are the most prominent hypoxia-regulated transcription factors in this regard. HIFs bind to hypoxia-response elements (HREs) in the promoter region of target genes, whose expression and translation allows the organism, amongst other factors, to cope with decreased environmental O2 partial pressure (pO2). However, prolonged HIF activation can contribute to major structural alterations, especially in the lung, resulting in the development of pulmonary hypertension (PH). PH is characterized by a rise in pulmonary arterial pressure associated with pulmonary arterial remodelling, concomitant with a reduced intravascular lumen area. Patients with PH develop right heart hypertrophy and eventually die from right heart failure. Thus, understanding the molecular mechanisms of HIF regulation in PH is critical for the identification of novel therapeutic strategies. This review addresses the relationship of hypoxia and the HIF system with pulmonary arterial dysfunction in PH. We particularly focus on the cellular and molecular mechanisms underlying the HIF-driven pathophysiological processes. PMID:26228924

  17. HEALTH AND ENVIRONMENTAL EFFECTS PROFILE FOR VANADIUM PENTOXIDE

    EPA Science Inventory

    The Health and Environmental Effects Profile for vanadium pentoxide was prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Solid Waste and Emergency Response to support listings of hazardou...

  18. Contribution of calcium-activated chloride channel to elevated pulmonary artery pressure in pulmonary arterial hypertension induced by high pulmonary blood flow

    PubMed Central

    Wang, Kai; Chen, Chuansi; Ma, Jianfa; Lao, Jinquan; Pang, Yusheng

    2015-01-01

    The correlation between calcium-activated chloride channel (CaCC) and pulmonary arterial hypertension (PAH) induced by high pulmonary blood flow remains uncertain. In this study, we investigated the possible role and effects of CaCC in this disease. Sixty rats were randomly assigned to normal, sham, and shunt groups. Rats in the shunt group underwent abdominal aorta and inferior vena cava shunt surgery. The pulmonary artery pressure was measured by catheterization. Pathological changes, right ventricle hypertrophy index (RVHI), arterial wall area/vessel area (W/V), and arterial wall thickness/vessel external diameter (T/D) were analyzed by optical microscopy. Electrophysiological characteristics of pulmonary arterial smooth muscle cells (PASMCs) were investigated using patch clamp technology. After 11 weeks of shunting, PAH and pulmonary vascular structural remodeling (PVSR) developed, accompanied by increased pulmonary pressure and pathological interstitial pulmonary changes. Compared with normal and sham groups, pulmonary artery pressure, RVHI, W/V, and T/D of the shunt group rats increased significantly. Electrophysiological results showed primary CaCC characteristics. Compared with normal and sham groups, membrane capacitance and current density of PASMCs in the shunt group increased significantly, which were subsequently attenuated following chloride channel blocker niflumic acid (NFA) treatment. To conclude, CaCC contributed to PAH induced by high pulmonary blood flow and may represent a potential target for treatment of PAH. PMID:25755701

  19. Contribution of calcium-activated chloride channel to elevated pulmonary artery pressure in pulmonary arterial hypertension induced by high pulmonary blood flow.

    PubMed

    Wang, Kai; Chen, Chuansi; Ma, Jianfa; Lao, Jinquan; Pang, Yusheng

    2015-01-01

    The correlation between calcium-activated chloride channel (CaCC) and pulmonary arterial hypertension (PAH) induced by high pulmonary blood flow remains uncertain. In this study, we investigated the possible role and effects of CaCC in this disease. Sixty rats were randomly assigned to normal, sham, and shunt groups. Rats in the shunt group underwent abdominal aorta and inferior vena cava shunt surgery. The pulmonary artery pressure was measured by catheterization. Pathological changes, right ventricle hypertrophy index (RVHI), arterial wall area/vessel area (W/V), and arterial wall thickness/vessel external diameter (T/D) were analyzed by optical microscopy. Electrophysiological characteristics of pulmonary arterial smooth muscle cells (PASMCs) were investigated using patch clamp technology. After 11 weeks of shunting, PAH and pulmonary vascular structural remodeling (PVSR) developed, accompanied by increased pulmonary pressure and pathological interstitial pulmonary changes. Compared with normal and sham groups, pulmonary artery pressure, RVHI, W/V, and T/D of the shunt group rats increased significantly. Electrophysiological results showed primary CaCC characteristics. Compared with normal and sham groups, membrane capacitance and current density of PASMCs in the shunt group increased significantly, which were subsequently attenuated following chloride channel blocker niflumic acid (NFA) treatment. To conclude, CaCC contributed to PAH induced by high pulmonary blood flow and may represent a potential target for treatment of PAH. PMID:25755701

  20. Inflammatory mechanisms of pulmonary injury induced by mustards.

    PubMed

    Malaviya, Rama; Sunil, Vasanthi R; Venosa, Alessandro; Vayas, Kinal N; Heck, Diane E; Laskin, Jeffrey D; Laskin, Debra L

    2016-02-26

    Exposure of humans and animals to vesicants, including sulfur mustard (SM) and nitrogen mustard (NM), causes severe and debilitating damage to the respiratory tract. Both acute and long term pathological consequences are observed in the lung following a single exposure to these vesicants. Evidence from our laboratories and others suggest that macrophages and the inflammatory mediators they release play an important role in mustard-induced lung injury. In this paper, the pathogenic effects of SM and NM on the lung are reviewed, along with the potential role of inflammatory macrophages and mediators they release in mustard-induced pulmonary toxicity. PMID:26478570

  1. Pulmonary leukosequestration induced by hind limb ischemia.

    PubMed Central

    Anner, H; Kaufman, R P; Kobzik, L; Valeri, C R; Shepro, D; Hechtman, H B

    1987-01-01

    Lower torso ischemia leads to acute respiratory failure, an event associated with the accumulation of inflammatory cells in the lungs. This study tests whether ischemia-induced eicosanoid synthesis leads to polymorphonuclear leukocyte (PMN) accumulation in the lungs. Anesthetized rats (N = 51) were randomized into five groups: nonischemic sham rats (N = 10); the remaining four groups were rats made ischemic for 4 hours with bilateral thigh tourniquets treated just before tourniquet release with saline vehicle (N = 17): the thromboxane (Tx) synthase inhibitor OKY-046 (Ono Pharmaceutica, Osaka, Japan) 2 mg/kg intravenously every 2 hours (N = 8); the lipoxygenase inhibitor diethylcarbamazine (DEC) (Sigma, St. Louis, MO) 0.2 mg/kg/min intravenously (N = 8); the platelet-activating factor receptor antagonist SRI (Sandoz Inc., East Hanover, NJ) 63-072 3 mg/kg intravenously every 30 minutes (N = 8). Four hours after ischemia, plasma TxB2 levels in the ischemic placebo-treated group was 3570 +/- 695 pg/mL, compared with 495 +/- 73 pg/mL in sham rats (p less than 0.001). Lung microscopy showed foci of proteinaceous exudate in alveoli and 121 +/- 10 PMN/20 high power fields (HPF) compared with 59 +/- 9 PMN/20 HPF in the sham group (p less than 0.001). One day after ischemia PMN accumulations remained elevated at 119 PMN/20 HPF. Pretreatment with OKY-046 led to reduced TxB2 levels of 149 +/- 17 pg/mL, normal lung histology, and 83 +/- 13 PMN/20 HPF, a value similar to that of the sham group and lower than that of the placebo-treated group (p less than 0.05). Treatment with DEC yielded TxB2 levels of 1419 +/- 492 pg/mL, which was lower than that of the placebo group (p less than 0.05) but higher than that of the sham group (p less than 0.05). Microscopy showed normal lungs with 79 +/- 7 PMN/20 HPF lower than the placebo group (p less than 0.05). SRI 63-072 did not inhibit Tx synthesis or leukosequestration in the lungs. Platelet counts decreased in all groups relative to sham

  2. Calcium antagonists, diltiazem and nifedipine, protect broilers against low temperature-induced pulmonary hypertension and pulmonary vascular remodeling.

    PubMed

    Yang, Ying; Gao, Mingyu; Guo, Yuming; Qiao, Jian

    2010-08-01

    This study was designed to determine whether calcium antagonists, diltiazem and nifedipine, can depress low temperature-induced pulmonary hypertension (PH) in broilers (also known as ascites) and to characterize their efficacy on hemodynamics and pulmonary artery function. Chicks were randomly allocated into six experimental groups and orally administered with vehicle, 5.0 mg/kg body weight (BW)/12 h nifedipine or 15.0 mg/kg BW/12 h diltiazem from 16 to 43 days of age under low temperature. The mean pulmonary arterial pressure (mPAP), the ascites heart index (AHI), the erythrocyte packed cell volume (PCV) and the relative percentage of medial pulmonary artery thickness were examined on days 29, 36 and 43. The data showed that administration of diltiazem protected broilers from low temperature-induced pulmonary hypertension and vascular remodeling. Although nifedipine prevented mPAP from increasing during the early stage, it did not suppress the development of PH during the late stage and did not keep heart rate (HR), PCV, AHI and the thickness of pulmonary small artery smooth muscle layer at the normal levels. Taken together, our results showed that diltiazem can effectively prevent low temperature-induced pulmonary hypertension in broilers with fewer side-effects and may be a potential compound for the prevention of this disease in poultry industry. PMID:20662820

  3. Hierarchically structured vanadium pentoxide-polymer hybrid materials.

    PubMed

    Tritschler, Ulrich; Zlotnikov, Igor; Zaslansky, Paul; Fratzl, Peter; Schlaad, Helmut; Cölfen, Helmut

    2014-05-27

    Biomimetic composite materials consisting of vanadium pentoxide (V2O5) and a liquid crystal (LC) "gluing" polymer were manufactured exhibiting six structural levels of hierarchy, formed through LC phases. The organic matrix was a polyoxazoline with pendant cholesteryl and carboxyl units, forming a lyotropic phase with the same structural orientation extending up to hundreds of micrometers upon shearing, and binding to V2O5 via hydrogen bridges. Composites consisting of V2O5-LC polymer hybrid fibers with a pronounced layered structuring were obtained. The V2O5-LC polymer hybrid fibers consist of aligned V2O5 ribbons, composed of self-assembled V2O5 sheets, encasing a chiral nematic polymer matrix. The structures of the V2O5-LC polymer composites strongly depend on the preparation method, i.e., the phase-transfer method from aqueous to organic medium, in which the polymer forms LC phases. Notably, highly defined micro- and nanostructures were obtained when initiating the synthesis using V2O5 tactoids with preoriented nanoparticle building units, even when using isotropic V2O5 dispersions. Shear-induced hierarchical structuring of the composites was observed, as characterized from the millimeter and micrometer down to the nanometer length scales using complementary optical and electron microscopy, SAXS, μCT, and mechanical nanoindentation. PMID:24716494

  4. Niflumic Acid Attenuated Pulmonary Artery Tone and Vascular Structural Remodeling of Pulmonary Arterial Hypertension Induced by High Pulmonary Blood Flow In Vivo.

    PubMed

    Wang, Kai; Ma, Jianfa; Pang, Yusheng; Lao, Jinquan; Pan, Xuanren; Tang, Qiaoyun; Zhang, Feng; Su, Danyan; Qin, Suyuan; Shrestha, Arnav Prasad

    2015-10-01

    Calcium-activated chloride channels (CaCCs) play a vital role in regulating pulmonary artery tone during pulmonary arterial hypertension (PAH) induced by high blood flow. The role of CaCCs inhibitor niflumic acid (NFA) in vivo during this process requires further investigation. We established the PAH model by abdominal shunt surgery and treated with NFA in vivo. Fifty rats were randomly divided into normal, sham, shunt, NFA group 1 (0.2 mg/kg), and NFA group 2 (0.4 mg/kg). Pathological changes, right ventricle hypertrophy index, arterial wall area/vessel area, and arterial wall thickness/vessel external diameter were analyzed. Then contraction reactions of pulmonary arteries were measured. Finally, the electrophysiological characteristics of pulmonary arterial smooth muscle cells were investigated using patch-clamp technology. After 11 weeks of shunting, PAH developed, accompanied with increased right ventricle hypertrophy index, arterial wall area/vessel area, and arterial wall thickness/vessel external diameter. In the NFA treatment groups, the pressure and pathological changes were alleviated. The pulmonary artery tone in the shunt group increased, whereas it decreased after NFA treatment. The current density of CaCC was higher in the shunt group, and it was decreased in the NFA treatment groups. In conclusion, NFA attenuated pulmonary artery tone and structural remodeling in PAH induced by high pulmonary blood flow in vivo. CaCCs were involved and the augmented current density was alleviated by NFA treatment. PMID:26132368

  5. Ligustrazine effect on lipopolysaccharide-induced pulmonary damage in rats.

    PubMed

    Wang, Huiqi; Chen, Yuanzhuo; Li, Wenjie; Li, Congye; Zhang, Xiangyu; Peng, Hu; Gao, Chengjin

    2015-09-01

    We investigated the effectiveness of ligustrazine (tetramethylpyrazine, TMP) in alleviating pulmonary damage induced by lipopolysaccharide (LPS). Twenty-four healthy male Sprague-Dawley rats were randomly divided into three groups: the blank group, LPS group, and TMP treatment group (TMP group). The LPS group was intraperitoneally injected with LPS (20mg/kg), and the TMP group was intraperitoneally injected with LPS (20mg/kg) and ligustrazine (80mg/kg). Blood gas analysis, hematoxylin-eosin staining dye extravasation and diffuse alveolar damage (DAD) score, the wet/dry lung tissue (W/D) ratios, the expression of CD31+ vascular endothelial microparticles (EMPs), tumor necrosis factor alpha (TNF-α) levels, and the protein expression of Rho-associated coiled-coil-forming protein kinase (ROCK) II and Toll-like receptor 4 (TLR4) were analyzed. Compared with the blank group, the arterial partial pressure of oxygen (PaO2) declined in both 1 and 4h (P<0.01), the W/D ratio and DAD score increased (P<0.01), and the TNF-α levels in serum, CD31+ EMPs, and protein expression of ROCK II and TLR4 were significantly increased (P<0.01) in the LPS group. Compared with the LPS group, PaO2 significantly increased in the TMP group at 4h (P<0.05), while the W/D ratio and DAD score were significantly decreased in the TMP group (P<0.01). TNF-α levels, CD31+ EMPs, and protein expression of ROCK II and TLR4 were significantly decreased in the TMP group compared with the LPS group (P<0.01). This study demonstrated that TMP can alleviate LPS-induced pulmonary damage by attenuating pulmonary vascular permeability and CD31+ EMP levels in the plasma, reducing the release of the inflammatory mediator TNF-α and inhibiting the protein expression of ROCK II and TLR4. PMID:26088147

  6. Waveguide lasers in ytterbium-doped tantalum pentoxide on silicon.

    PubMed

    Aghajani, A; Murugan, G S; Sessions, N P; Apostolopoulos, V; Wilkinson, J S

    2015-06-01

    A waveguide laser in an ytterbium-doped tantalum pentoxide film is reported. The waveguide is formed of a rib of sputtered tantalum pentoxide on top of oxidized silicon with an over-cladding of silica. Emission at a wavelength of 1025 nm was achieved with an absorbed pump power threshold and slope efficiency of ≈29  mW and 27%, respectively, for a cavity formed by a high reflector mirror and an estimated 12% Fresnel reflection from the bare end-face at the output. PMID:26030554

  7. Upregulation of Transient Receptor Potential Canonical Channels Contributes to Endotoxin-Induced Pulmonary Arterial Stenosis

    PubMed Central

    Chen, Gui-Lan; Jiang, Hongni; Zou, Fangdong

    2016-01-01

    Background Septic shock is a pathologic condition caused by endotoxin-producing bacteria, and often associated with severe pulmonary hypertension. Inflammation is a major systemic response to endotoxin; however, it is unknown whether endotoxin has a direct impact on pulmonary arteries that contributes to pathogenesis of pulmonary hypertension. Material/Methods Rat pulmonary arteries and primary pulmonary arterial smooth muscle cells (PASMCs) were cultured in vitro and treated with lipopolysaccharide (LPS) and blockers of transient receptor potential canonical (TRPC) channels. Neointimal growth and arterial stenosis were observed on cryosections of cultured pulmonary arteries. Proliferation of PASMCs was examined by a WST-1 (water-soluble tetrazolium salt) assay. Expression of TRPC genes in pulmonary arteries and PASMCs were detected and quantified by real-time polymerase chain reaction and Western blotting. Results LPS significantly induced neointimal growth and stenosis of pulmonary arteries and promoted proliferation of PASMCs. TRPC channel blockers 2-aminoethoxydiphenyl borate and SKF-96365 inhibited LPS-induced remodeling of pulmonary arteries and PASMC proliferation. Expression of TRPC1/3/4/6 was detected in pulmonary arteries and PASMCs. LPS treatment dramatically increased the expression of TRPC3 and TRPC4 at both messenger RNA and protein levels. Conclusions LPS stimulates stenosis of pulmonary arteries through enhancement of TRPC-mediated Ca2+ entry into PASMCs, which is caused by upregulation of TRPC3 and TRPC4 channels. PMID:27471122

  8. Eugenol attenuates pulmonary damage induced by diesel exhaust particles.

    PubMed

    Zin, Walter A; Silva, Ana G L S; Magalhães, Clarissa B; Carvalho, Giovanna M C; Riva, Douglas R; Lima, Crystianne C; Leal-Cardoso, Jose H; Takiya, Christina M; Valença, Samuel S; Saldiva, Paulo H N; Faffe, Débora S

    2012-03-01

    Environmentally relevant doses of inhaled diesel particles elicit pulmonary inflammation and impair lung mechanics. Eugenol, a methoxyphenol component of clove oil, presents in vitro and in vivo anti-inflammatory and antioxidant properties. Our aim was to examine a possible protective role of eugenol against lung injuries induced by diesel particles. Male BALB/c mice were divided into four groups. Mice received saline (10 μl in; CTRL group) or 15 μg of diesel particles DEP (15 μg in; DIE and DEUG groups). After 1 h, mice received saline (10 μl; CTRL and DIE groups) or eugenol (164 mg/kg; EUG and DEUG group) by gavage. Twenty-four hours after gavage, pulmonary resistive (ΔP1), viscoelastic (ΔP2) and total (ΔPtot) pressures, static elastance (Est), and viscoelastic component of elastance (ΔE) were measured. We also determined the fraction areas of normal and collapsed alveoli, amounts of polymorpho- (PMN) and mononuclear cells in lung parenchyma, apoptosis, and oxidative stress. Est, ΔP2, ΔPtot, and ΔE were significantly higher in the DIE than in the other groups. DIE also showed significantly more PMN, airspace collapse, and apoptosis than the other groups. However, no beneficial effect on lipid peroxidation was observed in DEUG group. In conclusion, eugenol avoided changes in lung mechanics, pulmonary inflammation, and alveolar collapse elicited by diesel particles. It attenuated the activation signal of caspase-3 by DEP, but apoptosis evaluated by TUNEL was avoided. Finally, it could not avoid oxidative stress as indicated by malondialdehyde. PMID:22194320

  9. Nebivolol has a beneficial effect in monocrotaline-induced pulmonary hypertension.

    PubMed

    Pankey, Edward A; Edward, Justin A; Swan, Kevin W; Bourgeois, Camille R T; Bartow, Matthew J; Yoo, Daniel; Peak, Taylor A; Song, Bryant M; Chan, Ryan A; Murthy, Subramanyam N; Prieto, Minolfa C; Giles, Thomas D; Kadowitz, Philip J

    2016-07-01

    Pulmonary hypertension is a rare disorder that, without treatment, is progressive and fatal within 3-4 years. Current treatment involves a diverse group of drugs that target the pulmonary vascular bed. In addition, strategies that increase nitric oxide (NO) formation have a beneficial effect in rodents and patients. Nebivolol, a selective β1 adrenergic receptor-blocking agent reported to increase NO production and stimulate β3 receptors, has vasodilator properties suggesting that it may be beneficial in the treatment of pulmonary hypertension. The present study was undertaken to determine whether nebivolol has a beneficial effect in monocrotaline-induced (60 mg/kg) pulmonary hypertension in the rat. These results show that nebivolol treatment (10 mg/kg, once or twice daily) attenuates pulmonary hypertension, reduces right ventricular hypertrophy, and improves pulmonary artery remodeling in monocrotaline-induced pulmonary hypertension. This study demonstrates the presence of β3 adrenergic receptor immunoreactivity in pulmonary arteries and airways and that nebivolol has pulmonary vasodilator activity. Studies with β3 receptor agonists (mirabegron, BRL 37344) and antagonists suggest that β3 receptor-mediated decreases in systemic arterial pressure occur independent of NO release. Our results suggest that nebivolol, a selective vasodilating β1 receptor antagonist that stimulates β3 adrenergic receptors and induces vasodilation by increasing NO production, may be beneficial in treating pulmonary hypertensive disorders. PMID:27172427

  10. Role of oxidative stress in thuringiensin-induced pulmonary toxicity

    SciTech Connect

    Tsai, S.-F. . E-mail: sftsai@tactri.gov.tw; Yang Chi; Liu, B.-L.; Hwang, J.-S.; Ho, S.-P. . E-mail: spho@dragon.nchu.edu.tw

    2006-10-15

    To understand the effect of thuringiensin on the lungs tissues, male Sprague-Dawley rats were administrated with thuringiensin by intratracheal instillation at doses 0.8, 1.6 and 3.2 mg/kg of body weight, respectively. The rats were sacrificed 4 h after treatment, and lungs were isolated and examined. Subsequently, an effective dose of 1.6 mg/kg was selected for the time course study (4, 8, 12, and 24 h). Intratracheal instillation of thuringiensin resulted in lung damage, as evidenced by increase in lung weight and decrease in alkaline phosphatase (10-54%), an enzyme localized primarily in pulmonary alveolar type II epithelial cells. Furthermore, the administration of thuringiensin caused increases in lipid peroxidation (21-105%), the indices of lung injury. In addition, the superoxide dismutase (SOD) and glutathione (GSH) activities of lung tissue extracts were measured to evaluate the effect of thuringiensin on antioxidant defense system. The SOD activity and GSH content in lung showed significant decreases in a dose-related manner with 11-21% and 15-37%, respectively. Those were further supported by the release of proinflammatory cytokines, as indicated by increases in IL-1{beta} (229-1017%) and TNF-{alpha} (234%) levels. Therefore, the results demonstrated that changes in the pulmonary oxidative-antioxidative status might play an important role in the thuringiensin-induced lung injury.

  11. IRIS Toxicological Review of Vanadium Pentoxide (Interagency Science Consultation Draft)

    EPA Science Inventory

    On September 30, 2011, the draft Toxicological Review of Vanadium Pentoxide and the charge to external peer reviewers were released for external peer review and public comment. The Toxicological Review and charge were reviewed internally by EPA and by other federal agencies and W...

  12. IRIS Toxicological Review of Vanadium Pentoxide (External Review Draft)

    EPA Science Inventory

    This vanadium pentoxide reassessment consists of an oral reference dose (RfD), an inhalation reference concentration (RfC), an inhalation unit risk (IUR) and a cancer weight of evidence descriptor. This is the first assessment developing an RfC or IUR for this compound. This as...

  13. Metformin Reduces Bleomycin-induced Pulmonary Fibrosis in Mice.

    PubMed

    Choi, Sun Mi; Jang, An Hee; Kim, Hyojin; Lee, Kyu Hwa; Kim, Young Whan

    2016-09-01

    Metformin has anti-inflammatory and anti-fibrotic effects. We investigated whether metformin has an inhibitory effect on bleomycin (BLM)-induced pulmonary fibrosis in a murine model. A total of 62 mice were divided into 5 groups: control, metformin (100 mg/kg), BLM, and BLM with metformin (50 mg/kg or 100 mg/kg). Metformin was administered to the mice orally once a day from day 1. We sacrificed half of the mice on day 10 and collected the bronchoalveolar lavage fluid (BALF) from their left lungs. The remaining mice were sacrificed and analyzed on day 21. The right lungs were harvested for histological analyses. The messenger RNA (mRNA) levels of epithelial-mesenchymal transition markers were determined via analysis of the harvested lungs on day 21. The mice treated with BLM and metformin (50 mg/kg or 100 mg/kg) showed significantly lower levels of inflammatory cells in the BALF compared with the BLM-only mice on days 10 and 21. The histological examination revealed that the metformin treatment led to a greater reduction in inflammation than the treatment with BLM alone. The mRNA levels of collagen, collagen-1, procollagen, fibronectin, and transforming growth factor-β in the metformin-treated mice were lower than those in the BLM-only mice on day 21, although statistical significance was observed only in the case of procollagen due to the small number of live mice in the BLM-only group. Additionally, treatment with metformin reduced fibrosis to a greater extent than treatment with BLM alone. Metformin suppresses the inflammatory and fibrotic processes of BLM-induced pulmonary fibrosis in a murine model. PMID:27510385

  14. Thrombospondin-1 null mice are resistant to hypoxia-induced pulmonary hypertension

    PubMed Central

    2010-01-01

    Background and objective Chronic hypoxia induces pulmonary hypertension in mice. Smooth muscle cell hyperplasia and medial thickening characterize the vasculature of these animals. Thrombospondin-1 null (TSP-1-/-) mice spontaneously develop pulmonary smooth muscle cell hyperplasia and medial thickening. In addition, TSP-1 produced by the pulmonary endothelium inhibits pulmonary artery smooth muscle cell growth. Based on these observations we sought to describe the pulmonary vascular changes in TSP-1-/- mice exposed to chronic hypoxia. Methods We exposed TSP-1-/- and wild type (WT) mice to a fraction of inspired oxygen (FiO2) of 0.1 for up to six weeks. Pulmonary vascular remodeling was evaluated using tissue morphometrics. Additionally, right ventricle systolic pressures (RVSP) and right ventricular hypertrophy by right ventricle/left ventricle + septum ratios (RV/LV+S) were measured to evaluate pulmonary hypertensive changes. Finally, acute pulmonary vasoconstriction response in both TSP-1-/- and WT mice was evaluated by acute hypoxia and U-46619 (a prostaglandin F2 analog) response. Results In hypoxia, TSP-1-/- mice had significantly lower RVSP, RV/LV+S ratios and less pulmonary vascular remodeling when compared to WT mice. TSP-1-/- mice also had significantly lower RVSP in response to acute pulmonary vasoconstriction challenges than their WT counterparts. Conclusion TSP-1-/- mice had diminished pulmonary vasoconstriction response and were less responsive to hypoxia-induced pulmonary hypertension than their wild type counterparts. This observation suggests that TSP-1 could play an active role in the pathogenesis of pulmonary hypertension associated with hypoxia. PMID:20441584

  15. Lysyl oxidase promotes epithelial-to-mesenchymal transition during paraquat-induced pulmonary fibrosis.

    PubMed

    Wang, Jinfeng; Zhu, Yong; Tan, Jiuting; Meng, Xiaoxiao; Xie, Hui; Wang, Ruilan

    2016-02-01

    Lysyl oxidase (LOX) is a copper-dependent amine oxidase that plays a critical role in pulmonary fibrosis. Our previous study demonstrated that epithelial-to-mesenchymal transition (EMT) was strongly associated with paraquat (PQ) induced pulmonary fibrosis. This present study was aimed to evaluate the potential involvement of LOX on EMT in the process of pulmonary fibrosis induced by PQ. We established an in vivo rat model and an in vitro cell model induced by PQ treatment and found that LOX protein expression was significantly up-regulated and collagen deposition was enhanced in rats. The EMT process was strongly found in A549 and RLE-6TN cells after PQ exposure. After inactivating LOX with an inhibitor, pulmonary fibrosis was significantly reduced and EMT was also suppressed. Additionally, small interfering RNA (siRNA) targeting LOX was used to silence LOX expression to observe EMT in A549 cells. As a result, LOX could promote the progress of EMT, and inactivating LOX alleviated the EMT process in PQ-induced pulmonary fibrosis and mesenchymal-to-epithelial transition (MET) occurred after inactivating LOX in vitro and in vivo. In conclusion, LOX could promote the progress of EMT and inactivating LOX alleviated EMT in PQ-induced pulmonary fibrosis. Therefore, LOX could potentially be a new candidate therapeutic target for pulmonary fibrosis induced by PQ by regulating the balance between EMT and MET. PMID:26670953

  16. Mice lacking the Raf-1 kinase inhibitor protein exhibit exaggerated hypoxia-induced pulmonary hypertension

    PubMed Central

    Morecroft, I; Doyle, B; Nilsen, M; Kolch, W; Mair, K; MacLean, MR

    2011-01-01

    BACKGROUND AND PURPOSE Increased pulmonary vascular remodelling, pulmonary arterial pressure and pulmonary vascular resistance characterize the development of pulmonary arterial hypertension (PAH). Activation of the Raf/mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK)1/2 is thought to play an important role in PAH and Raf-1 kinase inhibitor protein (RKIP), negatively regulates this pathway. This study investigated whether genetic deletion of RKIP (and hence ERK1/2 up-regulation) resulted in a pulmonary hypertensive phenotype in mice and investigated a role for RKIP in mitogen-regulated proliferative responses in lung fibroblasts. EXPERIMENTAL APPROACH Pulmonary vascular haemodynamics and remodelling were assessed in mice genetically deficient in RKIP (RKIP−/−) after 2 weeks of either normoxia or hypoxia. Immunoblotting and immunohistochemistry were used to examine phosphorylation of Raf-1, RKIP and ERK1/2 in mouse pulmonary arteries. In vitro, RKIP inhibition of mitogen signalling was analysed in CCL39 hamster lung fibroblasts. KEY RESULTS RKIP−/− mice demonstrated elevated indices of PAH and ERK1/2 phosphorylation compared with wild-type (WT) mice. Hypoxic RKIP−/− mice exhibited exaggerated PAH indices. Hypoxia increased phosphorylation of Raf-1, RKIP and ERK1/2 in WT mouse pulmonary arteries and Raf-1 phosphorylation in RKIP−/− mouse pulmonary arteries. In CCL39 cells, inhibition of RKIP potentiated mitogen-induced proliferation and phosphorylation of RKIP, and Raf-1. CONCLUSIONS AND IMPLICATIONS The lack of RKIP protein resulted in a pulmonary hypertensive phenotype, exaggerated in hypoxia. Hypoxia induced phosphorylation of RKIP signalling elements in WT pulmonary arteries. RKIP inhibition potentiated mitogen-induced proliferation in lung fibroblasts. These results provide evidence for the involvement of RKIP in suppressing the development of hypoxia-induced PAH in mice. PMID:21385176

  17. Calcitriol inhibits bleomycin-induced early pulmonary inflammatory response and epithelial-mesenchymal transition in mice.

    PubMed

    Tan, Zhu-Xia; Chen, Yuan-Hua; Xu, Shen; Qin, Hou-Ying; Zhang, Cheng; Zhao, Hui; Xu, De-Xiang

    2016-01-01

    Early pulmonary inflammation and epithelial-mesenchymal transition (EMT) play important roles during lung fibrosis. Increasing evidence demonstrates that calcitriol, the active form of vitamin D3, has anti-inflammatory activities. The aim of this study was to investigate the effects of calcitriol on bleomycin (BLM)-induced early pulmonary inflammation and subsequent EMT. Mice were intratracheally injected with BLM (3.0mg/kg). In three calcitriol+BLM groups, mice were intraperitoneal (i.p.) injected with different doses of calcitriol (0.2, 1.0 or 5.0 μg/kg) daily, beginning at 48 h before BLM injection. Twenty-four hours, seven and fourteen days after BLM injection, pulmonary inflammation and EMT were evaluated. As expected, BLM-induced infiltration of inflammatory cells in the lungs was attenuated by calcitriol. BLM-induced pulmonary inflammatory cytokines were repressed by calcitriol. Moreover, BLM-induced nuclear translocation of nuclear factor kappa B (NF-κB) p65 was blocked by calcitriol. In addition, BLM-induced phosphorylation of pulmonary p38 MAPK and protein kinase B (Akt) was inhibited by calcitriol. Further analysis showed that BLM-induced α-smooth muscle actin (α-SMA), a marker for EMT in the lungs, was significantly attenuated by calcitriol. BLM-induced transforming growth factor-beta 1 (TGF-β1) up-regulation and Smad phosphorylation were attenuated by calcitriol. In conclusion, calcitriol inhibits BLM-induced early pulmonary inflammation and subsequent EMT. PMID:26520185

  18. Genistein attenuates low temperature induced pulmonary hypertension in broiler chicks by modulating endothelial function.

    PubMed

    Yang, Ying; Gao, Mingyu; Wu, Zhenlong; Guo, Yuming

    2010-12-15

    Pulmonary arterial hypertension is characterized by high pulmonary blood pressure, vascular remodeling and right ventricular hypertrophy. In the present study, we investigated whether genistein would prevent the development of low temperature-induced pulmonary hypertension in broilers. Hemodynamic parameters, vascular remodeling, the expression of endothelial nitric oxide and endothelin-1 content in lung tissue were evaluated. The results demonstrated that genistein significantly reduced pulmonary arterial hypertension and suppressed pulmonary arterial vascular remodeling without affecting broilers' performance. The beneficial effects appeared to be mediated by restoring endothelial function especially endothelial nitric oxide and endothelin-1, two critical vasoactive molecules that associated with the development of hypertension. Genistein supplementation might be a potential therapeutic strategy for the treatment of pulmonary hypertension. PMID:20854807

  19. Sodium hydrosulfide prevents hypoxia-induced pulmonary arterial hypertension in broilers.

    PubMed

    Yang, Y; Zhang, B K; Liu, D; Nie, W; Yuan, J M; Wang, Z; Guo, Y M

    2012-01-01

    1. The aim of the study was to determine if H(2)S is involved in the development of hypoxia-induced pulmonary hypertension in broilers, a condition frequently observed in a variety of cardiac and pulmonary diseases. 2. Two-week-old broilers were reared under normoxic conditions or exposed to normobaric hypoxia (6 h/day) with tissue levels of H(2)S adjusted by administering sodium hydrosulfide (NaHS, 10 µmol/kg body weight/day). Mean pulmonary arterial pressure, right ventricular mass, plasma and tissue H(2)S levels, the expression of cystathionine-β-synthase (CSE) and vascular remodeling were determined at 35 d of age. 3. Exposure to hypoxia-induced pulmonary arterial hypertension was characterized by elevated pulmonary pressure, right ventricular hypertrophy and vascular remodeling. This was accompanied by decreased expression of CSE and decreased concentrations of plasma and tissue H(2)S. 4. Hypoxia-induced pulmonary hypertension was significantly reduced by administration of NaHS but this protective effect was largely abolished by D, L-propargylglycerine, an inhibitor of CSE. 5. The results indicate that H(2)S is involved in the development of hypoxia-induced pulmonary hypertension. Supplementing NaHS or H(2)S could be a strategy for reducing hypoxia-induced hypertension in broilers. PMID:23281754

  20. Effect of alpha and beta adrenergic blockade on epinephrine induced pulmonary insufficiency.

    PubMed

    Berk, J L; Hagen, J F; Koo, R

    1976-04-01

    Recent studies demonstrated that epinephrine causes significant pulmonary A-V shunting. This study reports the effect of alpha and beta adrenergic blockade on this shunting. Sixty-three anesthetized mongrel dogs were ventilated with a mechanical respirator. Measurements of (1) the pulmonary shunt, (2) cardiac output, (3) mean pulmonary artery, pulmonary capillary wedge and systemic pressures, and (4) pulmonary and systemic vascular resistances were obtained at 5, 15 and 30 minute intervals during the first hour and hourly for 5 hours. Fifteen dogs received no treatment. All others received epinephrine hydrochloride, 2 mug/kg/min for 5 hours. Ten received epinephrine only. Ten were pretreated with propranolol hydrochloride, 250 mug/kg, 12 with phenoxybenzamine, 1 mg/kg, and 16 with phenoxybenzamine and propranolol. Propranolol significantly decreased the epinephrine induced pulmonary shunt at all times and was the most effective drug. Phenoxybenzamine decreased the early shunting, but less than propranolol, and did not decrease the late shunting. Blockade with propranolol and phenoxybenzamine was less effective than propranolol alone. Based on the observed hemodynamic changes it was suggested that beta blockade is effective in reducing epinephrine induced pulmonary insufficiency by favorably altering the flow and distribution of pulmonary blood flow which in turn decreases epinephrine induced ventilation-perfusion inequalities and capillary hypertension both of which result in shunting. Conversely phenoxybenzamine has an unfavorable effect on the pulmonary flow. These studies support previous work in animals and man which showed that beta adrenergic stimulation is important in the pathogenesis of pulmonary insufficiency. Because the amounts of epinephrine used produce blood levels observed in critical illness, these studies add support to a relationship between the increased catecholamine stimulation of critical illness and the associated and often unexplained

  1. The Chinese Herbal Medicine Formula mKG Suppresses Pulmonary Fibrosis of Mice Induced by Bleomycin

    PubMed Central

    Gao, Ying; Yao, Li-Fu; Zhao, Yang; Wei, Li-Man; Guo, Peng; Yu, Meng; Cao, Bo; Li, Tan; Chen, Hong; Zou, Zhong-Mei

    2016-01-01

    Pulmonary fibrosis (PF) is a serious progressive lung disease and it originates from inflammation-induced parenchymal injury with excessive extracellular matrix deposition to result in the destruction of the normal lung architecture. Modified Kushen Gancao Formula (mKG), derived from traditional Chinese herbal medicine, has a prominent anti-inflammatory effect. The present study is to explore the inhibitory effects of mKG on bleomycin (BLM)-induced pulmonary fibrosis in mice. mKG significantly decreased pulmonary alveolitis, fibrosis scores, and interleukin-6 (IL-6), interleukin-17 (IL-17), transforming growth factor-β (TGF-β) and hydroxyproline (HYP) levels in lung tissue of mice compared with BLM treatment. It markedly alleviated the increase of HYP content in the lung tissues and pathologic changes of pulmonary fibrosis caused by BLM instillation. In conclusion, mKG has an anti-fibrotic effect and might be employed as a therapeutic candidate agent for attenuating pulmonary fibrosis. PMID:26891294

  2. The Chinese Herbal Medicine Formula mKG Suppresses Pulmonary Fibrosis of Mice Induced by Bleomycin.

    PubMed

    Gao, Ying; Yao, Li-Fu; Zhao, Yang; Wei, Li-Man; Guo, Peng; Yu, Meng; Cao, Bo; Li, Tan; Chen, Hong; Zou, Zhong-Mei

    2016-01-01

    Pulmonary fibrosis (PF) is a serious progressive lung disease and it originates from inflammation-induced parenchymal injury with excessive extracellular matrix deposition to result in the destruction of the normal lung architecture. Modified Kushen Gancao Formula (mKG), derived from traditional Chinese herbal medicine, has a prominent anti-inflammatory effect. The present study is to explore the inhibitory effects of mKG on bleomycin (BLM)-induced pulmonary fibrosis in mice. mKG significantly decreased pulmonary alveolitis, fibrosis scores, and interleukin-6 (IL-6), interleukin-17 (IL-17), transforming growth factor-β (TGF-β) and hydroxyproline (HYP) levels in lung tissue of mice compared with BLM treatment. It markedly alleviated the increase of HYP content in the lung tissues and pathologic changes of pulmonary fibrosis caused by BLM instillation. In conclusion, mKG has an anti-fibrotic effect and might be employed as a therapeutic candidate agent for attenuating pulmonary fibrosis. PMID:26891294

  3. Exposure to nickel oxide nanoparticles induces pulmonary inflammation through NLRP3 inflammasome activation in rats.

    PubMed

    Cao, Zhengwang; Fang, Yiliang; Lu, Yonghui; Qian, Fenghua; Ma, Qinglong; He, Mingdi; Pi, Huifeng; Yu, Zhengping; Zhou, Zhou

    2016-01-01

    With recent advances in the manufacture and application of nickel oxide nanoparticles (NiONPs), concerns about their adverse effects on the respiratory system are increasing. However, the underlying cellular and molecular mechanisms of NiONP-induced pulmonary toxicity remain unclear. In this study, we focused on the impacts of NiONPs on pulmonary inflammation and investigated whether the NLRP3 inflammasome is involved in NiONP-induced pulmonary inflammation and injury. NiONP suspensions were administered by single intratracheal instillation to rats, and inflammatory responses were evaluated at 3 days, 7 days, or 28 days after treatment. NiONP exposure resulted in sustained pulmonary inflammation accompanied by inflammatory cell infiltration, alveolar proteinosis, and cytokine secretion. Expression of Nlrp3 was markedly upregulated by the NiONPs, which was accompanied by overexpression of the active form of caspase-1 (p20) and interleukin (IL)-1β secretion in vivo. NiONP-induced IL-1β secretion was partially prevented by co-treatment with a caspase-1 inhibitor in macrophages. Moreover, siRNA-mediated Nlrp3 knockdown completely attenuated NiONP-induced cytokine release and caspase-1 activity in macrophages in vitro. In addition, NiONP-induced NLRP3 inflammasome activation requires particle uptake and reactive oxygen species production. Collectively, our findings suggest that the NLRP3 inflammasome participates in NiONP-induced pulmonary inflammation and offer new strategies to combat the pulmonary toxicity induced by NiONPs. PMID:27524893

  4. Exposure to nickel oxide nanoparticles induces pulmonary inflammation through NLRP3 inflammasome activation in rats

    PubMed Central

    Cao, Zhengwang; Fang, Yiliang; Lu, Yonghui; Qian, Fenghua; Ma, Qinglong; He, Mingdi; Pi, Huifeng; Yu, Zhengping; Zhou, Zhou

    2016-01-01

    With recent advances in the manufacture and application of nickel oxide nanoparticles (NiONPs), concerns about their adverse effects on the respiratory system are increasing. However, the underlying cellular and molecular mechanisms of NiONP-induced pulmonary toxicity remain unclear. In this study, we focused on the impacts of NiONPs on pulmonary inflammation and investigated whether the NLRP3 inflammasome is involved in NiONP-induced pulmonary inflammation and injury. NiONP suspensions were administered by single intratracheal instillation to rats, and inflammatory responses were evaluated at 3 days, 7 days, or 28 days after treatment. NiONP exposure resulted in sustained pulmonary inflammation accompanied by inflammatory cell infiltration, alveolar proteinosis, and cytokine secretion. Expression of Nlrp3 was markedly upregulated by the NiONPs, which was accompanied by overexpression of the active form of caspase-1 (p20) and interleukin (IL)-1β secretion in vivo. NiONP-induced IL-1β secretion was partially prevented by co-treatment with a caspase-1 inhibitor in macrophages. Moreover, siRNA-mediated Nlrp3 knockdown completely attenuated NiONP-induced cytokine release and caspase-1 activity in macrophages in vitro. In addition, NiONP-induced NLRP3 inflammasome activation requires particle uptake and reactive oxygen species production. Collectively, our findings suggest that the NLRP3 inflammasome participates in NiONP-induced pulmonary inflammation and offer new strategies to combat the pulmonary toxicity induced by NiONPs. PMID:27524893

  5. Protective role of interleukin-10 in Ozone-induced pulmonary inflammation**

    EPA Science Inventory

    Background: The mechanisms underlying ozone (03)-induced pulmonary inflammation remain unclear. Interleukin-10 (IL-10) is an anti-inflammatory cytokine that is known to inhibit inflammatory mediators. Objectives: We investigated the molecular mechanisms underlying interleuken-10...

  6. Ozone-Induced Pulmonary Injury and Inflammation are Modulated by Adrenal-Derived Stress Hormones

    EPA Science Inventory

    Ozone exposure promotes pulmonary injury and inflammation. Previously we have characterized systemic changes that occur immediately after acute ozone exposure and are mediated by neuro-hormonal stress response pathway. Both HPA axis and sympathetic tone alterations induce the rel...

  7. Passivated iodine pentoxide oxidizer for potential biocidal nanoenergetic applications.

    PubMed

    Feng, Jingyu; Jian, Guoqiang; Liu, Qing; Zachariah, Michael R

    2013-09-25

    Iodine pentoxide (I2O5), also known as diiodine pentoxide, is a strong oxidizer which has been recently proposed as an iodine-rich oxidizer in nanoenergetic formulations, whose combustion products lead to molecular iodine as a biocidal agent. However, its highly hygroscopic nature hinders its performance as a strong oxidizer and an iodine releasing agent and prevents its implementation. In this work, we developed a gas phase assisted aerosol spray pyrolysis which enables creation of iron oxide passivated I2O5. Transmission electron microscopy elemental imaging as well as temperature-jump mass spectrometry confirmed the core shell nature of the material and the fact that I2O5 could be encapsulated in pure unhydrated form. Combustion performance finds an optimal coating thickness that enables combustion performance similar to a high performing CuO based thermite. PMID:23988006

  8. Pulmonary reactions caused by welding-induced decomposed trichloroethylene

    SciTech Connect

    Sjoegren, B.P.; Plato, N.; Alexandersson, R.; Eklund, A.; Falkenberg, C. )

    1991-01-01

    This is the report of a welder who performed argon-shielded electric arc welding in an atmosphere containing trichloroethylene. He developed immediate respiratory symptoms, pulmonary edema 12 hours after exposure, and recurring dyspnea ten days after exposure. These pulmonary reactions might be explained by inhalation of decomposition products of trichloroethylene such as dichloroacetyl chloride and phosgene.

  9. Inducible NO synthase inhibition attenuates shear stress-induced pulmonary vasodilation in the ovine fetus.

    PubMed

    Rairigh, R L; Storme, L; Parker, T A; le Cras, T D; Kinsella, J P; Jakkula, M; Abman, S H

    1999-03-01

    Recent studies have suggested that type II (inducible) nitric oxide (NO) synthase (NOS II) is present in the fetal lung, but its physiological roles are uncertain. Whether NOS II activity contributes to the NO-mediated fall in pulmonary vascular resistance (PVR) during shear stress-induced pulmonary vasodilation is unknown. We studied the hemodynamic effects of two selective NOS II antagonists [aminoguanidine (AG) and S-ethylisothiourea (EIT)], a nonselective NOS antagonist [nitro-L-arginine (L-NNA)], and a nonselective vasoconstrictor (U-46619) on PVR during partial compression of the ductus arteriosus (DA) in 20 chronically prepared fetal lambs (mean age 132 +/- 2 days, term 147 days). At surgery, catheters were placed in the left pulmonary artery (LPA) for selective drug infusion, an ultrasonic flow transducer was placed on the LPA to measure blood flow, and an inflatable vascular occluder was placed loosely around the DA for compression. On alternate days, a brief intrapulmonary infusion of normal saline (control), AG, EIT, L-NNA, or U-46619 was infused in random order into the LPA. The DA was compressed to increase mean pulmonary arterial pressure (MPAP) 12-15 mmHg above baseline values and held constant for 30 min. In control studies, DA compression reduced PVR by 42% from baseline values (P < 0.01). L-NNA treatment completely blocked the fall in PVR during DA compression. AG and EIT attenuated the decrease in PVR by 30 and 19%, respectively (P < 0.05). Nonspecific elevation in PVR by U-46619 did not affect the fall in PVR during DA compression. Immunostaining for NOS II identified this isoform in airway epithelium and vascular smooth muscle in the late-gestation ovine fetal lung. We conclude that selective NOS II antagonists attenuate but do not block shear stress-induced vasodilation in the fetal lung. We speculate that stimulation of NOS II activity, perhaps from smooth muscle cells, contributes in part to the NO-mediated fall in PVR during shear stress-induced

  10. Nitric oxide mediates bleomycin-induced angiogenesis and pulmonary fibrosis via regulation of VEGF.

    PubMed

    Iyer, Anand Krishnan V; Ramesh, Vani; Castro, Carlos A; Kaushik, Vivek; Kulkarni, Yogesh M; Wright, Clayton A; Venkatadri, Rajkumar; Rojanasakul, Yon; Azad, Neelam

    2015-11-01

    Pulmonary fibrosis is a progressive lung disease hallmarked by increased fibroblast proliferation, amplified levels of extracellular matrix deposition and increased angiogenesis. Although dysregulation of angiogenic mediators has been implicated in pulmonary fibrosis, the specific rate-limiting angiogenic markers involved and their role in the progression of pulmonary fibrosis remains unclear. We demonstrate that bleomycin treatment induces angiogenesis, and inhibition of the central angiogenic mediator VEGF using anti-VEGF antibody CBO-P11 significantly attenuates bleomycin-induced pulmonary fibrosis in vivo. Bleomycin-induced nitric oxide (NO) was observed to be the key upstream regulator of VEGF via the PI3k/Akt pathway. VEGF regulated other important angiogenic proteins including PAI-1 and IL-8 in response to bleomycin exposure. Inhibition of NO and VEGF activity significantly mitigated bleomycin-induced angiogenic and fibrogenic responses. NO and VEGF are key mediators of bleomycin-induced pulmonary fibrosis, and could serve as important targets against this debilitating disease. Overall, our data suggests an important role for angiogenic mediators in the pathogenesis of bleomycin-induced pulmonary fibrosis. PMID:25919965

  11. A Mechanistic Study on the Amiodarone-Induced Pulmonary Toxicity

    PubMed Central

    Al-Shammari, Bader; Khalifa, Mohamed; Bakheet, Saleh A.; Yasser, Moustafa

    2016-01-01

    Amiodarone- (AM-) induced pulmonary toxicity (AIPT) is still a matter of research and is poorly understood. In attempting to resolve this issue, we treated Sprague-Dawley rats with AM doses of 80 mg/kg/day/i.p. for one, two, three, and four weeks. The rats were weighed at days 7, 14, 21, and 28 and bronchoalveolar lavages (BAL) were obtained to determine total leukocyte count (TLC). For each group, lung weighing, histopathology, and homogenization were performed. Fresh homogenates were used for determination of ATP content, lipid peroxides, GSH, catalase, SOD, GPx, GR activities, NO, and hydroxyproline levels. The results showed a significant decrease in body weight and GSH depletion together with an increase in both lung weight and lung/body weight coefficient in the first week. Considerable increases in lung hydroxyproline level with some histopathological alterations were apparent. Treatment for two weeks produced a significant increase in BAL fluid, TLC, GR activity, and NO level in lung homogenate. The loss of cellular ATP and inhibition of most antioxidative protective enzymatic system appeared along with alteration in SOD activity following daily treatment for three weeks, while, in rats treated with AM for four weeks, more severe toxicity was apparent. Histopathological diagnosis was mostly granulomatous inflammation and interstitial pneumonitis in rats treated for three and four weeks, respectively. As shown, it is obvious that slow oedema formation is the only initiating factor of AIPT; all other mechanisms may occur as a consequence. PMID:26933474

  12. Aluminum-induced pulmonary fibrosis: do fibers play a role?

    PubMed

    Gilks, B; Churg, A

    1987-07-01

    A 50-yr-old man with a history of 19 yr of work in the aluminum smelting industry, including 14 years in the potrooms, was found to have diffuse interstitial fibrosis, slightly more severe in the upper zones. He died of respiratory insufficiency 5 yr after initial presentation. Analysis of lung by electron optical techniques revealed 15,000,000,000 nonfibrous particles and 1,300,000,000 fibrous particles of aluminum oxide/g dry lung, values representing approximately a 1,000-fold increase over background exposure. The nonfibrous particles had a geometric mean diameter of 0.4 mu, and the fibers had a geometric mean length of 1.0 mu, a width of 0.06 mu, and an aspect ratio of 16. X-ray diffraction demonstrated alpha but not gamma aluminum oxide. These studies indicate that previous suggestions relating aluminum-induced fibrosis to the presence of gamma aluminum oxide are not correct. Although pulmonary fibrosis in this case may be a response to a very high total aluminum particle burden, the presence of large numbers of fibers raises the possibility that fibers play a role in aluminum fibrosis. PMID:3605831

  13. Pulmonary oedema produced by scorpion venom augments a phenyldiguanide-induced reflex response in anaesthetized rats

    PubMed Central

    Deshpande, S B; Bagchi, S; Rai, O P; Aryya, N C

    1999-01-01

    The involvement of pulmonary oedema produced by scorpion venom in augmenting a phenyldiguanide (PDG)-induced reflex response was evaluated in urethane-anaesthetized rats. PDG-induced bradycardiac, hypotensive and apnoeic responses, expressed as time–response area, exhibited similarities before or after venom treatment. Hence, the time–response area of bradycardia was taken as a reflex parameter. Pulmonary oedema was determined by physical evaporation and histological methods. Exposure to Indian red scorpion (Buthus tamulus, BT; i.v.) venom for 30 min increased the pulmonary water content (P < 0.05; Student's t test) and augmented the PDG-induced bradycardiac reflex response by more than 2 times (P < 0.001). The increase of pulmonary water content was maximal with 100 μg kg−1 of venom and the augmentation was maximal with 10 μg kg−1. In a separate series of experiments, the venom (100 μg kg−1)-induced pulmonary oedema was confirmed by histological and physical methods. In this group also, the venom augmented the reflex to the same magnitude. Pulmonary oedema (physical and histological) and augmentation of the bradycardiac reflex response after BT venom (100 μg kg−1; i.v.) were absent in animals pretreated with aprotinin, a kallikrein-kinin inhibitor (6000 KIU; i.v.). Ondansetron (10 μg kg−1; i.v.), a 5-HT3 receptor antagonist, failed to block the venom-induced pulmonary oedema (physical and histological) but blocked the venom-induced augmentation of the reflex. The results of this study indicate that the venom-induced augmentation of the PDG reflex is associated with pulmonary oedema involving kinins utilizing 5-HT3 receptors. PMID:10581322

  14. Health and environmental-effects profile for vanadium pentoxide

    SciTech Connect

    Not Available

    1985-04-01

    The Health and Environmental Effects Profile for vanadium pentoxide was prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Solid Waste and Emergency Response to support listings of hazardous constituents of a wide range of waste streams under Section 3001 of the Resource Conservation and Recovery Act (RCRA) and to provide health-related limits for emergency actions under Section 101 of the Comprehensive Environmental Response, Compensation and Liability Act (CERCLA). Both published literature and information obtained from Agency program office files were evaluated as they pertained to potential human health, aquatic life, and environmental effects of hazardous-waste constituents. Quantitative estimates are presented, provided sufficient data are available. Existing data are insufficient to determine an Acceptable Daily Intake (ADI) or a carcinogenic potency factor for vanadium pentoxide. The Reportable Quantity (RQ) value of 1, 10, 100, 1000, or 5000 pounds is used to determine the quantity of a hazardous substance for which notification is required in the event of a release as specified by CERCLA based on chronic toxicity. The RQ value for vanadium pentoxide is 100.

  15. Rosuvastatin, sildenafil and their combination in monocrotaline-induced pulmonary hypertension in rat.

    PubMed

    Jasińska-Stroschein, Magdalena; Owczarek, Jacek; Wesołowska, Anna; Orszulak-Michalak, Daria

    2014-09-01

    There is considerable interest in the pleiotropic effects of statins and their potential role in the treatment of pulmonary hypertension. Previous experimental findings indicate that a combination of lipophilic statins with phosphodiesterase type-5 inhibitor, sildenafil, can offer preventive effects on rat monocrotaline-induced pulmonary hypertension. The present study is aimed to assess whether therapeutic regimen provides any benefits. Seven days after pulmonary hypertension induction, hydrophilic rosuvastatin and sildenafil were given for 14 days to male Wistar outbred rats. Right ventricular pressure, right ventricle mass and three biomarkers were evaluated after 21 days: brain natriuretic peptide, high-density lipoprotein cholesterol and vascular endothelial growth factor. The present study demonstrates that administration of hydrophilic statin with sildenafil results in reduction of pulmonary vascular remodeling and right ventricular pressure. The results of biochemical measurements may suggest that statins play a positive role in right ventricle function or the process of angiogenesis in pulmonary hypertension development. PMID:25296680

  16. The Critical Role of Dynamin-Related Protein 1 in Hypoxia-Induced Pulmonary Vascular Angiogenesis.

    PubMed

    Shen, Tingting; Wang, Na; Yu, Xiufeng; Shi, Jiucheng; Li, Qian; Zhang, Chen; Fu, Li; Wang, Shuang; Xing, Yan; Zheng, Xiaodong; Yu, Lei; Zhu, Daling

    2015-09-01

    Pulmonary arterial hypertension (PAH) is a lethal disease characterized by pulmonary vascular obstruction due in part to excessive pulmonary artery endothelial cells (PAECs) migration and proliferation. The mitochondrial fission protein dynamin-related protein-1 (DRP1) has important influence on pulmonary vascular remodeling. However, whether DRP1 participates in the development and progression of pulmonary vascular angiogenesis has not been reported previously. To test the hypothesis that DRP1 promotes the angiogenesis via promoting the proliferation, stimulating migration, and inhibiting the apoptosis of PAECs in mitochondrial Ca(2+)-dependent manner, we performed following studies. Using hemodynamic analysis and morphometric assay, we found that DRP1 mediated the elevation of right ventricular systemic pressure (RVSP), right heart hypertrophy, and increase of pulmonary microvessels induced by hypoxia. DRP1 inhibition reversed tube network formation in vitro stimulated by hypoxia. The mitochondrial Ca(2+) inhibited by hypoxia was recovered by DRP1 silencing. Moreover, pulmonary vascular angiogenesis promoted by DRP1 was reversed by the specific mitochondrial Ca(2+) uniporter inhibitor Ru360. In addition, DRP1 promoted the proliferation and migration of PAECs in mitochondrial Ca(2+)-dependent manner. Besides, DRP1 decreased mitochondrial membrane potential, reduced the DNA fragmentation, and inhibited the caspase-3 activation, which were all aggravated by Ru360. Therefore, these results indicate that the mitochondrial fission machinery promotes migration, facilitates proliferation, and prevents from apoptosis via mitochondrial Ca(2+)-dependent pathway in endothelial cells leading to pulmonary angiogenesis. PMID:25752284

  17. Carvacrol induces the apoptosis of pulmonary artery smooth muscle cells under hypoxia.

    PubMed

    Zhang, Qianlong; Fan, Kai; Wang, Peng; Yu, Juan; Liu, Ruxia; Qi, Hanping; Sun, Hongli; Cao, Yonggang

    2016-01-01

    The abnormal apoptosis of pulmonary artery smooth muscle cells (PASMCs) is an important pathophysiological process in pulmonary vascular remodeling and pulmonary arterial hypertension (PAH). Carvacrol, an essential oil compound from oregano and thyme, has displayed antimicrobial, antitumor, and antioxidant properties. Although carvacrol has pro-apoptosis properties in tumor cells, the underlying mechanisms of carvacrol in PASMC apoptosis remain unclear. Thus, in this study, we aim to investigate the role of carvacrol in pulmonary vascular remodeling and PASMC apoptosis in hypoxia. Right Ventricular Hypertrophy Measurements and pulmonary pathomorphology data show that the ratio of the heart weight/tibia length (HW/TL), the right ventricle/left ventricle plus septum (RV/LV+S) and the medial width of the pulmonary artery increased in chronic hypoxia and were reversed by carvacrol treatment under hypoxia. Additionally, carvacrol inhibited PASMC viability, attenuated oxidative stress, induced mitochondria membrane depolarization, increased the percentage of apoptotic cells, suppressed Bcl-2 expression, decreased procaspase-3 expression, promoted caspase-3 activation, and inhibited the ERK1/2 and PI3K/Akt pathway. Taken together, these findings suggest that carvacrol attenuates the pulmonary vascular remodeling and promotes PASMC apoptosis by acting on, at least in part, the intrinsic apoptotic pathway. This process might provide us new insight into the development of hypoxic pulmonary hypertension. PMID:26607464

  18. Resolution of pulmonary hypertension complication during venovenous perfusion-induced systemic hyperthermia application.

    PubMed

    Ballard-Croft, Cherry; Wang, Dongfang; Jones, Cameron; Wang, Jingkun; Pollock, Robert; Jubak, Bob; Topaz, Stephen; Zwischenberger, Joseph B

    2013-01-01

    We are developing a venovenous perfusion-induced systemic hyperthermia (vv-PISH) system for advanced cancer treatment. The vv-PISH system consistently delivered hyperthermia to adult healthy swine, but significant pulmonary hypertension developed during the heating phase. The goal of this study was to develop a method to prevent pulmonary hypertension. We hypothesized that pulmonary hypertension results from decreased priming solution air solubility, which causes pulmonary gas embolism. Healthy adult sheep (n = 3) were used to establish a standard vv-PISH sheep model without priming solution preheating. In subsequent sheep (n = 7), the priming solution was preheated (42-46°C) and the hyperthermia circuit flushed with CO2. All sheep survived the experiment and achieved 2 hours of 42°C hyperthermia. In the group lacking priming solution preheating, significant pulmonary hypertension (35-44 mm Hg) developed. In the sheep with priming solution preheating, pulmonary artery pressure was very stable without pulmonary hypertension. Blood electrolytes were in physiologic range, and complete blood counts were unaffected by hyperthermia. Blood chemistries revealed no significant liver or kidney damage. Our simple strategy of priming solution preheating completely resolved the problem of pulmonary hypertension as a milestone toward developing a safe and easy-to-use vv-PISH system for cancer treatment. PMID:23820278

  19. Oxidative stress-dependent activation of collagen synthesis is induced in human pulmonary smooth muscle cells by sera from patients with scleroderma-associated pulmonary hypertension

    PubMed Central

    2014-01-01

    Pulmonary arterial hypertension is a major complication of systemic sclerosis. Although oxidative stress, intima hyperplasia and a progressive vessel occlusion appear to be clearly involved, the fine molecular mechanisms underpinning the onset and progression of systemic sclerosis-associated pulmonary arterial hypertension remain largely unknown. Here we shows for the first time that an increase of NADPH-derived reactive oxygen species production induced by sera from systemic sclerosis patients with pulmonary arterial hypertension drives collagen type I promoter activity in primary human pulmonary artery smooth muscle cells, suggesting that antioxidant-based therapies should be considered in the treatment of systemic sclerosis-associated vascular diseases. PMID:25085432

  20. Effect of aerosolized milrinone during drug-induced pulmonary hypertension in lambs.

    PubMed

    Gelvez, Javier; Fakioglu, Harun; Olarte, Jose L; Soliz, Amed; Totapally, Balagangadhar R; Torbati, Dan

    2004-07-01

    We tested whether aerosolized milrinone in lambs selectively reduces drug-induced acute pulmonary hypertension without reducing the mean systemic blood pressure (MSBP). Seven, 2-3-week-old lambs were anesthetized (50 mg/kg ketamine), paralyzed (0.1 mg/kg vecuronium bromide) and mechanically ventilated. A femoral artery, pulmonary artery, and jugular vein were catheterized for continuous monitoring of MSBP, mean pulmonary artery pressure, periodic gas-exchange analyses, and determination of cardiac output by thermodilution technique. An Airlife Misty nebulizer was used in a dry state to establish a stable baseline of an inspired fraction of oxygen (FiO(2)) at 0.21. Acute pulmonary hypertension with hypoxemia was then induced by increasing the mean pulmonary artery pressure up to 30-35% of the MSBP using 2-6 microg/kg/min of Thromboxane A(2) mimetic (U-46619), intravenously. The lambs were then subjected to 15 min of saline nebulization without milrinone followed by 30 min saline nebulization with a relatively high concentration of milrinone (10 mg/ml, total dose of 40 mg). Aerosolized milrinone had no effect on systemic or pulmonary artery pressure during combined acute pulmonary hypertension and hypoxemia. We speculate that our nebulization procedures failed to deliver sufficient amount of milrinone for producing a detectable hemodynamic effect. PMID:15082033

  1. Resistance of the hamster to amiodarone-induced pulmonary toxicity following repeated intraperitoneal administration.

    PubMed

    Leeder, R G; Evans, C D; Brien, J F; Massey, T E

    1994-10-01

    Amiodarone is an effective antidysrhythmic agent, restricted in use by the development of pulmonary toxicity. Several in vivo animal models have been used to study amiodarone-induced pulmonary toxicity. Intratracheal administration of amiodarone to the hamster has been used as a model for the critical amiodarone-induced pulmonary fibrosis (AIPF). In order to investigate the cellular mechanism of human AIPF, which occurs following oral or intravenous administration, an animal model of AIPF resulting from systemic administration of the drug would appear to be preferable. We have evaluated pulmonary toxicity following repeated intraperitoneal amiodarone administration to the hamster. Intraperitoneal treatment of hamsters for 1, 4, or 7 weeks with amiodarone (100 mg/kg/day) did not lead to pulmonary toxicity based on wet lung weight, hydroxyproline content, or histological examination. Furthermore, when comparing 1- and 7-week treatment groups, there was no pulmonary accumulation of either amiodarone or desethylamiodarone beyond levels found at 1 week. Therefore, failure to develop pulmonary toxicity may be due to an inability to accumulate sufficient amiodarone and/or desethylamiodarone. Intratracheal administration of amiodarone to rodents remains the only in vivo animal model for studying the mechanism(s) of AIPF. PMID:8085270

  2. Protection from Radiation-Induced Pulmonary Fibrosis by Peripheral Targeting of Cannabinoid Receptor-1.

    PubMed

    Bronova, Irina; Smith, Brett; Aydogan, Bulent; Weichselbaum, Ralph R; Vemuri, Kiran; Erdelyi, Katalin; Makriyannis, Alex; Pacher, Pal; Berdyshev, Evgeny V

    2015-10-01

    Radiation-induced pulmonary fibrosis (RIF) is a severe complication of thoracic radiotherapy that limits its dose, intensity, and duration. The contribution of the endocannabinoid signaling system in pulmonary fibrogenesis is not known. Using a well-established mouse model of RIF, we assessed the involvement of cannabinoid receptor-1 (CB1) in the onset and progression of pulmonary fibrosis. Female C57BL/6 mice and CB1 knockout mice generated on C57BL/6 background received 20 Gy (2 Gy/min) single-dose thoracic irradiation that resulted in pulmonary fibrosis and animal death within 15 to 18 weeks. Some C57BL/6 animals received the CB1 peripherally restricted antagonist AM6545 at 1 mg/kg intraperitoneally three times per week. Animal survival and parameters of pulmonary inflammation and fibrosis were evaluated. Thoracic irradiation (20 Gy) was associated with marked pulmonary inflammation and fibrosis in mice and high mortality within 15 to 18 weeks after exposure. Genetic deletion or pharmacological inhibition of CB1 receptors with a peripheral CB1 antagonist AM6545 markedly attenuated or delayed the lung inflammation and fibrosis and increased animal survival. Our results show that CB1 signaling plays a key pathological role in the development of radiation-induced pulmonary inflammation and fibrosis, and peripherally restricted CB1 antagonists may represent a novel therapeutic approach against this devastating complication of radiotherapy/irradiation. PMID:26426981

  3. Drug-induced Hypersensitivity Syndrome Accompanied by Pulmonary Lesions Exhibiting Centrilobular Nodular Shadows.

    PubMed

    Sawata, Tetsuro; Bando, Masashi; Kogawara, Haruna; Nakayama, Masayuki; Mato, Naoko; Yamasawa, Hideaki; Takemura, Tamiko; Sugiyama, Yukihiko

    2016-01-01

    A 51-year-old woman diagnosed with Crohn's disease developed drug-induced hypersensitivity syndrome (DIHS) 12 and six weeks after starting the oral intake of mesalazine and trimethoprim/sulfamethoxazole, respectively. Chest CT showed centrilobular nodular shadows and a transbronchial lung biopsy (TBLB) revealed infiltration of inflammatory cells predominantly in the small pulmonary artery walls and bronchiolar walls. Regarding pulmonary lesions of DIHS, infiltrative shadows have sometimes been reported, whereas nodular shadows have rarely been documented. This is a valuable case report for considering the mechanism underlying the development of pulmonary lesions in case of DIHS. PMID:27150872

  4. Impact-Driven Thermite Reactions with Iodine Pentoxide and Silver Oxide

    NASA Astrophysics Data System (ADS)

    Russell, R.; Bless, S.; Pantoya, M.

    2011-04-01

    Thermite reactions using aluminum (Al) fuel and either iodine pentoxide (I2O5) or silver oxide (Ag2O) were initiated by high-velocity impact or thermal initiation and examined for their flame propagation behavior. In the impact-ignition experiments, the Al-Ag2O reaction produced more energy than the Al-I2O5 reaction; in the thermal-ignition experiments, the I2O5 reaction produced higher flame propagation rates (1,305 m/s compared with 531 m/s). The energy released from impact-initiated reactions is significantly enhanced by reducing the size of the oxide particles. Results suggest that the reaction propagation mechanisms may be the same, even though ignition is spurred by two different stimuli (mechanically induced compaction versus thermal).

  5. Elastase modifies bleomycin-induced pulmonary fibrosis in mice.

    PubMed

    Trajano, Larissa Alexsandra Silva Neto; Trajano, Eduardo Tavares Lima; Lanzetti, Manuella; Mendonça, Morena Scopel Amorim; Guilherme, Rafael Freitas; Figueiredo, Rodrigo Tinoco; Benjamim, Cláudia Farias; Valenca, Samuel Santos; Costa, Andréa Monte Alto; Porto, Luís Cristóvão

    2016-04-01

    Pulmonary fibrosis (PF) is characterized by excessive accumulation of collagen in the lungs. Emphysema is characterized by loss of the extracellular matrix (ECM) and alveolar enlargement. We studied the co-participation of elastase-induced mild emphysema in bleomycin-induced PF in mice by analyzing oxidative stress, inflammation and lung histology. C57BL/6 mice were divided into four groups: control; bleomycin (0.1U/mouse); elastase (using porcine pancreatic elastase (PPE)+bleomycin (3U/mouse 14 days before 0.1U/mouse of bleomycin; PPE+B); elastase (3U/mouse). Mice were humanely sacrificed 7, 14 and 21 days after treatment with bleomycin or vehicle. PF was observed 14 days and 21 days after bleomycin treatment but was observed after 14 days only in the PPE+B group. In the PPE+B group at 21 days, we observed many alveoli and alveolar septa with few PF areas. We also observed marked and progressive increases of collagens 7, 14 and 21 days after bleomycin treatment whereas, in the PPE+B group, collagen deposition was observed only at 14 days. There was a reduction in activities of the antioxidant enzymes superoxide dismutase (p<0.05), catalase (p<0.01) and glutathione peroxidase (p<0.01) parallel with an increase in nitrite (p<0.01) 21 days after bleomycin treatment compared with the control group. These endpoints were also reduced (p<0.05, p<0.05 and p<0.01, respectively) and increased (p<0.01) in the PPE+B group at 21 days compared with the control group. Interleukin (IL)-1β expression was upregulated (p<0.01) whereas IL-6 was downregulated (p<0.05) in the PPE+B group at 21 days compared with the control group. PF and emphysema did not coexist in our model of lung disease and despite increased levels of oxidative stress and inflammatory markers after combined stimulus (elastase and bleomycin) overall histology was improved to that of the nearest control group. PMID:26852294

  6. Key Role of ROS in the Process of 15-Lipoxygenase/15-Hydroxyeicosatetraenoiccid-Induced Pulmonary Vascular Remodeling in Hypoxia Pulmonary Hypertension

    PubMed Central

    Qiu, Yanli; Liu, Gaofeng; Sheng, Tingting; Yu, Xiufeng; Wang, Shuang; Zhu, Daling

    2016-01-01

    We previously reported that 15-lipoxygenase (15-LO) and its metabolite 15-hydroxyeicosatetraenoic acid (15-HETE) were up-regulated in pulmonary arterial cells from both pulmonary artery hypertension patients and hypoxic rats and that these factors mediated the progression of pulmonary hypertension (PH) by affecting the proliferation and apoptosis of pulmonary arterial (PA) cells. However, the underlying mechanisms of the remodeling induced by 15-HETE have remained unclear. As reactive oxygen species (ROS) and 15-LO are both induced by hypoxia, it is possible that ROS are involved in the events of hypoxia-induced 15-LO expression that lead to PH. We employed immunohistochemistry, tube formation assays, bromodeoxyuridine (BrdU) incorporation assays, and cell cycle analyses to explore the role of ROS in the process of 15-HETE-mediated hypoxic pulmonary hypertension (HPH). We found that exogenous 15-HETE facilitated the generation of ROS and that this effect was mainly localized to mitochondria. In particular, the mitochondrial electron transport chain and nicotinamide-adenine dinucleotide phosphate oxidase 4 (Nox4) were responsible for the significant 15-HETE-stimulated increase in ROS production. Moreover, ROS induced by 15-HETE stimulated endothelial cell (EC) migration and promoted pulmonary artery smooth muscle cell (PASMC) proliferation under hypoxia via the p38 MAPK pathway. These results indicated that 15-HETE-regulated ROS mediated hypoxia-induced pulmonary vascular remodeling (PVR) via the p38 MAPK pathway. PMID:26871724

  7. Therapeutic Benefits of Induced Pluripotent Stem Cells in Monocrotaline-Induced Pulmonary Arterial Hypertension.

    PubMed

    Huang, Wei-Chun; Ke, Meng-Wei; Cheng, Chin-Chang; Chiou, Shih-Hwa; Wann, Shue-Ren; Shu, Chih-Wen; Chiou, Kuan-Rau; Tseng, Ching-Jiunn; Pan, Hung-Wei; Mar, Guang-Yuan; Liu, Chun-Peng

    2016-01-01

    Pulmonary arterial hypertension (PAH) is characterized by progressive increases in vascular resistance and the remodeling of pulmonary arteries. The accumulation of inflammatory cells in the lung and elevated levels of inflammatory cytokines in the bloodstream suggest that inflammation may play a role in PAH. In this study, the benefits of induced pluripotent stem cells (iPSCs) and iPSC-conditioned medium (iPSC CM) were explored in monocrotaline (MCT)-induced PAH rats. We demonstrated that both iPSCs and iPSC CM significantly reduced the right ventricular systolic pressure and ameliorated the hypertrophy of the right ventricle in MCT-induced PAH rats in models of both disease prevention and disease reversal. In the prevention of MCT-induced PAH, iPSC-based therapy led to the decreased accumulation of inflammatory cells and down-regulated the expression of the IL-1β, IL-6, IL-12α, IL-12β, IL-23 and IFNγ genes in lung specimens, which implied that iPSC-based therapy may be involved in the regulation of inflammation. NF-κB signaling is essential to the inflammatory cascade, which is activated via the phosphorylation of the NF-κB molecule. Using the chemical inhibitor specifically blocked the phosphorylation of NF-κB, and in vitro assays of cultured human M1 macrophages implied that the anti-inflammation effect of iPSC-based therapy may contribute to the disturbance of NF-κB activation. Here, we showed that iPSC-based therapy could restore the hemodynamic function of right ventricle with benefits for preventing the ongoing inflammation in the lungs of MCT-induced PAH rats by regulating NF-κB phosphorylation. PMID:26840075

  8. Thymosin Beta 4 Protects Mice from Monocrotaline-Induced Pulmonary Hypertension and Right Ventricular Hypertrophy

    PubMed Central

    Wu, Liling; Gupta, Sudhiranjan

    2014-01-01

    Pulmonary hypertension (PH) is a progressive vascular disease of pulmonary arteries that impedes ejection of blood by the right ventricle. As a result there is an increase in pulmonary vascular resistance and pulmonary arterial pressure causing right ventricular hypertrophy (RVH) and RV failure. The pathology of PAH involves vascular cell remodeling including pulmonary arterial endothelial cell (PAEC) dysfunction and pulmonary arterial smooth muscle cell (PASMC) proliferation. Current therapies are limited to reverse the vascular remodeling. Investigating a key molecule is required for development of new therapeutic intervention. Thymosin beta-4 (Tβ4) is a ubiquitous G-actin sequestering protein with diverse biological function and promotes wound healing and modulates inflammatory responses. However, it remains unknown whether Tβ4 has any protective role in PH. The purpose of this study is to evaluate the whether Tβ4 can be used as a vascular-protective agent. In monocrotaline (MCT)-induced PH mouse model, we showed that mice treated with Tβ4 significantly attenuated the systolic pressure and RVH, compared to the MCT treated mice. Our data revealed for the first time that Tβ4 selectively targets Notch3-Col 3A-CTGF gene axis in preventing MCT-induced PH and RVH. Our study may provide pre-clinical evidence for Tβ4 and may consider as vasculo-protective agent for the treatment of PH induced RVH. PMID:25412097

  9. ECMO for pulmonary rescue in an adult with amiodarone-induced toxicity.

    PubMed

    Benassi, Filippo; Molardi, Alberto; Righi, Elena; Santangelo, Rosaria; Meli, Marco

    2015-05-01

    Amiodarone is a highly effective antiarrhythmic agent. Unfortunately amiodarone-induced pulmonary toxicity is described for medium-long term therapy. We describe a case of a 65-year-old man admitted to our department for breathlessness and with a history of recurrent episodes of atrial fibrillation for which he had been receiving amiodarone (200 mg/day) since 2008. Despite diuretic therapy, along with aspirin, statins and antibiotics the patient continued to complain of severe dyspnea and had a moderate fever. Thus, diagnostic hypotheses different from acute cardiac failure were considered, in particular non-cardiogenic causes of pulmonary infiltrates. Following suspicion of amiodarone-induced pulmonary toxicity, the drug was discontinued and corticosteroid therapy was initiated. Due to the deterioration of the clinical picture, we proceeded to intubation. After few hours from intubation we were forced to institute a veno-venous extracorporeal membrane oxygenation due to the worsening of pulmonary function. The patient's clinical condition improved which allowed us to remove the ECMO after 15 days of treatment. Indications for use of ECMO have expanded considerably. To our knowledge this is the first successful, reported article of a veno-venous ECMO used to treat amiodarone-induced toxicity in an adult. In patients with severe but potentially reversible pulmonary toxicity caused by amiodarone, extracorporeal life support can maintain pulmonary function and vital organ perfusion at the expense of low morbidity, while allowing time for drug clearance. PMID:24604330

  10. The unusual symmetric reopening effect induced by pulmonary surfactant

    PubMed Central

    Yamaguchi, Eiichiro; Giannetti, Matthew J.; Van Houten, Matthew J.; Forouzan, Omid; Shevkoplyas, Sergey S.

    2014-01-01

    This study investigates the stability of a finger of air as it propagates into a liquid-filled model of a liquid-filled model of a pulmonary bifurcation. We seek to elucidate the stability characteristics of the reopening of daughter airways, an event that may be important to the treatment of acute lung disease. To do so, we investigated the symmetry of reopening under conditions of nearly constant surface tension with 1) purified H2O or 2) an anionic surfactant (sodium dodecyl sulfate). Dynamic surface tension was investigated using pulmonary surfactant (Infasurf) with and without the presence of albumin. Flow visualization was accomplished using a microparticle image velocimetry (μ-PIV)/shadowgraph system through which we measured 1) the propagation velocity of the finger of air that reopens each daughter branch, and 2) the instantaneous and averaged velocity field of liquid phase surrounding the tip of the propagating bubble. Only pulmonary surfactant demonstrated the ability of maintaining a nearly symmetric propagation in the daughter channels, which is likely to lead to homogeneous airway reopening. In contrast, when pulmonary surfactant was inactivated by albumin or when the system was held at a nearly constant surface tension, reopening occurred asymmetrically. Our analysis suggests that Infasurf's dynamic surface tension qualities are important to stabilize the removal of liquid obstructions. This demonstrates a new important function of pulmonary surfactant for airway reopening of a multibranched network. PMID:24458752

  11. The Effects of Aquaporin-1 in Pulmonary Edema Induced by Fat Embolism Syndrome.

    PubMed

    Zhang, Yiwei; Tian, Kun; Wang, Yan; Zhang, Rong; Shang, Jiawei; Jiang, Wei; Wang, Aizhong

    2016-01-01

    This study was designed to investigate the role of aquaporin1 (AQP1) in the pathologic process of pulmonary edema induced by fat embolism syndrome (FES) and the effects of a free fatty acid (FFA) mixture on AQP1 expression in pulmonary microvascular endothelial cells (PMVECs). In vivo, edema was more serious in FES mice compared with the control group. The expression of AQP1 and the wet-to-dry lung weight ratio (W/D) in the FES group were significantly increased compared with the control group. At the same time, inhibition of AQP1 decreased the pathological damage resulting from pulmonary edema. Then we performed a study in vitro to investigate whether AQP1 was induced by FFA release in FES. The mRNA and protein level of AQP1 were increased by FFAs in a dose- and time-dependent manner in PMVECs. In addition, the up-regulation of AQP1 was blocked by the inhibitor of p38 kinase, implicating the p38 MAPK pathway as involved in the FFA-induced AQP1 up-regulation in PMVECs. Our results demonstrate that AQP1 may play important roles in pulmonary edema induced by FES and can be regarded as a new therapy target for treatment of pulmonary edema induced by FES. PMID:27455237

  12. The Effects of Aquaporin-1 in Pulmonary Edema Induced by Fat Embolism Syndrome

    PubMed Central

    Zhang, Yiwei; Tian, Kun; Wang, Yan; Zhang, Rong; Shang, Jiawei; Jiang, Wei; Wang, Aizhong

    2016-01-01

    This study was designed to investigate the role of aquaporin1 (AQP1) in the pathologic process of pulmonary edema induced by fat embolism syndrome (FES) and the effects of a free fatty acid (FFA) mixture on AQP1 expression in pulmonary microvascular endothelial cells (PMVECs). In vivo, edema was more serious in FES mice compared with the control group. The expression of AQP1 and the wet-to-dry lung weight ratio (W/D) in the FES group were significantly increased compared with the control group. At the same time, inhibition of AQP1 decreased the pathological damage resulting from pulmonary edema. Then we performed a study in vitro to investigate whether AQP1 was induced by FFA release in FES. The mRNA and protein level of AQP1 were increased by FFAs in a dose- and time-dependent manner in PMVECs. In addition, the up-regulation of AQP1 was blocked by the inhibitor of p38 kinase, implicating the p38 MAPK pathway as involved in the FFA-induced AQP1 up-regulation in PMVECs. Our results demonstrate that AQP1 may play important roles in pulmonary edema induced by FES and can be regarded as a new therapy target for treatment of pulmonary edema induced by FES. PMID:27455237

  13. Lack of Bcr and Abr Promotes Hypoxia-Induced Pulmonary Hypertension in Mice

    PubMed Central

    Lim, Min; Arutyunyan, Anna; Groffen, John; Heisterkamp, Nora

    2012-01-01

    Background Bcr and Abr are GTPase activating proteins that specifically downregulate activity of the small GTPase Rac in restricted cell types in vivo. Rac1 is expressed in smooth muscle cells, a critical cell type involved in the pathogenesis of pulmonary hypertension. The molecular mechanisms that underlie hypoxia-associated pulmonary hypertension are not well-defined. Methodology/Principal Findings Bcr and abr null mutant mice were compared to wild type controls for the development of pulmonary hypertension after exposure to hypoxia. Also, pulmonary arterial smooth muscle cells from those mice were cultured in hypoxia and examined for proliferation, p38 activation and IL-6 production. Mice lacking Bcr or Abr exposed to hypoxia developed increased right ventricular pressure, hypertrophy and pulmonary vascular remodeling. Perivascular leukocyte infiltration in the lungs was increased, and under hypoxia bcr−/− and abr−/− macrophages generated more reactive oxygen species. Consistent with a contribution of inflammation and oxidative stress in pulmonary hypertension-associated vascular damage, Bcr and Abr-deficient animals showed elevated endothelial leakage after hypoxia exposure. Hypoxia-treated pulmonary arterial smooth muscle cells from Bcr- or Abr-deficient mice also proliferated faster than those of wild type mice. Moreover, activated Rac1, phosphorylated p38 and interleukin 6 were increased in these cells in the absence of Bcr or Abr. Inhibition of Rac1 activation with Z62954982, a novel Rac inhibitor, decreased proliferation, p38 phosphorylation and IL-6 levels in pulmonary arterial smooth muscle cells exposed to hypoxia. Conclusions Bcr and Abr play a critical role in down-regulating hypoxia-induced pulmonary hypertension by deactivating Rac1 and, through this, reducing both oxidative stress generated by leukocytes as well as p38 phosphorylation, IL-6 production and proliferation of pulmonary arterial smooth muscle cells. PMID:23152932

  14. Rapidly reversible alterations of pulmonary epithelial permeability induced by smoking

    SciTech Connect

    Mason, G.R.; Uszler, J.M.; Effros, R.M.; Reid, E.

    1983-01-01

    A radioaerosol procedure using /sup 99m/Tc-DTPA (diethylene triamine penta acetate) was used to evaluate the permeability of the pulmonary epithelium in smokers and nonsmokers. The average clearance of this indicator from the lungs of smokers without significant airway obstruction exceeded that found in normal subjects by an average factor of more than five. This abnormality was observed throughout all lung regions. /sup 99m/Tc-DTPA clearance decreased rapidly during the week after smoking was discontinued. It is concluded that smoking results in a rapidly reversible increase in pulmonary epithelial permeability.

  15. Inhaled tezosentan reduces pulmonary hypertension in endotoxin-induced lung injury.

    PubMed

    Persson, Björn P; Rossi, Patrik; Weitzberg, Eddie; Oldner, Anders

    2009-10-01

    The vasoconstrictive and proinflammatory peptide endothelin 1 (ET-1) is highly involved in the pathogenesis of sepsis and associated lung injury. Systemic administration of ET-receptor antagonists has been beneficial in experimental pulmonary hypertension. We wanted to study the effects of inhaled tezosentan, a dual endothelin-receptor antagonist on endotoxin-induced pulmonary hypertension, deterioration of gas exchange, and edema formation. After 2 h of endotoxemia, 28 anesthetized, mechanically ventilated pigs were randomized to either inhaled tezosentan 0.5 mg x kg (TEZO(0.5), n = 7), 0.05 mg x kg (TEZO(0.05), n = 7), intravenous 0.5 mg x kg (TEZO(iv), n = 7), or control (n = 7). Cardiopulmonary hemodynamics and gas-exchange parameters were recorded as well as extravascular lung water and pulmonary capillary pressure. In addition, plasma levels of tezosentan and ET-1 were analyzed. The protocol lasted for 5 h. Endotoxin-induced pulmonary hypertension (mean pulmonary artery pressure) was efficiently reduced by all treatments (TEZO(0.5) 24 +/- 2, TEZO(0.05) 27 +/- 2, TEZO(iv) 26 +/- 1, and control 37 +/- 2 mmHg at 4 h). TEZO(0.5) and TEZO(iv) also reduced pulmonary capillary pressure. All treatments led to a modest reduction in extravascular lung water, whereas no effects were noted on oxygenation or systemic circulation. Despite similar effects on pulmonary hypertension systemic treatment resulted in significantly higher plasma levels of ET-1 (twofold) and tezosentan (10- to 100-fold). Inhalation of the dual ET-receptor antagonist tezosentan was feasible and efficiently counteracted endotoxin-induced pulmonary hypertension. These effects were obtained with only minor systemic uptake of tezosentan and without affecting circulating levels of plasma ET-1 as compared with intravenous administration. PMID:19197226

  16. Heme biosynthesis modulation via δ-aminolevulinic acid administration attenuates chronic hypoxia-induced pulmonary hypertension

    PubMed Central

    Alhawaj, Raed; Patel, Dhara; Kelly, Melissa R.; Sun, Dong

    2015-01-01

    This study examines how heme biosynthesis modulation with δ-aminolevulinic acid (ALA) potentially functions to prevent 21-day hypoxia (10% oxygen)-induced pulmonary hypertension in mice and the effects of 24-h organoid culture with bovine pulmonary arteries (BPA) with the hypoxia and pulmonary hypertension mediator endothelin-1 (ET-1), with a focus on changes in superoxide and regulation of micro-RNA 204 (miR204) expression by src kinase phosphorylation of signal transducer and activator of transcription-3 (STAT3). The treatment of mice with ALA attenuated pulmonary hypertension (assessed through echo Doppler flow of the pulmonary valve, and direct measurements of right ventricular systolic pressure and right ventricular hypertrophy), increases in pulmonary arterial superoxide (detected by lucigenin), and decreases in lung miR204 and mitochondrial superoxide dismutase (SOD2) expression. ALA treatment of BPA attenuated ET-1-induced increases in mitochondrial superoxide (detected by MitoSox), STAT3 phosphorylation, and decreases in miR204 and SOD2 expression. Because ALA increases BPA protoporphyrin IX (a stimulator of guanylate cyclase) and cGMP-mediated protein kinase G (PKG) activity, the effects of the PKG activator 8-bromo-cGMP were examined and found to also attenuate the ET-1-induced increase in superoxide. ET-1 increased superoxide production and the detection of protoporphyrin IX fluorescence, suggesting oxidant conditions might impair heme biosynthesis by ferrochelatase. However, chronic hypoxia actually increased ferrochelatase activity in mouse pulmonary arteries. Thus, a reversal of factors increasing mitochondrial superoxide and oxidant effects that potentially influence remodeling signaling related to miR204 expression and perhaps iron availability needed for the biosynthesis of heme by the ferrochelatase reaction could be factors in the beneficial actions of ALA in pulmonary hypertension. PMID:25659899

  17. Sol-gel derived PZT films doped with vanadium pentoxide

    SciTech Connect

    Shen Hongfang; Guo Qing; Zhao Zhiman; Cao Guozhong

    2009-11-15

    The present research investigated the sol-gel preparation, dielectric and ferroelectric properties of PZT films doped with 5 mol% vanadium oxide. Stable PZTV sols can be readily formed, and homogeneous, micrometer thick and pinhole-free PZTV films were obtained by using spin coating followed with rapid annealing. The X-ray diffraction patterns revealed that no parasitic or secondary phases were formed in the sol-gel PZT films with the addition of vanadium oxide. The material doped with vanadium pentoxide showed enhanced dielectric constant and remanent polarization with reduced loss tangent and coercive field.

  18. Changes in pulmonary arterial wall mechanical properties and lumenal architecture with induced vascular remodeling

    NASA Astrophysics Data System (ADS)

    Molthen, Robert C.; Heinrich, Amy E.; Haworth, Steven T.; Dawson, Christopher A.

    2004-04-01

    To explore and quantify pulmonary arterial remodeling we used various methods including micro-CT, high-resolution 3-dimensional x-ray imaging, to examine the structure and function of intact pulmonary vessels in isolated rat lungs. The rat is commonly used as an animal model for studies of pulmonary hypertension (PH) and the accompanying vascular remodeling, where vascular remodeling has been defined primarily by changes in the vessel wall composition in response to hypertension inducing stimuli such as chronic hypoxic exposure (CHE) or monocrotaline (MCT) injection. Little information has been provided as to how such changes affect the vessel wall mechanical properties or the lumenal architecture of the pulmonary arterial system that actually account for the hemodynamic consequences of the remodeling. In addition, although the link between primary forms of pulmonary hypertension and inherited genetics is well established, the role that genetic coding plays in hemodynamics and vascular remodeling is not. Therefore, we are utilizing Fawn-Hooded (FH), Sprague-Dawley (SD) and Brown Norway (BN)rat strains along with unique imaging methods to parameterize both vessel distensibility and lumenal morphometry using a principal pulmonary arterial pathway analysis based on self-consistency. We have found for the hypoxia model, in addition to decreased body weight, increased hematocrit, increased right ventricular hypertrophy, the distensibility of the pulmonary arteries is shown to decrease significantly in the presence of remodeling.

  19. The Effect of TIP on Pneumovirus-Induced Pulmonary Edema in Mice

    PubMed Central

    van den Berg, Elske; Bem, Reinout A.; Bos, Albert P.; Lutter, Rene; van Woensel, Job B. M.

    2014-01-01

    Background Pulmonary edema plays a pivotal role in the pathophysiology of respiratory syncytial virus (RSV)-induced respiratory failure. In this study we determined whether treatment with TIP (AP301), a synthetic cyclic peptide that mimics the lectin-like domain of human TNF, decreases pulmonary edema in a mouse model of severe human RSV infection. TIP is currently undergoing clinical trials as a therapy for pulmonary permeability edema and has been shown to decrease pulmonary edema in different lung injury models. Methods C57BL/6 mice were infected with pneumonia virus of mice (PVM) and received TIP or saline (control group) by intratracheal instillation on day five (early administration) or day seven (late administration) after infection. In a separate set of experiments the effect of multiple dose administration of TIP versus saline was tested. Pulmonary edema was determined by the lung wet-to-dry (W/D) weight ratio and was assessed at different time-points after the administration of TIP. Secondary outcomes included clinical scores and lung cellular response. Results TIP did not have an effect on pulmonary edema in different dose regimens at different time points during PVM infection. In addition, TIP administration did not affect clinical severity scores or lung cellular response. Conclusion In this murine model of severe RSV infection TIP did not affect pulmonary edema nor course of disease. PMID:25047452

  20. Keratinocyte growth factor protects against elastase-induced pulmonary emphysema in mice.

    PubMed

    Plantier, Laurent; Marchand-Adam, Sylvain; Antico Arciuch, Valeria G; Antico, Valeria G; Boyer, Laurent; De Coster, Cécile; Marchal, Joëlle; Bachoual, Rafik; Mailleux, Arnaud; Boczkowski, Jorge; Crestani, Bruno

    2007-11-01

    Pulmonary emphysema is characterized by persistent inflammation and progressive alveolar destruction. The keratinocyte growth factor (KGF) favorably influences alveolar maintenance and repair and possesses anti-inflammatory properties. We aimed to determine whether exogenous KGF prevented or corrected elastase-induced pulmonary emphysema in vivo. Treatment with 5 mg x kg(-1) x day(-1) KGF before elastase instillation prevented pulmonary emphysema. This effect was associated with 1) a sharp reduction in bronchoalveolar lavage fluid total protein and inflammatory cell recruitment, 2) a reduction in the pulmonary expression of the chemokines CCL2 (or monocyte chemoattractant protein-1) and CXCL2 (or macrophage inflammatory protein-2alpha) and of the adhesion molecules ICAM-1 and VCAM-1, 3) a reduction in matrix metalloproteinase (MMP)-2 and MMP-9 activity at day 3, and 4) a major reduction in DNA damage detected by terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL) in alveolar cells at day 7. Treatment with KGF after elastase instillation had no effect on elastase-induced emphysema despite the conserved expression of the KGF receptor in the lungs of elastase-instilled animals as determined by immunohistochemistry. In vitro, KGF abolished the elastase-induced increase in CCL2, CXCL2, and ICAM-1 mRNA in the MLE-12 murine alveolar epithelial cell line. We conclude that KGF pretreatment protected against elastase-induced pulmonary inflammation, activation of MMPs, alveolar cell DNA damage, and subsequent emphysema in mice. PMID:17766584

  1. Swimming-induced immersion pulmonary edema while snorkeling can be rapidly life-threatening: case reports.

    PubMed

    Cochard, G; Henckes, A; Deslandes, S; Noël-Savina, E; Bedossa, M; Gladu, G; Ozier, Y

    2013-01-01

    It is well known that immersion pulmonary edema can be life-threatening for divers using a self-contained underwater breathing apparatus (scuba). Swimming-induced pulmonary edema in otherwise healthy individuals is not an object of dispute but its real severity is not well known and is probably underestimated. We report two cases of life-threatening acute respiratory distress while swimming and snorkeling, one of which is well documented for swimming-induced pulmonary edema. The interest of these case reports lies in the suddenness of these life-threatening events. Such accidents can mimic a loss of consciousness due to cardiac dysrhythmia and lead to drowning. In the case of swimming-induced pulmonary edema, the prognosis is far better than for a cardiac disorder, but it is also dependent on the efficiency of the supervision. Swimmers, divers, race organizers and supervising physicians should be given knowledge of this pathology and its potentially acute occurrence. Adequate organizational dispositions are mandatory to prevent swimming-induced pulmonary edema-related deaths. PMID:24224285

  2. 4-Phenylbutyric Acid Induces Protection against Pulmonary Arterial Hypertension in Rats

    PubMed Central

    Long, Mei; Wang, Jie; Liu, Fen; Gai, Min-Tao; Aierken, Alidan; Li, Ming-Yuan; Li, Qian; Wu, Lei-Qi; Ma, Yi-Tong; Hujiaaihemaiti, Minawaer

    2016-01-01

    Background Endoplasmic reticulum (ER) stress has been implicated in the pathophysiology of various pulmonary diseases via the activation of the unfolded protein response. However, the role of ER stress in pulmonary arterial hypertension (PAH) remains unclear. The well-known chemical chaperone 4-phenylbutyric acid (4-PBA) inhibits ER stress signaling. We hypothesized that known chemical chaperones, including 4-PBA, would inhibit the activation of ER stress and prevent and/or reverse PAH. Methods and Results Male Wistar rats were randomly divided into four groups: a normal control group (NORMAL group), a PAH group, and two PAH model plus 4-PBA treatment groups. The latter two groups included rats receiving 4-PBA by gavage each day as a preventive measure (the PRE group, with PBA starting on the day of PAH induction and continuing for 4 weeks) or as a reversal measure (the REV group, with PBA starting on the third week of PAH induction and continuing for 2 weeks). The PAH model was induced by intraperitoneally administering monocrotaline. The mean pulmonary artery pressure and mean right ventricular pressure were lower in the REV and PRE groups than in the NORMAL group. Furthermore, 4-PBA improved pulmonary arterial remodeling and suppressed the expression of ER stress indicators. Conclusion Our findings indicate that PAH induces ER stress and provokes pulmonary arterial and right ventricular remodeling. Additionally, we show that attenuation of ER stress has the potential to be an effective therapeutic strategy for protecting pulmonary arteries. PMID:27304885

  3. Preventive effects of vitamin D treatment on bleomycin-induced pulmonary fibrosis

    PubMed Central

    Zhang, Zongmei; Yu, Xiaoting; Fang, Xia; Liang, Aibin; Yu, Zhang; Gu, Pan; Zeng, Yu; He, Jian; Zhu, Hailong; Li, Shuai; Fan, Desheng; Han, Fei; Zhang, Lanjing; Yi, Xianghua

    2015-01-01

    Patients with pulmonary fibrosis often have low vitamin D levels, the effects of which are largely unknown. We here report that early vitamin D supplementation significantly reduced the severity of pulmonary fibrosis and inflammatory cell accumulationin in the bleomycin-induced pulmonary fibrosis mouse model on supplementary days 14, 21 and 28 (P < 0.001). Vitamin D supplementation also prevented some ultrastructural changes in response to bleomycin administration, including basement membrane thickening, interstitial fibrin deposition and microvilli flattening or disappearance on days 14, 21 and 28, and lamellar body swelling or vacuolation on days 21 and 28. The bleomycin group had rising hydroxyproline level on days 14, 21 and 28, whereas the vitamin D treatment group showed consistently lower hydroxyproline level but still higher than that of the control group (P < 0.001). Our immunohistochemistry and densitometry analyses showed less staining for α-smooth muscle actin, a myofibroblast marker, in the vitamin D group compared to the bleomycin group (P < 0.001). Thus, vitamin D treatment could prevent bleomycin-induced pulmonary fibrosis by delaying or suppressing ultrastructural changes, as well as attenuating hydroxyproline accumulation and inhibiting myofibroblastic proliferation. These data further our understanding of the roles of vitamin D in pulmonary fibrogenesis and in the treatment of pulmonary fibrosis. PMID:26627341

  4. Hypoxia inducible factor signaling and experimental persistent pulmonary hypertension of the newborn

    PubMed Central

    Wedgwood, Stephen; Lakshminrusimha, Satyan; Schumacker, Paul T.; Steinhorn, Robin H.

    2015-01-01

    Background: Mitochondrial reactive oxygen species (ROS) levels and nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) activity are increased in a lamb model of persistent pulmonary hypertension of the newborn (PPHN). These events can trigger hypoxia inducible factor (HIF) signaling in response to hypoxia, which has been shown to contribute to pulmonary vascular remodeling in rodent models of pulmonary hypertension. However, the role of HIF signaling in chronic intrauterine pulmonary hypertension is not well understood. Aim: To determine if HIF signaling is increased in the lamb model of PPHN, and to identify the underlying mechanisms. Results: PPHN was induced in lambs by antenatal ligation of the ductus arteriosus at 128 days gestation. After 9 days, lungs and pulmonary artery smooth muscle cells (PASMC) were isolated from control and PPHN lambs. HIF-1α expression was increased in PPHN lungs and HIF activity was increased in PPHN PASMC relative to controls. Hypoxia increased HIF activity to a greater degree in PPHN vs. control PASMC. Control PASMC were exposed to cyclic stretch at 1 Hz and 15% elongation for 24 h, as an in vitro model of vascular stress. Stretch increased HIF activity, which was attenuated by inhibition of mitochondrial complex III and NFκB. Conclusion: Increased HIF signaling in PPHN is triggered by stretch, via mechanisms involving mitochondrial ROS and NFκB. Hypoxia substantially amplifies HIF activity in PPHN vascular cells. Targeting these signaling molecules may attenuate and reverse pulmonary vascular remodeling associated with PPHN. PMID:25814954

  5. Fractal Dimension in Quantifying Experimental-Pulmonary-Hypertension-Induced Cardiac Dysfunction in Rats

    PubMed Central

    Pacagnelli, Francis Lopes; Sabela, Ana Karênina Dias de Almeida; Mariano, Thaoan Bruno; Ozaki, Guilherme Akio Tamura; Castoldi, Robson Chacon; do Carmo, Edna Maria; Carvalho, Robson Francisco; Tomasi, Loreta Casquel; Okoshi, Katashi; Vanderlei, Luiz Carlos Marques

    2016-01-01

    Background Right-sided heart failure has high morbidity and mortality, and may be caused by pulmonary arterial hypertension. Fractal dimension is a differentiated and innovative method used in histological evaluations that allows the characterization of irregular and complex structures and the quantification of structural tissue changes. Objective To assess the use of fractal dimension in cardiomyocytes of rats with monocrotaline-induced pulmonary arterial hypertension, in addition to providing histological and functional analysis. Methods Male Wistar rats were divided into 2 groups: control (C; n = 8) and monocrotaline-induced pulmonary arterial hypertension (M; n = 8). Five weeks after pulmonary arterial hypertension induction with monocrotaline, echocardiography was performed and the animals were euthanized. The heart was dissected, the ventricles weighed to assess anatomical parameters, and histological slides were prepared and stained with hematoxylin/eosin for fractal dimension analysis, performed using box-counting method. Data normality was tested (Shapiro-Wilk test), and the groups were compared with non-paired Student t test or Mann Whitney test (p < 0.05). Results Higher fractal dimension values were observed in group M as compared to group C (1.39 ± 0.05 vs. 1.37 ± 0.04; p < 0.05). Echocardiography showed lower pulmonary artery flow velocity, pulmonary acceleration time and ejection time values in group M, suggesting function worsening in those animals. Conclusion The changes observed confirm pulmonary-arterial-hypertension-induced cardiac dysfunction, and point to fractal dimension as an effective method to evaluate cardiac morphological changes induced by ventricular dysfunction. PMID:27223643

  6. Hypoxia-induced Deoxycytidine Kinase Contributes to Epithelial Proliferation in Pulmonary Fibrosis

    PubMed Central

    Weng, Tingting; Poth, Jens M.; Karmouty-Quintana, Harry; Garcia-Morales, Luis J.; Melicoff, Ernestina; Luo, Fayong; Chen, Ning-yuan; Evans, Christopher M.; Bunge, Raquel R.; Bruckner, Brian A.; Loebe, Matthias; Volcik, Kelly A.; Eltzschig, Holger K.

    2014-01-01

    Rationale: Idiopathic pulmonary fibrosis (IPF) is a deadly lung disease with few therapeutic options. Apoptosis of alveolar epithelial cells, followed by abnormal tissue repair characterized by hyperplastic epithelial cell formation, is a pathogenic process that contributes to the progression of pulmonary fibrosis. However, the signaling pathways responsible for increased proliferation of epithelial cells remain poorly understood. Objectives: To investigate the role of deoxycytidine kinase (DCK), an important enzyme for the salvage of deoxynucleotides, in the progression of pulmonary fibrosis. Methods: DCK expression was examined in the lungs of patients with IPF and mice exposed to bleomycin. The regulation of DCK expression by hypoxia was studied in vitro and the importance of DCK in experimental pulmonary fibrosis was examined using a DCK inhibitor and alveolar epithelial cell-specific knockout mice. Measurements and Main Results: DCK was elevated in hyperplastic alveolar epithelial cells of patients with IPF and in mice exposed to bleomycin. Increased DCK was localized to cells associated with hypoxia, and hypoxia directly induced DCK in alveolar epithelial cells in vitro. Hypoxia-induced DCK expression was abolished by silencing hypoxia-inducible factor 1α and treatment of bleomycin-exposed mice with a DCK inhibitor attenuated pulmonary fibrosis in association with decreased epithelial cell proliferation. Furthermore, DCK expression, and proliferation of epithelial cells and pulmonary fibrosis was attenuated in mice with conditional deletion of hypoxia-inducible factor 1α in the alveolar epithelium. Conclusions: Our findings suggest that the induction of DCK after hypoxia plays a role in the progression of pulmonary fibrosis by contributing to alveolar epithelial cell proliferation. PMID:25358054

  7. Early Detection of Schistosoma Egg-Induced Pulmonary Granulomas in a Returning Traveler.

    PubMed

    Coron, Noémie; Le Govic, Yohann; Kettani, Sami; Pihet, Marc; Hemery, Sandrine; de Gentile, Ludovic; Chabasse, Dominique

    2016-03-01

    We report the case of a French traveler who developed acute pulmonary schistosomiasis 2 months after visiting Benin. He presented with a 1-month history of fever, cough, and thoracic pain. Initial investigations revealed hypereosinophilia and multiple nodular lesions on chest computed tomography scan. Lung biopsies were performed 2 months later because of migrating chest infiltrates and increasing eosinophilia. Histological examination showed schistosomal egg-induced pulmonary granulomas with ova exhibiting a prominent terminal spine, resembling Schistosoma haematobium. However, egg shells were Ziehl-Neelsen positive, raising the possibility of a Schistosoma intercalatum or a Schistosoma guineensis infection. Moreover, involvement of highly infectious hybrid species cannot be excluded considering the atypical early pulmonary oviposition. This case is remarkable because of the rarity of pulmonary schistosomiasis, its peculiar clinical presentation and difficulties in making species identification. It also emphasizes the need to consider schistosomiasis diagnosis in all potentially exposed travelers with compatible symptoms. PMID:26787142

  8. Hypoxia-induced pulmonary arterial hypertension augments lung injury and airway reactivity caused by ozone exposure.

    PubMed

    Zychowski, Katherine E; Lucas, Selita N; Sanchez, Bethany; Herbert, Guy; Campen, Matthew J

    2016-08-15

    Ozone (O3)-related cardiorespiratory effects are a growing public health concern. Ground level O3 can exacerbate pre-existing respiratory conditions; however, research regarding therapeutic interventions to reduce O3-induced lung injury is limited. In patients with chronic obstructive pulmonary disease, hypoxia-associated pulmonary hypertension (HPH) is a frequent comorbidity that is difficult to treat clinically, yet associated with increased mortality and frequency of exacerbations. In this study, we hypothesized that established HPH would confer vulnerability to acute O3 pulmonary toxicity. Additionally, we tested whether improvement of pulmonary endothelial barrier integrity via rho-kinase inhibition could mitigate pulmonary inflammation and injury. To determine if O3 exacerbated HPH, male C57BL/6 mice were subject to either 3 weeks continuous normoxia (20.9% O2) or hypoxia (10.0% O2), followed by a 4-h exposure to either 1ppm O3 or filtered air (FA). As an additional experimental intervention fasudil (20mg/kg) was administered intraperitoneally prior to and after O3 exposures. As expected, hypoxia significantly increased right ventricular pressure and hypertrophy. O3 exposure in normoxic mice caused lung inflammation but not injury, as indicated by increased cellularity and edema in the lung. However, in hypoxic mice, O3 exposure led to increased inflammation and edema, along with a profound increase in airway hyperresponsiveness to methacholine. Fasudil administration resulted in reduced O3-induced lung injury via the enhancement of pulmonary endothelial barrier integrity. These results indicate that increased pulmonary vascular pressure may enhance lung injury, inflammation and edema when exposed to pollutants, and that enhancement of pulmonary endothelial barrier integrity may alleviate such vulnerability. PMID:27286659

  9. Vanadium pentoxide nanoparticles mimic vanadium haloperoxidases and thwart biofilm formation.

    PubMed

    Natalio, Filipe; André, Rute; Hartog, Aloysius F; Stoll, Brigitte; Jochum, Klaus Peter; Wever, Ron; Tremel, Wolfgang

    2012-08-01

    Marine biofouling--the colonization of small marine microorganisms on surfaces that are directly exposed to seawater, such as ships' hulls--is an expensive problem that is currently without an environmentally compatible solution. Biofouling leads to increased hydrodynamic drag, which, in turn, causes increased fuel consumption and greenhouse gas emissions. Tributyltin-free antifouling coatings and paints based on metal complexes or biocides have been shown to efficiently prevent marine biofouling. However, these materials can damage the environment through metal leaching (for example, of copper and zinc) and bacteria resistance. Here, we show that vanadium pentoxide nanowires act like naturally occurring vanadium haloperoxidases to prevent marine biofouling. In the presence of bromide ions and hydrogen peroxide, the nanowires catalyse the oxidation of bromide ions to hypobromous acid (HOBr). Singlet molecular oxygen ((1)O(2)) is formed and this exerts strong antibacterial activity, which prevents marine biofouling without being toxic to marine biota. Vanadium pentoxide nanowires have the potential to be an alternative approach to conventional anti-biofouling agents. PMID:22751222

  10. Nanometer sized tantalum pentoxide fibers prepared by electrospinning

    SciTech Connect

    Dharmaraj, N.; Kim, H.Y.

    2006-03-09

    Novel, porous tantalum pentoxide (Ta{sub 2}O{sub 5}) nanofibers with 150-250 nm diameter were obtained by high temperature calcination of the as-electrospun tantalum pentoxide/poly(vinyl acetate) (PVAc) composite fibers prepared by sol-gel processing and electrospinning technique. Surface analysis, structure and elemental composition of these as-electrospun and as-calcinated Ta{sub 2}O{sub 5} nanofibers have been studied by scanning electron microscope (SEM) equipped with an energy dispersive X-ray analysis (EDX), high resolution field emission scanning electron microscopy (FE-SEM), atomic force microscopy (AFM), X-ray diffraction patterns (XRD) and FT-IR. High-resolution FE-SEM images showed the porous nature of Ta{sub 2}O{sub 5} nanofibers. EDX analysis revealed the perfect stoichiometry of the nanofibers as Ta{sub 2}O{sub 5}. A linear correlation was noted between the calcination temperature and orthorhombic crystalline phase evolution of Ta{sub 2}O{sub 5}.

  11. Vanadium pentoxide nanoparticles mimic vanadium haloperoxidases and thwart biofilm formation

    NASA Astrophysics Data System (ADS)

    Natalio, Filipe; André, Rute; Hartog, Aloysius F.; Stoll, Brigitte; Jochum, Klaus Peter; Wever, Ron; Tremel, Wolfgang

    2012-08-01

    Marine biofouling--the colonization of small marine microorganisms on surfaces that are directly exposed to seawater, such as ships' hulls--is an expensive problem that is currently without an environmentally compatible solution. Biofouling leads to increased hydrodynamic drag, which, in turn, causes increased fuel consumption and greenhouse gas emissions. Tributyltin-free antifouling coatings and paints based on metal complexes or biocides have been shown to efficiently prevent marine biofouling. However, these materials can damage the environment through metal leaching (for example, of copper and zinc) and bacteria resistance. Here, we show that vanadium pentoxide nanowires act like naturally occurring vanadium haloperoxidases to prevent marine biofouling. In the presence of bromide ions and hydrogen peroxide, the nanowires catalyse the oxidation of bromide ions to hypobromous acid (HOBr). Singlet molecular oxygen (1O2) is formed and this exerts strong antibacterial activity, which prevents marine biofouling without being toxic to marine biota. Vanadium pentoxide nanowires have the potential to be an alternative approach to conventional anti-biofouling agents.

  12. Inhibition of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) reverses experimental pulmonary hypertension.

    PubMed

    Hameed, Abdul G; Arnold, Nadine D; Chamberlain, Janet; Pickworth, Josephine A; Paiva, Claudia; Dawson, Sarah; Cross, Simon; Long, Lu; Zhao, Lan; Morrell, Nicholas W; Crossman, David C; Newman, Christopher M H; Kiely, David G; Francis, Sheila E; Lawrie, Allan

    2012-10-22

    Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by the progressive narrowing and occlusion of small pulmonary arteries. Current therapies fail to fully reverse this vascular remodeling. Identifying key pathways in disease pathogenesis is therefore required for the development of new-targeted therapeutics. We have previously reported tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) immunoreactivity within pulmonary vascular lesions from patients with idiopathic PAH and animal models. Because TRAIL can induce both endothelial cell apoptosis and smooth muscle cell proliferation in the systemic circulation, we hypothesized that TRAIL is an important mediator in the pathogenesis of PAH. We demonstrate for the first time that TRAIL is a potent stimulus for pulmonary vascular remodeling in human cells and rodent models. Furthermore, antibody blockade or genetic deletion of TRAIL prevents the development of PAH in three independent rodent models. Finally, anti-TRAIL antibody treatment of rodents with established PAH reverses pulmonary vascular remodeling by reducing proliferation and inducing apoptosis, improves hemodynamic indices, and significantly increases survival. These preclinical investigations are the first to demonstrate the importance of TRAIL in PAH pathogenesis and highlight its potential as a novel therapeutic target to direct future translational therapies. PMID:23071256

  13. Inhibition of tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) reverses experimental pulmonary hypertension

    PubMed Central

    Hameed, Abdul G.; Arnold, Nadine D.; Chamberlain, Janet; Pickworth, Josephine A.; Paiva, Claudia; Dawson, Sarah; Cross, Simon; Long, Lu; Zhao, Lan; Morrell, Nicholas W.; Crossman, David C.; Newman, Christopher M.H.; Kiely, David G.; Francis, Sheila E.

    2012-01-01

    Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by the progressive narrowing and occlusion of small pulmonary arteries. Current therapies fail to fully reverse this vascular remodeling. Identifying key pathways in disease pathogenesis is therefore required for the development of new-targeted therapeutics. We have previously reported tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) immunoreactivity within pulmonary vascular lesions from patients with idiopathic PAH and animal models. Because TRAIL can induce both endothelial cell apoptosis and smooth muscle cell proliferation in the systemic circulation, we hypothesized that TRAIL is an important mediator in the pathogenesis of PAH. We demonstrate for the first time that TRAIL is a potent stimulus for pulmonary vascular remodeling in human cells and rodent models. Furthermore, antibody blockade or genetic deletion of TRAIL prevents the development of PAH in three independent rodent models. Finally, anti-TRAIL antibody treatment of rodents with established PAH reverses pulmonary vascular remodeling by reducing proliferation and inducing apoptosis, improves hemodynamic indices, and significantly increases survival. These preclinical investigations are the first to demonstrate the importance of TRAIL in PAH pathogenesis and highlight its potential as a novel therapeutic target to direct future translational therapies. PMID:23071256

  14. Aloe vera affects changes induced in pulmonary tissue of mice caused by cigarette smoke inhalation.

    PubMed

    Koul, Ashwani; Bala, Shashi; Yasmeen; Arora, Neha

    2015-09-01

    This study was undertaken to determine the influence of Aloe vera (AV) on changes induced in pulmonary tissue of cigarette smoke (CS) inhaling mice. CS inhalation for 4 weeks caused pulmonary damage as evident by histoarchitectural alterations and enhanced serum and tissue lactate dehydrogenase (LDH) activities. CS inhalation also led to increased mucin production as revealed by mucicarmine and Alcian Blue-Periodic Acid Schiff (AB-PAS) staining. Studies on bronchoalveolar lavage fluid (balf) of CS exposed animals revealed structural changes in phospholipids and increase in surface tension when compared with control counterparts. These changes were accompanied by enhanced nitric oxide (NO) levels, citrulline levels, peroxidative damage, and differential modulation of antioxidant defense system. AV administration (seven weeks, 500 mg/kg b.w. daily) to CS inhaling mice led to modulation of CS induced pulmonary changes as revealed by lesser degree of histoarchitectural alterations, lesser mucin production, decreased NO levels, citrulline levels, peroxidative damage, and serum LDH activity. AV treatment to CS inhaling mice was associated with varying response to antioxidant defense system, however balf of CS + AV treated animals did not exhibit appreciable changes when compared with that of CS exposed animals. These observations suggest that AV has the potential to modulate CS induced changes in the pulmonary tissue which could have implications in management of CS associated pulmonary diseases, however, further investigations are required to explore its complete mechanism of action. PMID:24615921

  15. miR-29 inhibits bleomycin-induced pulmonary fibrosis in mice.

    PubMed

    Xiao, Jun; Meng, Xiao-Ming; Huang, Xiao R; Chung, Arthur Ck; Feng, Yu-Lin; Hui, David Sc; Yu, Cheuk-Man; Sung, Joseph Jy; Lan, Hui Y

    2012-06-01

    Loss of microRNA-29 (miR-29) is known to be a mechanism of transforming growth factor-β (TGF-β)-mediated pulmonary fibrosis, but the therapeutic implication of miR-29 for pulmonary fibrosis remains unexplored. The present study investigated whether miR-29 had therapeutic potential for lung disease induced by bleomycin in mice. In addition, the signaling mechanisms that regulated miR-29 expression were investigated in vivo and in vitro. We found that miR-29 was a downstream target gene of Smad3 and negatively regulated by TGF-β/Smad signaling in fibrosis. This was evidenced by the findings that mice or pulmonary fibroblasts null for Smad3 were protected against bleomycin or TGF-β1-induced loss of miR-29 along with fibrosis in vivo and in vitro. Interestingly, overexpression of miR-29 could in turn negatively regulated TGF-β and connective tissue growth factor (CTGF) expression and Smad3 signaling. Therefore, Sleeping Beauty (SB)-mediated miR-29 gene transfer into normal and diseased lung tissues was capable of preventing and treating pulmonary fibrosis including inflammatory macrophage infiltration induced by bleomycin in mice. In conclusion, miR-29 is negatively regulated by TGF-β/Smad3 and has a therapeutic potential for pulmonary fibrosis. SB-mediated miR-29 gene therapy is a non-invasive therapeutic strategy for lung disease associated with fibrosis. PMID:22395530

  16. Molecular insights into the progression of crystalline silica-induced pulmonary toxicity in rats

    PubMed Central

    Sellamuthu, Rajendran; Umbright, Christina; Roberts, Jenny R.; Cumpston, Amy; McKinney, Walter; Chen, Bean T.; Frazer, David; Li, Shengqiao; Kashon, Michael; Joseph, Pius

    2015-01-01

    Identification of molecular target(s) and mechanism(s) of silica-induced pulmonary toxicity is important for the intervention and/or prevention of diseases associated with exposure to silica. Rats were exposed to crystalline silica by inhalation (15 mg m−3, 6 h per day, 5 days) and global gene expression profile was determined in the lungs by microarray analysis at 1, 2, 4, 8 and 16 weeks following termination of silica exposure. The number of significantly differentially expressed genes (>1.5-fold change and <0.01 false discovery rate P-value) detected in the lungs during the post-exposure time intervals analyzed exhibited a steady increase in parallel with the progression of silica-induced pulmonary toxicity noticed in the rats. Quantitative real-time PCR analysis of a representative set of 10 genes confirmed the microarray findings. The number of biological functions, canonical pathways and molecular networks significantly affected by silica exposure, as identified by the bioinformatics analysis of the significantly differentially expressed genes detected during the post-exposure time intervals, also exhibited a steady increase similar to the silica-induced pulmonary toxicity. Genes involved in oxidative stress, inflammation, respiratory diseases, cancer, and tissue remodeling and fibrosis were significantly differentially expressed in the rat lungs; however, unresolved inflammation was the single most significant biological response to pulmonary exposure to silica. Excessive mucus production, as implicated by significant overexpression of the pendrin coding gene, SLC26A4, was identified as a potential novel mechanism for silica-induced pulmonary toxicity. Collectively, the findings of our study provided insights into the molecular mechanisms underlying the progression of crystalline silica-induced pulmonary toxicity in the rat. Published 2012. This article is a US Government work and is in the public domain in the USA. PMID:22431001

  17. Agranulocytosis Induced by Ethambutol in a Patient with Pulmonary Tuberculosis

    PubMed Central

    Moon, Kyoung Min; Chung, So Hee; Kim, Ju Ri; Kim, Jin Young; Jung, Sun Young; Cho, Yongseon

    2015-01-01

    We report a case of agranulocytosis caused by ethambutol in a 79-year-old man with pulmonary tuberculosis. He was referred for fever and skin rash developed on 21th day after antituberculosis drugs (isoniazid, rifampicin, ethambutol, and pyrazinamide) intake. Complete blood count at the time of diagnosis of pulmonary tuberculosis was normal. On the seventh admission day, agranulocytosis was developed with absolute neutrophil count of 70/µL. We discontinued all antituberculosis drugs, and then treated with granulocyte colony-stimulating factor. Three days later, the number of white blood cell returned to normal. We administered isoniazid, pyrazinamide, and ethambutol in order with an interval. However, fever and skin rash developed again when adding ethambutol, so we discontinued ethambutol. After these symptoms disappeared, we added rifampicin and ethambutol in order with an interval. However after administering ethambutol, neutropenia developed, so we discontinued ethambutol again. He was cured with isoniazid, rifampicin, and pyrazinamide for 9 months. PMID:25861347

  18. /sup 67/Ga scanning in talc-induced pulmonary granulomatosis

    SciTech Connect

    Brown, D.G.; Aguirre, A.; Weaver, A.

    1980-04-01

    We describe a case of pulmonary granulomatosis in a user who habitually injected methylphenidate (Ritalin) intravenously; symptomatic and objective improvement occurred with corticosteroid therapy. A scan of the lungs using raioactive /sup 67/Ga showed an increased concentration of /sup 67/Ga throughout both lungs. There was a reduction in abnormal accumulation of /sup 67/Ga, improvement in the arterial oxygen pressure and the diffusing capacity for carbon monoxide, and a reduction in the infiltrate on the chest x-ray film two months after the institution of therapy. Before treatment the patient's symptoms and arterial deoxygenation increased despite the cessation of her drug abuse, thus raising the question of a self-perpetuating inflammatory process in a case of pulmonary deposition of talc.

  19. Role of posterior hypothalamus in hypobaric hypoxia induced pulmonary edema.

    PubMed

    Sharma, R K; Choudhary, R C; Reddy, M K; Ray, A; Ravi, K

    2015-01-01

    To investigate the role of posterior hypothalamus and central neurotransmitters in the pulmonary edema due to hypobaric hypoxia, rats were placed in a high altitude simulation chamber (barometric pressure-294.4 mmHg) for 24 h. Exposure to hypobaric hypoxia resulted in increases in mean arterial blood pressure, renal sympathetic nerve activity, right ventricular systolic pressure, lung wet to dry weight ratio and Evans blue dye leakage. There was a significant attenuation in these responses to hypobaric hypoxia (a) after lesioning posterior hypothalamus and (b) after chronic infusion of GABAA receptor agonist muscimol into posterior hypothalamus. No such attenuation was evident with the chronic infusion of the nitric oxide donor SNAP into the posterior hypothalamus. It is concluded that in hypobaric hypoxia, there is over-activity of posterior hypothalamic neurons probably due to a local decrease in GABA-ergic inhibition which increases the sympathetic drive causing pulmonary hypertension and edema. PMID:25448396

  20. Ulinastatin attenuates pulmonary endothelial glycocalyx damage and inhibits endothelial heparanase activity in LPS-induced ARDS.

    PubMed

    Wang, Lipeng; Huang, Xiao; Kong, Guiqing; Xu, Haixiao; Li, Jiankui; Hao, Dong; Wang, Tao; Han, Shasha; Han, Chunlei; Sun, Yeying; Liu, Xiangyong; Wang, Xiaozhi

    2016-09-16

    Acute respiratory distress syndrome (ARDS) is a syndrome of acute respiratory failure characterized by major pathologic mechanisms of increased microvascular permeability and inflammation. The glycocalyx lines on the endothelial surface, which determines the vascular permeability, and heparanase play pivotal roles in the degradation of heparan sulfate (HS). HS is the major component of the glycocalyx. The aim of this study is to examine the effects of Ulinastatin (UTI) on vascular permeability and pulmonary endothelial glycocalyx dysfunction induced by lipopolysaccharide (LPS). In our study, C57BL/6 mice and human umbilical vein endothelial cells were stimulated with LPS to induce injury models. After 6 h of LPS stimulation, pulmonary pathological changes, pulmonary edema, and vascular permeability were notably attenuated by UTI. UTI inhibited LPS-induced endothelial glycocalyx destruction and significantly decreased the production of HS as determined by ELISA and immunofluorescence. UTI also reduced the active form of heparanase (50 kDa) expression and heparanase activity. Moreover, lysosome pH was investigated because heparanase (65 kDa) can be reduced easily in its active form at 50 kDa in a low pH environment within lysosome. Results showed that UTI could inhibit LPS-induced pH elevation in lysosome. In conclusion, UTI protects pulmonary endothelial glycocalyx integrity and inhibits heparanase activity during LPS-induced ARDS. PMID:27498004

  1. Brain natriuretic peptide levels in six basic underwater demolitions/SEAL recruits presenting with swimming induced pulmonary edema (SIPE).

    PubMed

    Shearer, Damon; Mahon, Richard

    2009-01-01

    Swimming induced pulmonary edema (SIPE) is associated with both SCUBA diving and strenuous surface swimming; however, the majority of reported cases and clinically observed cases tend to occur during or after aggressive surface swimming. Capillary stress failure appears to be central to the pathophysiology of this disorder. Regional pulmonary capillaries are exposed to relatively high pressures secondary to increased vascular volume, elevation of pulmonary vascular resistance, and regional differences in perfusion secondary to forces of gravity and high cardiac output. Acute pulmonary edema can be classified as either cardiogenic or noncardiogenic or both. Cardiogenic pulmonary edema occurs when the pulmonary capillary hydrostatic pressure exceeds plasma oncotic pressure. Noncardiogenic pulmonary edema occurs when pulmonary capillary permeability is increased. Given the pathophysiology noted above, SIPE can be described as a cardiogenic pulmonary edema, at least in part, since an increased transalveolar pressure gradient has been implicated in the pathogenesis of SIPE. Brain natriuretic peptide (BNP) is used in the clinical setting to differentiate cardiac from pulmonary sources of dyspnea, specifically to diagnose cardiogenic pulmonary edema. During clinical management, BNP levels were drawn on six BUD/S recruits simultaneously presenting with pulmonary complaints consistent with SIPE, after an extended surface bay swim. This paper analyzes that data after de-identification and reviews the pathophysiology and clinical management of SIPE. PMID:19739476

  2. Variability in Ozone-Induced Pulmonary Injury and Inflammation in Healthy and Cardiovascular Compromised Rat Models

    EPA Science Inventory

    The molecular bases for variability in air pollutant-induced pulmonary injury due to underlying cardiovascular (CVD) and/or metabolic diseases are unknown. We hypothesized that healthy and genetic CVD-prone rat models will exhibit exacerbated response to acute ozone exposure depe...

  3. METAL-INDUCED LATE PULMONARY INJURY IS REDUCED BY OZONE (O3) COEXPOSURE

    EPA Science Inventory

    METAL-INDUCED LATE PULMONARY INJURY IS REDUCED BY OZONE (O3) COEXPOSURE. UP Kodavanti, MCJ Schladweiler, WP Watkinson, JP Nolan, PA Evansky, ER Lappi, G Ross, JH Richards, and DL Costa. NHEERL, ORD, US Environmental Protection Agency, Research Triangle Park, NC USA.
    Ambient ...

  4. URBAN PARTICLE-INDUCED PULMONARY ARTERY CONSTRUCTION IS MEDIATED BY SUPEROXIDE PRODUCTION

    EPA Science Inventory

    URBAN PARTICLE-INDUCED PULMONARY ARTERY CONSTRICTION IS MEDIATED BY SUPEROXIDE PRODUCTION.Jacqueline D. Carter, Zhuowei Li, Lisa A. Dailey, Yuh-Chin T. Huang. CEMALB, University of North Carolina, and ORD, US EPA, Chapel Hill, North Carolina.

    Exposure to particulate matter...

  5. DIESEL AND CARBON PARTICLES ENHANCE HOUSE DUST MITE-INDUCED PULMONARY HYPERSENSITIVITY IN BROWN NORWAY RATS

    EPA Science Inventory

    Diesel and Carbon Particles Enhance House Dust Mite-Induced Pulmonary Hypersensitivity in Brown Norway Rats. P. Singh1, M.J. Daniels2, D. Winsett2, J. Richards2, K. Crissman2, M. Madden2 and M.I. Gilmour2. 1NCSU, Raleigh, NC and 2 USEPA, Research Triangle Park, NC.

    Ep...

  6. Single-Walled Carbon Nanotubes Induce Pulmonary and Vascular Response Following Intratracheal Instillation

    EPA Science Inventory

    Carbon-based nanotubes have been shown to induce varying degrees of pulmonary response in rodents influenced by the dose, the extent of agglomeration, the chemistry of the suspension solution, and the functional properties. We hypothesized that low concentrations of non-modified ...

  7. A 45-Year-Old Man With Recurrent Dyspnea and Hemoptysis during Exercise: Exercise-Induced Pulmonary Hemorrhage/Edema

    PubMed Central

    Kim, Dae Sung; Lee, Minhyeok; Kwon, Oh Jung; Jeong, Inbeom; Son, Ji Woong; Na, Moon Jun

    2015-01-01

    A 45-year-old man presented with dyspnea and hemoptysis during exercise. A chest computed tomography (CT) revealed multifocal diffuse patchy ground glass opacity and interlobular septal thickening in both the lungs. Permeability pulmonary edema or pulmonary hemorrhage was suspected. Serologic studies for autoimmune disorders and vasculitis were negative. There was no laboratory evidence of coagulopathy, other hematopoietic disease or infectious disease. Considering correlation with exercise, we diagnosed exercise-induced pulmonary hemorrhage (EIPH) or exercise-induced pulmonary edema (EIPE). The patient was managed with antifibrinolytics, antibiotics, and antitussive agent. After a week, follow-up chest CT revealed completely resolved pulmonary hemorrhage. About 2 months after the first event, he visited again with dyspnea and hemoptysis during running. In the present study, we report a case of recurrent pulmonary hemorrhage after exercise. PMID:26508928

  8. Chronic Normobaric Hypoxia Induces Pulmonary Hypertension in Rats: Role of NF-κB.

    PubMed

    Fan, Junming; Fan, Xiaofang; Li, Yang; Ding, Lu; Zheng, Qingqing; Guo, Jinbin; Xia, Dongmei; Xue, Feng; Wang, Yongyu; Liu, Shufang; Gong, Yongsheng

    2016-03-01

    Junming Fan, Xiaofang Fan, Yang Li, Lu Ding, Qingqing Zheng, Jinbin Guo, Dongmei Xia, Feng Xue, Yongyu Wang, Shufang Liu, and Yongsheng Gong. Chronic normobaric hypoxia induces pulmonary hypertension in rats: role of NF-κB. High Alt Med Biol 17:43-49, 2016.-To investigate whether nuclear factor-kappa B (NF-κB) activation is involved in chronic normobaric hypoxia-induced pulmonary hypertension (PH), rats were treated with saline or an NF-κB inhibitor, pyrrolidine dithiocarbamate (PDTC, 150 mg/kg, sc, twice daily), and exposed to normoxia or chronic normobaric hypoxia with a fraction of inspired oxygen of ∼0.1 for 14 days. Lung tissue levels of NF-κB activity, and interleukin (IL)-1β, IL-6, and cyclooxygenase-2 mRNAs, were determined, and mean pulmonary arterial pressure, right ventricular hypertrophy, and right heart function were evaluated. Compared to the normoxia exposure group, rats exposed to chronic normobaric hypoxia showed an increased NF-κB activity, measured by increased nuclear translocation of p50 and p65 proteins, an increased inflammatory gene expression in the lungs, elevated mean pulmonary arterial blood pressure and mean right ventricular pressure, right ventricular hypertrophy, as assessed by right ventricle-to-left ventricle plus septum weight ratio, and right heart dysfunction. Treatment of hypoxia-exposed rats with PDTC inhibited NF-κB activity, decreased pulmonary arterial blood pressure and right ventricular pressure, and ameliorated right ventricular hypertrophy and right heart dysfunction. Hypoxia exposure increased protein kinase C activity and promoted pulmonary artery smooth muscle cell proliferation in vitro. Our data suggest that NF-κB activation may contribute to chronic normobaric hypoxia-induced PH. PMID:26788753

  9. Characterization on RF magnetron sputtered niobium pentoxide thin films

    SciTech Connect

    Usha, N.; Sivakumar, R.; Sanjeeviraja, C.

    2014-10-15

    Niobium pentoxide (Nb{sub 2}O{sub 5}) thin films with amorphous nature were deposited on microscopic glass substrates at 100°C by rf magnetron sputtering technique. The effect of rf power on the structural, morphological, optical, and vibrational properties of Nb{sub 2}O{sub 5} films have been investigated. Optical study shows the maximum average transmittance of about 87% and the optical energy band gap (indirect allowed) changes between 3.70 eV and 3.47 eV. AFM result indicates the smooth surface nature of the samples. Photoluminescence measurement showed the better optical quality of the deposited films. Raman spectra show the LO-TO splitting of Nb-O stretching of Nb{sub 2}O{sub 5} films.

  10. Loss of Matrix Metalloproteinase-13 Attenuates Murine Radiation-Induced Pulmonary Fibrosis

    SciTech Connect

    Flechsig, Paul; Hartenstein, Bettina; Teurich, Sybille; Dadrich, Monika; Hauser, Kai; Abdollahi, Amir; Groene, Hermann-Josef; Angel, Peter; Huber, Peter E.

    2010-06-01

    Purpose: Pulmonary fibrosis is a disorder of the lungs with limited treatment options. Matrix metalloproteinases (MMPs) constitute a family of proteases that degrade extracellular matrix with roles in fibrosis. Here we studied the role of MMP13 in a radiation-induced lung fibrosis model using a MMP13 knockout mouse. Methods and Materials: We investigated the role of MMP13 in lung fibrosis by investigating the effects of MMP13 deficiency in C57Bl/6 mice after 20-Gy thoracic irradiation (6-MV Linac). The morphologic results in histology were correlated with qualitative and quantitative results of volume computed tomography (VCT), magnetic resonance imaging (MRI), and clinical outcome. Results: We found that MMP13 deficient mice developed less pulmonary fibrosis than their wildtype counterparts, showed attenuated acute pulmonary inflammation (days after irradiation), and a reduction of inflammation during the later fibrogenic phase (5-6 months after irradiation). The reduced fibrosis in MMP13 deficient mice was evident in histology with reduced thickening of alveolar septi and reduced remodeling of the lung architecture in good correlation with reduced features of lung fibrosis in qualitative and quantitative VCT and MRI studies. The partial resistance of MMP13-deficient mice to fibrosis was associated with a tendency towards a prolonged mouse survival. Conclusions: Our data indicate that MMP13 has a role in the development of radiation-induced pulmonary fibrosis. Further, our findings suggest that MMP13 constitutes a potential drug target to attenuate radiation-induced lung fibrosis.

  11. Early Amiodarone-Induced Pulmonary Toxicity after Endovascular Aneurysm Repair: A Case Report.

    PubMed

    Yoon, Uzung; Marinelli, Laura; Ali, Sayed; Huberfeld, Seymour; Barrera, Rafael; Chang, John B

    2016-09-01

    Amiodarone is an antiarrhythmic drug that has been commonly used to treat supraventricular and ventricular arrhythmias. This drug is an iodine-containing compound that tends to accumulate in several organs, including the lungs. Especially, its main metabolically active metabolite desethylamiodarone can adversely affect many organs. A very well-known severe complication of amiodarone therapy is the amiodarone-induced pulmonary toxicity. This article presents the case study of an 82-year-old male patient with acute amiodarone-induced pulmonary toxicity. The patient underwent endovascular aneurysm repair for rapidly increasing abdominal aortic aneurysm. During the postoperative period the patient developed rapid atrial fibrillation and amiodarone therapy was initiated. Subsequently, the patient went into acute respiratory failure and was requiring high supplemental oxygen support and a chest X-ray revealed bilateral pulmonary infiltrates. During the hospital course the patient required mechanical ventilator support. With discontinuation of amiodarone, supportive therapy and steroid treatment patient symptoms significantly improved. Amiodarone-induced pulmonary toxicity must be considered in the differential diagnosis of all patients on the medication with progressive or acute respiratory symptoms. Early discontinuation of amiodarone and aggressive corticosteroid therapy should be considered as a viable treatment strategy. PMID:27574388

  12. Atomized paclitaxel liposome inhalation treatment of bleomycin-induced pulmonary fibrosis in rats.

    PubMed

    Zhou, Y; Zhu, W P; Cai, X J; Chen, M

    2016-01-01

    We sought to determine the efficacy of atomized paclitaxel liposome inhalation treatment of pulmonary fibrosis in a bleomycin-induced rat model. Forty male Sprague-Dawley rats were randomly divided into four groups: healthy control, pulmonary fibrosis without treatment, paclitaxel liposome inhalation-treated, and intravenous paclitaxel liposome-treated. Fibrosis was induced by bleomycin injection. A total of 20 mg/kg paclitaxel liposome was administered by inhalation every other day for a total of 10 doses. The intravenous group received 5 mg/kg paclitaxel liposome on days 1, 7, 14, and 21. We observed the general condition, weight change, survival index, and pathological changes in the lung tissue of the rats. Quantitative analysis of collagen types I and III and transforming growth factor (TGF)-β1 expression in the lungs was also performed. The paclitaxel liposome inhalation and intravenous delivery methods improved survival index and pulmonary fibrosis Ashcroft score, and decreased the thickness of the alveolar interval. No obvious difference was found between the two groups. Compared with the untreated group, paclitaxel liposome inhalation and intravenous injection significantly reduced the levels of collagen types I and III and TGF-β1 expression equally. In conclusion, atomized paclitaxel liposome inhalation protects against severe pulmonary fibrosis in a bleomycin-induced rat model. This delivery method has less systemic side effects and increased safety over intravenous injection. PMID:27173212

  13. Proliferation of pulmonary artery smooth muscle cells in the development of ascites syndrome in broilers induced by low ambient temperature.

    PubMed

    Wang, J; Qiao, J; Zhao, L H; Li, K; Wang, H; Xu, T; Tian, Y; Gao, M; Wang, X

    2007-12-01

    Pulmonary vascular remodelling, mainly characterized by arterial medial thickening, is an important pathological feature of broiler ascites syndrome (AS). Since vascular smooth muscle cells (VSMC) form the major cellular component of arterial medial layer, we speculate that VSMC proliferation is one of the causes of pulmonary arterial medial thickening in ascitic broilers. Hence, the present study was designed to investigate the role of VSMC proliferation in pulmonary vascular remodelling in development of AS induced by low ambient temperature. Broilers in control group (22 +/- 1.5 degrees C) and low temperature group (11 +/- 2 degrees C) were sampled every week at 15-50 days of age. Proliferative indexes of VSMC in pulmonary arteries were assessed with proliferating cell nuclear antigen, and the relative medial thickness (RMT) and relative wall area (RWA), as indexes of pulmonary vascular remodelling, were examined by computer-image analysing system. The results showed that the high incidence (18.75%) of AS was induced by low temperature, and a significantly increased VSMC proliferation was observed in pulmonary arteries in the low temperature group at 22-50 days of age (P < 0.05). In addition, RMT and RWA in pulmonary arteries were significantly elevated in the low temperature group from 36 days of age (P < 0.05), indicating that pulmonary vascular remodelling occurred following VSMC proliferation in AS. Our data suggest that proliferation of VSMC may facilitate pulmonary vascular remodelling and have a pivotal role in AS induced by low ambient temperature. PMID:18045340

  14. Endothelin-1 and endothelin-3 induce chemotaxis and replication of pulmonary artery fibroblasts.

    PubMed

    Peacock, A J; Dawes, K E; Shock, A; Gray, A J; Reeves, J T; Laurent, G J

    1992-11-01

    The remodeling of pulmonary vessels that occurs in association with pulmonary hypertension involves, in part, thickening of the adventitia. The stimulus for this process is not understood. One explanation is that endothelial cells secrete a growth factor that expands the local population of fibroblasts by acting as a chemoattractant and mitogen. Endothelins are a family of potent newly discovered vasoactive peptides. One of these compounds, endothelin-1 (ET-1), is secreted by endothelial cells and is known to constrict pulmonary vessels. Another, endothelin-3 (ET-3), is not secreted by endothelial cells and is less potent as a pulmonary vasoconstrictor. We hypothesized that the endothelins may have the capacity both to constrict these vessels and to initiate fibroblast chemotaxis and replication. Here we investigated the effects of both ET-1 and ET-3 on the chemotaxis and replication of fibroblasts derived from pulmonary vessels. Cells were isolated from rat pulmonary arteries, cultured in medium and 10% newborn calf serum, and used between passages 2 and 5. Chemotaxis was assessed using a modified Boyden chamber with a polycarbonate filter (pore size, 8 microns) separating cells in the upper chambers from endothelin in the lower chambers. Replication was assessed both by direct cell counts and by a colorimetric assay based on uptake and subsequent release of methylene blue. Both ET-1 and ET-3 induced chemotaxis of pulmonary artery fibroblasts and did so in a dose-dependent fashion. The maxima for both peptides occurred at a concentration of about 10(-7) M, when chemotaxis was greatest for ET-1 (22 +/- 1.4 versus 14 +/- 1.8 cells/grid [mean +/- SEM], (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1419025

  15. Acetaminophen Use: An Unusual Cause of Drug-Induced Pulmonary Eosinophilia

    PubMed Central

    Saint-Pierre, Mathieu D.; Moran-Mendoza, Onofre

    2016-01-01

    Pulmonary eosinophilia (PE) can be found in very diverse pathological processes. Several medications have also been associated with this entity. Acetaminophen is a medication commonly used in multiple different drug formulations, many of which are available without a prescription. It has however been associated with pulmonary eosinophilia (eosinophilic pneumonia) in a few cases in Japan. We describe the case of a 68-year-old Caucasian female who presented with new persistent dry cough and dyspnea on exertion after she started using up to 4 grams of acetaminophen on a daily basis. Chest imaging revealed peripheral lower lung zone ground glass and reticular opacities, and increased eosinophils were present on bronchoalveolar lavage (BAL). The patient's symptoms markedly improved upon acetaminophen cessation, and significantly decreased eosinophils were seen on repeat BAL. To our knowledge, this is the first case of likely acetaminophen-induced pulmonary eosinophilia reported outside Japan. PMID:27445539

  16. Protective Role of Andrographolide in Bleomycin-Induced Pulmonary Fibrosis in Mice

    PubMed Central

    Zhu, Tao; Zhang, Wei; Xiao, Min; Chen, Hongying; Jin, Hong

    2013-01-01

    Idiopathic pulmonary fibrosis (IPF) is a chronic devastating disease with poor prognosis. Multiple pathological processes, including inflammation, epithelial mesenchymal transition (EMT), apoptosis, and oxidative stress, are involved in the pathogenesis of IPF. Recent findings suggested that nuclear factor-κB (NF-κB) is constitutively activated in IPF and acts as a central regulator in the pathogenesis of IPF. The aim of our study was to reveal the value of andrographolide on bleomycin-induced inflammation and fibrosis in mice. The indicated dosages of andrographolide were administered in mice with bleomycin-induced pulmonary fibrosis. On day 21, cell counts of total cells, macrophages, neutrophils and lymphocytes, alone with TNF-α in bronchoalveolar lavage fluid (BALF) were measured. HE staining and Masson’s trichrome (MT) staining were used to observe the histological alterations of lungs. The Ashcroft score and hydroxyproline content of lungs were also measured. TGF-β1 and α-SMA mRNA and protein were analyzed. Activation of NF-κB was determined by western blotting and electrophoretic mobility shift assay (EMSA). On day 21 after bleomycin stimulation, andrographolide dose-dependently inhibited the inflammatory cells and TNF-α in BALF. Meanwhile, our data demonstrated that the Ashcroft score and hydroxyproline content of the bleomycin-stimulated lung were reduced by andrographolide administration. Furthermore, andrographloide suppressed TGF-β1 and α-SMA mRNA and protein expression in bleomycin-induced pulmonary fibrosis. Meanwhile, andrographolide significantly dose-dependently inhibited the ratio of phospho-NF-κB p65/total NF-κB p65 and NF-κB p65 DNA binding activities. Our findings indicate that andrographolide compromised bleomycin-induced pulmonary inflammation and fibrosis possibly through inactivation of NF-κB. Andrographolide holds promise as a novel drug to treat the devastating disease of pulmonary fibrosis. PMID:24300094

  17. Inhibition of chlorine-induced pulmonary inflammation and edema by mometasone and budesonide

    SciTech Connect

    Chen, Jing; Mo, Yiqun; Schlueter, Connie F.; Hoyle, Gary W.

    2013-10-15

    Chlorine gas is a widely used industrial compound that is highly toxic by inhalation and is considered a chemical threat agent. Inhalation of high levels of chlorine results in acute lung injury characterized by pneumonitis, pulmonary edema, and decrements in lung function. Because inflammatory processes can promote damage in the injured lung, anti-inflammatory therapy may be of potential benefit for treating chemical-induced acute lung injury. We previously developed a chlorine inhalation model in which mice develop epithelial injury, neutrophilic inflammation, pulmonary edema, and impaired pulmonary function. This model was used to evaluate nine corticosteroids for the ability to inhibit chlorine-induced neutrophilic inflammation. Two of the most potent corticosteroids in this assay, mometasone and budesonide, were investigated further. Mometasone or budesonide administered intraperitoneally 1 h after chlorine inhalation caused a dose-dependent inhibition of neutrophil influx in lung tissue sections and in the number of neutrophils in lung lavage fluid. Budesonide, but not mometasone, reduced the levels of the neutrophil attractant CXCL1 in lavage fluid 6 h after exposure. Mometasone or budesonide also significantly inhibited pulmonary edema assessed 1 day after chlorine exposure. Chlorine inhalation resulted in airway hyperreactivity to inhaled methacholine, but neither mometasone nor budesonide significantly affected this parameter. The results suggest that mometasone and budesonide may represent potential treatments for chemical-induced lung injury. - Highlights: • Chlorine causes lung injury when inhaled and is considered a chemical threat agent. • Corticosteroids may inhibit lung injury through their anti-inflammatory actions. • Corticosteroids inhibited chlorine-induced pneumonitis and pulmonary edema. • Mometasone and budesonide are potential rescue treatments for chlorine lung injury.

  18. Attenuation of the extract from Moringa oleifera on monocrotaline-induced pulmonary hypertension in rats.

    PubMed

    Chen, Kang-Hu; Chen, Yi-Jui; Yang, Chao-Hsun; Liu, Kuo-Wei; Chang, Junn-Liang; Pan, Shwu-Fen; Lin, Tzer-Bin; Chen, Mei-Jung

    2012-02-29

    The purpose of this study was to determine the effects of an extract from Moringa oleifera (MO) on the development of monocrotaline (MCT)-induced pulmonary hypertension (PH) in Wistar rats. An ethanol extraction was performed on dried MO leaves, and HPLC analysis identified niaziridin and niazirin in the extract. PH was induced with a single subcutaneous injection of MCT (60 mg/kg) which resulted in increases in pulmonary arterial blood pressure (Ppa) and in thickening of the pulmonary arterial medial layer in the rats. Three weeks after induction, acute administration of the MO extract to the rats decreased Ppa in a dose-dependent manner that reached statistical significance at a dose of 4.5 mg of freeze-dried extract per kg body weight. The reduction in Ppa suggested that the extract directly relaxed the pulmonary arteries. To assay the effects of chronic administration of the MO extract on PH, control, MCT and MCT+MO groups were designated. Rats in the control group received a saline injection; the MCT and MCT+MO groups received MCT to induce PH. During the third week after MCT treatment, the MCT+MO group received daily i.p. injections of the MO extract (4.5 mg of freeze-dried extract/kg of body weight). Compared to the control group, the MCT group had higher Ppa and thicker medial layers in the pulmonary arteries. Chronic treatments with the MO extract reversed the MCT-induced changes. Additionally, the MCT group had a significant elevation in superoxide dismutase activity when normalized by the MO extract treatments. In conclusion, the MO extract successfully attenuated the development of PH via direct vasodilatation and a potential increase in antioxidant activity. PMID:22242951

  19. Differential Activation of Airway Eosinophils Induces IL-13 Mediated Allergic Th2 Pulmonary Responses in Mice

    PubMed Central

    Jacobsen, EA; Doyle, AD; Colbert, DC; Zellner, KR; Protheroe, CA; LeSuer, WE; Lee, NA.; Lee, JJ

    2015-01-01

    Background Eosinophils are hallmark cells of allergic Th2 respiratory inflammation. However, the relative importance of eosinophil activation and the induction of effector functions such as the expression of IL-13 to allergic Th2 pulmonary disease remain to be defined. Methods Wild type or cytokine deficient (IL-13−/− or IL-4−/−) eosinophils treated with cytokines (GM-CSF, IL-4, IL-33) were adoptively transferred into eosinophil-deficient recipient mice subjected to allergen provocation using established models of respiratory inflammation. Allergen-induced pulmonary changes were assessed. Results In contrast to the transfer of untreated blood eosinophils to the lungs of recipient eosinophildeficient mice, which induced no immune/inflammatory changes either in the lung or lung draining lymph nodes (LDLNs), pretreatment of blood eosinophils with GM-CSF prior to transfer elicited trafficking of these eosinophils to LDLNs. In turn, these LDLN eosinophils elicited the accumulation of dendritic cells and CD4+ T cells to these same LDLNs without inducing pulmonary inflammation. However, exposure of eosinophils to GM-CSF, IL-4 and IL-33 prior to transfer induced not only immune events in the LDLN, but also allergen-mediated increases in airway Th2 cytokine/chemokine levels, the subsequent accumulation of CD4+ T cells as well as alternatively activated (M2) macrophages, and the induction of pulmonary histopathologies. Significantly, this allergic respiratory inflammation was dependent on eosinophil-derived IL-13 whereas IL-4 expression by eosinophils had no significant role. Conclusion The data demonstrate the differential activation of eosinophils as a function of cytokine exposure and suggest that eosinophil-specific IL-13 expression by activated cells is a necessary component of the subsequent allergic Th2 pulmonary pathologies. PMID:26009788

  20. 17(R)-resolvin D1 ameliorates bleomycin-induced pulmonary fibrosis in mice.

    PubMed

    Yatomi, Masakiyo; Hisada, Takeshi; Ishizuka, Tamotsu; Koga, Yasuhiko; Ono, Akihiro; Kamide, Yosuke; Seki, Kaori; Aoki-Saito, Haruka; Tsurumaki, Hiroaki; Sunaga, Noriaki; Kaira, Kyoichi; Dobashi, Kunio; Yamada, Masanobu; Okajima, Fumikazu

    2015-12-01

    Idiopathic pulmonary fibrosis (IPF) is a destructive inflammatory disease with limited therapeutic options. Inflammation plays an integral role in the development of pulmonary fibrosis. Unresolved inflammatory responses can lead to substantial tissue injury, chronic inflammation, and fibrosis. The resolvins are a family of endogenous ω-3 fatty acid derived-lipid mediators of inflammation resolution. Resolvin D1 (RvD1) displays potent anti-inflammatory, pro-resolving activity, without causing immunosuppression. Its epimer, 17(R)-resolvin D1 (17(R)-RvD1), exhibits equivalent functionality to RvD1. In addition, 17(R)-RvD1 is resistant to rapid inactivation by eicosanoid oxidoreductases. In the present study, we tested the hypothesis that 17(R)-RvD1 can provide a therapeutic benefit in IPF by reducing inflammation and pulmonary fibrosis, while leaving the normal immune response intact. Mice were exposed to bleomycin (BLM) via micro-osmotic pump to induce pulmonary fibrosis, and were then treated with 17(R)-RvD1 or vehicle by intraperitoneal injection. Administration of 17(R)-RvD1 from the start of BLM treatment attenuated neutrophil alveolar infiltration, lung collagen content, and Interleukin-1β (IL-1β), transforming growth factor-β1 (TGF-β1), connective tissue growth factor (CTGF), and type I collagen mRNA expression, along with subsequent reduction in histologically detectable fibrosis. The 17(R)-RvD1-induced infiltration of inflammatory cells was inhibited by an antagonist of lipoxin A4 receptor/formyl peptide receptor 2 (ALX/FPR2). The administration of 17(R)-RvD1 at the later fibrotic stage also improved the lung failure. These results suggest that 17(R)-RvD1 attenuates pulmonary fibrosis by promoting the resolution of neutrophilic inflammation and also provides pulmonary restoration. These data highlight the therapeutic potential of 17(R)-RvD1 in the management of this intractable disease. PMID:26660549

  1. Gadolinium chloride attenuates sepsis-induced pulmonary apoptosis and acute lung injury.

    PubMed

    Kishta, Osama A; Goldberg, Peter; Husain, Sabah N A

    2012-01-01

    Gadolinium chloride (GdCl3), a Kupffer cells inhibitor, attenuates acute lung injury; however, the mechanisms behind this effect are not completely elucidated. We tested the hypothesis that GdCl3 acts through the inhibition of lung parenchymal cellular apoptosis. Two groups of rats were injected intraperitoneally with saline or E. coli lipopolysaccharide. In two additional groups, rats were injected with GdCl3 24 hrs prior to saline or LPS administration. At 12 hrs, lung injury, inflammation, and apoptosis were studied. Lung water content, myeloperoxidase activity, pulmonary apoptosis and mRNA levels of interleukin-1 β , -2, -5, -6, -10 and TNF- α rose significantly in LPS-injected animals. Pretreatment with GdCl3 significantly reduced LPS-induced elevation of pulmonary water content, myeloperoxidase activity, cleaved caspase-3 intensity, and attenuated pulmonary TUNEL-positive cells. GdCl3 pre-treatment upregulated IL-1 β , -2 and -10 pulmonary gene expression without significantly affecting the others. These results suggest that GdCl3 attenuates acute lung injury through its effects on pulmonary parenchymal apoptosis. PMID:24049647

  2. Biomarker expression in lung of rabbit with pulmonary fibrosis induced by ammonium perchlorate.

    PubMed

    Wu, Feng-hong; Guo, Hui-xia; Lin, Ming-fang; Chen, Zhi-ze; Zhou, Xuan; Peng, Kai-liang

    2011-04-01

    Ammonium perchlorate (AP), an oxidizer, has been used in solid propellants. Although AP exposure has been suspected as a risk factor for the development of pulmonary fibrosis, data are still inconclusive. To evaluate the pulmonary toxicity and the potential pulmonary fibrosis caused by occupational exposure to this compound, 25 male rabbits were randomly allocated into five groups to receive AP or bleomycin or saline by intratracheal injection. All rabbits were sacrificed and total RNA from the lungs was extracted. Expressions of types I and III collagens, transforming growth factor-β(1) (TGF-β(1)) and tumour necrosis factor-α (TNF-α) messenger RNA (mRNA) were measured by reverse transcription-polymerase chain reaction (RT-PCR). The expressions of type I and III collagen mRNA in low, moderate and high dose AP groups were significantly higher (p < 0.01 or p < 0.05) than that in the saline group. There was also a significant increased level of TGF-β(1) and TNF-α mRNA in the three AP groups compared with saline control group (p < 0.01 or p < 0.05). These results reveal that AP can increase gene expressions of types I, III collagens, TGF-β(1) and TNF-α in lung of rabbits exposed to AP. The overexpression of these biomarkers were considered as effective indicator linking to the development of pulmonary fibrosis and finally demonstrated that AP has potential to induce pulmonary fibrosis. PMID:20937628

  3. Platelet-activating factor induces selective pulmonary arterial hyperreactivity in isolated perfused rabbit lungs.

    PubMed

    Ohar, J A; Waller, K S; Dahms, T E

    1993-07-01

    The role of vasoreactivity in PAF-induced pulmonary hypertension (PHT) was assessed in isolated, perfused rabbit lungs. We evaluated the steady-state pulmonary vascular response to five vasoconstrictors: PGF2 alpha, norepinephrine, angiotensin II, PAF, and KCl. Pulmonary arterial pressure and pulmonary vascular resistance (PVR) were significantly greater in lungs of rabbits treated with PAF for 28 days than in control rabbits in response to PGF2 alpha and norepinephrine. When resistance was partitioned by the vascular occlusion method, at baseline the vascular resistance was equally distributed between arterial and venous segments in both experimental groups. Arterial resistance accounted for approximately 76% of PVR during norepinephrine injection and 60% of PVR during PGF2 alpha injection in PAF-treated lungs. Whereas arterial resistance accounted for approximately 63% of PVR during norepinephrine injection and 52% of PVR during PGF2 alpha injection in control lungs, there was no significant difference in the response to angiotensin II, acute PAF, and KCl in lungs from chronic PAF-treated rabbits compared with responses in control rabbit lungs, though the pressor response to acute PAF tended to be blunted in PAF-treated lungs. Chronic PAF treatment results in enhanced pulmonary arterial reactivity to selected autacoids in isolated perfused lungs. PMID:8317792

  4. Arginase inhibition protects against hypoxia‑induced pulmonary arterial hypertension.

    PubMed

    Jiang, Wenjin; Sun, Bolin; Song, Xuepeng; Zheng, Yanbo; Wang, Ligang; Wang, Tao; Liu, Sheng

    2015-09-01

    The present study aimed to determine the role of arginase (Arg) in pulmonary arterial hypertension (PAH). In vitro, human pulmonary artery smooth muscle cells (HPASMCs) were cultured under hypoxic conditions with, or without, the Arg inhibitor, S‑(2‑boronoethyl)‑l‑cysteine (BEC), for 48 h, following which the proliferation of the HPASMCs was determined using MTT and cell counting assays. For the in vivo investigation, 30 male rats were randomly divided into the following three groups (n=10 per group): i) control group, ii) PAH group and iii) BEC group, in which the right ventricle systolic pressure (RVSP) of the rats was assessed. The levels of cyclin D1, cyclin‑dependent kinase (CDK)4 and p27 were measured in vitro and in vivo. The phosphorylation levels of Akt and extracellular‑related kinase (ERK) were also measured in HPASMCs. In vitro, compared with the hypoxia group, Arg inhibition reduced HPASMC proliferation and reduced the expression levels of cyclin D1, CDK4, phosphorylated (p‑)Akt and p‑ERK. By contrast, Arg inhibition increased the expression of p27. In vivo, compared with the control group, the expression levels of cyclin D1 and CDK4 were reduced in the PAH group, however, the expression of p27 and the RVSP increased. In the BEC group, the opposite effects were observed. Therefore, it was suggested that Arg inhibition may reduce the RVSP of PAH rats and reduce HPASMC proliferation by decreasing the expression levels of cyclin D1 and CDK4, increasing the expression of p27, and partly reducing the phosphorylation of Akt and ERK. PMID:26126810

  5. Grouping nanomaterials to predict their potential to induce pulmonary inflammation.

    PubMed

    Braakhuis, Hedwig M; Oomen, Agnes G; Cassee, Flemming R

    2016-05-15

    The rapidly expanding manufacturing, production and use of nanomaterials have raised concerns for both worker and consumer safety. Various studies have been published in which induction of pulmonary inflammation after inhalation exposure to nanomaterials has been described. Nanomaterials can vary in aspects such as size, shape, charge, crystallinity, chemical composition, and dissolution rate. Currently, efforts are made to increase the knowledge on the characteristics of nanomaterials that can be used to categorise them into hazard groups according to these characteristics. Grouping helps to gather information on nanomaterials in an efficient way with the aim to aid risk assessment. Here, we discuss different ways of grouping nanomaterials for their risk assessment after inhalation. Since the relation between single intrinsic particle characteristics and the severity of pulmonary inflammation is unknown, grouping of nanomaterials by their intrinsic characteristics alone is not sufficient to predict their risk after inhalation. The biokinetics of nanomaterials should be taken into account as that affects the dose present at a target site over time. The parameters determining the kinetic behaviour are not the same as the hazard-determining parameters. Furthermore, characteristics of nanomaterials change in the life-cycle, resulting in human exposure to different forms and doses of these nanomaterials. As information on the biokinetics and in situ characteristics of nanomaterials is essential but often lacking, efforts should be made to include these in testing strategies. Grouping nanomaterials will probably be of the most value to risk assessors when information on intrinsic characteristics, life-cycle, biokinetics and effects are all combined. PMID:26603513

  6. Curcumin attenuates elastase- and cigarette smoke-induced pulmonary emphysema in mice.

    PubMed

    Suzuki, Masaru; Betsuyaku, Tomoko; Ito, Yoko; Nagai, Katsura; Odajima, Nao; Moriyama, Chinatsu; Nasuhara, Yasuyuki; Nishimura, Masaharu

    2009-04-01

    Curcumin, a yellow pigment obtained from turmeric (Curcumina longa), is a dietary polyphenol that has been reported to possess anti-inflammatory and antioxidant properties. The effect of curcumin against the development of pulmonary emphysema in animal models is unknown. The aim of this study was to determine whether curcumin is able to attenuate the development of pulmonary emphysema in mice. Nine-week-old male C57BL/6J mice were treated with intratracheal porcine pancreatic elastase (PPE) or exposed to mainstream cigarette smoke (CS) (60 min/day for 10 consecutive days or 5 days/wk for 12 wk) to induce pulmonary inflammation and emphysema. Curcumin (100 mg/kg) or vehicle was administrated daily by oral gavage 1 h and 24 h before intratracheal PPE treatment and daily thereafter throughout a 21-day period in PPE-exposed mice and 1 h before each CS exposure in CS-exposed mice. As a result, curcumin treatment significantly inhibited PPE-induced increase of neutrophils in bronchoalveolar lavage fluid at 6 h and on day 1 after PPE administration, with an increase in antioxidant gene expression at 6 h and significantly attenuated PPE-induced air space enlargement on day 21. It was also found that curcumin treatment significantly inhibited CS-induced increase of neutrophils and macrophages in bronchoalveolar lavage fluid after 10 consecutive days of CS exposure and significantly attenuated CS-induced air space enlargement after 12 wk of CS exposure. In conclusion, oral curcumin administration attenuated PPE- and CS-induced pulmonary inflammation and emphysema in mice. PMID:19168576

  7. [Progress on pathogenesis and treatment of paraquat-induced pulmonary fibrosis].

    PubMed

    Shao, Xue; Chen, Jiang-Hua

    2014-11-01

    Paraquat (PQ) is a highly effective herbicide with contact toxicity. PQ mainly accumulates in the lungs after absorption into the blood circulation. The respiratory function failure caused by PQ-induced lung injury, especially the irreversible pulmonary fibrosis in late phase, is the leading cause of death in patients with PQ poisoning. The mechanism of PQ poisoning is still unclear. Now it is speculated that oxidative stress and inflammation injury are the main pathogenic mechanisms, and abnormal gene expression, mitochondrial damage, loss of pulmonary surfactant, cytokine network and unbalanced matrix metalloproteinases/tissue inhibitors may be also involved in the pathogenesis. In addition to reducing poison absorption and increasing its removal, the current clinical treatment is mainly composed of antioxidant and anti-immune response, but has poor therapeutic effects. Although many novel methods of treatment have been proposed, most of them are still in the experimental stage. It is a hot spot to clarify the mechanism of PQ poisoning and to seek safe and effective treatment of pulmonary fibrosis. This article reviews the research progress on pathogenesis and treatment of PQ-induced pulmonary fibrosis. PMID:25644573

  8. Role of vascular endothelial growth factor signaling in Schistosoma-induced experimental pulmonary hypertension

    PubMed Central

    2014-01-01

    Abstract There is significant evidence that Th2 (T helper 2)-mediated inflammation supports the pathogenesis of both human and experimental animal models of pulmonary hypertension (PH). A key immune regulator is vascular endothelial growth factor (VEGF), which is produced by Th2 inflammation and can itself contribute to Th2 pulmonary responses. In this study, we interrogated the role of VEGF signaling in a murine model of schistosomiasis-induced PH with a phenotype of significant intrapulmonary Th2 inflammation, vascular remodeling, and elevated right ventricular pressures. We found that VEGF receptor blockade partially suppressed the levels of the Th2 inflammatory cytokines interleukin (IL)-4 and IL-13 in both the lung and the liver after Schistosoma mansoni exposure and suppressed pulmonary vascular remodeling. These findings suggest that VEGF positively contributes to schistosomiasis-induced vascular inflammation and remodeling, and they also provide evidence for a VEGF-dependent signaling pathway necessary for pulmonary vascular remodeling and inflammation in this model. PMID:25006448

  9. Activation of AMPK Prevents Monocrotaline-Induced Extracellular Matrix Remodeling of Pulmonary Artery

    PubMed Central

    Li, Shaojun; Han, Dong; Zhang, Yonghong; Xie, Xinming; Ke, Rui; Zhu, Yanting; Liu, Lu; Song, Yang; Yang, Lan; Li, Manxiang

    2016-01-01

    Background The current study was performed to investigate the effect of adenosine monophosphate (AMP) – activated protein kinase (AMPK) activation on the extracellular matrix (ECM) remodeling of pulmonary arteries in pulmonary arterial hypertension (PAH) and to address its potential mechanisms. Material/Methods PAH was induced by a single intraperitoneal injection of monocrotaline (MCT) into Sprague-Dawley rats. Metformin (MET) was administered to activate AMPK. Immunoblotting was used to determine the phosphorylation and expression of AMPK and expression of tissue inhibitor of metalloproteinase-1 (TIMP-1). Gelatin zymography was performed to determine the activity of matrix metalloproteinase-2 (MMP-2) and MMP-9. Results Activation of AMPK by MET significantly reduced the right ventricle systolic pressure and the right ventricular hypertrophy in MCT-induced rat PAH model, and partially inhibited the ECM remodeling of pulmonary arteries. These effects were coupled with the decrease of MMP-2/9 activity and TIMP-1 expression. Conclusions This study suggests that activation of AMPK benefits PAH by inhibiting ECM remodeling of pulmonary arteries. Enhancing AMPK activity might have potential value in clinical treatment of PAH. PMID:26978596

  10. “A small leak will sink a great ship”: hypoxia-inducible factor and group III pulmonary hypertension

    PubMed Central

    Bryant, Andrew J.; Scott, Edward W.

    2016-01-01

    Pulmonary hypertension complicating idiopathic pulmonary fibrosis, also known as secondary pulmonary hypertension, represents a major source of morbidity and mortality in affected patients. While the study of primary pulmonary arterial hypertension has yielded several therapies, the same is not true for the treatment of pulmonary hypertension secondary to pulmonary fibrosis. Recent studies have indicated an important role of hypoxia-inducible factor (HIF) – a regulatory protein that is vital in adaptation to hypoxic conditions – in the development of secondary pulmonary hypertension. HIF influences development of hypoxia-induced pulmonary hypertension through alteration in voltage-gated potassium channels and homeostatic calcium regulation, resulting in disruption of endothelial cell-cell communication, and eventual vascular remodeling. This article summarizes salient literature related to HIF and secondary pulmonary hypertension, in addition to proposing a final common pathway in known mechanistic pathways that result in endothelial barrier integrity loss – vascular “leak” – primarily through a shared endothelial-epithelial signaling protein family, CCN.

  11. Morphine blocks the Mesobuthus tamulus venom-induced augmentation of phenyldiguanide reflex and pulmonary edema in anesthetized rats

    PubMed Central

    Akella, Aparna; Tiwari, Anil K.; Rai, Om P.; Deshpande, Shripad B.

    2016-01-01

    Objective: Pulmonary edema, a manifestation of scorpion envenomation syndrome, is attributed to cardiogenic or noncardiogenic factors. Morphine is a drug used for cardiogenic pulmonary edema and its effect on Mesobuthus tamulus (MBT) venom-induced changes is not known. Therefore, we hypothesized that morphine blocks the MBT venom-induced augmentation of phenyldiguanide (PDG) reflex and pulmonary edema. Materials and Methods: Experiments were performed on anesthetized adult female rats. Trachea and jugular vein were cannulated, and the electrocardiographic potentials were recorded by connecting needle electrodes in limb lead II configuration. PDG (10 ΅g/kg, IV, bolus injection) responses were elicited by bolus injection initially, after saline/morphine (1 mg/kg) and after injecting MBT venom (100 μg/kg). The time-response area of the PDG-induced bradycardiac response after treatment was calculated as % of the initial PDG response area. At the end of experiments, lungs were excised for determination of pulmonary water content. Results: PDG produced bradycardiac response that lasted for >60 s. MBT venom augmented the PDG reflex response by 2.5 times. In morphine pretreated group, augmentation of bradycardiac response induced by MBT venom was absent. MBT venom increased the pulmonary water content, and the increase was absent in morphine pretreated animals. Conclusion: The results reveal that morphine prevents the MBT venom-induced augmentation of PDG reflex response and pulmonary edema. Thus, morphine can be useful in scorpion envenomation syndrome associated with pulmonary edema. PMID:26997727

  12. Effects of NOX1 on fibroblastic changes of endothelial cells in radiation‑induced pulmonary fibrosis.

    PubMed

    Choi, Seo-Hyun; Kim, Miseon; Lee, Hae-June; Kim, Eun-Ho; Kim, Chun-Ho; Lee, Yoon-Jin

    2016-05-01

    Lung fibrosis is a major complication in radiation‑induced lung damage following thoracic radiotherapy, while the underlying mechanism has remained to be elucidated. The present study performed immunofluorescence and immunoblot assays on irradiated human pulmonary artery endothelial cells (HPAECs) with or without pre‑treatment with VAS2870, a novel NADPH oxidase (NOX) inhibitor, or small hairpin (sh)RNA against NOX1, ‑2 or ‑4. VAS2870 reduced the cellular reactive oxygen species content induced by 5 Gy radiation in HPAECs and inhibited phenotypic changes in fibrotic cells, including increased alpha smooth muscle actin and vimentin, and decreased CD31 and vascular endothelial cadherin expression. These fibrotic changes were significantly inhibited by treatment with NOX1 shRNA, but not by NOX2 or NOX4 shRNA. Next, the role of NOX1 in pulmonary fibrosis development was assessed in the lung tissues of C57BL/6J mice following thoracic irradiation using trichrome staining. Administration of an NOX1‑specific inhibitor suppressed radiation‑induced collagen deposition and fibroblastic changes in the endothelial cells (ECs) of these mice. The results suggested that radiation‑induced pulmonary fibrosis may be efficiently reduced by specific inhibition of NOX1, an effect mediated by reduction of fibrotic changes of ECs. PMID:27053172

  13. Effects of NOX1 on fibroblastic changes of endothelial cells in radiation-induced pulmonary fibrosis

    PubMed Central

    CHOI, SEO-HYUN; KIM, MISEON; LEE, HAE-JUNE; KIM, EUN-HO; KIM, CHUN-HO; LEE, YOON-JIN

    2016-01-01

    Lung fibrosis is a major complication in radiation-induced lung damage following thoracic radiotherapy, while the underlying mechanism has remained to be elucidated. The present study performed immunofluorescence and immunoblot assays on irradiated human pulmonary artery endothelial cells (HPAECs) with or without pre-treatment with VAS2870, a novel NADPH oxidase (NOX) inhibitor, or small hairpin (sh)RNA against NOX1, -2 or -4. VAS2870 reduced the cellular reactive oxygen species content induced by 5 Gy radiation in HPAECs and inhibited phenotypic changes in fibrotic cells, including increased alpha smooth muscle actin and vimentin, and decreased CD31 and vascular endothelial cadherin expression. These fibrotic changes were significantly inhibited by treatment with NOX1 shRNA, but not by NOX2 or NOX4 shRNA. Next, the role of NOX1 in pulmonary fibrosis development was assessed in the lung tissues of C57BL/6J mice following thoracic irradiation using trichrome staining. Administration of an NOX1-specific inhibitor suppressed radiation-induced collagen deposition and fibroblastic changes in the endothelial cells (ECs) of these mice. The results suggested that radiation-induced pulmonary fibrosis may be efficiently reduced by specific inhibition of NOX1, an effect mediated by reduction of fibrotic changes of ECs. PMID:27053172

  14. Antagonism of Stem Cell Factor/c-kit Signaling Attenuates Neonatal Chronic Hypoxia-Induced Pulmonary Vascular Remodeling

    PubMed Central

    Young, Karen C; Torres, Eneida; Hehre, Dorothy; Wu, Shu; Suguihara, Cleide; Hare, Joshua M.

    2015-01-01

    Background Accumulating evidence suggests that c-kit positive cells are present in the remodeled pulmonary vasculature bed of patients with pulmonary hypertension (PH). Whether stem cell factor (SCF)/ c-kit regulated pathways potentiate pulmonary vascular remodeling is unknown. Here, we tested the hypothesis that attenuated c-kit signaling would decrease chronic hypoxia-induced pulmonary vascular remodeling by decreasing pulmonary vascular cell mitogenesis. Methods Neonatal FVB/NJ mice treated with non-immune IgG (PL), or c-kit neutralizing antibody (ACK2) as well as c-kit mutant mice (WBB6F1- Kit W− v/ +) and their congenic controls, were exposed to normoxia (FiO2=0.21) or hypoxia (FiO2=0.12) for two weeks. Following this exposure, right ventricular systolic pressure (RVSP), right ventricular hypertrophy (RVH), pulmonary vascular cell proliferation and remodeling were evaluated. Results As compared to chronically hypoxic controls, c-kit mutant mice had decreased RVSP, RVH, pulmonary vascular remodeling and proliferation. Consistent with these findings, administration of ACK2 to neonatal mice with chronic hypoxia-induced PH decreased RVSP, RVH, pulmonary vascular cell proliferation and remodeling. This attenuation in PH was accompanied by decreased extracellular signal-regulated protein kinase (ERK) 1/2 activation. Conclusion SCF/c-kit signaling may potentiate chronic hypoxia-induced vascular remodeling by modulating ERK activation. Inhibition of c-kit activity may be a potential strategy to alleviate PH. PMID:26705118

  15. Neutrophilic oxidative stress mediates organic dust-induced pulmonary inflammation and airway hyperresponsiveness.

    PubMed

    McGovern, Toby K; Chen, Michael; Allard, Benoit; Larsson, Kjell; Martin, James G; Adner, Mikael

    2016-01-15

    Airway exposure to organic dust (OD) from swine confinement facilities induces airway inflammation dominated by neutrophils and airway hyperresponsiveness (AHR). One important neutrophilic innate defense mechanism is the induction of oxidative stress. Therefore, we hypothesized that neutrophils exacerbate airway dysfunction following OD exposure by increasing oxidant burden. BALB/C mice were given intranasal challenges with OD or PBS (1/day for 3 days). Mice were untreated or treated with a neutrophil-depleting antibody, anti-Ly6G, or the antioxidant dimethylthiourea (DMTU) prior to OD exposure. Twenty-four hours after the final exposure, we measured airway responsiveness in response to methacholine (MCh) and collected bronchoalveolar lavage fluid to assess pulmonary inflammation and total antioxidant capacity. Lung tissue was harvested to examine the effect of OD-induced antioxidant gene expression and the effect of anti-Ly6G or DMTU. OD exposure induced a dose-dependent increase of airway responsiveness, a neutrophilic pulmonary inflammation, and secretion of keratinocyte cytokine. Depletion of neutrophils reduced OD-induced AHR. DMTU prevented pulmonary inflammation involving macrophages and neutrophils. Neutrophil depletion and DMTU were highly effective in preventing OD-induced AHR affecting large, conducting airways and tissue elastance. OD induced an increase in total antioxidant capacity and mRNA levels of NRF-2-dependent antioxidant genes, effects that are prevented by administration of DMTU and neutrophil depletion. We conclude that an increase in oxidative stress and neutrophilia is critical in the induction of OD-induced AHR. Prevention of oxidative stress diminishes neutrophil influx and AHR, suggesting that mechanisms driving OD-induced AHR may be dependent on neutrophil-mediated oxidant pathways. PMID:26545900

  16. Dynamic optical limiting experiments on vanadium dioxide and vanadium pentoxide thin films irradiated by a laser beam

    SciTech Connect

    Wang Weiping; Luo Yongquan; Zhang Dayong; Luo Fei

    2006-05-10

    Vanadium dioxide (VO2) and vanadium pentoxide (V2O5) thin films are irradiated by a near-infrared continuous-wave laser beam and the dynamic optical limiting performance is measured. The temperature varying with time of the films induced by a laser beam is also recorded by an IR thermal sensor. Under the irradiation of a laser beam with an intensity of 255 W/cm2 and a spot diameter of 2 mm, the laser beam transmittance of the VO2 film decreases from 47% before phase transition to 28% after phase transition, and the response time is {approx}200 ms; the laser beam transmittance of the V2O5 film decreases from 51% before phase transition to 24% after phase transition, and the response time is {approx}40 ms. The optical limiting is realized by this laser heating-induced phase transition.

  17. Lung transcriptional profiling: insights into the mechanisms of ozone-induced pulmonary injury in Wistar Kyoto rats

    EPA Science Inventory

    Acute ozone-induced pulmonary injury and inflammation are well characterized in rats; however, mechanistic understanding of the pathways involved is limited. We hypothesized that acute exposure of healthy rats to ozone will cause transcriptional alterations, and comprehensive ana...

  18. Involvement of calcium-sensing receptors in hypoxia-induced vascular remodeling and pulmonary hypertension by promoting phenotypic modulation of small pulmonary arteries.

    PubMed

    Peng, Xue; Li, Hong-Xia; Shao, Hong-Jiang; Li, Guang-Wei; Sun, Jian; Xi, Yu-Hui; Li, Hong-Zhu; Wang, Xin-Yan; Wang, Li-Na; Bai, Shu-Zhi; Zhang, Wei-Hua; Zhang, Li; Yang, Guang-Dong; Wu, Ling-Yun; Wang, Rui; Xu, Chang-Qing

    2014-11-01

    Phenotype modulation of pulmonary artery smooth muscle cells (PASMCs) plays an important role during hypoxia-induced vascular remodeling and pulmonary hypertension (PAH). We had previously shown that calcium-sensing receptor (CaSR) is expressed in rat PASMCs. However, little is known about the role of CaSR in phenotypic modulation of PASMCs in hypoxia-induced PAH as well as the underlying mechanisms. In this study, we investigated whether CaSR induces the proliferation of PASMCs in small pulmonary arteries from both rats and human with PAH. PAH was induced by exposing rats to hypoxia for 7-21 days. The mean pulmonary arterial pressure (mPAP), right ventricular hypertrophy index (RVI), the percentage of medial wall thickness to the external diameter (WT %), and cross-sectional total vessel wall area to the total area (WA %) of small pulmonary arteries were determined by hematoxylin and eosin (HE), masson trichrome and Weigert's staining. The protein expressions of matrix metalloproteinase (MMP)-2 and MMP-9, the tissue inhibitors of metalloproteinase (TIMP)-3, CaSR, proliferating cell nuclear antigen (PCNA), phosphorylated extracellular signal-regulated kinase (p-ERK), and smooth muscle cell (SMC) phenotype marker proteins in rat small pulmonary arteries, including calponin, SMα-actin (SMAα), and osteopontin (OPN), were analyzed by immunohistochemistry and Western blotting, respectively. In addition, immunohistochemistry was applied to paraffin-embedded human tissues from lungs of normal human and PAH patients with chronic heart failure (PAH/CHF). Compared with the control group, mPAP, RVI, WT % and WA % in PAH rats were gradually increased with the prolonged hypoxia. At the same time, the expressions of CaSR, MMP-2, MMP-9, TIMP-3, PCNA, OPN, and p-ERK were markedly increased, while the expressions of SMAα and calponin were significantly reduced in lung tissues or small pulmonary arteries of PAH rats. Neomycin (an agonist of CaSR) enhanced but NPS2390 (an

  19. Impact-driven, pulmonary emboli of osseous fat in exercise-induced bronchospasm.

    PubMed

    Simkin, Peter A; Snitily, Brian K

    2015-11-01

    Exercise induced bronchospasm (EIB) affects approximately 10% of normal individuals with higher prevalence rates among children, obese adults, and competitive athletes. Although hyperpnea with dry air is the best known cause, the problem is multifactorial with atopy, asthma and chlorine all playing established roles. To date, no clear mechanism has connected musculoskeletal loading with the ensuing pulmonary compromise. This paper reviews evidence that impact-driven pulses in subchondral bone pressure may push osseous fat cells into the local venous sinusoids. The resultant showers of microemboli must then travel to the lung where lysis of membrane phospholipids leads to leukotriene formation with resultant inflammation and bronchial hypersensitivity. Concurrently, the same emboli deliver triglyceride fuels for further physical activity. Thus, pulmonary microemboli derived from osseous fat may resolve the seeming paradox of athletic excellence in persons afflicted with exercise-induced bronchospasm. PMID:26328480

  20. Elastase-induced pulmonary emphysema: insights from experimental models.

    PubMed

    Antunes, Mariana A; Rocco, Patricia R M

    2011-12-01

    Several distinct stimuli can be used to reproduce histological and functional features of human emphysema, a leading cause of disability and death. Since cigarette smoke is the main cause of emphysema in humans, experimental researches have attempted to reproduce this situation. However, this is an expensive and cumbersome method of emphysema induction, and simpler, more efficacious alternatives have been sought. Among these approaches, elastolytic enzymes have been widely used to reproduce some characteristics of human cigarette smoke-induced disease, such as: augmentation of airspaces, inflammatory cell influx into the lungs, and systemic inflammation. Nevertheless, the use of elastase-induced emphysema models is still controversial, since the disease pathways involved in elastase induction may differ from those occurring in smoke-induced emphysema. This indicates that the choice of an emphysema model may impact the results of new therapies or drugs being tested. The aim of this review is to compare the mechanisms of disease induction in smoke and elastase emphysema models, to describe the differences among various elastase models, and to establish the advantages and disadvantages of elastase-induced emphysema models. More studies are required to shed light on the mechanisms of elastase-induced emphysema. PMID:22159348

  1. Targeted activation of endothelin-1 exacerbates hypoxia-induced pulmonary hypertension

    SciTech Connect

    Satwiko, Muhammad Gahan; Ikeda, Koji; Nakayama, Kazuhiko; Yagi, Keiko; Hocher, Berthold; Hirata, Ken-ichi; Emoto, Noriaki

    2015-09-25

    Pulmonary arterial hypertension (PAH) is a fatal disease that eventually results in right heart failure and death. Current pharmacologic therapies for PAH are limited, and there are no drugs that could completely cure PAH. Enhanced activity of endothelin system has been implicated in PAH severity and endothelin receptor antagonists have been used clinically to treat PAH. However, there is limited experimental evidence on the direct role of enhanced endothelin system activity in PAH. Here, we investigated the correlation between endothelin-1 (ET-1) and PAH using ET-1 transgenic (ETTG) mice. Exposure to chronic hypoxia increased right ventricular pressure and pulmonary arterial wall thickness in ETTG mice compared to those in wild type mice. Of note, ETTG mice exhibited modest but significant increase in right ventricular pressure and vessel wall thickness relative to wild type mice even under normoxic conditions. To induce severe PAH, we administered SU5416, a vascular endothelial growth factor receptor inhibitor, combined with exposure to chronic hypoxia. Treatment with SU5416 modestly aggravated hypoxia-induced pulmonary hypertension, right ventricular hypertrophy, and pulmonary arterial vessel wall thickening in ETTG mice in association with increased interleukin-6 expression in blood vessels. However, there was no sign of obliterative endothelial cell proliferation and plexiform lesion formation in the lungs. These results demonstrated that enhanced endothelin system activity could be a causative factor in the development of PAH and provided rationale for the inhibition of endothelin system to treat PAH. - Highlights: • Role of endothelin-1 in pulmonary arterial hypertension (PAH) was investigated. • The endothelin-1 transgenic (ETTG) and wild type (WT) mice were analyzed. • ETTG mice spontaneously developed PAH under normoxia conditions. • SU5416 further aggravated PAH in ETTG mice. • Enhanced endothelin system activity could be a causative factor in

  2. Pneumonectomy combined with SU5416 induces severe pulmonary hypertension in rats.

    PubMed

    Happé, C M; de Raaf, M A; Rol, N; Schalij, I; Vonk-Noordegraaf, A; Westerhof, N; Voelkel, N F; de Man, F S; Bogaard, H J

    2016-06-01

    The SU5416 + hypoxia (SuHx) rat model is a commonly used model of severe pulmonary arterial hypertension. While it is known that exposure to hypoxia can be replaced by another type of hit (e.g., ovalbumin sensitization) it is unknown whether abnormal pulmonary blood flow (PBF), which has long been known to invoke pathological changes in the pulmonary vasculature, can replace the hypoxic exposure. Here we studied if a combination of SU5416 administration combined with pneumonectomy (PNx), to induce abnormal PBF in the contralateral lung, is sufficient to induce severe pulmonary arterial hypertension (PAH) in rats. Sprague Dawley rats were subjected to SuPNx protocol (SU5416 + combined with left pneumonectomy) or standard SuHx protocol, and comparisons between models were made at week 2 and 6 postinitiation. Both SuHx and SuPNx models displayed extensive obliterative vascular remodeling leading to an increased right ventricular systolic pressure at week 6 Similar inflammatory response in the lung vasculature of both models was observed alongside increased endothelial cell proliferation and apoptosis. This study describes the SuPNx model, which features severe PAH at 6 wk and could serve as an alternative to the SuHx model. Our study, together with previous studies on experimental models of pulmonary hypertension, shows that the typical histopathological findings of PAH, including obliterative lesions, inflammation, increased cell turnover, and ongoing apoptosis, represent a final common pathway of a disease that can evolve as a consequence of a variety of insults to the lung vasculature. PMID:27036867

  3. Role of ASIC1 in the development of chronic hypoxia-induced pulmonary hypertension

    PubMed Central

    Nitta, Carlos H.; Osmond, David A.; Herbert, Lindsay M.; Beasley, Britta F.; Resta, Thomas C.; Walker, Benjimen R.

    2013-01-01

    Chronic hypoxia (CH) associated with respiratory disease results in elevated pulmonary vascular intracellular Ca2+ concentration, which elicits enhanced vasoconstriction and promotes vascular arterial remodeling and thus has important implications in the development of pulmonary hypertension (PH). Store-operated Ca2+ entry (SOCE) contributes to this elevated intracellular Ca2+ concentration and has also been linked to acute hypoxic pulmonary vasoconstriction (HPV). Since our laboratory has recently demonstrated an important role for acid-sensing ion channel 1 (ASIC1) in mediating SOCE, we hypothesized that ASIC1 contributes to both HPV and the development of CH-induced PH. To test this hypothesis, we examined responses to acute hypoxia in isolated lungs and assessed the effects of CH on indexes of PH, arterial remodeling, and vasoconstrictor reactivity in wild-type (ASIC1+/+) and ASIC1 knockout (ASIC1−/−) mice. Restoration of ASIC1 expression in pulmonary arterial smooth muscle cells from ASIC1−/− mice rescued SOCE, confirming the requirement for ASIC1 in this response. HPV responses were blunted in lungs from ASIC1−/− mice. Both SOCE and receptor-mediated Ca2+ entry, along with agonist-dependent vasoconstrictor responses, were diminished in small pulmonary arteries from control ASIC−/− mice compared with ASIC+/+ mice. The effects of CH to augment receptor-mediated vasoconstrictor and SOCE responses in vessels from ASIC1+/+ mice were not observed after CH in ASIC1−/− mice. In addition, ASIC1−/− mice exhibited diminished right ventricular systolic pressure, right ventricular hypertrophy, and arterial remodeling in response to CH compared with ASIC1+/+ mice. Taken together, these data demonstrate an important role for ASIC1 in both HPV and the development of CH-induced PH. PMID:24186095

  4. Gender differences in ozone-induced pulmonary and metabolic health effects

    EPA Science Inventory

    SOT 2015 abstractGender differences in ozone-induced pulmonary and metabolic health effectsU.P. Kodavanti1, V.L. Bass2, M.C. Schladweiler1, C.J. Gordon3, K.A. Jarema3, P. Phillips3, A.D. Ledbetter1, D.B. Miller4, S. Snow5, J.E. Richards1. 1 EPHD, NHEERL, USEPA, Research Triangle ...

  5. The Preventive Effect of Atorvastatin on Paraquat-Induced Pulmonary Fibrosis in the Rats

    PubMed Central

    Khodayar, Mohammad Javad; Kiani, Milad; Hemmati, Ali Asghar; Rezaie, Anahita; Zerafatfard, Mohammad Rahim; Rashidi Nooshabadi, Mohammad Reza; Goudarzi, Mehdi

    2014-01-01

    Purpose: Pulmonary fibrosis is a potentially lethal inflammatory disease and there has been no effective medication for this progressive disease up to now. As a model, different therapeutic approaches have been applied for paraquat-induced pulmonary injury and fibrosis. Atorvastatin besides cholesterol-lowering effects possesses anti-inflammatory and anti-oxidant properties. The current study was designed to investigate the preventive anti-fibrotic effects of atorvastatin on paraquat-induced pulmonary fibrosis in rats. Methods: The rats were randomly divided into five experimental groups. Group I, control group (saline), group II received a single oral dose of 20 mg/kg paraquat with no treatment and III, IV and V groups received atorvastatin at the doses of 10, 20, and 40 mg/kg/day orally one week before and three weeks after paraquat administration, respectively. The rats were sacrificed 21 days after paraquat. Lung hydroxyproline and serum levels of malondialdehyde (MDA) were determined and lung indices and semi-quantitative histopathological changes were evaluated. Results: Paraquat could significantly increase the serum MDA and lung hydroxyproline levels. Elevated content of tissue hydroxyproline and serum levels of malondialdehyde induced by paraquat, attenuated by atorvastatin at the doses of 10, 20 and 40 mg/kg. Furthermore, histopathological findings and the amount of lung indices showed the beneficial preventive role of atorvastatin in rat pulmonary fibrosis induced by paraquat. Conclusion: In conclusion, the present data show that atorvastatin alleviate the toxic effects of paraquat under the experimental circumstances and may be a useful agent in cases who are in contact or poisoned with paraquat. PMID:25436189

  6. Effect of chronic sodium nitrite therapy on monocrotaline-induced pulmonary hypertension.

    PubMed

    Pankey, Edward A; Badejo, Adeleke M; Casey, David B; Lasker, George F; Riehl, Russel A; Murthy, Subramanyam N; Nossaman, Bobby D; Kadowitz, Philip J

    2012-06-30

    Pulmonary hypertension (PH) is a rare disorder that without treatment is progressive and often fatal within 3 years. The treatment of PH involves the use of a diverse group of drugs and lung transplantation. Although nitrite was once thought to be an inactive metabolite of endothelial-derived nitric oxide (NO), there is increasing evidence that nitrite may be useful in the treatment of PH, but the mechanism by which nitrite exerts its beneficial effect remains uncertain. The purpose of this study was to investigate the effect of chronic sodium nitrite treatment in a PH model in the rat. Following induction of PH with a single injection of monocrotaline, 60 mg; daily ip injections of sodium nitrite (3mg/kg) starting on day 14 and continuing for 21 days, resulted in a significantly lower pulmonary arterial pressure on day 35 when compared to values in untreated animals with monocrotaline-induced PH. In monocrotaline-treated rats, daily treatment with ip nitrite injections for 21 days decreased right ventricular mass and pathologic changes in small pulmonary arteries. Nitrite therapy did not change systemic arterial pressure or cardiac output when values were measured on day 35. The decreases in pulmonary arterial pressure in response to iv injections of sodium nitroprusside, sodium nitrite, and BAY 41-8543 were not different in rats with monocrotaline-induced pulmonary hypertension and rats with chronic nitrite therapy when compared to responses in animals in which pulmonary arterial pressure was increased with U46619. These findings are consistent with the hypothesis that the mechanisms that convert nitrite to vasoactive NO, activate soluble guanylyl cyclase and mediate the vasodilator response to NO or an NO derivative are not impaired. The present data are consistent with the results of a previous study in monocrotaline-induced PH in which systemic arterial pressure and cardiac output were not evaluated and are consistent with the hypothesis that nitrite is

  7. Effect of Chronic Sodium Nitrite Therapy on Monocrotaline-Induced Pulmonary Hypertension

    PubMed Central

    Pankey, Edward A.; Badejo, Adeleke M.; Casey, David B.; Lasker, George F.; Riehl, Russel A.; Murthy, Subramanyam N.; Nossaman, Bobby D.; Kadowitz, Philip J.

    2012-01-01

    Pulmonary hypertension (PH) is a rare disorder that without treatment is progressive and often fatal within 3 years. The treatment of PH involves the use of a diverse group of drugs and lung transplantation. Although nitrite was once thought to be an inactive metabolite of endothelial-derived nitric oxide (NO), there is increasing evidence that nitrite may be useful in the treatment of PH, but the mechanism by which nitrite exerts its beneficial effect remains uncertain. The purpose of this study was to investigate the effect of chronic sodium nitrite treatment in a PH model in the rat. Following induction of PH with a single injection of monocrotaline, 60 mg; daily ip injections of sodium nitrite (3 mg/kg) starting on day 14 and continuing for 21 days, resulted in a significantly lower pulmonary arterial pressure on day 35 when compared to values in untreated animals with monocrotaline-induced PH. In monocrotaline-treated rats, daily treatment with ip nitrite injections for 21 days decreased right ventricular mass and pathologic changes in small pulmonary arteries. Nitrite therapy did not change systemic arterial pressure or cardiac output when values were measured on day 35. The decreases in pulmonary arterial pressure in response to iv injections of sodium nitroprusside, sodium nitrite, and BAY 41-8543 were not different in rats with monocrotaline-induced pulmonary hypertension and rats with chronic nitrite therapy when compared to responses in animals in which pulmonary arterial pressure was increased with U46619. These findings are consistent with the hypothesis that the mechanisms that convert nitrite to vasoactive NO, activate soluble guanylyl cyclase and mediate the vasodilator response to NO or an NO derivative are not impaired. The present data are consistent with the results of a previous study in monocrotaline-induced PH in which systemic arterial pressure and cardiac output were not evaluated and are consistent with the hypothesis that nitrite is

  8. Inhibition of pulmonary adenoma in diethylnitrosamine-induced rats by Rhizoma paridis saponins.

    PubMed

    Man, Shuli; Li, Jing; Fan, Wei; Chai, Hongyan; Liu, Zhen; Gao, Wenyuan

    2015-11-01

    Nowadays, people pay more and more attention to the natural products based on their multiple targets in the antitumor treatment. In our previous research, Rhizoma paridis saponins (RPS) were regarded as potent anticancer agent that elicits programmed cell death and inhibits metastases in murine lung adenocarcinoma in vivo. In the present study, we set up a rat model of diethylnitrosamine (DEN) induced pulmonary adenoma to evaluate the antitumor effects of RPS again. After 20 weeks treatment, rats were sacrificed in order to perform histopathological examinations, blood biochemistry, immunohistochemistry, western blot, PCR and metabonomics. As a result, DEN induced pulmonary adenoma generation in the lungs and damaged hepatocytes and hepatoma formation in the livers. RPS effectively attenuated hepatotoxic and inhibited pulmonary adenoma through down-regulating expression of MMP-9 and up-regulating level of TIMP-2 in DEN-induced rats. Meanwhile, RPS remarkably decreased energy metabolism, and glycine, serine and threonine metabolism to block the tumor growth. In conclusion, RPS would be a potent anticancer agent used in the prospective application. PMID:26196122

  9. Structural and functional prevention of hypoxia-induced pulmonary hypertension by individualized exercise training in mice.

    PubMed

    Weissmann, Norbert; Peters, Dorothea M; Klöpping, Christina; Krüger, Karsten; Pilat, Christian; Katta, Susmitha; Seimetz, Michael; Ghofrani, Hossein A; Schermuly, Ralph T; Witzenrath, Martin; Seeger, Werner; Grimminger, Friedrich; Mooren, Frank C

    2014-06-01

    Pulmonary hypertension (PH) is a disease with a poor prognosis characterized by a vascular remodeling process and an increase in pulmonary vascular resistance. While a variety of reports demonstrated that exercise training exerts beneficial effects on exercise performance and quality of life in PH patients, it is not known how physical exercise affects vascular remodeling processes occurring in hypoxia-induced PH. Therefore, we investigated the effect of individualized exercise training on the development of hypoxia-induced PH in mice. Training effects were compared with pharmacological treatment with the phosphodiesterase 5 inhibitor Sildenafil or a combination of training plus Sildenafil. Trained mice who received Sildenafil showed a significantly improved walking distance (from 88.9 ± 8.1 to 146.4 ± 13.1 m) and maximum oxygen consumption (from 93.3 ± 2.9 to 105.5 ± 2.2% in combination with Sildenafil, to 102.2 ± 3.0% with placebo) compared with sedentary controls. Right ventricular systolic pressure, measured by telemetry, was at the level of healthy normoxic animals, whereas right heart hypertrophy did not benefit from training. Most interestingly, the increase in small pulmonary vessel muscularization was prevented by training. Respective counterregulatory processes were detected for the nitric oxide-soluble guanylate cyclase-phosphodiesterase system. We conclude that individualized daily exercise can prevent vascular remodeling in hypoxia-induced PH. PMID:24705723

  10. Hypoxia-inducible factors in human pulmonary arterial hypertension: a link to the intrinsic myeloid abnormalities.

    PubMed

    Farha, Samar; Asosingh, Kewal; Xu, Weiling; Sharp, Jacqueline; George, Deepa; Comhair, Suzy; Park, Margaret; Tang, W H Wilson; Loyd, James E; Theil, Karl; Tubbs, Raymond; Hsi, Eric; Lichtin, Alan; Erzurum, Serpil C

    2011-03-31

    Pulmonary arterial hypertension (PAH) is a proliferative vasculopathy characterized by high circulating CD34(+)CD133(+) proangiogenic progenitors, and endothelial cells that have pathologic expression of hypoxia-inducible factor 1 α (HIF-1α). Here, CD34(+)CD133(+) progenitor cell numbers are shown to be higher in PAH bone marrow, blood, and pulmonary arteries than in healthy controls. The HIF-inducible myeloid-activating factors erythropoietin, stem cell factor (SCF), and hepatocyte growth factor (HGF) are also present at higher than normal levels in PAH blood, and related to disease severity. Primary endothelial cells harvested from human PAH lungs produce greater HGF and progenitor recruitment factor stromal-derived factor 1 α (SDF-1α) than control lung endothelial cells, and thus may contribute to bone marrow activation. Even though PAH patients had normal numbers of circulating blood elements, hematopoietic alterations in myeloid and erythroid lineages and reticulin fibrosis identified a subclinical myeloproliferative process. Unexpectedly, evaluation of bone marrow progenitors and reticulin in nonaffected family members of patients with familial PAH revealed similar myeloid abnormalities. Altogether, the results show that PAH is linked to myeloid abnormalities, some of which may be related to increased production of HIF-inducible factors by diseased pulmonary vasculature, but findings in nonaffected family suggest myeloid abnormalities may be intrinsic to the disease process. PMID:21258008

  11. Hypoxia-inducible factors in human pulmonary arterial hypertension: a link to the intrinsic myeloid abnormalities

    PubMed Central

    Asosingh, Kewal; Xu, Weiling; Sharp, Jacqueline; George, Deepa; Comhair, Suzy; Park, Margaret; Tang, W. H. Wilson; Loyd, James E.; Theil, Karl; Tubbs, Raymond; Hsi, Eric; Lichtin, Alan

    2011-01-01

    Pulmonary arterial hypertension (PAH) is a proliferative vasculopathy characterized by high circulating CD34+CD133+ proangiogenic progenitors, and endothelial cells that have pathologic expression of hypoxia-inducible factor 1 α (HIF-1α). Here, CD34+CD133+ progenitor cell numbers are shown to be higher in PAH bone marrow, blood, and pulmonary arteries than in healthy controls. The HIF-inducible myeloid-activating factors erythropoietin, stem cell factor (SCF), and hepatocyte growth factor (HGF) are also present at higher than normal levels in PAH blood, and related to disease severity. Primary endothelial cells harvested from human PAH lungs produce greater HGF and progenitor recruitment factor stromal-derived factor 1 α (SDF-1α) than control lung endothelial cells, and thus may contribute to bone marrow activation. Even though PAH patients had normal numbers of circulating blood elements, hematopoietic alterations in myeloid and erythroid lineages and reticulin fibrosis identified a subclinical myeloproliferative process. Unexpectedly, evaluation of bone marrow progenitors and reticulin in nonaffected family members of patients with familial PAH revealed similar myeloid abnormalities. Altogether, the results show that PAH is linked to myeloid abnormalities, some of which may be related to increased production of HIF-inducible factors by diseased pulmonary vasculature, but findings in nonaffected family suggest myeloid abnormalities may be intrinsic to the disease process. PMID:21258008

  12. Silibinin attenuates methotrexate-induced pulmonary injury by targeting oxidative stress

    PubMed Central

    KALEMCI, SERDAR; TOPAL, YASAR; CELIK, SERKAN YASAR; YILMAZ, NIGAR; BEYDILLI, HALIL; KOSAR, MEHMET ILKAY; DIRICAN, NIGAR; ALTUNTAS, IRFAN

    2015-01-01

    The aim of the present study was to assess the protective effect of silibinin against methotrexate (MTX)-induced pulmonary toxicity. Rats were divided into four groups (MTX, MTX + silibinin, silibinin and control. MTX was injected intraperitoneally (i.p) into female Wistar rats (10 mg/kg/day for 3 days), which resulted in significant increases in the serum levels of alanine aminotransferase, aspartate aminotransferase and oxidant enzymes, including nitric oxide and myeloperoxidase. Furthermore, significant reductions were detected in the serum activity levels of the antioxidative enzymes, glutathione peroxidase and superoxide dismutase, when compared with the control group. However, administration of silibinin (100 mg/kg/day for 10 days, i.p.) was shown to ameliorate the MTX-induced pulmonary toxicity, as indicated by the normalization of the oxidative stress parameters. Furthermore, silibinin treatment was demonstrated to reduce the histopathological changes associated with MTX. In conclusion, silibinin exhibited protective effects against MTX-induced pulmonary toxicity, which may be attributed to its antioxidant activity. PMID:26622344

  13. [Role of endogenous hydrogen sulfide in pulmonary hypertension induced by lipopolysaccharide].

    PubMed

    Huang, Xin-Li; Zhou, Xiao-Hong; Wei, Peng; Zhang, Xiao-Jing; Meng, Xiang-Yan; Xian, Xiao-Hui

    2008-04-25

    The purpose of the present study was to explore the role of endogenous hydrogen sulfide (H2S) in pulmonary arterial hypertension induced by endotoxin. Adult male Sprague-Dawley (SD) rats were randomly divided into four groups: Control group (0.5 mL/kg body weight of normal saline, i.v.), lipopolysaccharide (LPS)-treated group (5 mg/kg body weight of LPS, i.v.), LPS + NaHS (5 mg/kg body weight of LPS, i.v., and 28 μmol/kg body weight of NaHS, i.p.) and LPS + PPG group (5 mg/kg body weight of LPS, i.v., and 30 μmol/kg body weight of PPG, i.p.). Rats were anesthetized with 20% urethane (1 g/kg body weight, i.p.). A polyethylene catheter was inserted into the pulmonary artery through the right external jugular vein to measure the mean pulmonary arterial pressure (mPAP) for 7 h, and then the pulmonary artery was isolated rapidly by the method described previously. Pulmonary arterial activity was detected. H2S concentration and cystathionine γ-lyase (CSE) activity in pulmonary artery tissues were determined by biochemical method. CSE mRNA expression was detected by competitive reverse transcriptase-polymerase chain reaction (RT-PCR). Compared with control, LPS significantly increased mPAP [(1.82±0.29) kPa vs (1.43±0.26) kPa, P<0.01], decreased H2S production [(26.33±7.84) vs (42.92±8.73) pmol/g wet tissue per minute, P<0.01), and reduced endothelium-dependent relaxation response [(75.72±7.22)% vs (86.40±4.40) %, P<0.01) induced by ACh (1×10(-6) mol/L). These effects were partly reversed by co-administration of NaHS and enhanced by co-administration of PPG. Both CSE activity and CSE mRNA expression were consistent with H2S production. It is suggested that the inhibitory effect of LPS on endothelium-dependent relaxation results in pulmonary hypertension, which might be mediated through H(2)S. PMID:18425308

  14. Adiponectin attenuates lung fibroblasts activation and pulmonary fibrosis induced by paraquat.

    PubMed

    Yao, Rong; Cao, Yu; He, Ya-rong; Lau, Wayne Bond; Zeng, Zhi; Liang, Zong-an

    2015-01-01

    Pulmonary fibrosis is one of the most common complications of paraquat (PQ) poisoning, which demands for more effective therapies. Accumulating evidence suggests adiponectin (APN) may be a promising therapy against fibrotic diseases. In the current study, we determine whether the exogenous globular APN isoform protects against pulmonary fibrosis in PQ-treated mice and human lung fibroblasts, and dissect the responsible underlying mechanisms. BALB/C mice were divided into control group, PQ group, PQ + low-dose APN group, and PQ + high-dose APN group. Mice were sacrificed 3, 7, 14, and 21 days after PQ treatment. We compared pulmonary histopathological changes among different groups on the basis of fibrosis scores, TGF-β1, CTGF and α-SMA pulmonary content via Western blot and real-time quantitative fluorescence-PCR (RT-PCR). Blood levels of MMP-9 and TIMP-1 were determined by ELISA. Human lung fibroblasts WI-38 were divided into control group, PQ group, APN group, and APN receptor (AdipoR) 1 small-interfering RNA (siRNA) group. Fibroblasts were collected 24, 48, and 72 hours after PQ exposure for assay. Cell viability and apoptosis were determined via Kit-8 (CCK-8) and fluorescein Annexin V-FITC/PI double labeling. The protein and mRNA expression level of collagen type III, AdipoR1, and AdipoR2 were measured by Western blot and RT-PCR. APN treatment significantly decreased the lung fibrosis scores, protein and mRNA expression of pulmonary TGF-β1, CTGF and α-SMA content, and blood MMP-9 and TIMP-1 in a dose-dependent manner (p<0.05). Pretreatment with APN significantly attenuated the reduced cell viability and up-regulated collagen type III expression induced by PQ in lung fibroblasts, (p<0.05). APN pretreatment up-regulated AdipoR1, but not AdipoR2, expression in WI-38 fibroblasts. AdipoR1 siRNA abrogated APN-mediated protective effects in PQ-exposed fibroblasts. Taken together, our data suggests APN protects against PQ-induced pulmonary fibrosis in a dose

  15. Adiponectin Attenuates Lung Fibroblasts Activation and Pulmonary Fibrosis Induced by Paraquat

    PubMed Central

    He, Ya-rong; Lau, Wayne Bond; Zeng, Zhi; Liang, Zong-an

    2015-01-01

    Pulmonary fibrosis is one of the most common complications of paraquat (PQ) poisoning, which demands for more effective therapies. Accumulating evidence suggests adiponectin (APN) may be a promising therapy against fibrotic diseases. In the current study, we determine whether the exogenous globular APN isoform protects against pulmonary fibrosis in PQ-treated mice and human lung fibroblasts, and dissect the responsible underlying mechanisms. BALB/C mice were divided into control group, PQ group, PQ + low-dose APN group, and PQ + high-dose APN group. Mice were sacrificed 3, 7, 14, and 21 days after PQ treatment. We compared pulmonary histopathological changes among different groups on the basis of fibrosis scores, TGF-β1, CTGF and α-SMA pulmonary content via Western blot and real-time quantitative fluorescence-PCR (RT-PCR). Blood levels of MMP-9 and TIMP-1 were determined by ELISA. Human lung fibroblasts WI-38 were divided into control group, PQ group, APN group, and APN receptor (AdipoR) 1 small-interfering RNA (siRNA) group. Fibroblasts were collected 24, 48, and 72 hours after PQ exposure for assay. Cell viability and apoptosis were determined via Kit-8 (CCK-8) and fluorescein Annexin V-FITC/PI double labeling. The protein and mRNA expression level of collagen type III, AdipoR1, and AdipoR2 were measured by Western blot and RT-PCR. APN treatment significantly decreased the lung fibrosis scores, protein and mRNA expression of pulmonary TGF-β1, CTGF and α-SMA content, and blood MMP-9 and TIMP-1 in a dose-dependent manner (p<0.05). Pretreatment with APN significantly attenuated the reduced cell viability and up-regulated collagen type III expression induced by PQ in lung fibroblasts, (p<0.05). APN pretreatment up-regulated AdipoR1, but not AdipoR2, expression in WI-38 fibroblasts. AdipoR1 siRNA abrogated APN-mediated protective effects in PQ-exposed fibroblasts. Taken together, our data suggests APN protects against PQ-induced pulmonary fibrosis in a dose

  16. Regulation of macroautophagy in amiodarone‐induced pulmonary fibrosis

    PubMed Central

    Mahavadi, Poornima; Knudsen, Lars; Venkatesan, Shalini; Henneke, Ingrid; Hegermann, Jan; Wrede, Christoph; Ochs, Matthias; Ahuja, Saket; Chillappagari, Shashi; Ruppert, Clemens; Seeger, Werner; Korfei, Martina

    2015-01-01

    Abstract Amiodarone (AD) is an iodinated benzofuran derivative, especially known for its antiarrhythmic properties. It exerts serious side‐effects even in patients receiving low doses. AD is well‐known to induce apoptosis of type II alveolar epithelial cells (AECII), a mechanism that has been suggested to play an important role in AD‐induced lung fibrosis. The precise molecular mechanisms underlying this disease are, however, still unclear. Because of its amphiphilic nature, AD becomes enriched in the lysosomal compartments, affecting the general functions of these organelles. Hence, in this study, we aimed to assess the role of autophagy, a lysosome‐dependent homeostasis mechanism, in driving AECII apoptosis in response to AD. In vitro, AD‐treated MLE12 and primary AECII cells showed increased proSP‐C and LC3B positive vacuolar structures and underwent LC3B‐dependent apoptosis. In addition, AD‐induced autophagosome‐lysosome fusion and increased autophagy flux were observed. In vivo, in C57BL/6 mice, LC3B was localised at the limiting membrane of lamellar bodies, which were closely connected to the autophagosomal structures in AECIIs. Our data suggest that AD causes activation of macroautophagy in AECIIs and extensive autophagy‐dependent apoptosis of alveolar epithelial cells. Targeting the autophagy pathway may therefore represent an attractive treatment modality in AD‐induced lung fibrosis.

  17. Regulation of macroautophagy in amiodarone-induced pulmonary fibrosis.

    PubMed

    Mahavadi, Poornima; Knudsen, Lars; Venkatesan, Shalini; Henneke, Ingrid; Hegermann, Jan; Wrede, Christoph; Ochs, Matthias; Ahuja, Saket; Chillappagari, Shashi; Ruppert, Clemens; Seeger, Werner; Korfei, Martina; Guenther, Andreas

    2015-10-01

    Amiodarone (AD) is an iodinated benzofuran derivative, especially known for its antiarrhythmic properties. It exerts serious side-effects even in patients receiving low doses. AD is well-known to induce apoptosis of type II alveolar epithelial cells (AECII), a mechanism that has been suggested to play an important role in AD-induced lung fibrosis. The precise molecular mechanisms underlying this disease are, however, still unclear. Because of its amphiphilic nature, AD becomes enriched in the lysosomal compartments, affecting the general functions of these organelles. Hence, in this study, we aimed to assess the role of autophagy, a lysosome-dependent homeostasis mechanism, in driving AECII apoptosis in response to AD. In vitro, AD-treated MLE12 and primary AECII cells showed increased proSP-C and LC3B positive vacuolar structures and underwent LC3B-dependent apoptosis. In addition, AD-induced autophagosome-lysosome fusion and increased autophagy flux were observed. In vivo, in C57BL/6 mice, LC3B was localised at the limiting membrane of lamellar bodies, which were closely connected to the autophagosomal structures in AECIIs. Our data suggest that AD causes activation of macroautophagy in AECIIs and extensive autophagy-dependent apoptosis of alveolar epithelial cells. Targeting the autophagy pathway may therefore represent an attractive treatment modality in AD-induced lung fibrosis. PMID:27499909

  18. Combined inhibition of TGFβ and PDGF signaling attenuates radiation-induced pulmonary fibrosis

    PubMed Central

    Dadrich, Monika; Nicolay, Nils H.; Flechsig, Paul; Bickelhaupt, Sebastian; Hoeltgen, Line; Roeder, Falk; Hauser, Kai; Tietz, Alexandra; Jenne, Jürgen; Lopez, Ramon; Roehrich, Manuel; Wirkner, Ute; Lahn, Michael; Huber, Peter E.

    2016-01-01

    ABSTRACT Background: Radiotherapy (RT) is a mainstay for the treatment of lung cancer, but the effective dose is often limited by the development of radiation-induced pneumonitis and pulmonary fibrosis. Transforming growth factor β (TGFβ) and platelet-derived growth factor (PDGF) play crucial roles in the development of these diseases, but the effects of dual growth factor inhibition on pulmonary fibrosis development remain unclear. Methods: C57BL/6 mice were treated with 20 Gy to the thorax to induce pulmonary fibrosis. PDGF receptor inhibitors SU9518 and SU14816 (imatinib) and TGFβ receptor inhibitor galunisertib were applied individually or in combinations after RT. Lung density and septal fibrosis were measured by high-resolution CT and MRI. Lung histology and gene expression analyses were performed and Osteopontin levels were studied. Results: Treatment with SU9518, SU14816 or galunisertib individually attenuated radiation-induced pulmonary inflammation and fibrosis and decreased radiological and histological signs of lung damage. Combining PDGF and TGFβ inhibitors showed to be feasible and safe in a mouse model, and dual inhibition significantly attenuated radiation-induced lung damage and extended mouse survival compared to blockage of either pathway alone. Gene expression analysis of irradiated lung tissue showed upregulation of PDGF and TGFβ-dependent signaling components by thoracic irradiation, and upregulation patterns show crosstalk between downstream mediators of the PDGF and TGFβ pathways. Conclusion: Combined small-molecule inhibition of PDGF and TGFβ signaling is a safe and effective treatment for radiation-induced pulmonary inflammation and fibrosis in mice and may offer a novel approach for treatment of fibrotic lung diseases in humans. Translational statement: RT is an effective treatment modality for cancer with limitations due to acute and chronic toxicities, where TGFβ and PDGF play a key role. Here, we show that a combined

  19. Combined inhibition of TGFβ and PDGF signaling attenuates radiation-induced pulmonary fibrosis.

    PubMed

    Dadrich, Monika; Nicolay, Nils H; Flechsig, Paul; Bickelhaupt, Sebastian; Hoeltgen, Line; Roeder, Falk; Hauser, Kai; Tietz, Alexandra; Jenne, Jürgen; Lopez, Ramon; Roehrich, Manuel; Wirkner, Ute; Lahn, Michael; Huber, Peter E

    2016-05-01

    Background : Radiotherapy (RT) is a mainstay for the treatment of lung cancer, but the effective dose is often limited by the development of radiation-induced pneumonitis and pulmonary fibrosis. Transforming growth factor β (TGFβ) and platelet-derived growth factor (PDGF) play crucial roles in the development of these diseases, but the effects of dual growth factor inhibition on pulmonary fibrosis development remain unclear. Methods : C57BL/6 mice were treated with 20 Gy to the thorax to induce pulmonary fibrosis. PDGF receptor inhibitors SU9518 and SU14816 (imatinib) and TGFβ receptor inhibitor galunisertib were applied individually or in combinations after RT. Lung density and septal fibrosis were measured by high-resolution CT and MRI. Lung histology and gene expression analyses were performed and Osteopontin levels were studied. Results : Treatment with SU9518, SU14816 or galunisertib individually attenuated radiation-induced pulmonary inflammation and fibrosis and decreased radiological and histological signs of lung damage. Combining PDGF and TGFβ inhibitors showed to be feasible and safe in a mouse model, and dual inhibition significantly attenuated radiation-induced lung damage and extended mouse survival compared to blockage of either pathway alone. Gene expression analysis of irradiated lung tissue showed upregulation of PDGF and TGFβ-dependent signaling components by thoracic irradiation, and upregulation patterns show crosstalk between downstream mediators of the PDGF and TGFβ pathways. Conclusion : Combined small-molecule inhibition of PDGF and TGFβ signaling is a safe and effective treatment for radiation-induced pulmonary inflammation and fibrosis in mice and may offer a novel approach for treatment of fibrotic lung diseases in humans. Translational statement : RT is an effective treatment modality for cancer with limitations due to acute and chronic toxicities, where TGFβ and PDGF play a key role. Here, we show that a combined inhibition of

  20. Effects of buthionine sulfoximine on the development of ozone-induced pulmonary fibrosis.

    PubMed

    Sun, J D; Pickrell, J A; Harkema, J R; McLaughlin, S I; Hahn, F F; Henderson, R F

    1988-10-01

    The capacity of reduced glutathione (GSH) to protect lung tissue against ozone-induced pulmonary fibrosis was investigated. Male B6C3F1 mice were exposed to 0, 0.2, 0.5, and 1.0 ppm ozone for 23 hr/day for 14 days. During exposures and/or for a period of 90 days after exposures, subgroups of mice at each exposure level were given drinking water containing 30 mM L-buthionine-S,R-sulfoximine (BSO) to lower in vivo levels of GSH. These BSO treatments reduced blood glutamylcysteine synthetase (GCS) activity (regulatory enzyme for GSH biosynthesis) and lung nonprotein sulfhydryl (NPSH) levels in nonexposed animals by approximately half. In contrast, ozone exposures increased blood GCS activity and lung NPSH levels in a concentration-dependent manner, with smaller increases in the BSO-treated mice. Immediately after exposures, an ozone-related inflammatory response was seen in lungs, but no histopathological signs of developing fibrosis were evident. Ninety days later, mice exposed to 1 ppm ozone and not treated with BSO had modest evidence of pulmonary fibrosis. Mice exposed to 1 ppm ozone and treated with BSO during this post-exposure period (regardless of BSO treatment during exposures) showed histopathological evidence of exacerbated pulmonary fibrosis, compared to similarly exposed mice not treated with BSO postexposure. These results indicated that interference with the body's normal defense mechanisms against oxidant damage, including suppression of GSH biosynthesis, exacerbates the subsequent development of pulmonary fibrosis. PMID:2901982

  1. Puerarin Induces Mitochondria-Dependent Apoptosis in Hypoxic Human Pulmonary Arterial Smooth Muscle Cells

    PubMed Central

    Chen, Chan; Chen, Chun; Wang, Zhiyi; Wang, Liangxing; Yang, Lehe; Ding, Minjiao; Ding, Cheng; Sun, Yu; Lin, Quan; Huang, Xiaoying; Du, Xiaohong; Zhao, Xiaowei; Wang, Chuangyi

    2012-01-01

    Background Pulmonary vascular medial hypertrophy in hypoxic pulmonary arterial hypertension (PAH) is caused in part by decreased apoptosis in pulmonary artery smooth muscle cells (PASMCs). Puerarin, an isoflavone purified from the Chinese medicinal herb kudzu, ameliorates chronic hypoxic PAH in animal models. Here we investigated the effects of puerarin on apoptosis of hypoxic human PASMCs (HPASMCs), and to determine the possible underlying mechanisms. Methodology/Principal Findings HPASMCs were cultured for 24 h in normoxia or hypoxia (5% O2) conditions with and without puerarin. Cell number and viability were determined with a hemacytometer or a cell counting kit. Apoptosis was detected with a TUNEL test, rhodamine-123 (R-123) fluorescence, a colorimetric assay, western blots, immunohistochemical staining and RT-PCR. Hypoxia inhibited mitochondria-dependent apoptosis and promoted HPASMC growth. In contrast, after puerarin (50 µM or more) intervention, cell growth was inhibited and apoptosis was observed. Puerarin-induced apoptosis in hypoxic HPASMCs was accompanied by reduced mitochondrial membrane potential, cytochrome c release from the mitochondria, caspase-9 activation, and Bcl-2 down-regulation with concurrent Bax up-regulation. Conclusions/Significance Puerarin promoted apoptosis in hypoxic HPASMCs by acting on the mitochondria-dependent pathway. These results suggest a new mechanism of puerarin relevant to the management of clinical hypoxic pulmonary hypertension. PMID:22457823

  2. CD4(+)CD25(hi)Foxp3(+) Cells Exacerbate Bleomycin-Induced Pulmonary Fibrosis.

    PubMed

    Birjandi, Shirin Z; Palchevskiy, Vyacheslav; Xue, Ying Ying; Nunez, Stefanie; Kern, Rita; Weigt, S Sam; Lynch, Joseph P; Chatila, Talal A; Belperio, John A

    2016-08-01

    Idiopathic pulmonary fibrosis is a fatal lung disease with a median survival of 2 to 5 years. A decade of studies has downplayed inflammation contributing to its pathogenesis. However, these studies preceded the discovery of regulatory T cells (Tregs) and all of their functions. On the basis of human studies demonstrating Tregs can decrease graft-versus-host disease and vasculitides, there is consideration of their use to treat idiopathic pulmonary fibrosis. We hypothesized that Treg therapy would attenuate the fibroplasia involved in a preclinical murine model of pulmonary fibrosis. IL-2 complex was used in vivo to expand CD4(+)CD25(hi)Foxp3(+) cells in the lung during intratracheal bleomycin challenge; however, this unexpectedly led to an increase in lung fibrosis. More important, this increase in fibrosis was a lymphocyte-dependent process. We corroborated these results using a CD4(+)CD25(hi)Foxp3(+) cellular-based therapy. Mechanistically, we demonstrated that CD4(+)CD25(hi)Foxp3(+) cells undergo alterations during bleomycin challenge and the IL-2 complex had no effect on profibrotic (eg, transforming growth factor-β) or type 17 immune response cytokines; however, there was a marked down-regulation of the type 1 and augmentation of the type 2 immune response cytokines from the lungs. Collectively, our animal studies show that a specific lung injury can induce Treg alterations, which can augment pulmonary fibrosis. PMID:27317904

  3. Oxidant and enzymatic antioxidant status (gene expression and activity) in the brain of chickens with cold-induced pulmonary hypertension

    NASA Astrophysics Data System (ADS)

    Hassanpour, Hossein; Khalaji-Pirbalouty, Valiallah; Nasiri, Leila; Mohebbi, Abdonnaser; Bahadoran, Shahab

    2015-11-01

    To evaluate oxidant and antioxidant status of the brain (hindbrain, midbrain, and forebrain) in chickens with cold-induced pulmonary hypertension, the measurements of lipid peroxidation, protein oxidation, antioxidant capacity, enzymatic activity, and gene expression (for catalase, glutathione peroxidase, and superoxide dismutases) were done. There were high lipid peroxidation/protein oxidation and low antioxidant capacity in the hindbrain of cold-induced pulmonary hypertensive chickens compared to control ( P < 0.05). In the hypertensive chickens, superoxide dismutase activity was decreased (forebrain, midbrain, and hindbrain), while catalase activity was increased (forebrain and midbrain) ( P < 0.05). Glutathione peroxidase activity did not change. Relative gene expression of catalase and superoxide dismutases (1 and 2) was downregulated, while glutathione peroxidase was upregulated in the brain of the cold-induced pulmonary hypertensive chickens. Probably, these situations in the oxidant and antioxidant status of the brain especially hindbrain may change its function at cardiovascular center and sympathetic nervous system to exacerbate pulmonary hypertension.

  4. Hypoxia induces hypersensitivity and hyperreactivity to thromboxane receptor agonist in neonatal pulmonary arterial myocytes.

    PubMed

    Hinton, M; Mellow, L; Halayko, A J; Gutsol, A; Dakshinamurti, S

    2006-02-01

    PPHN, caused by perinatal hypoxia or inflammation, is characterized by an increased thromboxane-prostacyclin ratio and pulmonary vasoconstriction. We examined effects of hypoxia on myocyte thromboxane responsiveness. Myocytes from 3rd-6th generation pulmonary arteries of newborn piglets were grown to confluence and synchronized in contractile phenotype by serum deprivation. On the final 3 days of culture, myocytes were exposed to 10% O2 for 3 days; control myocytes from normoxic piglets were cultured in 21% O2. PPHN was induced in newborn piglets by 3-day hypoxic exposure (Fi(O2) 0.10); pulmonary arterial myocytes from these animals were maintained in normoxia. Ca2+ mobilization to thromboxane mimetic U-46619 and ATP was quantified using fura-2 AM. Three-day hypoxic exposure in vitro results in increased basal [Ca2+]i, faster and heightened peak Ca2+ response, and decreased U-46619 EC50. These functional changes persist in myocytes exposed to hypoxia in vivo but cultured in 21% O2. Blockade of Ca2+ entry and store refilling do not alter peak U-46619 Ca2+ responses in hypoxic or normoxic myocytes. Blockade of ryanodine-sensitive or IP3-gated intracellular Ca2+ channels inhibits hypoxic augmentation of peak U-46619 response. Ca2+ response to ryanodine alone is undetectable; ATP-induced Ca2+ mobilization is unaltered by hypoxia, suggesting no independent increase in ryanodine-sensitive or IP3-linked intracellular Ca2+ pool mobilization. We conclude hypoxia has a priming effect on neonatal pulmonary arterial myocytes, resulting in increased resting Ca2+, thromboxane hypersensitivity, and hyperreactivity. We postulate that hypoxia increases agonist-induced TP-R-linked IP3 pathway activation. Myocyte thromboxane hyperresponsiveness persists in culture after removal from the initiating hypoxic stimulus, suggesting altered gene expression. PMID:16214814

  5. Asbestos-induced pulmonary fibrosis is augmented in 8-oxoguanine DNA glycosylase knockout mice.

    PubMed

    Cheresh, Paul; Morales-Nebreda, Luisa; Kim, Seok-Jo; Yeldandi, Anjana; Williams, David B; Cheng, Yuan; Mutlu, Gökhan M; Budinger, G R Scott; Ridge, Karen; Schumacker, Paul T; Bohr, Vilhelm A; Kamp, David W

    2015-01-01

    Asbestos causes asbestosis and malignancies by mechanisms that are not fully established. Alveolar epithelial cell (AEC) injury and repair are crucial determinants of the fibrogenic potential of noxious agents such as asbestos. We previously showed that mitochondrial reactive oxygen species mediate asbestos-induced AEC intrinsic apoptosis and that mitochondrial human 8-oxoguanine-DNA glycosylase 1 (OGG1), a DNA repair enzyme, prevents oxidant-induced AEC apoptosis. We reasoned that OGG1 deficiency augments asbestos-induced pulmonary fibrosis. Compared with intratracheal instillation of PBS (50 μl) or titanium dioxide (100 μg/50 μl), crocidolite or Libby amphibole asbestos (100 μg/50 μl) each augmented pulmonary fibrosis in wild-type C57BL/6J (WT) mice after 3 weeks as assessed by histology, fibrosis score, lung collagen via Sircol, and type 1 collagen expression; these effects persisted at 2 months. Compared with WT mice, Ogg1 homozygous knockout (Ogg1(-/-)) mice exhibit increased pulmonary fibrosis after crocidolite exposure and apoptosis in cells at the bronchoalveolar duct junctions as assessed via cleaved caspase-3 immunostaining. AEC involvement was verified by colocalization studies using surfactant protein C. Asbestos increased endoplasmic reticulum stress in the lungs of WT and Ogg1(-/-) mice. Compared with WT, alveolar type 2 cells isolated from Ogg1(-/-) mice have increased mtDNA damage, reduced mitochondrial aconitase expression, and increased P53 and cleaved caspase-9 expression, and these changes were enhanced 3 weeks after crocidolite exposure. These findings suggest an important role for AEC mtDNA integrity maintained by OGG1 in the pathogenesis of pulmonary fibrosis that may represent a novel therapeutic target. PMID:24918270

  6. Inactivation of p53 Is Sufficient to Induce Development of Pulmonary Hypertension in Rats

    PubMed Central

    Jacquin, S.; Rincheval, V.; Mignotte, B.; Richard, S.; Humbert, M.; Mercier, O.; Londoño-Vallejo, A.; Fadel, E.; Eddahibi, S.

    2015-01-01

    Objective Pulmonary artery smooth muscle cells (PA-SMCs) in pulmonary arterial hypertension (PAH) show similarities to cancer cells. Due to the growth-suppressive and pro-apoptotic effects of p53 and its inactivation in cancer, we hypothesized that the p53 pathway could be altered in PAH. We therefore explored the involvement of p53 in the monocrotaline (MCT) rat model of pulmonary hypertension (PH) and the pathophysiological consequences of p53 inactivation in response to animal treatment with pifithrin-α (PFT, an inhibitor of p53 activity). Methods and Results PH development was assessed by pulmonary arterial pressure, right ventricular hypertrophy and arterial wall thickness. The effect of MCT and PFT on lung p53 pathway expression was evaluated by western blot. Fourteen days of daily PFT treatment (2.2 mg/kg/day), similar to a single injection of MCT (60 mg/kg), induced PH and aggravated MCT-induced PH. In the first week after MCT administration and prior to PH development, p53, p21 and MDM2 protein levels were significantly reduced; whereas PFT administration effectively altered the protein level of p53 targets. Anti-apoptotic and pro-proliferative effects of PFT were revealed by TUNEL and MTT assays on cultured human PA-SMCs treated with 50 μM PFT. Conclusions Pharmacological inactivation of p53 is sufficient to induce PH with a chronic treatment by PFT, an effect related to its anti-apoptotic and pro-proliferative properties. The p53 pathway was down-regulated during the first week in the rat MCT model. These in vivo experiments implicate the p53 pathway at the initiation stages of PH pathogenesis. PMID:26121334

  7. Correlation between friction and thickness of vanadium-pentoxide nanowires

    NASA Astrophysics Data System (ADS)

    Kim, Taekyeong

    2015-11-01

    We investigated the correlation between friction and thickness of vanadium-pentoxide nanowires (V2O5 NWs) by using friction/atomic force microscopy (FFM/AFM). We observed that the friction signal generally increased with thickness in the FFM/AFM image of the V2O5 NWs. We constructed a two-dimensional (2D) correlation distribution of the frictional force and the thickness of the V2O5 NWs and found that they are strongly correlated; i.e., thicker NWs had higher friction. We also generated a histogram for the correlation factors obtained from each distribution and found that the most probable factor is ~0.45. Furthermore, we found that the adhesion force between the tip and the V2O5 NWs was about -3 nN, and that the friction increased with increasing applied load for different thicknesses of V2O5 NWs. Our results provide an understanding of tribological and nanomechanical studies of various one-dimensional NWs for future fundamental research.

  8. Impact of interleukin-6 on hypoxia-induced pulmonary hypertension and lung inflammation in mice

    PubMed Central

    Savale, Laurent; Tu, Ly; Rideau, Dominique; Izziki, Mohamed; Maitre, Bernard; Adnot, Serge; Eddahibi, Saadia

    2009-01-01

    Background Inflammation may contribute to the pathogenesis of various forms of pulmonary hypertension (PH). Recent studies in patients with idiopathic PH or PH associated with underlying diseases suggest a role for interleukin-6 (IL-6). Methods To determine whether endogenous IL-6 contributes to mediate hypoxic PH and lung inflammation, we studied IL-6-deficient (IL-6-/-) and wild-type (IL-6+/+) mice exposed to hypoxia for 2 weeks. Results Right ventricular systolic pressure, right ventricle hypertrophy, and the number and media thickness of muscular pulmonary vessels were decreased in IL-6-/- mice compared to wild-type controls after 2 weeks' hypoxia, although the pressure response to acute hypoxia was similar in IL-6+/+ and IL-6-/- mice. Hypoxia exposure of IL-6+/+ mice led to marked increases in IL-6 mRNA and protein levels within the first week, with positive IL-6 immunostaining in the pulmonary vessel walls. Lung IL-6 receptor and gp 130 (the IL-6 signal transducer) mRNA levels increased after 1 and 2 weeks' hypoxia. In vitro studies of cultured human pulmonary-artery smooth-muscle-cells (PA-SMCs) and microvascular endothelial cells revealed prominent synthesis of IL-6 by PA-SMCs, with further stimulation by hypoxia. IL-6 also markedly stimulated PA-SMC migration without affecting proliferation. Hypoxic IL-6-/- mice showed less inflammatory cell recruitment in the lungs, compared to hypoxic wild-type mice, as assessed by lung protein levels and immunostaining for the specific macrophage marker F4/80, with no difference in lung expression of adhesion molecules or cytokines. Conclusion These data suggest that IL-6 may be actively involved in hypoxia-induced lung inflammation and pulmonary vascular remodeling in mice. PMID:19173740

  9. Calcilytics enhance sildenafil-induced antiproliferation in idiopathic pulmonary arterial hypertension.

    PubMed

    Yamamura, Aya; Yagi, Satomi; Ohara, Naoki; Tsukamoto, Kikuo

    2016-08-01

    Idiopathic pulmonary arterial hypertension (IPAH) is a progressive and fatal disease of the pulmonary artery resulting from currently unidentified etiology. IPAH is pathologically characterized as sustained vasoconstriction and vascular remodeling of the pulmonary artery. Phosphodiesterase type 5 (PDE5) inhibitors have been clinically used in the treatment of IPAH. Recently, we have shown that Ca(2+)-sensing receptor (CaSR) antagonists, or calcilytics, inhibit excessive cell proliferation of pulmonary arterial smooth muscle cells (PASMCs) from IPAH patients. In this study, the additive or synergistic effect of calcilytics on antiproliferation following PDE5 inhibition was examined in IPAH-PASMCs by MTT assay. Treatment with sildenafil blocked the excessive cell proliferation of IPAH-PASMCs in a concentration-dependent manner with an IC50 value of 16.9μM. However, sildenafil (0.03-100μM) did not affect the cell growth of PASMCs from normal subjects and patients with chronic thromboembolic pulmonary hypertension (CTEPH). Co-treatment with 0.3μM NPS2143, a calcilytic, additively enhanced the antiproliferative effect induced by sildenafil (3 or 30μM) in IPAH-PASMCs. Additionally, the inhibitory effect of calcilytics, NPS2143 or Calhex 231 (1 or 10μM), on excessive cell proliferation of IPAH-PASMCs was synergistic increased in the presence of 1μM sildenafil. Similar results were obtained by BrdU incorporation assay. These findings reveal that calcilytics additively/synergistically enhance the antiproliferative activity mediated by PDE5 inhibition, suggesting that a combination therapy of a PDE5 inhibitor with a calcilytic may be useful as a novel therapeutic approach for IPAH. PMID:27164419

  10. Chronic biliary obstruction induces pulmonary intravascular phagocytosis and endotoxin sensitivity in rats.

    PubMed Central

    Chang, S W; Ohara, N

    1994-01-01

    Endotoxin sensitivity varies among animal species and appears to correlate with the presence of pulmonary intravascular macrophage (PIM). In rats, which lack PIM, we investigated the hypothesis that chronic cholestatic liver injury leads to induction of PIM and endotoxin sensitivity. Rats were randomized to either common bile duct ligation (BDL) or sham-surgery and studied at 1 wk (acute cholestasis), 2 wk (cholestasis, early cirrhosis), and 4 wk (cholestasis, established cirrhosis) after surgery. Intravascularly injected fluorescent latex microspheres (1 micron diameter) were taken up by large phagocytic cells in lung parenchyma of BDL rats (at 2 and 4 wk), while no uptake was observed in lungs from control rats. Electronmicroscopy revealed accumulation of large, mononuclear, macrophage-like cells containing ingested latex particles within the pulmonary capillaries. Pulmonary intravascular phagocytosis, as reflected in lung uptake of 99mTc microaggregated albumin (Microlite, mean particle diameter = 1 micron), averaged 0.7 +/- 0.1% (mean +/- SEM) of total injected dose in 13 control rats and progressively increased with time after BDL (1 wk, 1.7 +/- 0.2%; 2 wk, 10.0 +/- 3.0%; 4 wk 35.1 +/- 5.9%). Rats with biliary cirrhosis were markedly sensitive to the lethal effects of low dose endotoxin and demonstrated marked lung edema at the time of death. Furthermore, the lung uptake of intravascular 125I-lipopolysaccharide was increased five-fold in cirrhotic rats. We conclude that chronic biliary obstruction leads to the induction of pulmonary intravascular phagocytes and enhances endotoxin sensitivity in rats. Pulmonary intravascular phagocytosis in patients with advanced cirrhosis may account for their increased susceptibility to sepsis-induced adult respiratory distress syndrome. Images PMID:7962547

  11. Passion fruit peel extract attenuates bleomycin-induced pulmonary fibrosis in mice.

    PubMed

    Chilakapati, Shanmuga Reddy; Serasanambati, Mamatha; Manikonda, Pavan Kumar; Chilakapati, Damodar Reddy; Watson, Ronald Ross

    2014-08-01

    Idiopathic pulmonary fibrosis is a progressive fatal lung disease characterized by excessive collagen deposition, with no effective treatments. We investigated the efficacy of natural products with high anti-inflammatory activity, such as passion fruit peel extract (PFPE), in a mouse model of bleomycin-induced pulmonary fibrosis (PF). C57BL/6J mice were subjected to a single intratracheal instillation of bleomycin to induce PF. Daily PFPE treatment significantly reduced loss of body mass and mortality rate in mice compared with those treated with bleomycin. While bleomycin-induced PF resulted in elevated total numbers of inflammatory cells, macrophages, lymphocytes, and neutrophils in bronchoalveolar lavage fluid on both days 7 and 21, PFPE administration significantly attenuated these phenomena compared with bleomycin group. On day 7, the decreased superoxide dismutase and myeloperoxidase activities observed in the bleomycin group were significantly restored with PFPE treatment. On day 21, enhanced hydroxyproline deposition in the bleomycin group was also suppressed by PFPE administration. PFPE treatment significantly attenuated extensive inflammatory cell infiltration and accumulation of collagen in lung tissue sections of bleomycin-induced mice on days 7 and 21, respectively. Our results indicate that administration of PFPE decreased bleomycin-induced PF because of anti-inflammatory and antioxidant activities. PMID:24933624

  12. Chop Deficiency Protects Mice Against Bleomycin-induced Pulmonary Fibrosis by Attenuating M2 Macrophage Production.

    PubMed

    Yao, Yingying; Wang, Yi; Zhang, Zhijun; He, Long; Zhu, Jianghui; Zhang, Meng; He, Xiaoyu; Cheng, Zhenshun; Ao, Qilin; Cao, Yong; Yang, Ping; Su, Yunchao; Zhao, Jianping; Zhang, Shu; Yu, Qilin; Ning, Qin; Xiang, Xudong; Xiong, Weining; Wang, Cong-Yi; Xu, Yongjian

    2016-05-01

    C/EBP homologous protein (Chop) has been shown to have altered expression in patients with idiopathic pulmonary fibrosis (IPF), but its exact role in IPF pathoaetiology has not been fully addressed. Studies conducted in patients with IPF and Chop(-/-) mice have dissected the role of Chop and endoplasmic reticulum (ER) stress in pulmonary fibrosis pathogenesis. The effect of Chop deficiency on macrophage polarization and related signalling pathways were investigated to identify the underlying mechanisms. Patients with IPF and mice with bleomycin (BLM)-induced pulmonary fibrosis were affected by the altered Chop expression and ER stress. In particular, Chop deficiency protected mice against BLM-induced lung injury and fibrosis. Loss of Chop significantly attenuated transforming growth factor β (TGF-β) production and reduced M2 macrophage infiltration in the lung following BLM induction. Mechanistic studies showed that Chop deficiency repressed the M2 program in macrophages, which then attenuated TGF-β secretion. Specifically, loss of Chop promoted the expression of suppressors of cytokine signaling 1 and suppressors of cytokine signaling 3, and through which Chop deficiency repressed signal transducer and activator of transcription 6/peroxisome proliferator-activated receptor gamma signaling, the essential pathway for the M2 program in macrophages. Together, our data support the idea that Chop and ER stress are implicated in IPF pathoaetiology, involving at least the induction and differentiation of M2 macrophages. PMID:26883801

  13. Astilbin alleviates LPS-induced ARDS by suppressing MAPK signaling pathway and protecting pulmonary endothelial glycocalyx.

    PubMed

    Kong, Guiqing; Huang, Xiao; Wang, Lipeng; Li, Yan; Sun, Ting; Han, Shasha; Zhu, Weiwei; Ma, Mingming; Xu, Haixiao; Li, Jiankui; Zhang, Xiaohua; Liu, Xiangyong; Wang, Xiaozhi

    2016-07-01

    Acute respiratory distress syndrome (ARDS) is a devastating disorder that is characterized by increased vascular endothelial permeability and inflammation. Unfortunately, no effective treatment beyond supportive care is available for ARDS. Astilbin, a flavonoid compound isolated from Rhizoma Smilacis Glabrae, has been used for anti-hepatic, anti-arthritic, and anti-renal injury treatments. This study examined the effects of Astilbin on pulmonary inflammatory activation and endothelial cell barrier dysfunction caused by Gram-negative bacterial endotoxin lipopolysaccharide (LPS). Endothelial cells from human umbilical veins or male Kunming mice were pretreated with Astilbin 24h before LPS stimulation. Results showed that Astilbin significantly attenuated the pulmonary histopathological changes and neutrophil infiltration 6h after the LPS challenge. Astilbin suppressed the activities of myeloperoxidase and malondialdehyde, as well as the expression of tumor necrosis factor-α and interleukin-6 in vivo and in vitro. As indices of pulmonary edema, lung wet-to-dry weight ratios, were markedly decreased by Astilbin pretreatment. Western blot analysis also showed that Astilbin inhibited LPS-induced activation of mitogen-activated protein kinase (MAPK) pathways in lung tissues. Furthermore, Astilbin significantly inhibited the activity of heparanase and reduced the production of heparan sulfate in the blood serum as determined by ELISA. These findings indicated that Astilbin can alleviate LPS-induced ARDS, which potentially contributed to the suppression of MAPK pathway activation and the degradation of endothelial glycocalyx. PMID:27111514

  14. Assessment of acute radiation-induced pulmonary changes using computed tomography.

    PubMed

    Mah, K; Poon, P Y; Van Dyk, J; Keane, T; Majesky, I F; Rideout, D F

    1986-01-01

    In a prospective study of acute radiation-induced pulmonary changes, CT scans of 54 patients were performed before and at preselected times during the 6 months following fractionated radiation therapy of the thorax. The CT films were evaluated independently by three diagnostic radiologists and 36 patients were scored as having postirradiation pulmonary findings. The average interobserver agreement for this scoring was approximately 85%. The end point was observed as an increase in lung density within the irradiated volume on a follow-up CT examination. All 36 patients demonstrated lung opacities in an irregular, homogeneous, or nonhomogeneous pattern within the radiation beam boundaries. In addition, the following characteristics were observed at various frequencies in these 36 patients: extension of the changes across anatomic tissue boundaries (50%), air bronchograms (25%), loss of lung volume (15%), and pleural thickening (15%). Confinement of the findings within the irradiated volume was the only specific characteristic of postirradiation changes. In two patients the changes appeared as sharply defined, nodular opacities and were considered to be atypical of radiation damage. These were subsequently confirmed to be metastases. Prospective assessment of an adequate number of patients has helped to establish the CT appearance of acute radiation-induced pulmonary effects and, hence, to minimize its confusion with malignancies and other abnormalities. PMID:3745541

  15. Inhibitory effects of amines from Citrus reticulata on bleomycin-induced pulmonary fibrosis in rats

    PubMed Central

    ZHOU, XIAN-MEI; CAO, ZHEN-DONG; XIAO, NA; SHEN, QI; LI, JIAN-XIN

    2016-01-01

    Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal lung disease for which, thus far, there are no effective treatments. The pericarp of Citrus reticulata, as a traditional herbal drug, has been used for the clinical treatment of lung-related diseases in China for many years. In the present study, the amines from the pericarp of Citrus reticulata were isolated, and their hydrochlorides were prepared. The results of screening using cultured human embryonic lung fibroblasts (hELFs) revealed that, of the amines, 4-methoxyphenethylamine hydrochloride (designated as amine hydrochloride 1) possessed the most potent inhibitory effect. Further in vivo experiments using a rat model of bleomycin-induced pulmonary fibrosis demonstrated that the oral administration of amine hydrochloride 1 significantly lowered the hydroxyproline content in both serum and lung tissue, and alleviated pulmonary alveolitis and fibrosis. Immunohistochemical analysis revealed that amine hydrochloride 1 exerted its inhibitory effect against IPF through the downregulation of lung transforming growth factor (TGF)-β1 protein expression. Our results demonstrated that amine hydrochloride 1 prevented the development of bleomycin-induced lung fibrosis in rats. Thus, our data suggest that the amines from the pericarp of Citrus reticulata have therapeutic potential for use in the treatment of IPF. PMID:26675886

  16. Exercise-induced interstitial pulmonary edema at sea-level in young and old healthy humans

    PubMed Central

    Taylor, Bryan J.; Carlson, Alex R.; Miller, Andrew D.; Johnson, Bruce D.

    2014-01-01

    We asked whether aged adults are more susceptible to exercise-induced pulmonary edema relative to younger individuals. Lung diffusing capacity for carbon monoxide (DLCO), alveolar-capillary membrane conductance (Dm) and pulmonary-capillary blood volume (Vc) were measured before and after exhaustive discontinuous incremental exercise in 10 young (YNG; 27±3 yr) and 10 old (OLD; 69±5 yr) males. In YNG subjects, Dm increased (11±7%, P=0.031), Vc decreased (−10±9%, P=0.01) and DLCO was unchanged (30.5±4.1 vs. 29.7±2.9 ml/min/mmHg, P=0.44) pre- to post-exercise. In OLD subjects, DLCO and Dm increased (11±14%, P=0.042; 16±14%, P=0.025) but Vc was unchanged (58±23 vs. 56±23 ml, P=0.570) pre- to post-exercise. Group-mean Dm/Vc was greater after vs. before exercise in the YNG and OLD subjects. However, Dm/Vc was lower post-exercise in 2 of the 10 YNG (−7±4%) and 2 of the 10 OLD subjects (−10±5%). These data suggest that exercise decreases interstitial lung fluid in most YNG and OLD subjects, with a small number exhibiting evidence for exercise-induced pulmonary edema. PMID:24200644

  17. Intermedin/adrenomedullin-2 is a hypoxia-induced endothelial peptide that stabilizes pulmonary microvascular permeability

    PubMed Central

    Aslam, Muhammad; Paddenberg, Renate; Quanz, Karin; Chang, Chia L.; Park, Jae-Il; Gries, Barbara; Rafiq, Amir; Faulhammer, Petra; Goldenberg, Anna; Papadakis, Tamara; Noll, Thomas; Hsu, Sheau Y. T.; Weissmann, Norbert; Kummer, Wolfgang

    2009-01-01

    Accumulating evidence suggests a pivotal role of the calcitonin receptor-like receptor (CRLR) signaling pathway in preventing damage of the lung by stabilizing pulmonary barrier function. Intermedin (IMD), also termed adrenomedullin-2, is the most recently identified peptide targeting this receptor. Here we investigated the effect of hypoxia on the expression of IMD in the murine lung and cultured murine pulmonary microvascular endothelial cells (PMEC) as well as the role of IMD in regulating vascular permeability. Monoclonal IMD antibodies were generated, and transcript levels were assayed by quantitative RT-PCR. The promoter region of IMD gene was analyzed, and the effect of hypoxia-inducible factor (HIF)-1α on IMD expression was investigated in HEK293T cells. Isolated murine lungs and a human lung microvascular endothelial cell monolayer model were used to study the effect of IMD on vascular permeability. IMD was identified as a pulmonary endothelial peptide by immunohistochemistry and RT-PCR. Hypoxia caused an upregulation of IMD mRNA in the murine lung and PMEC. As shown by these results, HIF-1α enhances IMD promoter activity. Our functional studies showed that IMD abolished the increase in pressure-induced endothelial permeability. Moreover, IMD decreased basal and thrombin-induced hyperpermeability of an endothelial cell monolayer in a receptor-dependent manner and activated PKA in these cells. In conclusion, IMD is a novel hypoxia-induced gene and a potential interventional agent for the improvement of endothelial barrier function in systemic inflammatory responses and hypoxia-induced vascular leakage. PMID:19684198

  18. A Comparative Study of Induced Sputum and Bronchial Washings in Diagnosing Sputum Smear Negative Pulmonary Tuberculosis

    PubMed Central

    Mandava, Venu; Namballa, Usha Rani; Makala, Sravani

    2016-01-01

    Introduction Tuberculosis is one of the most important public health problem worldwide. Detecting patients with active pulmonary Koch’s disease is an important component of tuberculosis control programs. However, at times in patients even with a compatible clinical picture, sputum smears do not reveal acid-fast bacilli and smear-negative pulmonary tuberculosis remains a common problem. Aim The present study is aimed to compare the results of induced sputum and bronchial washings smear in patients suspected to have sputum smear negative pulmonary tuberculosis. Materials and Methods A prospective study conducted from August 2014 to July 2015, comprising 120 patients fulfilling study criteria. Patients with respiratory symptoms and chest roentgenogram suspicious of pulmonary tuberculosis with no previous history of anti-tuberculosis treatment and two spontaneous sputum smear samples negative for acid fast bacilli were included. Patients with active haemoptysis and sputum positive were excluded from the study. Sputum induction was done by using 5-10 ml of 3% hypertonic saline through ultrasonic nebulizer taking safety precautions. All the patient underwent fibreoptic bronchoscopy after six hours fasting on the same day. About 20 ml of normal saline instilled into the suspected pathology area and washings were taken with gentle suction. The sample processing and fluorescent staining for acid fast bacilli was done in a designated microscopy lab. Results Out of 120 sputum smear negative pulmonary tuberculosis patients, induced sputum smear examination detected acid fast bacilli in 76 patients (63.3%) and acid fast bacilli detected from bronchial washings in 94 patients (78.3%). Smear positivity was higher in cavitary and infiltrative lesions as compared to consolidation and infrahilar pattern disease. Conclusion Even though both induced sputum and bronchial washings procedures were valuable for the diagnosis of sputum smear negative, sputum induction with hypertonic

  19. Pulmonary Hypertension

    PubMed Central

    Newman, John H.

    2005-01-01

    The modern era in cardiopulmonary medicine began in the 1940s, when Cournand and Richards pioneered right-heart catheterization. Until that time, no direct measurement of central vascular pressure had been performed in humans. Right-heart catheterization ignited an explosion of insights into function and dysfunction of the pulmonary circulation, cardiac performance, ventilation–perfusion relationships, lung–heart interactions, valvular function, and congenital heart disease. It marked the beginnings of angiocardiography with its diagnostic implications for diseases of the left heart and peripheral circulation. Pulmonary hypertension was discovered to be the consequence of a large variety of diseases that either raised pressure downstream of the pulmonary capillaries, induced vasoconstriction, increased blood flow to the lung, or obstructed the pulmonary vessels, either by embolism or in situ fibrosis. Hypoxic vasoconstriction was found to be a major cause of acute and chronic pulmonary hypertension, and surprising vasoreactivity of the pulmonary vascular bed was discovered to be present in many cases of severe pulmonary hypertension, initially in mitral stenosis. Diseases as disparate as scleroderma, cystic fibrosis, kyphoscoliosis, sleep apnea, and sickle cell disease were found to have shared consequences in the pulmonary circulation. Some of the achievements of Cournand and Richards and their scientific descendents are discussed in this article, including success in the diagnosis and treatment of idiopathic pulmonary arterial hypertension, chronic thromboembolic pulmonary hypertension, and management of hypoxic pulmonary hypertension. PMID:15994464

  20. Exercise-induced pulmonary hemorrhage in a nonathlete: case report and review of physiology.

    PubMed

    Diwakar, Amit; Schmidt, Gregory A

    2014-04-01

    The integrity of the pulmonary blood-gas barrier is vulnerable to intense exercise in elite athletes, similar to the phenomenon of exercise-induced pulmonary hemorrhage in thoroughbred racehorses. A 50-year-old previously healthy man presented with acute onset shortness of breath, dry cough, and hypoxemia after engaging in an extremely vigorous game of handball. CT scan of the chest showed diffuse patchy air-space disease. Bronchoalveolar lavage revealed diffuse alveolar hemorrhage. Infectious etiologies and bleeding diatheses were excluded by laboratory testing. Serological tests for ANCA-associated vasculitis, lupus, and Goodpasture's disease also were negative. A transthoracic echocardiogram was normal. The patient recovered completely on supportive therapy in less than 72 h. This case demonstrates strenuous exercise as a cause of diffuse alveolar hemorrhage in a previously healthy male with no apparent underlying cardiopulmonary disease. PMID:24532148

  1. Pulmonary Aluminosis Diagnosed with In-air Microparticle Induced X-ray Emission Analysis of Particles.

    PubMed

    Chino, Haruka; Hagiwara, Eri; Sugisaki, Midori; Baba, Tomonori; Koga, Yasuhiko; Hisada, Takeshi; Kaira, Kyoichi; Okudela, Koji; Takemura, Tamiko; Dobashi, Kunio; Ogura, Takashi

    2015-01-01

    We herein present a case of pulmonary aluminosis diagnosed with in-air microparticle induced X-ray emission (in-air micro-PIXE) analysis. The diagnosis of pulmonary aluminosis was supported by the occupational exposure to aluminum, ground glass opacity and ill-defined centrilobular nodular opacities seen in high resolution CT, and respiratory bronchioles accompanied by pigmented dust by histological examination by in-air micro-PIXE analysis of the lung tissues. The possibility of developing this rare condition should not be underestimated in workers at high-risk jobs. This is an important report showing the usefulness of an in-air micro-PIXE analysis for the early diagnosis of aluminosis. PMID:26278298

  2. Polyhexamethylene guanidine phosphate aerosol particles induce pulmonary inflammatory and fibrotic responses.

    PubMed

    Kim, Ha Ryong; Lee, Kyuhong; Park, Chang We; Song, Jeong Ah; Shin, Da Young; Park, Yong Joo; Chung, Kyu Hyuck

    2016-03-01

    Polyhexamethylene guanidine (PHMG) phosphate was used as a disinfectant for the prevention of microorganism growth in humidifiers, without recognizing that a change of exposure route might cause significant health effects. Epidemiological studies reported that the use of humidifier disinfectant containing PHMG-phosphate can provoke pulmonary fibrosis. However, the pulmonary toxicity of PHMG-phosphate aerosol particles is unknown yet. This study aimed to elucidate the toxicological relationship between PHMG-phosphate aerosol particles and pulmonary fibrosis. An in vivo nose-only exposure system and an in vitro air-liquid interface (ALI) co-culture model were applied to confirm whether PHMG-phosphate induces inflammatory and fibrotic responses in the respiratory tract. Seven-week-old male Sprague-Dawley rats were exposed to PHMG-phosphate aerosol particles for 3 weeks and recovered for 3 weeks in a nose-only exposure chamber. In addition, three human lung cells (Calu-3, differentiated THP-1 and HMC-1 cells) were cultured at ALI condition for 12 days and were treated with PHMG-phosphate at set concentrations and times. The reactive oxygen species (ROS) generation, airway barrier injuries and inflammatory and fibrotic responses were evaluated in vivo and in vitro. The rats exposed to PHMG-phosphate aerosol particles in nanometer size showed pulmonary inflammation and fibrosis including inflammatory cytokines and fibronectin mRNA increase, as well as histopathological changes. In addition, PHMG-phosphate triggered the ROS generation, airway barrier injuries and inflammatory responses in a bronchial ALI co-culture model. Those results demonstrated that PHMG-phosphate aerosol particles cause pulmonary inflammatory and fibrotic responses. All features of fibrogenesis by PHMG-phosphate aerosol particles closely resembled the pathology of fibrosis that was reported in epidemiological studies. Finally, we expected that PHMG-phosphate infiltrated into the lungs in the form

  3. Concentrated ambient air particles induce vasoconstriction of small pulmonary arteries in rats.

    PubMed Central

    Batalha, Joao R F; Saldiva, Paulo H N; Clarke, Robert W; Coull, Brent A; Stearns, Rebecca C; Lawrence, Joy; Murthy, G G Krishna; Koutrakis, Petros; Godleski, John J

    2002-01-01

    The objective of this study was to determine whether short-term exposures to concentrated ambient particles (CAPs) alter the morphology of small pulmonary arteries in normal rats and rats with chronic bronchitis (CB). Sprague-Dawley male rats were exposed to CAPs, using the Harvard Ambient Particle Concentrator, or to particle-free air (sham) under identical conditions during 3 consecutive days (5 hr/day) in six experimental sets. CB was induced by exposure to 276 +/- 9 ppm of sulfur dioxide (5 hr/day, 5 days/week, 6 weeks). Physicochemical characterization of CAPs included measurements of particle mass, size distribution, and composition. Rats were sacrificed 24 hr after the last CAPs exposure. Histologic slides were prepared from random sections of lung lobes and coded for blinded analysis. The lumen/wall area (L/W) ratio was determined morphometrically on transverse sections of small pulmonary arteries. When all animal data (normal and CB) were analyzed together, the L/W ratios decreased as concentrations of fine particle mass, silicon, lead, sulfate, elemental carbon, and organic carbon increased. In separate univariate analyses of animal data, the association for sulfate was significant only in normal rats, whereas silicon was significantly associated in both CB and normal rats. In multivariate analyses including all particle factors, the association with silicon remained significant. Our results indicate that short-term CAPs exposures (median, 182.75 micro g/m3; range, 73.50-733.00 micro g/m3) can induce vasoconstriction of small pulmonary arteries in normal and CB rats. This effect was correlated with specific particle components and suggests that the pulmonary vasculature might be an important target for ambient air particle toxicity. PMID:12460797

  4. Dihydroartemisinin supresses inflammation and fibrosis in bleomycine-induced pulmonary fibrosis in rats

    PubMed Central

    Yang, Dongxia; Yuan, Wendan; Lv, Changjun; Li, Naie; Liu, Tongshen; Wang, Liang; Sun, Yufei; Qiu, Xueshan; Fu, Qiang

    2015-01-01

    Pulmonary fibrosis is a respiratory disease with a high mortality rate and its pathogenesis involves multiple mechanisms including epithelial cell injury, fibroblast proliferation, inflammation, and collagen coagulation. The treatment regimens still fail to recover this disease. We have previously found that dihydroartemisinin inhibits the development of pulmonary fibrosis in rats. This study aimed to determine the mechanisms of dihydroartemisinin in bleomycin-induced pulmonary fibrosis. The experimental rats were divided into six groups as normal saline control group (NS group), bleomycin group (BLM group), dihydroartemisinin-1, -2, or -3 group (DHA-1, DHA-2 and DHA-3 group) and dexamethasone group (DXM group). In BLM group, rats were treated with intratracheal instillation of bleomycin. NS group received the same volume of saline instead of bleomycin. In DHA-1, DHA-2 and DHA-3 group, in addition to intratracheal instillation of bleomycin, respectively, dihydroartemisinin (25 mg/kg, 50 mg/kg, 100 mg/kg daily) was administrated by intraperitoneal instillation. In DXM group, rats were treated with intraperitoneal instillation of dexamethasone as control. Immunocytochemical assay, reverse transcription PCR and western blot were used for detecting the expression of TGF-β1, TNF-α, α-SMA and NF-κB in lung tissues. What’s more, morphological change and collagen deposition were analyzed by hematoxylin-eosin staining and Masson staining. Collagen synthesis was detected by hydroxyproline chromatometry. Results showed that dihydroartemisinin significantly decreased the amount of inflammatory cytokines and collagen synthesis, and inhibited fibroblast proliferation in bleomycin-induced pulmonary fibrosis (P < 0.001). This study provides experimental evidence that dihydroartemisinin could decrease cytokines, alveolar inflammation and attenuates lung injury and fibrosis. PMID:25973011

  5. Acute radiation-induced pulmonary damage: a clinical study on the response to fractionated radiation therapy.

    PubMed

    Mah, K; Van Dyk, J; Keane, T; Poon, P Y

    1987-02-01

    Acute radiation-induced pulmonary damage can be a significant cause of morbidity in radiation therapy of the thorax. A prospective, clinical study was conducted to obtain dose-response data on acute pulmonary damage caused by fractionated radiation therapy. The endpoint was a visible increase in lung density within the irradiated volume on a computed tomographic (CT) examination as observed independently by three diagnostic radiologists. Fifty-four patients with various malignancies of the thorax completed the study. CT chest scans were taken before and at preselected times following radiotherapy. To represent different fractionation schedules of equivalent biological effect, the estimated single dose (ED) model, ED = D X N-0.377 X T-0.058 was used in which D was the average lung dose within the high dose region in cGy, N was the number of fractions, and T was the overall treatment time in days. Patients were grouped according to ED and the percent incidence of pulmonary damage for each group was determined. Total average lung doses ranged from 29.8 Gy to 53.6 Gy given in 10 to 30 fractions over a range of 12 to 60 days. Five patient groups with incidence ranging from 30% (ED of 930) to 90% (ED of 1150) were obtained. The resulting dose-response curve predicted a 50% incidence level at an ED value (ED50) of 1000 +/- 40 ED units. This value represents fractionation schedules equivalent to a total average lung dose of 32.9 Gy given in 15 fractions over 19 days. Over the linear portion of the dose-response curve, a 5% increase in ED (or total dose if N and T remain constant), predicts a 12% increase in the incidence of acute radiation-induced pulmonary damage. PMID:3818385

  6. Pulmonary hypertension

    MedlinePlus

    Pulmonary arterial hypertension; Sporadic primary pulmonary hypertension; Familial primary pulmonary hypertension; Idiopathic pulmonary arterial hypertension; Primary pulmonary hypertension; PPH; Secondary pulmonary ...

  7. Regulatory T Cells Promote β-Catenin–Mediated Epithelium-to-Mesenchyme Transition During Radiation-Induced Pulmonary Fibrosis

    SciTech Connect

    Xiong, Shanshan; Pan, Xiujie; Xu, Long; Yang, Zhihua; Guo, Renfeng; Gu, Yongqing; Li, Ruoxi; Wang, Qianjun; Xiao, Fengjun; Du, Li; Zhou, Pingkun; Zhu, Maoxiang

    2015-10-01

    Purpose: Radiation-induced pulmonary fibrosis results from thoracic radiation therapy and severely limits radiation therapy approaches. CD4{sup +}CD25{sup +}FoxP3{sup +} regulatory T cells (Tregs) as well as epithelium-to-mesenchyme transition (EMT) cells are involved in pulmonary fibrosis induced by multiple factors. However, the mechanisms of Tregs and EMT cells in irradiation-induced pulmonary fibrosis remain unclear. In the present study, we investigated the influence of Tregs on EMT in radiation-induced pulmonary fibrosis. Methods and Materials: Mice thoraxes were irradiated (20 Gy), and Tregs were depleted by intraperitoneal injection of a monoclonal anti-CD25 antibody 2 hours after irradiation and every 7 days thereafter. Mice were treated on days 3, 7, and 14 and 1, 3, and 6 months post irradiation. The effectiveness of Treg depletion was assayed via flow cytometry. EMT and β-catenin in lung tissues were detected by immunohistochemistry. Tregs isolated from murine spleens were cultured with mouse lung epithelial (MLE) 12 cells, and short interfering RNA (siRNA) knockdown of β-catenin in MLE 12 cells was used to explore the effects of Tregs on EMT and β-catenin via flow cytometry and Western blotting. Results: Anti-CD25 antibody treatment depleted Tregs efficiently, attenuated the process of radiation-induced pulmonary fibrosis, hindered EMT, and reduced β-catenin accumulation in lung epithelial cells in vivo. The coculture of Tregs with irradiated MLE 12 cells showed that Tregs could promote EMT in MLE 12 cells and that the effect of Tregs on EMT was partially abrogated by β-catenin knockdown in vitro. Conclusions: Tregs can promote EMT in accelerating radiation-induced pulmonary fibrosis. This process is partially mediated through β-catenin. Our study suggests a new mechanism for EMT, promoted by Tregs, that accelerates radiation-induced pulmonary fibrosis.

  8. Leflunomide Induces Pulmonary and Hepatic CYP1A Enzymes via Aryl Hydrocarbon Receptor.

    PubMed

    Patel, Ananddeep; Zhang, Shaojie; Paramahamsa, Maturu; Jiang, Weiwu; Wang, Lihua; Moorthy, Bhagavatula; Shivanna, Binoy

    2015-12-01

    Emerging evidence indicates that the aryl hydrocarbon receptor (AhR) plays a crucial role in normal physiologic homeostasis. Additionally, aberrant AhR signaling leads to several pathologic states in the lung and liver. Activation of AhR transcriptionally induces phase I (CYP1A) detoxifying enzymes. Although the effects of the classic AhR ligands such as 3-methylcholanthrene and dioxins on phase 1 enzymes are well studied in rodent lung, liver, and other organs, the toxicity profiles limit their use as therapeutic agents in humans. Hence, there is a need to identify and investigate nontoxic AhR ligands not only to understand the AhR biology but also to develop the AhR as a clinically relevant therapeutic target. Leflunomide is a Food and Drug Administration-approved drug in humans that is known to have AhR agonist activity in vitro. Whether it activates AhR and induces phase 1 enzymes in vivo is unknown. Therefore, we tested the hypothesis that leflunomide will induce pulmonary and hepatic CYP1A enzymes in C57BL/6J wild-type mice, but not in AhR-null mice. We performed real-time reverse-transcription polymerase chain reaction analyses for CYP1A1/2 mRNA expression, western blot assays for CYP1A1/2 protein expression, and ethoxyresorufinO-deethylase assay for CYP1A1 catalytic activity. Leflunomide increased CYP1A1/A2 mRNA, protein, and enzymatic activities in wild-type mice. In contrast, leflunomide failed to increase pulmonary and hepatic CYP1A enzymes in AhR-null mice. In conclusion, we provide evidence that leflunomide induces pulmonary and hepatic CYP1A enzymes via the AhR. PMID:26417045

  9. Stanniocalcin-1 ameliorates lipopolysaccharide-induced pulmonary oxidative stress, inflammation, and apoptosis in mice.

    PubMed

    Tang, Shih-En; Wu, Chin-Pyng; Wu, Shu-Yu; Peng, Chung-Kan; Perng, Wann-Cherng; Kang, Bor-Hwang; Chu, Shi-Jye; Huang, Kun-Lun

    2014-06-01

    Stanniocalcin-1 (STC1) is an endogenous glycoprotein whose anti-inflammatory effects occur through induction of uncoupling proteins to reduce oxidative stress. In this study, we tested the hypothesis that exogenous recombinant human STC1 (rhSTC1) protects against lipopolysaccharide (LPS)-induced acute lung injury in mice. Anesthetized C57BL/6 mice underwent intratracheal spraying of LPS (20 µg/10 g body wt), and lung injury was assessed 24h later by analyzing pulmonary edema, bronchoalveolar lavage fluid, and lung histopathology. Lung inflammation, oxidative stress, and expression of STC1 and its downstream uncoupling protein 2 (UCP2) were analyzed at specific time points. Expression of UCP2 was suppressed initially but was subsequently upregulated after STC1 elevation in response to intratracheal administration of LPS. Intratracheal rhSTC1 treatment 1h before or after LPS spraying significantly attenuated pulmonary inflammation, oxidative stress, cell apoptosis, and acute lung injury. Pretreatment with STC1 short interfering RNA 48 h before LPS spraying inhibited the expression of STC1 and UCP2 and significantly increased the extent of lung injury. These findings suggest that STC1 is an endogenous stress protein that may counteract LPS-induced lung injury by inhibiting the inflammatory cascade and inducing antioxidant and antiapoptotic mechanisms. However, the potential clinical application of STC1 and the direct linkage between UCP2 and LPS-induced lung injury remain to be further investigated. PMID:24685991

  10. The HMGB1-RAGE axis mediates traumatic brain injury-induced pulmonary dysfunction in lung transplantation.

    PubMed

    Weber, Daniel J; Gracon, Adam S A; Ripsch, Matthew S; Fisher, Amanda J; Cheon, Bo M; Pandya, Pankita H; Vittal, Ragini; Capitano, Maegan L; Kim, Youngsong; Allette, Yohance M; Riley, Amanda A; McCarthy, Brian P; Territo, Paul R; Hutchins, Gary D; Broxmeyer, Hal E; Sandusky, George E; White, Fletcher A; Wilkes, David S

    2014-09-01

    Traumatic brain injury (TBI) results in systemic inflammatory responses that affect the lung. This is especially critical in the setting of lung transplantation, where more than half of donor allografts are obtained postmortem from individuals with TBI. The mechanism by which TBI causes pulmonary dysfunction remains unclear but may involve the interaction of high-mobility group box-1 (HMGB1) protein with the receptor for advanced glycation end products (RAGE). To investigate the role of HMGB1 and RAGE in TBI-induced lung dysfunction, RAGE-sufficient (wild-type) or RAGE-deficient (RAGE(-/-)) C57BL/6 mice were subjected to TBI through controlled cortical impact and studied for cardiopulmonary injury. Compared to control animals, TBI induced systemic hypoxia, acute lung injury, pulmonary neutrophilia, and decreased compliance (a measure of the lungs' ability to expand), all of which were attenuated in RAGE(-/-) mice. Neutralizing systemic HMGB1 induced by TBI reversed hypoxia and improved lung compliance. Compared to wild-type donors, lungs from RAGE(-/-) TBI donors did not develop acute lung injury after transplantation. In a study of clinical transplantation, elevated systemic HMGB1 in donors correlated with impaired systemic oxygenation of the donor lung before transplantation and predicted impaired oxygenation after transplantation. These data suggest that the HMGB1-RAGE axis plays a role in the mechanism by which TBI induces lung dysfunction and that targeting this pathway before transplant may improve recipient outcomes after lung transplantation. PMID:25186179

  11. Immune Modulatory Effects of IL-22 on Allergen-Induced Pulmonary Inflammation

    PubMed Central

    Fang, Ping; Zhou, Li; Zhou, Yuqi; Kolls, Jay K.; Zheng, Tao; Zhu, Zhou

    2014-01-01

    IL-22 is a Th17/Th22 cytokine that is increased in asthma. However, recent animal studies showed controversial findings in the effects of IL-22 in allergic asthma. To determine the role of IL-22 in ovalbumin-induced allergic inflammation we generated inducible lung-specific IL-22 transgenic mice. Transgenic IL-22 expression and signaling activity in the lung were determined. Ovalbumin (OVA)-induced pulmonary inflammation, immune responses, and airway hyperresponsiveness (AHR) were examined and compared between IL-22 transgenic mice and wild type controls. Following doxycycline (Dox) induction, IL-22 protein was readily detected in the large (CC10 promoter) and small (SPC promoter) airway epithelial cells. IL-22 signaling was evidenced by phosphorylated STAT3. After OVA sensitization and challenge, compared to wild type littermates, IL-22 transgenic mice showed decreased eosinophils in the bronchoalveolar lavage (BAL), and in lung tissue, decreased mucus metaplasia in the airways, and reduced AHR. Among the cytokines and chemokines examined, IL-13 levels were reduced in the BAL fluid as well as in lymphocytes from local draining lymph nodes of IL-22 transgenic mice. No effect was seen on the levels of serum total or OVA-specific IgE or IgG. These findings indicate that IL-22 has immune modulatory effects on pulmonary inflammatory responses in allergen-induced asthma. PMID:25254361

  12. Electrical and optical properties of thin films of hydrated vanadium pentoxide featuring electrochromic effect

    NASA Astrophysics Data System (ADS)

    Yakovleva, D. S.; Malinenko, V. P.; Pergament, A. L.; Stefanovich, G. B.

    2007-12-01

    Thin films of hydrated vanadium pentoxide (V2O5 · nH2O) exhibit the phenomenon of electrochromism, whereby a film reversibly changes its color under the action of an applied electric field. A specific feature of this phenomenon is that it takes place in a “dry” planar system, in the absence of an electrolyte, which makes this system promising for various applications. We have studied changes in the optical and electrical properties of hydrated vanadium pentoxide films under the conditions of electrochromic coloration.

  13. Etanercept reduces late endotoxin-induced pulmonary hypertension in the pig.

    PubMed

    Mutschler, D; Wikström, G; Lind, L; Larsson, A; Lagrange, A; Eriksson, M

    2006-09-01

    To evaluate whether etanercept, a tumor necrosis factor (TNF)-blocking agent, may counteract hemodynamic deterioration in endotoxemic shock, we designed a prospective, randomized placebo-controlled trial with parallel groups, consisting of 13 pigs aged 10-14 weeks receiving general anesthesia. Five pigs were given 25 mg of etanercept, 1 h before the start of a 4-h continuous infusion of endotoxin. Another 5 pigs were given the corresponding volume of saline, 1 h before the start of a 4-h continuous infusion of endotoxin. Three pigs were given 25 mg of etanercept, 1 hr before the start of a 4-h continuous infusion of saline. At 1 h of endotoxemia, mean pulmonary arterial pressure (MPAP) and pulmonary vascular resistance index (PVRI) increased identically in both groups of pigs receiving endotoxin. Thereafter, two distinct different patterns in hemodynamics were observed. TNF-blocked pigs showed significantly lower MPAP and PVRI compared to controls. In the etanercept-treated endotoxemic pigs, Doppler analysis of the diastolic mitral inflow demonstrated a significantly increased E/A-ratio (early mitral wave inflow was divided by the atrial wave) at 2 h. The TNFblocking agent etanercept normalized two hemodynamic features of endotoxin-induced septic shock in pigs: (1) the sustained pulmonary hypertension and (2) diastolic dysfunction. PMID:16978070

  14. Antifibrotic effects of CXCR4 antagonist in bleomycin-induced pulmonary fibrosis in mice.

    PubMed

    Makino, Hideki; Aono, Yoshinori; Azuma, Momoyo; Kishi, Masami; Yokota, Yuki; Kinoshita, Katsuhiro; Takezaki, Akio; Kishi, Jun; Kawano, Hiroshi; Ogawa, Hirohisa; Uehara, Hisanori; Izumi, Keisuke; Sone, Saburo; Nishioka, Yasuhiko

    2013-01-01

    Circulating fibrocytes had been reported to migrate into the injured lungs, and contribute to fibrogenesis via chemokine-chemokine receptor systems including CXCL12-CXCR4 axis. Here we hypothesized that blockade of CXCR4 might inhibit the migration of fibrocytes to the injured lungs and the subsequent pulmonary fibrosis. To explore the antifibrotic effects of blockade of CXCR4, we used a specific antagonist for CXCR4, AMD3100, in bleomycin-induced pulmonary fibrosis model in mice. Administration of AMD3100 significantly improved the loss of body weight of mice treated with bleomycin, and inhibited the fibrotic lesion in subpleural areas of the lungs. The quantitative analysis demonstrated that treatment with AMD3100 reduced the collagen content and fibrotic score (Aschcroft score) in the lungs. Although AMD3100 did not affect cell classification in bronchoalveolar lavage fluid on day 7, the percentage of lymphocytes was reduced by AMD3100 on day 14. AMD3100 directly inhibited the migration of human fibrocytes in response to CXCL12 in vitro, and reduced the trafficking of fibrocytes into the lungs treated with bleocmycin in vivo. These results suggest that the blockade of CXCR4 might be useful strategy for therapy of patients with pulmonary fibrosis via inhibiting the migration of circulating fibrocytes. PMID:23614921

  15. Calorie Restriction Attenuates Monocrotaline-induced Pulmonary Arterial Hypertension in Rats

    PubMed Central

    Ding, Mingge; Lei, Jingyi; Qu, Yinxian; Zhang, Huan; Xin, Weichuan; Ma, Feng; Liu, Shuwen; Li, Zhichao; Jin, Faguang

    2015-01-01

    Abstract: Calorie restriction (CR) is one of the most effective nonpharmacological interventions protecting against cardiovascular disease, such as hypertension in the systemic circulation. However, whether CR could attenuate pulmonary arterial hypertension (PAH) is largely unknown. The PAH model was developed by subjecting the rats to a single subcutaneous injection of monocrotaline. CR lowered mean pulmonary arterial pressure (mPAP) and reduced vascular remodeling and right ventricular hypertrophy in PAH rats. Meanwhile, CR attenuated endothelial dysfunction as evidenced by increased relaxation in response to acetylcholine. The beneficial effects of CR were associated with restored sirtuin-1 (SIRT1) expression and endothelial nitric oxide synthase (eNOS) phosphorylation and reduced eNOS acetylation in pulmonary arteries of PAH rats. To further clarify the role of SIRT1 in the protective effects of CR, adenoviral vectors for overexpression of SIRT1 were administered intratracheally at 1 day before monocrotaline injection. Overexpression of SIRT1 exhibited similar beneficial effects on mPAP and endothelial function, and increased eNOS phosphorylation and reduced eNOS acetylation in the absence of CR. Moreover, SIRT1 overexpression attenuated the increase in mPAP in hypoxia-induced PAH animals. Overall, the present data demonstrate that CR may serve as an effective treatment of PAH, and targeting the SIRT1/eNOS pathway may improve treatment of PAH. PMID:25636073

  16. ERK5 negatively regulates tobacco smoke-induced pulmonary epithelial–mesenchymal transition

    PubMed Central

    Liang, Zhaofeng; Xie, Wei; Wu, Rui; Geng, Hao; Zhao, Li; Xie, Chunfeng; Li, Xiaoting; Huang, Cong; Zhu, Jianyun; Zhu, Mingming; Zhu, Weiwei; Wu, Jieshu; Geng, Shanshan; Zhong, Caiyun

    2015-01-01

    As the primary cause of lung cancer, tobacco smoke (TS) promotes the initiation and progression of lung tumorigenesis. Epithelial-mesenchymal transition (EMT) is a crucial process involved in cell malignant transformation. The role of ERK5, the lesser studied member of MAPKs family, in regulating TS-triggered pulmonary EMT has not been investigated. Normal human bronchial epithelial cells and BALB/c mice were used as in vitro and in vivo TS exposure models. Exposure of normal human bronchial epithelial cells to TS for 7 days induced morphological change, enhanced migratory and invasive capacities, reduced epithelial marker expression and increased mesenchymal marker expression. Importantly, we demonstrated for the first time that ERK5 negatively regulated TS-mediated lung epithelial EMT, as evidenced by the findings that TS suppressed ERK5 activation, and that TS-triggered EMT was mimicked with ERK5 inhibition and reversed by ERK5 overexpression. The negative regulation of ERK5 on pulmonary EMT was further confirmed in mice exposed to TS for 12 weeks. Taken together, our data suggest that ERK5 negatively regulates TS-mediated pulmonary EMT. These findings provide new insight into the molecular mechanisms of TS-associated lung tumorigenesis and may open up new avenues in the search for potential target of lung cancer intervention. PMID:25965818

  17. Evidence of local exercise-induced systemic oxidative stress in chronic obstructive pulmonary disease patients.

    PubMed

    Couillard, A; Koechlin, C; Cristol, J P; Varray, A; Prefaut, C

    2002-11-01

    Chronic inactivity may not be the sole factor involved in the myopathy of chronic obstructive pulmonary disease (COPD) patients. One hypothesis is that exercise-induced oxidative stress that leads to muscle alterations may also be involved. This study investigated whether exercise localised to a peripheral muscle group would induce oxidative stress in COPD patients. Eleven COPD patients (FEV1 1.15+/-0.4 L (mean+/-SD)) and 12 healthy age-matched subjects with a similar low quantity of physical activity performed endurance exercise localised to a peripheral muscle group, the quadriceps of the dominant leg. The authors measured plasma levels of thiobarbituric reactive substances (TBARs) as an index of oxidative stress, the release in superoxide anion (O2*-) by stimulated phagocytes as an oxidant, and blood vitamin E as one antioxidant. Quadriceps endurance was significantly lower in the COPD patients compared with healthy subjects (136+/-16 s versus 385+/-69 s (mean+/-SEM), respectively). A significant increase in TBARs 6 h after quadriceps exercise was only found in the COPD patients. In addition, significantly higher O2*- release and lower blood vitamin E levels were found in COPD patients than in controls at rest. This blood vitamin E level was significantly correlated with the resting level of plasma TBARs in the COPD patients. This study mainly showed that quadriceps exercise induced systemic oxidative stress in chronic obstructive pulmonary disease patients and that vitamin E levels were decreased in these patients at rest. The exact relevance of these findings to chronic obstructive pulmonary disease myopathy needs to be elucidated. PMID:12449164

  18. Role of inducible nitric oxide synthase-derived nitric oxide in lipopolysaccharide plus interferon-gamma-induced pulmonary inflammation.

    PubMed

    Zeidler, Patti C; Millecchia, Lyndell M; Castranova, Vincent

    2004-02-15

    Exposure of mice to lipopolysaccharide (LPS) plus interferon-gamma (IFN-gamma) increases nitric oxide (NO) production, which is proposed to play a role in the resulting pulmonary damage and inflammation. To determine the role of inducible nitric oxide synthase (iNOS)-induced NO in this lung reaction, the responses of inducible nitric oxide synthase knockout (iNOS KO) versus C57BL/6J wild-type (WT) mice to aspirated LPS + IFN-gamma were compared. Male mice (8-10 weeks) were exposed to LPS (1.2 mg/kg) + IFN-gamma (5000 U/mouse) or saline. At 24 or 72 h postexposure, lungs were lavaged with saline and the acellular fluid from the first bronchoalveolar lavage (BAL) was analyzed for total antioxidant capacity (TAC), lactate dehydrogenase (LDH) activity, albumin, tumor necrosis factor-alpha (TNF-alpha), and macrophage inflammatory protein-2 (MIP-2). The cellular fraction of the total BAL was used to determine alveolar macrophage (AM) and polymorphonuclear leukocyte (PMN) counts, and AM zymosan-stimulated chemiluminescence (AM-CL). Pulmonary responses 24 h postexposure to LPS + IFN-gamma were characterized by significantly decreased TAC, increased BAL AMs and PMNs, LDH, albumin, TNF-alpha, and MIP-2, and enhanced AM-CL to the same extent in both WT and iNOS KO mice. Responses 72 h postexposure were similar; however, significant differences were found between WT and iNOS KO mice. iNOS KO mice demonstrated a greater decline in total antioxidant capacity, greater BAL PMNs, LDH, albumin, TNF-alpha, and MIP-2, and an enhanced AM-CL compared to the WT. These data suggest that the role of iNOS-derived NO in the pulmonary response to LPS + IFN-gamma is anti-inflammatory, and this becomes evident over time. PMID:14962504

  19. Role of Cardiovascular Disease-associated iron overload in Libby amphibole-induced acute pulmonary injury and inflammation

    EPA Science Inventory

    Pulmonary toxicity induced by asbestos is thought to be mediated through redox-cycling of fiber-bound and bioavailable iron (Fe). We hypothesized that Libby amphibole (LA)-induced cute lung injury will be exacerbated in rat models of cardiovascular disease (CVD)-associated Fe-ove...

  20. CHRONIC PULMONARY LPS TOLERANCE INDUCES SELECTIVE IMMUNOSUPPRESSION WHILE MAINTAINING THE NEUTROPHILIC RESPONSE

    PubMed Central

    Natarajan, Sudha; Kim, Jiyoun; Remick, Daniel G.

    2013-01-01

    LPS challenge causes potent activation of innate immunity. Because LPS is ubiquitously present in ambient air, repeated inhalation may lead to activation of the pulmonary immune response. If this activation is unregulated, chronic LPS inhalation would lead to persistent inflammation and organ damage. We hypothesized that the lung uses the mechanism of LPS tolerance to maintain the balance between hypoinflammatory and hyperinflammatory states. We developed a model of chronic pulmonary LPS tolerance induced by pulmonary exposure to 1 μg LPS for 4 consecutive days. Mice were challenged with 10 μg of LPS 24 h later. TNF-α protein was significantly decreased in the bronchoalveolar lavage fluid of tolerant versus nontolerant mice, whereas IL-6 levels were significantly increased in the tolerant group. Tolerant mice were also protected from airway hyperresponsiveness. M2 and M3 muscarinic receptor mRNA was significantly decreased in the lungs of tolerant mice, suggesting a mechanism for the decreased airway hyperresponsiveness. CXCL2 was significantly reduced in tolerant mice, but CXCL1 was equivalent between groups. No difference was seen in neutrophil recruitment to the alveolar space. Interestingly, LPS tolerance does not confer cross-tolerance to the Toll-like receptor (TLR) 2 stimulus Pam3Cys. TNF-α and IL-6 concentrations were significantly increased in LPS-tolerant mice challenged with Pam3Cys; however, chemokine concentrations were unaffected. Our data show that repeated LPS inhalation results in differential regulation of cytokines but does not inhibit neutrophil recruitment. This unrestricted neutrophil recruitment may represent a mechanism by which individuals may be protected from pulmonary bacterial infection and pneumonia. PMID:19487981

  1. Hydroxysafflor Yellow A Attenuates Bleomycin-induced Pulmonary Fibrosis in Mice.

    PubMed

    Jin, Ming; Wu, Yan; Wang, Lin; Zang, Baoxia; Tan, Li

    2016-04-01

    Hydroxysafflor yellow A (HSYA) is an active component of Carthamus tinctorius L., and we want to investigate whether HSYA attenuates pulmonary fibrosis induced by bleomycin (BLM) in mice. The mice received a BLM via oropharyngeal aspiration, and HSYA was intraperitoneally injected. Arterial blood gas analysis was performed. Morphological changes and hydroxyproline content were measured. mRNA expression of transforming growth factor-β1 (TGF-β1), connective tissue growth factor, α-smooth muscle actin (α-SMA), and collagen I was measured by real-time polymerase chain reaction. α-SMA-positive cells in lung tissues were detected by immunohistochemical staining. A549 cell was cultured, and morphological changes were observed after TGF-β1 and HSYA treatment. mRNA expression was detected by real-time polymerase chain reaction. Phosphorylation of Smad3 was evaluated by western blotting. HSYA decreased the lung consolidation area and collagen deposition in mice with pulmonary fibrosis. The blood gas changes due to BLM were attenuated by HSYA. HSYA also alleviated the BLM-induced increase of TGF-β1, connective tissue growth factor, α-SMA, and collagen I mRNA levels. HSYA treatment inhibited the increase of α-SMA expression, Smad3 phosphorylation, the morphological changes in lung tissue. HSYA inhibits Smad3 phosphorylation and elevated expression of collagen I mRNA in epithelial-mesenchymal transition induced by TGF-β1. PMID:26777519

  2. Protective effects of methylsulfonylmethane on hemodynamics and oxidative stress in monocrotaline-induced pulmonary hypertensive rats.

    PubMed

    Mohammadi, Sadollah; Najafi, Moslem; Hamzeiy, Hossein; Maleki-Dizaji, Nasrin; Pezeshkian, Masoud; Sadeghi-Bazargani, Homayon; Darabi, Masoud; Mostafalou, Sara; Bohlooli, Shahab; Garjani, Alireza

    2012-01-01

    Methylsulfonylmethane (MSM) is naturally occurring organic sulfur that is known as a potent antioxidant/anti-inflammatory compound. The aim of this study was to investigate the effect of MSM on hemodynamics functions and oxidative stress in rats with monocrotaline- (MCT-) induced pulmonary arterial hypertension (PAH). Wistar rats were randomly assigned to 38-days treatment. MSM was administered to rats at 100, 200, and 400 mg/kg/day doses 10 days before a single dose of 60 mg/kg, IP, MCT. Hemodynamics of ventricles were determined by Powerlab AD instrument. Blood samples were obtained to evaluate changes in the antioxidative system including activities of catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx), and the level of reduced glutathione (GSH) and malondialdehyde (MDA). Improvements in cardiopulmonary hemodynamics were observed in the MSM-treated pulmonary arterial hypertensive rats, with a significant reduction in right ventricular systolic pressure (RSVP) and an increase in the mean arterial pressure (MAP). The values of CAT, SOD, GSH-px activities, and GSH were significantly lower in MCT-induced PAH (P < 0.01), but they were recovered to control levels of MSM-treated groups. Our present results suggest that long-term administration of the MSM attenuates MCT-induced PAH in rats through modulation of oxidative stress and antioxidant defense. PMID:23118745

  3. Primary breast cancer induces pulmonary vascular hyperpermeability and promotes metastasis via the VEGF-PKC pathway.

    PubMed

    Jiang, Man; Qin, Chengyong; Han, Mingyong

    2016-06-01

    The lung is one of the most frequent target organs for breast cancer metastasis. When breast cancer cells from a primary tumor do not colonize the lung, which we named the premetastatic phase, the microenvironment of the lung has already been influenced by the primary tumor. However, little is known about the exact premetastatic alteration and regulatory mechanisms of the lung. Here, we used 4T1 cells (a mouse breast cancer cell line which can specifically metastasize to the lung) to build a mouse breast cancer model. We found that primary breast tumor induced increased pulmonary vascular permeability in the premetastatic phase, which facilitated the leakage of rhodamine-dextran and the extravasation of intravenous therapy injected cancer cells. Furthermore, tight junctions (TJs) were disrupted, and the expression of zonula occludens-1(ZO-1), one of the most important components of tight junctions, was decreased in the premetastatic lung. In addition, elevated serum vascular endothelial growth factor (VEGF) was involved in the destabilization of tight junctions and the VEGF antagonist bevacizumab reversed the primary tumor-induced vascular hyperpermeability. Moreover, activation of the protein kinase C (PKC) pathway disrupted the integrity of TJs and accordingly, the disruption could be alleviated by blocking VEGF. Taken together, these data demonstrate that primary breast cancer may induce tight junction disruptions in the premetastatic lung via the VEGF-PKC pathway and promote pulmonary vascular hyperpermeability before metastasis. © 2015 Wiley Periodicals, Inc. PMID:26152457

  4. Targeting mitochondrial reactive oxygen species to modulate hypoxia-induced pulmonary hypertension.

    PubMed

    Adesina, Sherry E; Kang, Bum-Yong; Bijli, Kaiser M; Ma, Jing; Cheng, Juan; Murphy, Tamara C; Michael Hart, C; Sutliff, Roy L

    2015-10-01

    Pulmonary hypertension (PH) is characterized by increased pulmonary vascular remodeling, resistance, and pressures. Reactive oxygen species (ROS) contribute to PH-associated vascular dysfunction. NADPH oxidases (Nox) and mitochondria are major sources of superoxide (O(2)(•-)) and hydrogen peroxide (H(2)O(2)) in pulmonary vascular cells. Hypoxia, a common stimulus of PH, increases Nox expression and mitochondrial ROS (mtROS) production. The interactions between these two sources of ROS generation continue to be defined. We hypothesized that mitochondria-derived O(2)(•-) (mtO(2)(•-)) and H(2)O(2) (mtH(2)O(2)) increase Nox expression to promote PH pathogenesis and that mitochondria-targeted antioxidants can reduce mtROS, Nox expression, and hypoxia-induced PH. Exposure of human pulmonary artery endothelial cells to hypoxia for 72 h increased mtO(2)(•-) and mtH(2)O(2). To assess the contribution of mtO(2)(•-) and mtH(2)O(2) to hypoxia-induced PH, mice that overexpress superoxide dismutase 2 (Tg(hSOD2)) or mitochondria-targeted catalase (MCAT) were exposed to normoxia (21% O(2)) or hypoxia (10% O(2)) for three weeks. Compared with hypoxic control mice, MCAT mice developed smaller hypoxia-induced increases in RVSP, α-SMA staining, extracellular H(2)O(2) (Amplex Red), Nox2 and Nox4 (qRT-PCR and Western blot), or cyclinD1 and PCNA (Western blot). In contrast, Tg(hSOD2) mice experienced exacerbated responses to hypoxia. These studies demonstrate that hypoxia increases mtO(2)(•-) and mtH(2)O(2). Targeting mtH(2)O(2) attenuates PH pathogenesis, whereas targeting mtO(2)(•-) exacerbates PH. These differences in PH pathogenesis were mirrored by RVSP, vessel muscularization, levels of Nox2 and Nox4, proliferation, and H(2)O(2) release. These studies suggest that targeted reductions in mtH(2)O(2) generation may be particularly effective in preventing hypoxia-induced PH. PMID:26073127

  5. Diesel exhaust induced pulmonary and cardiovascular impairment: The role of hypertension intervention

    SciTech Connect

    Kodavanti, Urmila P.; Thomas, Ronald F.; Ledbetter, Allen D.; Schladweiler, Mette C.; Bass, Virginia; Krantz, Q. Todd; King, Charly; Nyska, Abraham; Richards, Judy E.; Andrews, Debora; Gilmour, M. Ian

    2013-04-15

    Exposure to diesel exhaust (DE) and associated gases is linked to cardiovascular impairments; however, the susceptibility of hypertensive individuals is poorly understood. The objectives of this study were (1) to determine cardiopulmonary effects of gas-phase versus whole-DE and (2) to examine the contribution of systemic hypertension in pulmonary and cardiovascular effects. Male Wistar Kyoto (WKY) rats were treated with hydralazine to reduce blood pressure (BP) or L-NAME to increase BP. Spontaneously hypertensive (SH) rats were treated with hydralazine to reduce BP. Control and drug-pretreated rats were exposed to air, particle-filtered exhaust (gas), or whole DE (1500 μg/m{sup 3}), 4 h/day for 2 days or 5 days/week for 4 weeks. Acute and 4-week gas and DE exposures increased neutrophils and γ-glutamyl transferase (γ-GT) activity in lavage fluid of WKY and SH rats. DE (4 weeks) caused pulmonary albumin leakage and inflammation in SH rats. Two-day DE increased serum fatty acid binding protein-3 (FABP-3) in WKY. Marked increases occurred in aortic mRNA after 4-week DE in SH (eNOS, TF, tPA, TNF-α, MMP-2, RAGE, and HMGB-1). Hydralazine decreased BP in SH while L-NAME tended to increase BP in WKY; however, neither changed inflammation nor BALF γ-GT. DE-induced and baseline BALF albumin leakage was reduced by hydralazine in SH rats and increased by L-NAME in WKY rats. Hydralazine pretreatment reversed DE-induced TF, tPA, TNF-α, and MMP-2 expression but not eNOS, RAGE, and HMGB-1. ET-1 was decreased by HYD. In conclusion, antihypertensive drug treatment reduces gas and DE-induced pulmonary protein leakage and expression of vascular atherogenic markers. - Highlights: ► Acute diesel exhaust exposure induces pulmonary inflammation in healthy rats. ► In hypertensive rats diesel exhaust effects are seen only after long term exposure. ► Normalizing blood pressure reverses lung protein leakage caused by diesel exhaust. ► Normalizing blood pressure reverses

  6. MCPIP1 mediates silica-induced cell migration in human pulmonary fibroblasts.

    PubMed

    Liu, Haijun; Dai, Xiaoniu; Cheng, Yusi; Fang, Shencun; Zhang, Yingming; Wang, Xingang; Zhang, Wei; Liao, Hong; Yao, Honghong; Chao, Jie

    2016-01-15

    Silicosis is a systemic disease caused by inhaling silicon dioxide (SiO2). Phagocytosis of SiO2 in the lungs initiates an inflammatory cascade that results in fibroblast proliferation and migration followed by fibrosis. According to previous data from our laboratory, monocyte chemotactic protein-1 (MCP-1) plays a critical role in fibroblast proliferation and migration in conventional two-dimensional (2D) monolayer cultures. The present study aimed to explore the downstream cascade of MCP-1 in both 2D and three-dimensional (3D) cell culture models of silicosis. Experiments using primary cultured adult human pulmonary fibroblasts (HPF-a) demonstrated the following: 1) SiO2 treatment induces expression of MCP-1-induced protein (MCPIP1) in a time- and dose-dependent manner in both 2D and 3D cultures; 2) the MAPK and phosphatidylinositol-3-kinase (PI3K)/Akt pathways are involved in SiO2-induced MCPIP1 expression; and 3) MCPIP1 induction mediates the SiO2-induced increase in cell migration in both 2D and 3D cultures. The effect of MCP-1 in silicosis occurs mainly through MCPIP1, which, in turn, mediates the observed SiO2-induced increase in pulmonary fibroblast migration. However, the time frame for MCPIP1 induction differed between 2D and 3D cultures, indicating that, compared with conventional 2D cell culture systems, 3D culture may be useful for analyses of fibroblast physiology under conditions that more closely resemble in vivo environments. Our study determined the link between fibroblast-derived MCPIP1 and SiO2-induced cell migration, and this finding provides novel evidence of the potential of MCPIP1 in the development of novel therapeutic strategies for silicosis. PMID:26608530

  7. Secreted Phosphoprotein 1 and Sex-Specific Differences in Silica-Induced Pulmonary Fibrosis in Mice

    PubMed Central

    Latoche, Joseph D.; Ufelle, Alexander Chukwuma; Fazzi, Fabrizio; Ganguly, Koustav; Leikauf, George D.; Fattman, Cheryl L.

    2016-01-01

    Background: Fibrotic lung diseases occur predominantly in males, and reports describe better survival in affected females. Male mice are more sensitive to silica-induced lung fibrosis than silica-treated female mice. Secreted phosphoprotein 1 (SPP1, also known as osteopontin) increases in pulmonary fibrosis, and Spp1 transcription may be regulated by estrogen or estrogen receptor–related receptors. Objective: We determined whether differences in silica-induced SPP1 levels contribute to sex differences in lung fibrosis. Methods: Male and female mice were treated with 0.2 g/kg intratracheal silica, and lung injury was assessed 1, 3, or 14 days post-exposure. Gene-targeted (Spp1–/–) mice, control Spp1+/+ (C57BL/6J) mice, ovariectomized (OVX) female mice, and estrogen-treated male mice were treated with silica, and lung injury was assessed. Results: Silica-induced SPP1 in lung tissue, bronchoalveolar lavage, and serum increased more in male than in female mice. Following silica treatment, bronchoalveolar lavage cell infiltrates decreased in female Spp1–/– mice compared with female Spp1+/+ mice, and lung hydroxyproline decreased in male Spp1–/– mice compared with male Spp1+/+ mice. OVX female mice had increased lung SPP1 expression in response to silica compared with silica-treated sham female mice. Silica-induced lung collagen and hydroxyproline (markers of fibrosis), and SPP1 levels decreased in estrogen-treated males compared with untreated males. Conclusion: These findings suggest that sex-specific differences in SPP1 levels contribute to the differential sensitivity of male and female mice to the development of silica-induced fibrosis. Citation: Latoche JD, Ufelle AC, Fazzi F, Ganguly K, Leikauf GD, Fattman CL. 2016. Secreted phosphoprotein 1 and sex-specific differences in silica-induced pulmonary fibrosis in mice. Environ Health Perspect 124:1199–1207; http://dx.doi.org/10.1289/ehp.1510335 PMID:26955063

  8. Impact of a CXCL12/CXCR4 Antagonist in Bleomycin (BLM) Induced Pulmonary Fibrosis and Carbon Tetrachloride (CCl4) Induced Hepatic Fibrosis in Mice.

    PubMed

    Chow, Leola N; Schreiner, Petra; Ng, Betina Y Y; Lo, Bernard; Hughes, Michael R; Scott, R Wilder; Gusti, Vionarica; Lecour, Samantha; Simonson, Eric; Manisali, Irina; Barta, Ingrid; McNagny, Kelly M; Crawford, Jason; Webb, Murray; Underhill, T Michael

    2016-01-01

    Modulation of chemokine CXCL12 and its receptor CXCR4 has been implicated in attenuation of bleomycin (BLM)-induced pulmonary fibrosis and carbon tetrachloride (CCl4)-induced hepatic injury. In pulmonary fibrosis, published reports suggest that collagen production in the injured lung is derived from fibrocytes recruited from the circulation in response to release of pulmonary CXCL12. Conversely, in hepatic fibrosis, resident hepatic stellate cells (HSC), the key cell type in progression of fibrosis, upregulate CXCR4 expression in response to activation. Further, CXCL12 induces HSC proliferation and subsequent production of collagen I. In the current study, we evaluated AMD070, an orally bioavailable inhibitor of CXCL12/CXCR4 in alleviating BLM-induced pulmonary and CCl4-induced hepatic fibrosis in mice. Similar to other CXCR4 antagonists, treatment with AMD070 significantly increased leukocyte mobilization. However, in these two models of fibrosis, AMD070 had a negligible impact on extracellular matrix deposition. Interestingly, our results indicated that CXCL12/CXCR4 signaling has a role in improving mortality associated with BLM induced pulmonary injury, likely through dampening an early inflammatory response and/or vascular leakage. Together, these findings indicate that the CXCL12-CXCR4 signaling axis is not an effective target for reducing fibrosis. PMID:26998906

  9. Impact of a CXCL12/CXCR4 Antagonist in Bleomycin (BLM) Induced Pulmonary Fibrosis and Carbon Tetrachloride (CCl4) Induced Hepatic Fibrosis in Mice

    PubMed Central

    Chow, Leola N.; Schreiner, Petra; Ng, Betina Y. Y.; Lo, Bernard; Hughes, Michael R.; Scott, R. Wilder; Gusti, Vionarica; Lecour, Samantha; Simonson, Eric; Manisali, Irina; Barta, Ingrid; McNagny, Kelly M.; Crawford, Jason; Webb, Murray; Underhill, T. Michael

    2016-01-01

    Modulation of chemokine CXCL12 and its receptor CXCR4 has been implicated in attenuation of bleomycin (BLM)-induced pulmonary fibrosis and carbon tetrachloride (CCl4)-induced hepatic injury. In pulmonary fibrosis, published reports suggest that collagen production in the injured lung is derived from fibrocytes recruited from the circulation in response to release of pulmonary CXCL12. Conversely, in hepatic fibrosis, resident hepatic stellate cells (HSC), the key cell type in progression of fibrosis, upregulate CXCR4 expression in response to activation. Further, CXCL12 induces HSC proliferation and subsequent production of collagen I. In the current study, we evaluated AMD070, an orally bioavailable inhibitor of CXCL12/CXCR4 in alleviating BLM-induced pulmonary and CCl4-induced hepatic fibrosis in mice. Similar to other CXCR4 antagonists, treatment with AMD070 significantly increased leukocyte mobilization. However, in these two models of fibrosis, AMD070 had a negligible impact on extracellular matrix deposition. Interestingly, our results indicated that CXCL12/CXCR4 signaling has a role in improving mortality associated with BLM induced pulmonary injury, likely through dampening an early inflammatory response and/or vascular leakage. Together, these findings indicate that the CXCL12-CXCR4 signaling axis is not an effective target for reducing fibrosis. PMID:26998906

  10. Arginase inhibition prevents bleomycin-induced pulmonary hypertension, vascular remodeling, and collagen deposition in neonatal rat lungs.

    PubMed

    Grasemann, Hartmut; Dhaliwal, Rupinder; Ivanovska, Julijana; Kantores, Crystal; McNamara, Patrick J; Scott, Jeremy A; Belik, Jaques; Jankov, Robert P

    2015-03-15

    Arginase is an enzyme that limits substrate L-arginine bioavailability for the production of nitric oxide by the nitric oxide synthases and produces L-ornithine, which is a precursor for collagen formation and tissue remodeling. We studied the pulmonary vascular effects of arginase inhibition in an established model of repeated systemic bleomycin sulfate administration in neonatal rats that results in pulmonary hypertension and lung injury mimicking the characteristics typical of bronchopulmonary dysplasia. We report that arginase expression is increased in the lungs of bleomycin-exposed neonatal rats and that treatment with the arginase inhibitor amino-2-borono-6-hexanoic acid prevented the bleomycin-induced development of pulmonary hypertension and deposition of collagen. Arginase inhibition resulted in increased L-arginine and L-arginine bioavailability and increased pulmonary nitric oxide production. Arginase inhibition also normalized the expression of inducible nitric oxide synthase, and reduced bleomycin-induced nitrative stress while having no effect on bleomycin-induced inflammation. Our data suggest that arginase is a promising target for therapeutic interventions in neonates aimed at preventing lung vascular remodeling and pulmonary hypertension. PMID:25595650

  11. TNF potentiates PAF-induced pulmonary vasoconstriction in the rat: role of neutrophils and thromboxane A2.

    PubMed

    Chang, S W

    1994-12-01

    Both tumor necrosis factor (TNF) and platelet-activating factor (PAF) are released during sepsis and are important mediators of septic lung injury. I investigated the interactions of TNF and PAF on vasoactive responses in the pulmonary circulation. In isolated rat lungs perfused with a cell- and plasma-free physiological salt solution, PAF (0.01- and 0.1-micrograms boluses) caused transient dose-dependent pulmonary arterial and venous constrictions. In vivo pretreatment of the rats with TNF (0.02 or 0.2 mg/kg i.v.) 1 h before lung isolation increased lung myeloperoxidase activity and markedly enhanced PAF-induced pulmonary vasoconstriction without affecting the pressor responses to angiotensin II or hypoxia. In contrast, pretreatment with lipopolysaccharide (10 mg/kg), which increased lung myeloperoxidase to the same extent as TNF, caused only a modest enhancement of PAF-induced vasoconstriction associated with reduced pressor responses to angiotensin II and hypoxia. Ex vivo perfusion of isolated lungs with TNF for 1 h did not affect PAF vasoconstriction. The TNF-induced potentiation of PAF vasoconstriction was not altered by depletion of circulating neutrophils with vinblastine but was blocked by Dazmegrel, a thromboxane synthase inhibitor. Thus, TNF potentiates PAF-induced pulmonary vasoconstriction by an in vivo mechanism that is neutrophil independent but thromboxane dependent. This TNF-PAF interaction likely contributes to the development of pulmonary hypertension during sepsis. PMID:7896627

  12. Effects of lung recruitment maneuvers on splanchnic organ perfusion during endotoxin-induced pulmonary arterial hypertension.

    PubMed

    Daudel, Fritz; Gorrasi, José; Bracht, Hendrik; Brandt, Sebastian; Krejci, Vladimir; Jakob, Stephan M; Takala, Jukka; Rothen, Hans Ulrich

    2010-11-01

    Lung recruitment maneuvers (RMs), used to reopen atelectatic lung units and to improve oxygenation during mechanical ventilation, may result in hemodynamic impairment. We hypothesize that pulmonary arterial hypertension aggravates the consequences of RMs in the splanchnic circulation. Twelve anesthetized pigs underwent laparotomy and prolonged postoperative ventilation. Systemic, regional, and organ blood flows were monitored. After 6 h (= baseline), a recruitment maneuver was performed with sustained inflation of the lungs. Thereafter, the pigs were randomly assigned to group C (control, n = 6) or group E with endotoxin-induced pulmonary arterial hypertension (n = 6). Endotoxemia resulted in a normotensive and hyperdynamic state and a deterioration of the oxygenation index by 33%. The RM was then repeated in both groups. Pulmonary artery pressure increased during lipopolysaccharide infusion from 17 ± 2 mmHg (mean ± SD) to 31 ± 10 mmHg and remained unchanged in controls (P < 0.05). During endotoxemia, RM decreased aortic pulse pressure from 37 ± 14 mmHg to 27 ± 13 mmHg (mean ± SD, P = 0.024). The blood flows of the renal artery, hepatic artery, celiac trunk, superior mesenteric artery, and portal vein decreased to 71% ± 21%, 69% ± 20%, 76% ± 16%, 79% ± 18%, and 81% ± 12%, respectively, of baseline flows before RM (P < 0.05 all). Organ perfusion of kidney cortex, kidney medulla, liver, and jejunal mucosa in group E decreased to 65% ± 19%, 77% ± 13%, 66% ± 26%, and 71% ± 12%, respectively, of baseline flows (P < 0.05 all). The corresponding recovery to at least 90% of baseline regional blood flow and organ perfusion lasted 1 to 5 min. Importantly, the decreases in regional blood flows and organ perfusion and the time to recovery of these flows did not differ from the controls. In conclusion, lipopolysaccharide-induced pulmonary arterial hypertension does not aggravate the RM-induced significant but short-lasting decreases in systemic, regional, and

  13. Pulmonary gas exchange during histamine-induced bronchoconstriction in asthmatic subjects.

    PubMed

    Burke, T V; Küng, M; Burki, N K

    1989-10-01

    Bronchial provocation for testing airway hyperreactivity is now well-established. However, the effects of histamine-induced bronchoconstriction on pulmonary gas exchange in man have not been systematically studied. We empirically noted marked decreases in PaO2 in some asthmatic subjects following induced bronchoconstriction. Nine subjects with mild, stable asthma were studied, each on two separate days. The first determined the dose of inhaled histamine necessary to decrease FEV1 by 20 percent and the relationship to lung volume and to pulmonary resistance by the interrupter technique (Rint). On the second day arterial blood gases, ventilation, Rint, and the anatomic (VDan) and physiologic (VDphys) dead spaces were measured simultaneously. There was a significant (p less than 0.05), profound fall in PaO2 (mean, -21.8 mm Hg) and in P(A-a)O2 (mean +14.7 mm Hg) within 5 min after bronchoconstriction, associated with a significant (p less than 0.05) increase in respiratory frequency (mean +5.1 min-1); and decrease in tidal volume (mean, -0.3 L). The ratio VDphys/VT increased significantly (p less than 0.05; mean change, +0.08) even though VDan and VDphys did not. Bronchoconstriction induced the broadening of ventilation (V)/perfusion (Q) ratios, with, most likely, an increase in areas of high V/Q. Histamine-induced bronchoconstriction in mild asthma results in a marked fall in PaO2 due to induced V/Q inequality. Therefore, histamine airway challenge should be used with caution in patients with any preexisting hypoxemia. PMID:2791669

  14. Pulmonary oxygen toxicity in rats treated with cytochrome P-450 inducers

    SciTech Connect

    Ebel, R.E.; Barlow, R.L.; Gregory, E.M.

    1987-05-01

    Pulmonary oxygen toxicity is assumed to result from damage caused by superoxide (O/sub 2//sup -/) hydrogen peroxide (H/sub 2/O/sub 2/) and/or hydroxyl radical (OH) produced by the partial reduction of molecular oxygen (O/sub 2/). The microsomal cytochrome P-450 (P-450) monooxygenase system is known to produce O/sub 2//sup -/ and H/sub 2/O/sub 2/. They have studied the influence of monooxygenase induction using phenobarbital (PB) and ..beta..-naphthoflavone (..beta..-NF) on O/sub 2/ toxicity in the rat. PB- or ..beta..-NF induce hepatic P-450 but only ..beta..-NF induces pulmonary P-450. Pulmonary microsomes produced O/sub 2//sup -/ and H/sub 2/O/sub 2/ at rates (expressed per mg microsomal protein) which did not vary as a function of pretreatment. Rats were exposed to 100% O/sub 2/ for up to 3 days. After 3 days of O/sub 2/, lung weights were about 50% above controls regardless of pretreatment. The microsomal monooxygenase enzymes (P-450, b/sub 5/ and NADPH P-450 reductase) were quantified in liver and lung. Lung microsomal P-450 was reduced after 3 days of O/sub 2/ exposure regardless of pretreatment. The protective enzymes (catalase, superoxide dismutase (SOD) and glutathione (GSH) peroxidase) and non-protein sulfhydryl groups (NPSH) were also quantified in lung and liver samples. Lung NPSH and GSH peroxidase were increased after 3 days of O/sub 2/ exposure regardless of pretreatment while SOD was increased in controls and PB- but not ..beta..-NF-treated rats. Three of 14 ..beta..-NF-treated rats died during O/sub 2/ exposure while no animals in the control or PB-treated groups died.

  15. Inhaled Diesel Emissions Generated with Cerium Oxide Nanoparticle Fuel Additive Induce Adverse Pulmonary and Systemic Effects

    PubMed Central

    Snow, Samantha J.; McGee, John; Miller, Desinia B.; Bass, Virginia; Schladweiler, Mette C.; Thomas, Ronald F.; Krantz, Todd; King, Charly; Ledbetter, Allen D.; Richards, Judy; Weinstein, Jason P.; Conner, Teri; Willis, Robert; Linak, William P.; Nash, David; Wood, Charles E.; Elmore, Susan A.; Morrison, James P.; Johnson, Crystal L.; Gilmour, Matthew Ian; Kodavanti, Urmila P.

    2014-01-01

    Diesel exhaust (DE) exposure induces adverse cardiopulmonary effects. Cerium oxide nanoparticles added to diesel fuel (DECe) increases fuel burning efficiency but leads to altered emission characteristics and potentially altered health effects. Here, we evaluated whether DECe results in greater adverse pulmonary effects compared with DE. Male Sprague Dawley rats were exposed to filtered air, DE, or DECe for 5 h/day for 2 days. N-acetyl glucosaminidase activity was increased in bronchial alveolar lavage fluid (BALF) of rats exposed to DECe but not DE. There were also marginal but insignificant increases in several other lung injury biomarkers in both exposure groups (DECe > DE for all). To further characterize DECe toxicity, rats in a second study were exposed to filtered air or DECe for 5 h/day for 2 days or 4 weeks. Tissue analysis indicated a concentration- and time-dependent accumulation of lung and liver cerium followed by a delayed clearance. The gas-phase and high concentration of DECe increased lung inflammation at the 2-day time point, indicating that gas-phase components, in addition to particles, contribute to pulmonary toxicity. This effect was reduced at 4 weeks except for a sustained increase in BALF γ-glutamyl transferase activity. Histopathology and transmission electron microscopy revealed increased alveolar septa thickness due to edema and increased numbers of pigmented macrophages after DECe exposure. Collectively, these findings indicate that DECe induces more adverse pulmonary effects on a mass basis than DE. In addition, lung accumulation of cerium, systemic translocation to the liver, and delayed clearance are added concerns to existing health effects of DECe. PMID:25239632

  16. Inhaled diesel emissions generated with cerium oxide nanoparticle fuel additive induce adverse pulmonary and systemic effects.

    PubMed

    Snow, Samantha J; McGee, John; Miller, Desinia B; Bass, Virginia; Schladweiler, Mette C; Thomas, Ronald F; Krantz, Todd; King, Charly; Ledbetter, Allen D; Richards, Judy; Weinstein, Jason P; Conner, Teri; Willis, Robert; Linak, William P; Nash, David; Wood, Charles E; Elmore, Susan A; Morrison, James P; Johnson, Crystal L; Gilmour, Matthew Ian; Kodavanti, Urmila P

    2014-12-01

    Diesel exhaust (DE) exposure induces adverse cardiopulmonary effects. Cerium oxide nanoparticles added to diesel fuel (DECe) increases fuel burning efficiency but leads to altered emission characteristics and potentially altered health effects. Here, we evaluated whether DECe results in greater adverse pulmonary effects compared with DE. Male Sprague Dawley rats were exposed to filtered air, DE, or DECe for 5 h/day for 2 days. N-acetyl glucosaminidase activity was increased in bronchial alveolar lavage fluid (BALF) of rats exposed to DECe but not DE. There were also marginal but insignificant increases in several other lung injury biomarkers in both exposure groups (DECe > DE for all). To further characterize DECe toxicity, rats in a second study were exposed to filtered air or DECe for 5 h/day for 2 days or 4 weeks. Tissue analysis indicated a concentration- and time-dependent accumulation of lung and liver cerium followed by a delayed clearance. The gas-phase and high concentration of DECe increased lung inflammation at the 2-day time point, indicating that gas-phase components, in addition to particles, contribute to pulmonary toxicity. This effect was reduced at 4 weeks except for a sustained increase in BALF γ-glutamyl transferase activity. Histopathology and transmission electron microscopy revealed increased alveolar septa thickness due to edema and increased numbers of pigmented macrophages after DECe exposure. Collectively, these findings indicate that DECe induces more adverse pulmonary effects on a mass basis than DE. In addition, lung accumulation of cerium, systemic translocation to the liver, and delayed clearance are added concerns to existing health effects of DECe. PMID:25239632

  17. Hypoxic preconditioning with cobalt ameliorates hypobaric hypoxia induced pulmonary edema in rat.

    PubMed

    Shukla, Dhananjay; Saxena, Saurabh; Purushothaman, Jayamurthy; Shrivastava, Kalpana; Singh, Mrinalini; Shukla, Shirish; Malhotra, Vineet Kumar; Mustoori, Sairam; Bansal, Anju

    2011-04-10

    Exposure to high altitude results in hypobaric hypoxia which is considered as an acute physiological stress and often leads to high altitude maladies such as high altitude pulmonary edema (HAPE) and high altitude cerebral edema (HACE). The best way to prevent high altitude injuries is hypoxic preconditioning which has potential clinical usefulness and can be mimicked by cobalt chloride. Preconditioning with cobalt has been reported to provide protection in various tissues against ischemic injury. However, the effect of preconditioning with cobalt against high altitude induced pulmonary edema has not been investigated in vivo. Therefore, in the present study, rats pretreated with saline or cobalt (12.5mg/kg body weight) for 7days were exposed to hypobaric hypoxia of 9142m for 5h at 24°C. Formation of pulmonary edema was assessed by measuring transvascular leakage of sodium fluorescein dye and lung water content. Total protein content, albumin content, vascular endothelial growth factor (VEGF) and cytokine levels were measured in bronchoalveolar lavage fluid. Expression of HO-1, MT, NF-κB DNA binding activity and lung tissue pathology were evaluated to determine the effect of preconditioning on HAPE. Hypobaric hypoxia induced increase in transvascular leakage of sodium fluorescein dye, lung water content, lavage total protein, albumin, VEGF levels, pro-inflammatory cytokine levels, tissue expression of cell adhesion molecules and NF-κB DNA binding activity were reduced significantly after hypoxic preconditioning with cobalt. Expression of anti-inflammatory protein HO-1, MT, TGF-β and IL-6 were increased after hypoxic preconditioning. These data suggest that hypoxic preconditioning with cobalt has protective effect against HAPE. PMID:21296072

  18. The Endothelial Prolyl-4-Hydroxylase Domain 2/Hypoxia-Inducible Factor 2 Axis Regulates Pulmonary Artery Pressure in Mice.

    PubMed

    Kapitsinou, Pinelopi P; Rajendran, Ganeshkumar; Astleford, Lindsay; Michael, Mark; Schonfeld, Michael P; Fields, Timothy; Shay, Sheila; French, Jaketa L; West, James; Haase, Volker H

    2016-05-15

    Hypoxia-inducible factors 1 and 2 (HIF-1 and -2) control oxygen supply to tissues by regulating erythropoiesis, angiogenesis and vascular homeostasis. HIFs are regulated in response to oxygen availability by prolyl-4-hydroxylase domain (PHD) proteins, with PHD2 being the main oxygen sensor that controls HIF activity under normoxia. In this study, we used a genetic approach to investigate the endothelial PHD2/HIF axis in the regulation of vascular function. We found that inactivation of Phd2 in endothelial cells specifically resulted in severe pulmonary hypertension (∼118% increase in right ventricular systolic pressure) but not polycythemia and was associated with abnormal muscularization of peripheral pulmonary arteries and right ventricular hypertrophy. Concurrent inactivation of either Hif1a or Hif2a in endothelial cell-specific Phd2 mutants demonstrated that the development of pulmonary hypertension was dependent on HIF-2α but not HIF-1α. Furthermore, endothelial HIF-2α was required for the development of increased pulmonary artery pressures in a model of pulmonary hypertension induced by chronic hypoxia. We propose that these HIF-2-dependent effects are partially due to increased expression of vasoconstrictor molecule endothelin 1 and a concomitant decrease in vasodilatory apelin receptor signaling. Taken together, our data identify endothelial HIF-2 as a key transcription factor in the pathogenesis of pulmonary hypertension. PMID:26976644

  19. Electrons and phonons in layered and monolayer vanadium pentoxide

    NASA Astrophysics Data System (ADS)

    Lambrecht, Walter R. L.

    Vanadium pentoxide (V2O5) is a layered material with the potential for interesting new properties when made in 2D mono- or few-layer form. Its band structure is characterized by a split-off conduction band. The lowest conduction band is separated from the rest of the conduction bands by about 1 eV and consists of V-dxy orbitals, non-bonding to the oxygens by symmetry. This narrow band has dispersion essentially along the direction of chains occurring in the layer. When this band becomes half-filled by doping, spin-splitting occurs accompanied by an antiferromagnetic coupling between nearest neighbors along the chain direction. This situation is well known to occur in the so-called ladder compound NaV2O5 , which was extensively studied in the late 90s as a potential spin-Peierls or charge ordering compound. However, the monolayer form of V2O5 may allow for other ways to control the doping by gating, removing vanadyl oxygens, adsorption of alkali metals, nanoribbon formation, etc. Our calculations predict a switch from antiferromagnetic to ferromagnetic coupling for doping slightly less than half filling of the split-off band. In this talk we will discuss our recent work on the electronic band structure of both bulk and monolayer V2O5 as well as the phonons. We find that the quasi-particle self-consistent GW method strongly overestimates the band gap. Lattice polarization corrections of the screening are required because of the large LO/TO phonon frequency ratios. Excitonic effects may also be expected to be fairly large. We find that some of the vibrational modes, notably the vanadyl-oxygen bond stretch perpendicular to the layer, unexpectedly shows a strong blue shift. This is explained in terms of reduced screening affecting the long-range dipole components of the force constants. Supported by AFOSR and DOE. Work done with Churna Bhandari, Mark van Schilfgaarde and Andre Schleiffe.

  20. IL‑33/ST2 pathway in a bleomycin‑induced pulmonary fibrosis model.

    PubMed

    Xu, Jiao; Zheng, Jinxu; Song, Ping; Zhou, Yanjuan; Guan, Shuhong

    2016-08-01

    The present study aimed to investigate the interleukin (IL)‑33/ST2 pathway in a model of acute pulmonary fibrosis, and to examine the pathogenesis of pulmonary fibrosis. The pulmonary fibrosis model was established by a single exposure to bleomycin (BLM group) endotracheally to represent idiopathic pulmonary fibrosis, and a control (Cont) group was treated with the same volume of saline. The degrees of acute injury, inflammation and fibrosis were detected using hematoxylin and eosin and Masson's staining. The IL‑33, ST2, myeloid differentiation primary response 88 (MyD88) and tumor necrosis factor receptor‑associated factor 6 (TRAF6) proteins were detected using Western blotting. The serum levels of IL‑4 and IL‑13 were detected using an enzyme‑linked immunosorbent assay. The results indicated that, compared with the Cont group, there were significant differences in the alveolitis scores in the BLM group on days 3, 7, 14 and 28 (P<0.01). The grades of fibrosis were also significantly different on days 7, 14 and 28 (P<0.01). On examining the dynamic protein expression levels of IL‑33, ST2, MyD88 and TRAF6, the expression of IL‑33 in the BLM group increased initially, and then decreased gradually following a peak on day 7. The significant differences between the BLM and Cont groups were observed on days 3 and 7 (P<0.05). Compared with the Cont group, the protein levels of ST2, MyD88 and TRAF6 in the BLM group exhibited an increasing trend from day 3, with significant differences, compared with the Cont group, on days 3, 7, 14 and 28 (P<0.05). On examination of the serum levels of IL‑4 and IL‑13 in each group, the levels of IL‑4 and IL‑13 in BLM group remained higher from day 7, with peaks on day 28, and were significantly different, compared with the Cont group, on days 7, 14 and 28 (P<0.05). In conclusion, the IL‑33/ST2 signaling pathway was found to be involved in the rodent model of pulmonary fibrosis induced by bleomycin

  1. 77 FR 5797 - Draft Toxicological Review of Vanadium Pentoxide: In Support of Summary Information on the...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-02-06

    ... vanadium pentoxide assessment in Federal Register Notices published September 30, 2011, (76 FR 60827) and November 9, 2011 (76 FR 69736). DATES: The peer review panel meeting on the draft assessment for Vanadium... Pennsylvania Avenue NW., Washington, DC 20460; telephone: (703) 347-8561; facsimile: (703) 347- 8691). If...

  2. Storage of potassium ions in layered vanadium pentoxide nanofiber electrodes for aqueous pseudocapacitors.

    PubMed

    Yeager, Matthew P; Du, Wenxin; Bishop, Brendan; Sullivan, Matthew; Xu, Wenqian; Su, Dong; Senanayake, Sanjaya D; Hanson, Jonathan; Teng, Xiaowei

    2013-12-01

    Spaced out: This paper investigates potassium-ion storage in vanadium pentoxide nanofibers (VNFs, K0.33 V2 O5 ) with a layered architecture. In situ XRD experiments reveal that the interplanar space of VNF expands/contracts upon extraction/insertion of potassium ions during the redox process. PMID:24124048

  3. Activated Wnt signaling induces myofibroblast differentiation of mesenchymal stem cells, contributing to pulmonary fibrosis.

    PubMed

    Sun, Zhaorui; Wang, Cong; Shi, Chaowen; Sun, Fangfang; Xu, Xiaomeng; Qian, Weiping; Nie, Shinan; Han, Xiaodong

    2014-05-01

    Acute lung injury may lead to fibrogenesis. However, no treatment is currently available. This study was conducted to determine the effects of bone marrow-derived mesenchymal stem cells (MSCs) in a model of HCl-induced acute lung injury in Sprague-Dawley (SD) rats. Stromal cell-derived factor (SDF)-1 and its receptor CXC chemokine receptor (CXCR)4 have been shown to participate in mobilizing MSCs. Adenovirus carrying the CXCR4 gene was used to transfect MSCs in order to increase the engraftment numbers of MSCs at injured sites. Histological examination data demonstrated that the engraftment of MSCs did not attenuate lung injury and pulmonary fibrosis. The results showed that engraftment of MSCs almost differentiated into myofibroblasts, but rarely differentiated into lung epithelial cells. Additionally, it was demonstrated that activated canonical Wnt/β-catenin signaling in injured lung tissue regulated the myofibroblast differentiation of MSCs in vivo. The in vitro study results demonstrated that activation of the Wnt/β-catenin signaling stimulated MSCs to express myofibroblast markers; however, this process was attenuated by Wnt antagonist DKK1. Therefore, the results demonstrated that the aberrant activation of Wnt signaling induces the myofibroblast differentiation of engrafted MSCs, thus contributing to pulmonary fibrosis following lung injury. PMID:24573542

  4. Omeprazole Attenuates Pulmonary Aryl Hydrocarbon Receptor Activation and Potentiates Hyperoxia-Induced Developmental Lung Injury in Newborn Mice.

    PubMed

    Shivanna, Binoy; Zhang, Shaojie; Patel, Ananddeep; Jiang, Weiwu; Wang, Lihua; Welty, Stephen E; Moorthy, Bhagavatula

    2015-11-01

    Hyperoxia contributes to the development of bronchopulmonary dysplasia (BPD) in human preterm infants and a similar lung phenotype characterized by alveolar simplification in newborn mice. Omeprazole (OM) is a proton pump inhibitor that is used to treat humans with gastric acid related disorders. OM-mediated aryl hydrocarbon receptor (AhR) activation attenuates acute hyperoxic lung injury (HLI) in adult mice. Whether OM activates pulmonary AhR and protects C57BL/6J newborn mice against hyperoxia-induced developmental lung (alveolar and pulmonary vascular simplification, inflammation, and oxidative stress) injury (HDLI) is unknown. Therefore, we tested the hypothesis that OM will activate pulmonary AhR and mitigate HDLI in newborn mice. Newborn mice were treated daily with i.p. injections of OM at doses of 10 (OM10) or 25 (OM25) mg/kg while being exposed to air or hyperoxia (FiO2 of 85%) for 14 days, following which their lungs were harvested to determine alveolarization, pulmonary vascularization, inflammation, oxidative stress, vascular injury, and AhR activation. To our surprise, hyperoxia-induced alveolar and pulmonary vascular simplification, inflammation, oxidative stress, and vascular injury were augmented in OM25-treated animals. These findings were associated with attenuated pulmonary vascular endothelial growth factor receptor 2 expression and decreased pulmonary AhR activation in the OM25 group. We conclude that contrary to our hypothesis, OM decreases functional activation of pulmonary AhR and potentiates HDLI in newborn mice. These observations are consistent with our previous findings, which suggest that AhR activation plays a protective role in HDLI in newborn mice. PMID:26272953

  5. Blocking follistatin-like 1 attenuates bleomycin-induced pulmonary fibrosis in mice.

    PubMed

    Dong, Yingying; Geng, Yan; Li, Lian; Li, Xiaohe; Yan, Xiaohua; Fang, Yinshan; Li, Xinxin; Dong, Siyuan; Liu, Xue; Li, Xue; Yang, Xiuhong; Zheng, Xiaohong; Xie, Ting; Liang, Jiurong; Dai, Huaping; Liu, Xinqi; Yin, Zhinan; Noble, Paul W; Jiang, Dianhua; Ning, Wen

    2015-02-01

    Progressive tissue fibrosis is a cause of major morbidity and mortality. Pulmonary fibrosis is an epithelial-mesenchymal disorder in which TGF-β1 plays a central role in pathogenesis. Here we show that follistatin-like 1 (FSTL1) differentially regulates TGF-β and bone morphogenetic protein signaling, leading to epithelial injury and fibroblast activation. Haplodeletion of Fstl1 in mice or blockage of FSTL1 with a neutralizing antibody in mice reduced bleomycin-induced fibrosis in vivo. Fstl1 is induced in response to lung injury and promotes the accumulation of myofibroblasts and subsequent fibrosis. These data suggest that Fstl1 may serve as a novel therapeutic target for treatment of progressive lung fibrosis. PMID:25584011

  6. Blocking follistatin-like 1 attenuates bleomycin-induced pulmonary fibrosis in mice

    PubMed Central

    Dong, Yingying; Geng, Yan; Li, Lian; Li, Xiaohe; Yan, Xiaohua; Fang, Yinshan; Li, Xinxin; Dong, Siyuan; Liu, Xue; Li, Xue; Yang, Xiuhong; Zheng, Xiaohong; Xie, Ting; Liang, Jiurong; Dai, Huaping; Liu, Xinqi; Yin, Zhinan; Noble, Paul W.

    2015-01-01

    Progressive tissue fibrosis is a cause of major morbidity and mortality. Pulmonary fibrosis is an epithelial-mesenchymal disorder in which TGF-β1 plays a central role in pathogenesis. Here we show that follistatin-like 1 (FSTL1) differentially regulates TGF-β and bone morphogenetic protein signaling, leading to epithelial injury and fibroblast activation. Haplodeletion of Fstl1 in mice or blockage of FSTL1 with a neutralizing antibody in mice reduced bleomycin-induced fibrosis in vivo. Fstl1 is induced in response to lung injury and promotes the accumulation of myofibroblasts and subsequent fibrosis. These data suggest that Fstl1 may serve as a novel therapeutic target for treatment of progressive lung fibrosis. PMID:25584011

  7. Thromboxane-induced actin polymerization in hypoxic neonatal pulmonary arterial myocytes involves Cdc42 signaling.

    PubMed

    Fediuk, Jena; Sikarwar, Anurag S; Nolette, Nora; Dakshinamurti, Shyamala

    2014-12-01

    In hypoxic pulmonary arterial (PA) myocytes, challenge with thromboxane mimetic U46619 induces marked actin polymerization and contraction, phenotypic features of persistent pulmonary hypertension of the newborn (PPHN). Rho GTPases regulate the actin cytoskeleton. We previously reported that U46619-induced actin polymerization in hypoxic PA myocytes occurs independently of the RhoA pathway and hypothesized involvement of the Cdc42 pathway. PA myocytes grown in normoxia or hypoxia for 72 h were stimulated with U46619, then analyzed for Rac/Cdc42 activation by affinity precipitation, phosphatidylinositide-3-kinase (PI3K) activity by phospho-Akt, phospho-p21-activated kinase (PAK) by immunoblot, and association of Cdc42 with neuronal Wiskott Aldrich Syndrome protein (N-WASp) by immunoprecipitation. The effect of Rac or PAK inhibition on filamentous actin was quantified by laser-scanning cytometry and by cytoskeletal fractionation; effects of actin-modifying agents were measured by isometric myography. Basal Cdc42 activity increased in hypoxia, whereas Rac activity decreased. U46619 challenge increased Cdc42 and Rac activity in hypoxic cells, independently of PI3K. Hypoxia increased phospho-PAK, unaltered by U46619. Association of Cdc42 with N-WASp decreased in hypoxia but increased after U46619 exposure. Hypoxia doubled filamentous-to-globular ratios of α- and γ-actin isoforms. Jasplakinolide stabilized γ-filaments, increasing force; cytochalasin D depolymerized all actin isoforms, decreasing force. Rac and PAK inhibition decreased filamentous actin in tissues although without decrease in force. Rho inhibition decreased myosin phosphorylation and force. Hypoxia induces actin polymerization in PA myocytes, particularly increasing filamentous α- and γ-actin, contributing to U46619-induced contraction. Hypoxic PA myocytes challenged with a thromboxane mimetic polymerize actin via the Cdc42 pathway, reflecting increased Cdc42 association with N-WASp. Mechanisms

  8. Agonist of growth hormone-releasing hormone reduces pneumolysin-induced pulmonary permeability edema

    PubMed Central

    Lucas, Rudolf; Sridhar, Supriya; Rick, Ferenc G.; Gorshkov, Boris; Umapathy, Nagavedi S.; Yang, Guang; Oseghale, Aluya; Verin, Alexander D.; Chakraborty, Trinad; Matthay, Michael A.; Zemskov, Evgeny A.; White, Richard; Block, Norman L.; Schally, Andrew V.

    2012-01-01

    Aggressive treatment with antibiotics in patients infected with Streptococcus pneumoniae induces release of the bacterial virulence factor pneumolysin (PLY). Days after lungs are sterile, this pore-forming toxin can still induce pulmonary permeability edema in patients, characterized by alveolar/capillary barrier dysfunction and impaired alveolar liquid clearance (ALC). ALC is mainly regulated through Na+ transport by the apically expressed epithelial sodium channel (ENaC) and the basolaterally expressed Na+/K+-ATPase in type II alveolar epithelial cells. Because no standard treatment is currently available to treat permeability edema, the search for novel therapeutic candidates is of high priority. We detected mRNA expression for the active receptor splice variant SV1 of the hypothalamic polypeptide growth hormone-releasing hormone (GHRH), as well as for GHRH itself, in human lung microvascular endothelial cells (HL-MVEC). Therefore, we have evaluated the effect of the GHRH agonist JI-34 on PLY-induced barrier and ALC dysfunction. JI-34 blunts PLY-mediated endothelial hyperpermeability in monolayers of HL-MVEC, in a cAMP-dependent manner, by means of reducing the phosphorylation of myosin light chain and vascular endothelial (VE)-cadherin. In human airway epithelial H441 cells, PLY significantly impairs Na+ uptake, but JI-34 restores it to basal levels by means of increasing cAMP levels. Intratracheal instillation of PLY into C57BL6 mice causes pulmonary alveolar epithelial and endothelial hyperpermeability as well as edema formation, all of which are blunted by JI-34. These findings point toward a protective role of the GHRH signaling pathway in PLY-induced permeability edema. PMID:22308467

  9. Phospholipase D signaling in serotonin-induced mitogenesis of pulmonary artery smooth muscle cells.

    PubMed

    Liu, Y; Fanburg, B L

    2008-09-01

    We have previously reported the participation of mitogen-activated protein, Rho, and phosphoinositide-3 (PI3) kinases in separate pathways in serotonin (5-HT)-induced proliferation of pulmonary artery smooth muscle cells (SMCs). In this study, we investigated the possible participation of phospholipase D (PLD) and phosphatidic acid (PA) in this growth process. 5-HT stimulated a time-dependent increase in [(3)H]phosphatidylbutanol and PA generation. Exposure of SMCs to 1-butanol or overexpression of an inactive mutant of human PLD1R898R blocked 5-HT-induced proliferation. Furthermore, 1-butanol inhibited 5-HT activation of S6K1 and S6 protein, downstream effectors of mammalian target of rapamycin (mTOR), by 80 and 72%, respectively, and partially blocked activation of extracellular signal-regulated kinase (ERK) by 30% but had no effect on other associated signaling pathways. Exogenous PA caused cellular proliferation and revitalized cyclin D1 expression by 5-HT of the 1-butanol-treated cells. PA also reproduced activations by 5-HT of mTOR, S6K1, and ERK. Transfection with inactive human PLD1 reduced 5-HT-induced activation of S6K1 by approximately 50%. Inhibition of 5-HT receptor 2A (R 2A) with ketaserin blocked PLD activation by 5-HT. Inhibition with PI3-kinase inhibitor failed to block either activation of PLD by 5-HT or PA-dependent S6K1 phosphorylation. Taken together, these results indicate that ligation of the 5-HTR 2A by 5-HT initiates PLD activation in SMCs, and that its product, PA, is an early signaling molecule in 5-HT-induced pulmonary artery SMC proliferation. Signaling by PA produces its downstream effects primarily through the mTOR/S6K1 pathway and to a lesser extent through the ERK pathway. Hydrolysis of cell membrane lipid may be important in vascular effects of 5-HT. PMID:18621911

  10. Interactive effects of cerium oxide and diesel exhaust nanoparticles on inducing pulmonary fibrosis

    PubMed Central

    Ma, Jane Y.C.; Young, Shih-Houng; Mercer, Robert R.; Barger, Mark; Schwegler-Berry, Diane; Ma, Joseph K.; Castranova, Vincent

    2015-01-01

    Cerium compounds have been used as a fuel-borne catalyst to lower the generation of diesel exhaust particles (DEPs), but are emitted as cerium oxide nanoparticles (CeO2) along with DEP in the diesel exhaust. The present study investigates the effects of the combined exposure to DEP and CeO2 on the pulmonary system in a rat model. Specific pathogen-free male Sprague–Dawley rats were exposed to CeO2 and/or DEP via a single intratracheal instillation and were sacrificed at various time points post-exposure. This investigation demonstrated that CeO2 induces a sustained inflammatory response, whereas DEP elicits a switch of the pulmonary immune response from Th1 to Th2. Both CeO2 and DEP activated AM and lymphocyte secretion of the proinflammatory cytokines IL-12 and IFN-γ respectively. However, only DEP enhanced the anti-inflammatory cytokine IL-10 production in response to ex vivo LPS or Concanavalin A challenge that was not affected by the presence of CeO2, suggesting that DEP suppresses host defense capability by inducing the Th2 immunity. The micrographs of lymph nodes show that the particle clumps in DEP + CeO2 were significantly larger than CeO2 or DEP, exhibiting dense clumps continuous throughout the lymph nodes. Morphometric analysis demonstrates that the localization of collagen in the lung tissue after DEP + CeO2 reflects the combination of DEP-exposure plus CeO2-exposure. At 4 weeks post-exposure, the histological features demonstrated that CeO2 induced lung phospholipidosis and fibrosis. DEP induced lung granulomas that were not significantly affected by the presence of CeO2 in the combined exposure. Using CeO2 as diesel fuel catalyst may cause health concerns. PMID:24793434

  11. Common and distinct mechanisms of induced pulmonary fibrosis by particulate and soluble chemical fibrogenic agents

    PubMed Central

    Dong, Jie; Yu, Xiaoqing; Porter, Dale W.; Battelli, Lori A.; Kashon, Michael L.

    2016-01-01

    Pulmonary fibrosis results from the excessive deposition of collagen fibers and scarring in the lungs with or without an identifiable cause. The mechanism(s) underlying lung fibrosis development is poorly understood, and effective treatment is lacking. Here we compared mouse lung fibrosis induced by pulmonary exposure to prototypical particulate (crystalline silica) or soluble chemical (bleomycin or paraquat) fibrogenic agents to identify the underlying mechanisms. Young male C57BL/6J mice were given silica (2 mg), bleomycin (0.07 mg), or paraquat (0.02 mg) by pharyngeal aspiration. All treatments induced significant inflammatory infiltration and collagen deposition, manifesting fibrotic foci in silica-exposed lungs or diffuse fibrosis in bleomycin or paraquat-exposed lungs on day 7 post-exposure, at which time the lesions reached their peaks and represented a junction of transition from an acute response to chronic fibrosis. Lung genomewide gene expression was analyzed, and differential gene expression was confirmed by quantitative RT-PCR, immunohistochemistry, and immunoblotting for representative genes to demonstrate their induced expression and localization in fibrotic lungs. Canonical signaling pathways, gene ontology, and upstream transcription networks modified by each agent were identified. In particular, these inducers elicited marked proliferative responses; at the same time, silica preferentially activated innate immune functions and the defense against foreign bodies, whereas bleomycin and paraquat boosted responses related to cell adhesion, platelet activation, extracellular matrix remodeling, and wound healing. This study identified, for the first time, the shared and unique genes, signaling pathways, and biological functions regulated by particulate and soluble chemical fibrogenic agents during lung fibrosis, providing insights into the mechanisms underlying human lung fibrotic diseases. PMID:26345256

  12. Common and distinct mechanisms of induced pulmonary fibrosis by particulate and soluble chemical fibrogenic agents.

    PubMed

    Dong, Jie; Yu, Xiaoqing; Porter, Dale W; Battelli, Lori A; Kashon, Michael L; Ma, Qiang

    2016-02-01

    Pulmonary fibrosis results from the excessive deposition of collagen fibers and scarring in the lungs with or without an identifiable cause. The mechanism(s) underlying lung fibrosis development is poorly understood, and effective treatment is lacking. Here we compared mouse lung fibrosis induced by pulmonary exposure to prototypical particulate (crystalline silica) or soluble chemical (bleomycin or paraquat) fibrogenic agents to identify the underlying mechanisms. Young male C57BL/6J mice were given silica (2 mg), bleomycin (0.07 mg), or paraquat (0.02 mg) by pharyngeal aspiration. All treatments induced significant inflammatory infiltration and collagen deposition, manifesting fibrotic foci in silica-exposed lungs or diffuse fibrosis in bleomycin or paraquat-exposed lungs on day 7 post-exposure, at which time the lesions reached their peaks and represented a junction of transition from an acute response to chronic fibrosis. Lung genome-wide gene expression was analyzed, and differential gene expression was confirmed by quantitative RT-PCR, immunohistochemistry, and immunoblotting for representative genes to demonstrate their induced expression and localization in fibrotic lungs. Canonical signaling pathways, gene ontology, and upstream transcription networks modified by each agent were identified. In particular, these inducers elicited marked proliferative responses; at the same time, silica preferentially activated innate immune functions and the defense against foreign bodies, whereas bleomycin and paraquat boosted responses related to cell adhesion, platelet activation, extracellular matrix remodeling, and wound healing. This study identified, for the first time, the shared and unique genes, signaling pathways, and biological functions regulated by particulate and soluble chemical fibrogenic agents during lung fibrosis, providing insights into the mechanisms underlying human lung fibrotic diseases. PMID:26345256

  13. Connective tissue growth factor stimulates the proliferation, migration and differentiation of lung fibroblasts during paraquat-induced pulmonary fibrosis.

    PubMed

    Yang, Zhizhou; Sun, Zhaorui; Liu, Hongmei; Ren, Yi; Shao, Danbing; Zhang, Wei; Lin, Jinfeng; Wolfram, Joy; Wang, Feng; Nie, Shinan

    2015-07-01

    It is well established that paraquat (PQ) poisoning can cause severe lung injury during the early stages of exposure, finally leading to irreversible pulmonary fibrosis. Connective tissue growth factor (CTGF) is an essential growth factor that is involved in tissue repair and pulmonary fibrogenesis. In the present study, the role of CTGF was examined in a rat model of pulmonary fibrosis induced by PQ poisoning. Histological examination revealed interstitial edema and extensive cellular thickening of interalveolar septa at the early stages of poisoning. At 2 weeks after PQ administration, lung tissue sections exhibited a marked thickening of the alveolar walls with an accumulation of interstitial cells with a fibroblastic appearance. Masson's trichrome staining revealed a patchy distribution of collagen deposition, indicating pulmonary fibrogenesis. Western blot analysis and immunohistochemical staining of tissue samples demonstrated that CTGF expression was significantly upregulated in the PQ-treated group. Similarly, PQ treatment of MRC-5 human lung fibroblast cells caused an increase in CTGF in a dose-dependent manner. Furthermore, the addition of CTGF to MRC-5 cells triggered cellular proliferation and migration. In addition, CTGF induced the differentiation of fibroblasts to myofibroblasts, as was evident from increased expression of α-smooth muscle actin (α-SMA) and collagen. These findings demonstrate that PQ causes increased CTGF expression, which triggers proliferation, migration and differentiation of lung fibroblasts. Therefore, CTGF may be important in PQ-induced pulmonary fibrogenesis, rendering this growth factor a potential pharmacological target for reducing lung injury. PMID:25815693

  14. Increase in caveolae and caveolin-1 expression modulates agonist-induced contraction and store- and receptor-operated Ca(2+) entry in pulmonary arteries of pulmonary hypertensive rats.

    PubMed

    Jiao, Hai-Xia; Mu, Yun-Ping; Gui, Long-Xin; Yan, Fu-Rong; Lin, Da-Cen; Sham, James S K; Lin, Mo-Jun

    2016-09-01

    Caveolin-1 (Cav-1) is a major component protein associated with caveolae in the plasma membrane and has been identified as a regulator of store-operated Ca(2+) entry (SOCE) and receptor-operated Ca(2+) entry (ROCE). However, the contributions of caveolae/Cav-1 of pulmonary arterial smooth muscle cells (PASMCs) to the altered Ca(2+) signaling pathways in pulmonary arteries (PAs) during pulmonary hypertension (PH) have not been fully characterized. The present study quantified caveolae number and Cav-1 expression, and determined the effects of caveolae disruption on ET-1, cyclopiazonic acid (CPA) and 1-Oleoyl-2-acetyl-glycerol (OAG)-induced contraction in PAs and Ca(2+) influx in PASMCs of chronic hypoxia (CH)- and monocrotaline (MCT)-induced PH rats. We found that the number of caveolae, and the Cav-1 mRNA and protein levels were increased significantly in PASMCs in both PH models. Disruption of caveolae by cholesterol depletion with methyl-β-cyclodextrin (MβCD) significantly inhibited the contractile response to ET-1, CPA and OAG in PAs of control rats. ET-1, SOCE and ROCE-mediated contractile responses were enhanced, and their susceptibility to MβCD suppression was potentiated in the two PH models. MβCD-induced inhibition was reversed by cholesterol repletion. Introduction of Cav-1 scaffolding domain peptide to mimic Cav-1 upregulation caused significant increase in CPA- and OAG-induced Ca(2+) entry in PASMCs of control, CH and MCT-treated groups. Our results suggest that the increase in caveolae and Cav-1 expression in PH contributes to the enhanced agonist-induced contraction of PA via modulation of SOCE and ROCE; and targeting caveolae/Cav-1 in PASMCs may provide a novel therapeutic strategy for the treatment of PH. PMID:27311393

  15. First Steps Towards an Understanding of a Mode ofCarcinogenic Action for Vanadium Pentoxide

    PubMed Central

    Schuler, Detlef; Chevalier, Hans-Jörg; Merker, Mandy; Morgenthal, Katja; Ravanat, Jean-Luc; Sagelsdorff, Peter; Walter, Marc; Weber, Klaus; Mcgregor, Douglas

    2011-01-01

    Inhalation of vanadium pentoxide clearly increases the incidence of alveolar/bronchiolar neoplasms in male and female B6C3F1 mice at all concentrations tested (1, 2 or 4 mg/m3), whereas responses in F344/N rats was, at most, ambiguous. While vanadium pentoxide is mutagenic in vitro and possibly in vivo in mice, this does not explain the species or site specificity of the neoplastic response. A nose-only inhalation study was conducted in female B6C3F1 mice (0, 0.25, 1 and 4 mg/m3, 6 h/day for 16 days) to explore histopathological, biochemical (α-tocopherol, glutathione and F2-isoprostane) and genetic (comet assays and 9 specific DNA-oxo-adducts) changes in the lungs. No treatment related histopathology was observed at 0.25 mg/m3. At 1 and 4 mg/m3, exposure-dependent increases were observed in lung weight, alveolar histiocytosis, sub-acute alveolitis and/or granulocytic infiltration and a generally time-dependent increased cell proliferation rate of histiocytes. Glutathione was slightly increased, whereas there were no consistent changes in α-tocopherol or 8-isoprostane F2α. There was no evidence for DNA strand breakage in lung or BAL cells, but there was an increase in 8-oxodGuo DNA lesions that could have been due to vanadium pentoxide induction of the lesions or inhibition of repair of spontaneous lesions. Thus, earlier reports of histopathological changes in the lungs after inhalation of vanadium pentoxide were confirmed, but no evidence has yet emerged for a genotoxic mode of action. Evidence is weak for oxidative stress playing any role in lung carcinogenesis at the lowest effective concentrations of vanadium pentoxide. PMID:22272055

  16. Glucagon like peptide-1 attenuates bleomycin-induced pulmonary fibrosis, involving the inactivation of NF-κB in mice.

    PubMed

    Gou, Si; Zhu, Tao; Wang, Wei; Xiao, Min; Wang, Xi-chen; Chen, Zhong-hua

    2014-10-01

    Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with high mortality and poor prognosis. Previous studies confirmed that NF-κB plays a critical role in the pathogenesis of pulmonary fibrosis and glucagon like peptide-1 (GLP-1) has a property of anti-inflammation by inactivation of NF-κB. Furthermore, the GLP-1 receptor was detected in the lung tissues. Our aim was to investigate the potential value and mechanisms of GLP-1 on BLM-induced pulmonary fibrosis in mice. Mice with BLM-induced pulmonary fibrosis were treated with or without GLP-1 administration. 28 days after BLM infusion, the number of total cells, macrophages, neutrophils, lymphocytes, and the content of TGF-β1 in BALF were measured. Hematoxylin-eosin (HE) staining and Masson's trichrome (MT) staining were performed. The Ashcroft score and hydroxyproline content were analyzed. RT-qPCR and western blot were used to evaluate the expression of α-SMA and VCAM-1. The phosphorylation of NF-κB p65 was also assessed by western blot. DNA binding of NF-κB p65 was measured through Trans(AM) p65 transcription factor ELISA kit. GLP-1 reduced inflammatory cell infiltration and the content of TGF-β1 in BLAF in mice with BLM injection. The Ashcroft score and hydroxyproline content were decreased by GLP-1 administration. Meanwhile, BLM-induced overexpression of α-SMA and VCAM-1 were blocked by GLP-1 treatment in mice. GLP-1 also reduced the ratio of phosphor-NF-κB p65/total-NF-κB p65 and NF-κB p65 DNA binding activity in BLM-induced pulmonary fibrosis in mice. Our data found that BLM-induced lung inflammation and pulmonary fibrosis were significantly alleviated by GLP-1 treatment in mice, possibly through inactivation of NF-κB. PMID:25111852

  17. Interactive effects of cerium oxide and diesel exhaust nanoparticles on inducing pulmonary fibrosis

    SciTech Connect

    Ma, Jane Y.C.; Young, Shih-Houng; Mercer, Robert R.; Barger, Mark; Schwegler-Berry, Diane; Ma, Joseph K.; Castranova, Vincent

    2014-07-15

    Cerium compounds have been used as a fuel-borne catalyst to lower the generation of diesel exhaust particles (DEPs), but are emitted as cerium oxide nanoparticles (CeO{sub 2}) along with DEP in the diesel exhaust. The present study investigates the effects of the combined exposure to DEP and CeO{sub 2} on the pulmonary system in a rat model. Specific pathogen-free male Sprague–Dawley rats were exposed to CeO{sub 2} and/or DEP via a single intratracheal instillation and were sacrificed at various time points post-exposure. This investigation demonstrated that CeO{sub 2} induces a sustained inflammatory response, whereas DEP elicits a switch of the pulmonary immune response from Th1 to Th2. Both CeO{sub 2} and DEP activated AM and lymphocyte secretion of the proinflammatory cytokines IL-12 and IFN-γ, respectively. However, only DEP enhanced the anti-inflammatory cytokine IL-10 production in response to ex vivo LPS or Concanavalin A challenge that was not affected by the presence of CeO{sub 2}, suggesting that DEP suppresses host defense capability by inducing the Th2 immunity. The micrographs of lymph nodes show that the particle clumps in DEP + CeO{sub 2} were significantly larger than CeO{sub 2} or DEP, exhibiting dense clumps continuous throughout the lymph nodes. Morphometric analysis demonstrates that the localization of collagen in the lung tissue after DEP + CeO{sub 2} reflects the combination of DEP-exposure plus CeO{sub 2}-exposure. At 4 weeks post-exposure, the histological features demonstrated that CeO{sub 2} induced lung phospholipidosis and fibrosis. DEP induced lung granulomas that were not significantly affected by the presence of CeO{sub 2} in the combined exposure. Using CeO{sub 2} as diesel fuel catalyst may cause health concerns. - Highlights: • DEP induced acute lung inflammation and switched immune response from Th1 to Th2. • DEP induced lung granulomas were not affected by the presence of CeO{sub 2}. • CeO{sub 2} induced sustained lung

  18. Mononuclear Phagocyte-Derived Microparticulate Caspase-1 Induces Pulmonary Vascular Endothelial Cell Injury

    PubMed Central

    Mitra, Srabani

    2015-01-01

    Lung endothelial cell apoptosis and injury occurs throughout all stages of acute lung injury (ALI/ARDS) and impacts disease progression. Lung endothelial injury has traditionally been focused on the role of neutrophil trafficking to lung vascular integrin receptors induced by proinflammatory cytokine expression. Although much is known about the pathogenesis of cell injury and death in ALI/ARDS, gaps remain in our knowledge; as a result of which there is currently no effective pharmacologic therapy. Enzymes known as caspases are essential for completion of the apoptotic program and secretion of pro-inflammatory cytokines. We hypothesized that caspase-1 may serve as a key regulator of human pulmonary microvascular endothelial cell (HPMVEC) apoptosis in ALI/ARDS. Our recent experiments confirm that microparticles released from stimulated monocytic cells (THP1) induce lung endothelial cell apoptosis. Microparticles pretreated with the caspase-1 inhibitor, YVAD, or pan-caspase inhibitor, ZVAD, were unable to induce cell death of HPMVEC, suggesting the role of caspase-1 or its substrate in the induction of HPMVEC cell death. Neither un-induced microparticles (control) nor direct treatment with LPS induced apoptosis of HPMVEC. Further experiments showed that caspase-1 uptake into HPMVEC and the induction of HPMVEC apoptosis was facilitated by caspase-1 interactions with microparticulate vesicles. Altering vesicle integrity completely abrogated apoptosis of HPMVEC suggesting an encapsulation requirement for target cell uptake of active caspase-1. Taken together, we confirm that microparticle centered caspase-1 can play a regulator role in endothelial cell injury. PMID:26710067

  19. Salidroside exerts protective effects against chronic hypoxia-induced pulmonary arterial hypertension via AMPKα1-dependent pathways

    PubMed Central

    Chen, Mayun; Cai, Hui; Yu, Chang; Wu, Peiliang; Fu, Yangyang; Xu, Xiaomei; Fan, Rong; Xu, Cunlai; Chen, Yanfan; Wang, Liangxing; Huang, Xiaoying

    2016-01-01

    Salidroside, an active ingredient isolated from Rhodiola rosea, has shown to exert protective effects against chronic hypoxia-induced pulmonary arterial hypertension (PAH). However, the underlying mechanisms were not well known. Based on our recent reports, we predicted the involvement of adenosine monophosphate-activated protein kinase (AMPK) mediated effects in salidroside regulation of PAH. Firstly, to prove the hypothesis, rats were exposed to chronic hypoxia and treated with increasing concentrations of salidroside or a selective AMPK activator-5’-aminoimidazole-4-carboxamide ribonucleoside (AICAR) for 4 weeks. After salidroside or AICAR treatment, the chronic hypoxia-induced right ventricular hypertrophy and pulmonary artery remodeling were attenuated. Then the effects of salidroside or AICAR on hypoxia-induced excess cellular proliferation and apoptosis resistance of pulmonary arterial smooth muscle cells (PASMCs), which contributed to pulmonary arterial remodeling, were investigated. Our results suggested salidroside, as well as AICAR, reversed hypoxia-induced PASMCs proliferation and apoptosis resistance while AMPK inhibitor Compound C enhanced the effects of hypoxia. To reveal the potential cellular mechanisms, activation of AMPKα1 and expression of the genes related to proliferation and apoptosis were analyzed in PASMCs after salidroside treatment under hypoxia conditions. The results demonstrated salidroside as well as AICAR might inhibit chronic hypoxia-induced PASMCs proliferation via AMPKα1-P53-P27/P21 pathway and reverse apoptosis resistance via AMPKα1-P53-Bax/Bcl-2-caspase 9-caspase 3 pathway. PMID:27069536

  20. The involvement of platelet activating factor in endotoxin-induced pulmonary platelet recruitment in the guinea-pig.

    PubMed Central

    Beijer, L.; Botting, J.; Crook, P.; Oyekan, A. O.; Page, C. P.; Rylander, R.

    1987-01-01

    1 Exposure of conscious guinea-pigs to an aerosol of endotoxin (25-100 micrograms ml-1) resulted in a dose-related, progressive accumulation of platelets in the thoracic region. Accumulation of 111indium oxine labelled erythrocytes was not observed following exposure to an aerosol of endotoxin (50 micrograms ml-1). 2 Pretreatment of guinea-pigs with the selective platelet activating factor (Paf)-antagonists. CV-3988 or brotizolam resulted in a dose-related inhibition of endotoxin-induced pulmonary platelet recruitment. Pretreatment of guinea-pigs with the selective Paf-antagonist BN 52021 resulted in significant inhibition of endotoxin-induced pulmonary platelet recruitment, although the effects of BN 52021 were not dose-related. 3 Pretreatment of guinea-pigs with indomethacin at doses known to inhibit cyclo-oxygenase did not inhibit endotoxin-induced pulmonary platelet recruitment, whereas higher doses of indomethacin produced a reduction in platelet recruitment in the lung. 4 Pretreatment of guinea-pigs with the anticoagulant heparin and the prostacyclin analogue ZK 36374 inhibited endotoxin-induced platelet recruitment. 5 These observations suggest that endotoxin-induced pulmonary platelet recruitment in the guinea-pig is secondary to the release of platelet activating factor, but not to cyclo-oxygenase products of arachidonic acid and may also involve activation of the coagulation cascade. PMID:2447993

  1. Long-Term Antibody and Immune Memory Response Induced by Pulmonary Delivery of the Influenza Iscomatrix Vaccine

    PubMed Central

    Vujanic, Ana; Snibson, Kenneth J.; Wee, Janet L. K.; Edwards, Stirling J.; Pearse, Martin J.; Scheerlinck, Jean-Pierre Y.

    2012-01-01

    Pulmonary delivery of an influenza Iscomatrix adjuvant vaccine induces a strong systemic and mucosal antibody response. Since an influenza vaccine needs to induce immunological memory that lasts at least 1 year for utility in humans, we examined the longevity of the immune response induced by such a pulmonary vaccination, with and without antigen challenge. Sheep were vaccinated in the deep lung with an influenza Iscomatrix vaccine, and serum and lung antibody levels were quantified for up to 1 year. The immune memory response to these vaccinations was determined following antigen challenge via lung delivery of influenza antigen at 6 months and 1 year postvaccination. Pulmonary vaccination of sheep with the influenza Iscomatrix vaccine induced antigen-specific antibodies in both sera and lungs that were detectable until 6 months postimmunization. Importantly, a memory recall response following antigenic challenge was detected at 12 months post-lung vaccination, including the induction of functional antibodies with hemagglutination inhibition activity. Pulmonary delivery of an influenza Iscomatrix vaccine induces a long-lived influenza virus-specific antibody and memory response of suitable length for annual vaccination against influenza. PMID:22072721

  2. Lung-specific loss of α3 laminin worsens bleomycin-induced pulmonary fibrosis.

    PubMed

    Morales-Nebreda, Luisa I; Rogel, Micah R; Eisenberg, Jessica L; Hamill, Kevin J; Soberanes, Saul; Nigdelioglu, Recep; Chi, Monica; Cho, Takugo; Radigan, Kathryn A; Ridge, Karen M; Misharin, Alexander V; Woychek, Alex; Hopkinson, Susan; Perlman, Harris; Mutlu, Gokhan M; Pardo, Annie; Selman, Moises; Jones, Jonathan C R; Budinger, G R Scott

    2015-04-01

    Laminins are heterotrimeric proteins that are secreted by the alveolar epithelium into the basement membrane, and their expression is altered in extracellular matrices from patients with pulmonary fibrosis. In a small number of patients with pulmonary fibrosis, we found that the normal basement membrane distribution of the α3 laminin subunit was lost in fibrotic regions of the lung. To determine if these changes play a causal role in the development of fibrosis, we generated mice lacking the α3 laminin subunit specifically in the lung epithelium by crossing mice expressing Cre recombinase driven by the surfactant protein C promoter (SPC-Cre) with mice expressing floxed alleles encoding the α3 laminin gene (Lama3(fl/fl)). These mice exhibited no developmental abnormalities in the lungs up to 6 months of age, but, compared with control mice, had worsened mortality, increased inflammation, and increased fibrosis after the intratracheal administration of bleomycin. Similarly, the severity of fibrosis induced by an adenovirus encoding an active form of transforming growth factor-β was worse in mice deficient in α3 laminin in the lung. Taken together, our results suggest that the loss of α3 laminin in the lung epithelium does not affect lung development, but plays a causal role in the development of fibrosis in response to bleomycin or adenovirally delivered transforming growth factor-β. Thus, we speculate that the loss of the normal basement membrane organization of α3 laminin that we observe in fibrotic regions from the lungs of patients with pulmonary fibrosis contributes to their disease progression. PMID:25188360

  3. Lung-Specific Loss of α3 Laminin Worsens Bleomycin-Induced Pulmonary Fibrosis

    PubMed Central

    Morales-Nebreda, Luisa I.; Rogel, Micah R.; Eisenberg, Jessica L.; Hamill, Kevin J.; Soberanes, Saul; Nigdelioglu, Recep; Chi, Monica; Cho, Takugo; Radigan, Kathryn A.; Ridge, Karen M.; Misharin, Alexander V.; Woychek, Alex; Hopkinson, Susan; Perlman, Harris; Mutlu, Gokhan M.; Pardo, Annie; Selman, Moises; Jones, Jonathan C. R.

    2015-01-01

    Laminins are heterotrimeric proteins that are secreted by the alveolar epithelium into the basement membrane, and their expression is altered in extracellular matrices from patients with pulmonary fibrosis. In a small number of patients with pulmonary fibrosis, we found that the normal basement membrane distribution of the α3 laminin subunit was lost in fibrotic regions of the lung. To determine if these changes play a causal role in the development of fibrosis, we generated mice lacking the α3 laminin subunit specifically in the lung epithelium by crossing mice expressing Cre recombinase driven by the surfactant protein C promoter (SPC-Cre) with mice expressing floxed alleles encoding the α3 laminin gene (Lama3fl/fl). These mice exhibited no developmental abnormalities in the lungs up to 6 months of age, but, compared with control mice, had worsened mortality, increased inflammation, and increased fibrosis after the intratracheal administration of bleomycin. Similarly, the severity of fibrosis induced by an adenovirus encoding an active form of transforming growth factor-β was worse in mice deficient in α3 laminin in the lung. Taken together, our results suggest that the loss of α3 laminin in the lung epithelium does not affect lung development, but plays a causal role in the development of fibrosis in response to bleomycin or adenovirally delivered transforming growth factor-β. Thus, we speculate that the loss of the normal basement membrane organization of α3 laminin that we observe in fibrotic regions from the lungs of patients with pulmonary fibrosis contributes to their disease progression. PMID:25188360

  4. Ambrisentan and tadalafil synergistically relax endothelin-induced contraction of rat pulmonary arteries.

    PubMed

    Liang, Faquan; Yang, Suya; Yao, Lina; Belardinelli, Luiz; Shryock, John

    2012-03-01

    Endothelin receptor antagonists and phosphodiesterase type 5 inhibitors are used to treat pulmonary arterial hypertension. We tested the hypothesis that a selective endothelin type A receptor antagonist (ambrisentan) and a phosphodiesterase type 5 inhibitor (tadalafil) may act synergistically to relax endothelin-constricted pulmonary arteries. Rat isolated intrapulmonary arterial rings contracted with 8 nmol/L endothelin-1 were relaxed by 10 nmol/L ambrisentan and 30 nmol/L tadalafil alone by 26±3% and 21±1%, respectively, whereas both drugs in combination acted synergistically to relax arterial rings by 83±6%. The nonselective endothelin type A and B receptor antagonists bosentan (100 nmol/L) and macitentan (30 nmol/L) alone relaxed endothelin-contracted rings by 30±5% and 24±3%, respectively. Combinations of 30 nmol/L tadalafil with 100 nmol/L bosentan or 30 nmol/L macitentan relaxed endothelin-contracted rings by 53±5% or 46±7%, respectively; these values are similar to the calculated sums of the individual effects of these compounds. Denudation of endothelium from pulmonary arterial rings abolished the vasodilator response to 30 nmol/L tadalafil and the synergistic vasorelaxant effect of tadalafil with ambrisentan. In the presence of 1 μmol/L BQ-788, a selective endothelin type B receptor antagonist, the vasorelaxant effects of 10 nmol/L ambrisentan and 30 nmol/L tadalafil were additive but not synergistic. These data can be interpreted to suggest that ambrisentan and tadalafil synergistically inhibit endothelin-1-induced constriction of rat intrapulmonary arteries and that endothelin type B receptors in endothelium are necessary to enable a synergistic vasorelaxant effect of the drug combination. PMID:22311911

  5. Diet-induced alterations in gut microflora contribute to lethal pulmonary damage in TLR2/TLR4 deficient mice

    PubMed Central

    Ji, Yewei; Sun, Shengyi; Goodrich, Julia K.; Kim, Hana; Poole, Angela C.; Duhamel, Gerald E.; Ley, Ruth E.; Qi, Ling

    2014-01-01

    SUMMARY Chronic intake of Western diet has driven an epidemic of obesity and metabolic syndrome, but how it induces mortality remains unclear. Here we show that chronic intake of a high-fat diet (HFD), not a low-fat diet (LFD), leads to severe pulmonary damage and mortality in mice deficient in Toll-like receptors (TLR) 2 and 4 (DKO hereafter). Diet-induced pulmonary lesions are blocked by antibiotics treatment and transmissible to wildtype mice upon either cohousing or fecal transplantation, pointing to the existence of bacterial pathogens. Indeed, diet and innate deficiency exert significant impact on gut microbiota composition. Thus, chronic intake of HFD promotes severe pulmonary damage and mortality in DKO mice in part via gut dysbiosis, a finding that may be important for immunodeficient patients, particularly those on chemotherapy or radiotherapy, where gut microbiota-caused conditions are often life-threatening. PMID:24953658

  6. Workshop summary: phosgene-induced pulmonary toxicity revisited: appraisal of early and late markers of pulmonary injury from animal models with emphasis on human significance.

    PubMed

    Pauluhn, J; Carson, A; Costa, D L; Gordon, T; Kodavanti, U; Last, J A; Matthay, M A; Pinkerton, K E; Sciuto, A M

    2007-08-01

    A workshop was held February 14, 2007, in Arlington, VA, under the auspices of the Phosgene Panel of the American Chemistry Council. The objective of this workshop was to convene inhalation toxicologists and medical experts from academia, industry and regulatory authorities to critically discuss past and recent inhalation studies of phosgene in controlled animal models. This included presentations addressing the benefits and limitations of rodent (mice, rats) and nonrodent (dogs) species to study concentration x time (C x t) relationships of acute and chronic types of pulmonary changes. Toxicological endpoints focused on the primary pulmonary effects associated with the acute inhalation exposure to phosgene gas and responses secondary to injury. A consensus was reached that the phosgene-induced increased pulmonary extravasation of fluid and protein can suitably be probed by bronchoalveolar lavage (BAL) techniques. BAL fluid analyses rank among the most sensitive methods to detect phosgene-induced noncardiogenic, pulmonary high-permeability edema following acute inhalation exposure. Maximum protein concentrations in BAL fluid occurred within 1 day after exposure, typically followed by a latency period up to about 15 h, which is reciprocal to the C x t exposure relationship. The C x t relationship was constant over a wide range of concentrations and single exposure durations. Following intermittent, repeated exposures of fixed duration, increased tolerance to recurrent exposures occurred. For such exposure regimens, chronic effects appear to be clearly dependent on the concentration rather than the cumulative concentration x time relationship. The threshold C x t product based on an increased BAL fluid protein following single exposure was essentially identical to the respective C x t product following subchronic exposure of rats based on increased pulmonary collagen and influx of inflammatory cells. Thus, the chronic outcome appears to be contingent upon the acute

  7. MicroRNA-365 in macrophages regulates Mycobacterium tuberculosis-induced active pulmonary tuberculosis via interleukin-6.

    PubMed

    Song, Qingzhang; Li, Hui; Shao, Hua; Li, Chunling; Lu, Xiao

    2015-01-01

    The present study is to investigate the relationship between microRNA (miR)-365 expression and the levels of interleukin (IL)-6 mRNA and protein in patients with active tuberculosis. From June 2011 to June 2014, 48 patients with active pulmonary tuberculosis induced by Mycobacterium tuberculosis were included in the study. In addition, 23 healthy subjects were enrolled as control. Macrophages were collected by pulmonary alveolus lavage. In addition, serum and mononuclear cells were isolated from peripheral blood. The levels of miR-365 and IL-6 in macrophages, mononuclear cells and serum were determined using quantitative real-time polymerase chain reaction. The protein expression of IL-6 in macrophages and mononuclear cells was measured using Western blotting, while that in serum was detected by enzyme-linked immunoabsorbent assay. Expression of IL-6 mRNA and protein was significantly enhanced in patients with active pulmonary tuberculosis. Increase of IL-6 protein concentration in serum was probably due to the release of IL-6 protein from mononuclear cells in the blood. In addition, miR-365 levels were significantly lowered in patients with active pulmonary tuberculosis. Up-regulated IL-6 expression in macrophages, mononuclear cells and serum in patients with active pulmonary tuberculosis is related to the down-regulation of miR-365, suggesting that miR-365 may regulate the occurrence and immune responses of active pulmonary tuberculosis via IL-6. PMID:26629035

  8. MicroRNA-365 in macrophages regulates Mycobacterium tuberculosis-induced active pulmonary tuberculosis via interleukin-6

    PubMed Central

    Song, Qingzhang; Li, Hui; Shao, Hua; Li, Chunling; Lu, Xiao

    2015-01-01

    The present study is to investigate the relationship between microRNA (miR)-365 expression and the levels of interleukin (IL)-6 mRNA and protein in patients with active tuberculosis. From June 2011 to June 2014, 48 patients with active pulmonary tuberculosis induced by Mycobacterium tuberculosis were included in the study. In addition, 23 healthy subjects were enrolled as control. Macrophages were collected by pulmonary alveolus lavage. In addition, serum and mononuclear cells were isolated from peripheral blood. The levels of miR-365 and IL-6 in macrophages, mononuclear cells and serum were determined using quantitative real-time polymerase chain reaction. The protein expression of IL-6 in macrophages and mononuclear cells was measured using Western blotting, while that in serum was detected by enzyme-linked immunoabsorbent assay. Expression of IL-6 mRNA and protein was significantly enhanced in patients with active pulmonary tuberculosis. Increase of IL-6 protein concentration in serum was probably due to the release of IL-6 protein from mononuclear cells in the blood. In addition, miR-365 levels were significantly lowered in patients with active pulmonary tuberculosis. Up-regulated IL-6 expression in macrophages, mononuclear cells and serum in patients with active pulmonary tuberculosis is related to the down-regulation of miR-365, suggesting that miR-365 may regulate the occurrence and immune responses of active pulmonary tuberculosis via IL-6. PMID:26629035

  9. Expression and kinetics of induced procoagulant activity in bovine pulmonary alveolar macrophages.

    PubMed

    Car, B D; Slauson, D O; Suyemoto, M M; Doré, M; Neilsen, N R

    1991-01-01

    Leukocytes, especially macrophages, are important cellular mediators of fibrin deposition and removal at tissue sites of inflammation. Pulmonary fibrin deposition is a prominent feature of bovine acute lung injury; therefore, we studied the resting and stimulated procoagulant responses of bovine pulmonary alveolar macrophages (PAM) and peripheral blood neutrophils (PMN). Freshly isolated normal PAM and PMN expressed negligible procoagulant activity. PAM stimulated with endotoxin lipopolysaccharide (LPS), 4 beta-phorbol 12-myristate 13-acetate (PMA) and bovine recombinant interleukin-1 beta (rBIL-1 beta) exhibited protein synthesis- and dose-dependent enhancement of procoagulant activity in 8-h cultures. Bovine recombinant granulocyte macrophage-colony stimulating factor (rBGM-CSF) and recombinant human gamma-interferon (rHIFN-gamma) did not induce procoagulant activity. The kinetics of LPS- and PMA-enhanced PAM procoagulant activity differed: LPS-induced enhancement developed earlier and more rapidly than PMA-induced enhancement. Pasteurella haemolytica LPS was more potent than Escherichia coli LPS in enhancing PAM procoagulant activity, while dexamethasone decreased both baseline and LPS- or PMA-stimulated activity by approximately 50%. PAM procoagulant activity resulted from tissue factor expression. Bovine PMN produced negligible procoagulant activity when stimulated, and are thus unlikely to be major contributors to procoagulant activity in bovine lung. Activity inhibitory to bovine tissue factor was present in both calf and adult sera, and was partly dependent on the presence of factor X for activity. Rapid induction of bovine PAM procoagulant activity by inflammatory mediators, and subsequent resistance to degradation, may thus combine to promote an alveolar microenvironment permissive to fibrin deposition in bovine acute lung injury. PMID:1959504

  10. Neotuberostemonine attenuates bleomycin-induced pulmonary fibrosis by suppressing the recruitment and activation of macrophages.

    PubMed

    Xiang, Juan; Cheng, Si; Feng, Tianlong; Wu, Yan; Xie, Weina; Zhang, Mian; Xu, Xianghong; Zhang, Chaofeng

    2016-07-01

    Neotuberostemonine (NTS) is one of the main antitussive alkaloids in the root of Stemona tuberosa Lour. This study aimed to investigate the effects of NTS on bleomycin (BLM)-induced pulmonary fibrosis in mice and the underlying mechanism. After BLM administration, NTS were orally administered to mice at 20 and 40mg/kg per day from days 8 to 21, with nintedanib as a positive control. The effect of NTS on BLM-induced mice was assessed via histopathological examination by HE and Masson's trichrome staining, TGF-β1 level and macrophage recruitment by immunohistochemical staining, expression of profibrotic media and M1/M2 polarization by western blot. RAW 264.7 cells were used to evaluate whether NTS (1, 10, 100μM) directly affected macrophages. The results revealed that NTS treatment significantly ameliorated lung histopathological changes and decreased inflammatory cell counts in the bronchoalveolar lavage fluid. The over-expression of collagen, α-SMA and TGF-β1 was reduced by NTS. Furthermore, NTS markedly lowered the expression of MMP-2 and TIMP-1 while raised the expression of MMP-9. A further analysis showed that NTS was able to decrease the recruitment of macrophages and to inhibit the M2 polarization in mice lung tissues. The experiment in vitro showed that NTS significantly reduced the arginase-1 (marker for M2) expression in a dose-dependent manner but down-regulated the iNOS (marker for M1) expression only at 100μM. In conclusion, our study demonstrated for the first time that NTS has a significant protective effect on BLM-induced pulmonary fibrosis through suppressing the recruitment and M2 polarization of macrophages. PMID:27144994

  11. Decreased proteasomal function accelerates cigarette smoke-induced pulmonary emphysema in mice.

    PubMed

    Yamada, Yosuke; Tomaru, Utano; Ishizu, Akihiro; Ito, Tomoki; Kiuchi, Takayuki; Ono, Ayako; Miyajima, Syota; Nagai, Katsura; Higashi, Tsunehito; Matsuno, Yoshihiro; Dosaka-Akita, Hirotoshi; Nishimura, Masaharu; Miwa, Soichi; Kasahara, Masanori

    2015-06-01

    Chronic obstructive pulmonary disease (COPD) is a disease common in elderly people, characterized by progressive destruction of lung parenchyma and chronic inflammation of the airways. The pathogenesis of COPD remains unclear, but recent studies suggest that oxidative stress-induced apoptosis in alveolar cells contributes to emphysematous lung destruction. The proteasome is a multicatalytic enzyme complex that plays a critical role in proteostasis by rapidly destroying misfolded and modified proteins generated by oxidative and other stresses. Proteasome activity decreases with aging in many organs including lungs, and an age-related decline in proteasomal function has been implicated in various age-related pathologies. However, the role of the proteasome system in the pathogenesis of COPD has not been investigated. Recently, we have established a transgenic (Tg) mouse model with decreased proteasomal chymotrypsin-like activity, showing age-related phenotypes. Using this model, we demonstrate here that decreased proteasomal function accelerates cigarette smoke (CS)-induced pulmonary emphysema. CS-exposed Tg mice showed remarkable airspace enlargement and increased foci of inflammation compared with wild-type controls. Importantly, apoptotic cells were found in the alveolar walls of the affected lungs. Impaired proteasomal activity also enhanced apoptosis in cigarette smoke extract (CSE)-exposed fibroblastic cells derived from mice and humans in vitro. Notably, aggresome formation and prominent nuclear translocation of apoptosis-inducing factor were observed in CSE-exposed fibroblastic cells isolated from Tg mice. Collective evidence suggests that CS exposure and impaired proteasomal activity coordinately enhance apoptotic cell death in the alveolar walls that may be involved in the development and progression of emphysema in susceptible individuals such as the elderly. PMID:25915723

  12. Right ventricular cyclic nucleotide signaling is decreased in hyperoxia-induced pulmonary hypertension in neonatal mice

    PubMed Central

    Heilman, Rachel P.; Lagoski, Megan B.; Lee, Keng Jin; Taylor, Joann M.; Kim, Gina A.; Berkelhamer, Sara K.; Steinhorn, Robin H.

    2015-01-01

    Pulmonary hypertension (PH) and right ventricular hypertrophy (RVH) affect 25–35% of premature infants with significant bronchopulmonary dysplasia (BPD), increasing morbidity and mortality. We sought to determine the role of phosphodiesterase 5 (PDE5) in the right ventricle (RV) and left ventricle (LV) in a hyperoxia-induced neonatal mouse model of PH and RVH. After birth, C57BL/6 mice were placed in room air (RA) or 75% O2 (CH) for 14 days to induce PH and RVH. Mice were euthanized at 14 days or recovered in RA for 14 days or 42 days prior to euthanasia at 28 or 56 days of age. Some pups received sildenafil or vehicle (3 mg·kg−1·dose−1 sc) every other day from P0. RVH was assessed by Fulton's index [RV wt/(LV + septum) wt]. PDE5 protein expression was analyzed via Western blot, PDE5 activity was measured by commercially available assay, and cGMP was measured by enzyme-linked immunoassay. Hyperoxia induced RVH in mice after 14 days, and RVH did not resolve until 56 days of age. Hyperoxia increased PDE5 expression and activity in RV, but not LV + S, after 14 days. PDE5 expression normalized by 28 days of age, but PDE5 activity did not normalize until 56 days of age. Sildenafil given during hyperoxia prevented RVH, decreased RV PDE5 activity, and increased RV cGMP levels. Mice with cardiac-specific overexpression of PDE5 had increased RVH in RA. These findings suggest normal RV PDE5 function is disrupted by hyperoxia, and elevated PDE5 contributes to RVH and remodeling. Therefore, in addition to impacting the pulmonary vasculature, sildenafil also targets PDE5 in the neonatal mouse RV and decreases RVH. PMID:25862831

  13. The Protective Effect of Naringin against Bleomycin-Induced Pulmonary Fibrosis in Wistar Rats

    PubMed Central

    Turgut, Nergiz H.; Kara, Haki; Elagoz, Sahende; Deveci, Koksal; Gungor, Huseyin; Arslanbas, Emre

    2016-01-01

    The aim of the current study was to investigate the protective effect of naringin on bleomycin-induced pulmonary fibrosis in rats. Twenty-four Wistar rats randomly divided into four groups (control, bleomycin alone, bleomycin + naringin 40, and bleomycin + naringin 80) were used. Rats were administered a single dose of bleomycin (5 mg/kg; via the tracheal cannula) alone or followed by either naringin 40 mg/kg (orally) or naringin 80 mg/kg (orally) or water (1 mL, orally) for 14 days. Rats and lung tissue were weighed to determine the lung index. TNF-α and IL-1β levels, hydroxyproline content, and malondialdehyde (MDA) levels were assayed. Glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) activities were determined. Tissue sections were stained with hematoxylin-eosin, Masson's trichrome, and 0.1% toluidine blue. TNF-α, IL-1β, and MDA levels and hydroxyproline content significantly increased (p < 0.01) and GPx and SOD activities significantly decreased in bleomycin group (p < 0.01). Naringin at a dose of 80 mg/kg body weight significantly decreased TNF-α and IL-1β activity, hydroxyproline content, and MDA level (p < 0.01) and increased GPx and SOD activities (p < 0.05). Histological evidence supported the results. These results show that naringin has the potential of reducing the toxic effects of bleomycin and may provide supportive therapy for conventional treatment methods for idiopathic pulmonary fibrosis. PMID:26977316

  14. Inhaled house dust mite induces pulmonary T helper 2 cytokine production

    PubMed Central

    Gregory, L. G.; Causton, B.; Murdoch, J. R.; Mathie, S. A.; O’Donnell, V.; Thomas, C. P.; Priest, F. M.; Quint, D. J.; Lloyd, C. M.

    2012-01-01

    Background Inhaled house dust mite (HDM) results in T-helper (TH) 2 type pathology in unsensitized mice, in conjunction with airway hyperreactivity and airway remodelling. However, the pulmonary cytokine and chemokine profile has not been reported. Methods We have performed a time course analysis of the characteristic molecular mediators and cellular influx in the bronchoalveolar lavage (BAL) and lung in order to define the pulmonary inflammatory response to inhaled HDM extract. Mice were exposed five times a week to soluble HDM extract for 3 weeks. Lung function was measured in groups of mice at intervals following the final HDM challenge. Recruitment of inflammatory cells and inflammatory mediator production was then assessed in BAL and lungs of individual mice. Results We found that Th2 cytokines were significantly increased in BAL and lung after HDM challenge from as early as 2 h post-final challenge. The levels of cytokines and chemokines correlated with the influx of eosinophils and Th2 cells to the different compartments of the lung. However, the production of key cytokines such as IL-4, IL-5 and IL-13 preceded the increase in airways resistance. Conclusion Inhaled HDM challenge induces a classical Th2 inflammatory mediator profile in the BAL and lung. These data are important for studies determining the efficacy of novel treatment strategies for allergic airways disease. PMID:19545261

  15. Massive Pulmonary Embolism in a Patient with Heparin Induced Thrombocytopenia: Successful Treatment with Dabigatran

    PubMed Central

    Bircan, Haci Ahmet; Alanoglu, Emine Guchan

    2016-01-01

    Heparin induced thrombocytopenia (HIT) is a rare, potentially fatal, immune-mediated complication of heparin therapy, associated with thrombosis and thrombocytopenia. In this study, a successful dabigatran administration in a case with massive pulmonary thromboembolism (mPTE) and HIT is presented. 57 years-old female, who was receiving low molecular weight heparin (LMWH) (0.4 mL once a daily, S.C. for 11 days) due to total knee replacement, was referred to our clinic with the hypotension and syncope attacks. Her echocardiography and pulmonary CT angiography findings were consistent with mPTE. We detected a serious decrease in her platelet count highly suggestive for HIT (plt: 54×103/µL). LMWH was discontinued and dabigatran was started (150 mg twice daily). After platelet count increased over 150×103/μL, dabigatran was switched to warfarin. Since heparin is widely used in medicine, all physicians need to be aware of this life threatening complication of heparin. Replacing heparin with an alternative anticoagulant such as dabigatran may become a life-saving strategy especially in case of HIT complicated with mPTE. PMID:27026768

  16. Pulmonary endothelial dysfunction induced by unilateral as compared to bilateral thoracic irradiation in rats

    SciTech Connect

    Ward, W.F.; Molteni, A.; Ts'Ao, C.H.; Solliday, N.H.

    1987-07-01

    Rats were sacrificed 2 months after a single dose of 10-30 Gy of /sup 60/Co gamma rays delivered to either a right unilateral or a bilateral thoracic port. Four indices of lung endothelial function were measured: the activities of angiotensin-converting enzyme (ACE) and plasminogen activator (PLA) and the production of prostacyclin (PGI2) and thromboxane (TXA2). The number of macrophages recovered by bronchoalveolar lavage (BAL) and the degree of right ventricular hypertrophy (an index of pulmonary hypertension) also were determined. Right lung ACE and PLA activity decreased linearly, and PGI2 and TXA2 production increased linearly with increasing radiation dose. The response curves for right unilateral and bilateral thoracic irradiation were not significantly different. In contrast, bilateral irradiation was more toxic than unilateral, since rats exposed to the former exhibited decreased body weight, an increased incidence of pleural effusions, an increase in the number of macrophages recovered by BAL, and right ventricular hypertrophy. These data demonstrate that pulmonary endothelial dysfunction induced by hemithorax irradiation represents a direct response of the endothelium to radiation injury and is not secondary to other phenomena such as shunting of function to the shielded lung.

  17. Molecular Mechanisms of Nanosized Titanium Dioxide–Induced Pulmonary Injury in Mice

    PubMed Central

    Sang, Xuezi; Cui, Yaling; Wang, Xiaochun; Gui, Suxin; Tan, Danlin; Zhu, Min; Zhao, Xiaoyang; Sheng, Lei; Wang, Ling; Hong, Fashui; Tang, Meng

    2013-01-01

    The pulmonary damage induced by nanosized titanium dioxide (nano-TiO2) is of great concern, but the mechanism of how this damage may be incurred has yet to be elucidated. Here, we examined how multiple genes may be affected by nano-TiO2 exposure to contribute to the observed damage. The results suggest that long-term exposure to nano-TiO2 led to significant increases in inflammatory cells, and levels of lactate dehydrogenase, alkaline phosphate, and total protein, and promoted production of reactive oxygen species and peroxidation of lipid, protein and DNA in mouse lung tissue. We also observed nano-TiO2 deposition in lung tissue via light and confocal Raman microscopy, which in turn led to severe pulmonary inflammation and pneumonocytic apoptosis in mice. Specifically, microarray analysis showed significant alterations in the expression of 847 genes in the nano-TiO2-exposed lung tissues. Of 521 genes with known functions, 361 were up-regulated and 160 down-regulated, which were associated with the immune/inflammatory responses, apoptosis, oxidative stress, the cell cycle, stress responses, cell proliferation, the cytoskeleton, signal transduction, and metabolic processes. Therefore, the application of nano-TiO2 should be carried out cautiously, especially in humans. PMID:23409001

  18. IKK NBD peptide inhibits LPS induced pulmonary inflammation and alters sphingolipid metabolism in a murine model.

    PubMed

    von Bismarck, Philipp; Winoto-Morbach, Supandi; Herzberg, Mona; Uhlig, Ulrike; Schütze, Stefan; Lucius, Ralph; Krause, Martin F

    2012-06-01

    Airway epithelial NF-κB is a key regulator of host defence in bacterial infections and has recently evolved as a target for therapeutical approaches. Evidence is accumulating that ceramide, generated by acid sphingomyelinase (aSMase), and sphingosine-1-phosphate (S1-P) are important mediators in host defence as well as in pathologic processes of acute lung injury. Little is known about the regulatory mechanisms of pulmonary sphingolipid metabolism in bacterial infections of the lung. The objective of this study was to evaluate the influence of NF-κB on sphingolipid metabolism in Pseudomonas aeruginosa LPS-induced pulmonary inflammation. In a murine acute lung injury model with intranasal Pseudomonas aeruginosa LPS we investigated TNF-α, KC (murine IL-8), IL-6, MCP-1 and neutrophilic infiltration next to aSMase activity and ceramide and S1-P lung tissue concentrations. Airway epithelial NF-κB was inhibited by topically applied IKK NBD, a cell penetrating NEMO binding peptide. This treatment resulted in significantly reduced inflammation and suppression of aSMase activity along with decreased ceramide and S1-P tissue concentrations down to levels observed in healthy animals. In conclusion our results confirm that changes in sphingolipid metabolim due to Pseudomonas aeruginosa LPS inhalation are regulated by NF-κB translocation. This confirms the critical role of airway epithelial NF-κB pathway for the inflammatory response to bacterial pathogens and underlines the impact of sphingolipids in inflammatory host defence mechanisms. PMID:22469869

  19. The Protective Effect of Naringin against Bleomycin-Induced Pulmonary Fibrosis in Wistar Rats.

    PubMed

    Turgut, Nergiz H; Kara, Haki; Elagoz, Sahende; Deveci, Koksal; Gungor, Huseyin; Arslanbas, Emre

    2016-01-01

    The aim of the current study was to investigate the protective effect of naringin on bleomycin-induced pulmonary fibrosis in rats. Twenty-four Wistar rats randomly divided into four groups (control, bleomycin alone, bleomycin + naringin 40, and bleomycin + naringin 80) were used. Rats were administered a single dose of bleomycin (5 mg/kg; via the tracheal cannula) alone or followed by either naringin 40 mg/kg (orally) or naringin 80 mg/kg (orally) or water (1 mL, orally) for 14 days. Rats and lung tissue were weighed to determine the lung index. TNF-α and IL-1β levels, hydroxyproline content, and malondialdehyde (MDA) levels were assayed. Glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) activities were determined. Tissue sections were stained with hematoxylin-eosin, Masson's trichrome, and 0.1% toluidine blue. TNF-α, IL-1β, and MDA levels and hydroxyproline content significantly increased (p < 0.01) and GPx and SOD activities significantly decreased in bleomycin group (p < 0.01). Naringin at a dose of 80 mg/kg body weight significantly decreased TNF-α and IL-1β activity, hydroxyproline content, and MDA level (p < 0.01) and increased GPx and SOD activities (p < 0.05). Histological evidence supported the results. These results show that naringin has the potential of reducing the toxic effects of bleomycin and may provide supportive therapy for conventional treatment methods for idiopathic pulmonary fibrosis. PMID:26977316

  20. Indomethacin pretreatment reduces ozone-induced pulmonary function decrements in human subjects

    SciTech Connect

    Schelegle, E.S.; Adams, W.C.; Siefkin, A.D.

    1987-12-01

    We studied whether O/sub 3/-induced pulmonary function decrements could be inhibited by the prostaglandin synthetase inhibitor, indomethacin, in healthy human subjects. Fourteen college-age males completed six 1-h exposure protocols consisting of no drug, placebo, and indomethacin (Indocin SR 75 mg every 12 h for 5 days) pretreatments, with filtered air and O/sub 3/ (0.35 ppm) exposures within each pretreatment. Pretreatments were delivered weekly in random order in a double-blind fashion. Ozone and filtered air exposures, separated by 72 h, were delivered in random order in a single-blind fashion. Exposures consisted of 1-h exercise on a bicycle ergometer with work loads set to elicit a mean minute ventilation of 60 L/min. Statistical analysis revealed significant (p less than 0.05) across pretreatment effects for FVC and FEV1, with no drug versus indomethacin and placebo versus indomethacin comparisons being significant. These findings suggest that cyclooxygenase products of arachidonic acid, which are sensitive to indomethacin inhibition, play a prominent role in the development of pulmonary function decrements consequent to acute O/sub 3/ exposure.

  1. Chinese Skullcap in Move Free Arthritis Supplement Causes Drug Induced Liver Injury and Pulmonary Infiltrates

    PubMed Central

    Dhanasekaran, Renumathy

    2013-01-01

    Herbal medications are being increasingly used by the American population especially for common conditions like arthritis. They have been reported to cause adverse effects, including significant hepatotoxicity, but reporting remains sporadic. We report here a patient who developed drug induced liver injury following the intake of Move Free, which is an over-the-counter arthritis supplement. We propose that Chinese skullcap, which is one of the herbal ingredients of the medication, is responsible for the adverse event. There was a strong temporal association between the intake of supplement and onset of symptoms, and also there have been a few recent case reports implicating the same component. A unique observation in our case is the occurrence of pulmonary infiltrates simultaneously with the hepatotoxicity, and this side effect has not been well documented before. Both the hepatic and pulmonary complications completely resolved over few weeks after the patient stopped taking the medication. Since these supplements are readily available over the counter, we feel that it is important to document possible adverse outcomes to raise awareness in the medical community and also among patients. PMID:25431706

  2. Massive Pulmonary Embolism in a Patient with Heparin Induced Thrombocytopenia: Successful Treatment with Dabigatran.

    PubMed

    Bircan, Haci Ahmet; Alanoglu, Emine Guchan

    2016-02-01

    Heparin induced thrombocytopenia (HIT) is a rare, potentially fatal, immune-mediated complication of heparin therapy, associated with thrombosis and thrombocytopenia. In this study, a successful dabigatran administration in a case with massive pulmonary thromboembolism (mPTE) and HIT is presented. 57 years-old female, who was receiving low molecular weight heparin (LMWH) (0.4 mL once a daily, S.C. for 11 days) due to total knee replacement, was referred to our clinic with the hypotension and syncope attacks. Her echocardiography and pulmonary CT angiography findings were consistent with mPTE. We detected a serious decrease in her platelet count highly suggestive for HIT (plt: 54×10(3)/µL). LMWH was discontinued and dabigatran was started (150 mg twice daily). After platelet count increased over 150×10(3)/μL, dabigatran was switched to warfarin. Since heparin is widely used in medicine, all physicians need to be aware of this life threatening complication of heparin. Replacing heparin with an alternative anticoagulant such as dabigatran may become a life-saving strategy especially in case of HIT complicated with mPTE. PMID:27026768

  3. Particle-induced pulmonary acute phase response may be the causal link between particle inhalation and cardiovascular disease

    PubMed Central

    Saber, Anne T; Jacobsen, Nicklas R; Jackson, Petra; Poulsen, Sarah Søs; Kyjovska, Zdenka O; Halappanavar, Sabina; Yauk, Carole L; Wallin, Håkan; Vogel, Ulla

    2014-01-01

    Inhalation of ambient and workplace particulate air pollution is associated with increased risk of cardiovascular disease. One proposed mechanism for this association is that pulmonary inflammation induces a hepatic acute phase response, which increases risk of cardiovascular disease. Induction of the acute phase response is intimately linked to risk of cardiovascular disease as shown in both epidemiological and animal studies. Indeed, blood levels of acute phase proteins, such as C-reactive protein and serum amyloid A, are independent predictors of risk of cardiovascular disease in prospective epidemiological studies. In this review, we present and review emerging evidence that inhalation of particles (e.g., air diesel exhaust particles and nanoparticles) induces a pulmonary acute phase response, and propose that this induction constitutes the causal link between particle inhalation and risk of cardiovascular disease. Increased levels of acute phase mRNA and proteins in lung tissues, bronchoalveolar lavage fluid and plasma clearly indicate pulmonary acute phase response following pulmonary deposition of different kinds of particles including diesel exhaust particles, nanoparticles, and carbon nanotubes. The pulmonary acute phase response is dose-dependent and long lasting. Conversely, the hepatic acute phase response is reduced relative to lung or entirely absent. We also provide evidence that pulmonary inflammation, as measured by neutrophil influx, is a predictor of the acute phase response and that the total surface area of deposited particles correlates with the pulmonary acute phase response. We discuss the implications of these findings in relation to occupational exposure to nanoparticles. How to cite this article: WIREs Nanomed Nanobiotechnol 2014, 6:517–531. doi: 10.1002/wnan.1279 PMID:24920450

  4. Daily activities are sufficient to induce dynamic pulmonary hyperinflation and dyspnea in chronic obstructive pulmonary disease patients

    PubMed Central

    Castro, Antonio A.M.; Kümpel, Claudia; Rangueri, Rosana Chaves; Oliveira, Maurício Dalcin; Dornelles, Rodrigo Alves; Brito, Emerson Roberto; Seki, Tânia Maria; Porto, Elias F

    2012-01-01

    OBJECTIVE: The aim of this study was to measure dynamic lung hyperinflation and its influence on dyspnea perception in moderate and severe chronic obstructive pulmonary disease patients after performing activities of daily living. METHODS: We measured inspiratory capacity, sensation of dyspnea, peripheral oxygen saturation, heart rate and respiratory rate in 19 chronic obstructive pulmonary disease patients. These measurements were taken at rest and after performing activities of daily living (e.g., going up and down a set of stairs, going up and down a ramp and sweeping and mopping a room). RESULT: The inspiratory capacity of patients at rest was significantly decreased compared to the capacity of patients after performing activities. The change in inspiratory capacity was -0.67 L after going up and down a ramp, -0.46 L after sweeping and mopping a room, and -0.55 L after climbing up and down a set of stairs. Dyspnea perception increased significantly between rest, sweeping and mopping, and going up and down a set of stairs. Dyspnea perception correlated positively with inspiratory capacity variation (r = 0.85) and respiratory rate (r = 0.37) and negatively with peripheral oxygen saturation (r = -0.28). CONCLUSION: Chronic obstructive pulmonary disease patients exhibited reductions in inspiratory capacity and increases in dyspnea perception during commonly performed activities of daily living, which may limit physical performance in these patients. PMID:22522756

  5. Role of Cigarette Smoke-Induced Aggresome Formation in Chronic Obstructive Pulmonary Disease-Emphysema Pathogenesis.

    PubMed

    Tran, Ian; Ji, Changhoon; Ni, Inzer; Min, Taehong; Tang, Danni; Vij, Neeraj

    2015-08-01

    Cigarette smoke (CS) exposure is known to induce proteostasis imbalance that can initiate accumulation of ubiquitinated proteins. Therefore, the primary goal of this study was to determine if first- and secondhand CS induces localization of ubiquitinated proteins in perinuclear spaces as aggresome bodies. Furthermore, we sought to determine the mechanism by which smoke-induced aggresome formation contributes to chronic obstructive pulmonary disease (COPD)-emphysema pathogenesis. Hence, Beas2b cells were treated with CS extract (CSE) for in vitro experimental analysis of CS-induced aggresome formation by immunoblotting, microscopy, and reporter assays, whereas chronic CS-exposed murine model and human COPD-emphysema lung tissues were used for validation. In preliminary analysis, we observed a significant (P < 0.01) increase in ubiquitinated protein aggregation in the insoluble protein fraction of CSE-treated Beas2b cells. We verified that CS-induced ubiquitin aggregrates are localized in the perinuclear spaces as aggresome bodies. These CS-induced aggresomes (P < 0.001) colocalize with autophagy protein microtubule-associated protein 1 light chain-3B(+) autophagy bodies, whereas U.S. Food and Drug Administration-approved autophagy-inducing drug (carbamazepine) significantly (P < 0.01) decreases their colocalization and expression, suggesting CS-impaired autophagy. Moreover, CSE treatment significantly increases valosin-containing protein-p62 protein-protein interaction (P < 0.0005) and p62 expression (aberrant autophagy marker; P < 0.0001), verifying CS-impaired autophagy as an aggresome formation mechanism. We also found that inhibiting protein synthesis by cycloheximide does not deplete CS-induced ubiquitinated protein aggregates, suggesting the role of CS-induced protein synthesis in aggresome formation. Next, we used an emphysema murine model to verify that chronic CS significantly (P < 0.0005) induces aggresome formation. Moreover, we

  6. Activity of endothelium-derived hyperpolarizing factor is augmented in monocrotaline-induced pulmonary hypertension of rat lungs.

    PubMed

    Morio, Yoshiteru; Homma, Noriyuki; Takahashi, Hideki; Yamamoto, Akihito; Nagaoka, Tetsutaro; Sato, Koichi; Muramatsu, Masashi; Fukuchi, Yoshinosuke

    2007-01-01

    The mechanism of endothelium-dependent vasodilator signaling involves three components such as nitric oxide, prostacyclin, and endothelium-derived hyperpolarizing factor (EDHF). Although EDHF is distinct from nitric oxide and prostacyclin, it requires activation of Ca(2+)-sensitive K(+) channels (K(Ca)) and cytochrome P(450) metabolites. However, the physiological role of EDHF in the pulmonary circulation is unclear. Thus, we tested if EDHF would regulate vascular tone in rat lungs of control and monocrotaline (MCT)-induced pulmonary hypertension. Inhibition of EDHF with a combination of K(Ca) blockers, charybdotoxin (50 nM) plus apamin (50 nM), increased baseline vascular tone in MCT-induced hypertensive lungs. Thapsigargin (TG; 100 nM), an inhibitor of Ca-ATPase, caused greater EDHF-mediated vasodilation in MCT-induced hypertensive lungs. TG-induced vasodilation was abolished with the charybdotoxin-apamin combination. Sulfaphenazole (10 muM), a cytochrome P(450) inhibitor, reduced the TG-induced vasodilation in MCT-induced hypertensive lungs. RT-PCR analysis exhibited an increase in K(Ca) mRNA in MCT-treated lungs. These results indicate the augmentation of tonic EDHF activity, at least in part, through the alteration in cytochrome P(450) metabolites and the upregulation of K(Ca) expression in MCT-induced pulmonary hypertension. PMID:17438361

  7. Serum Amyloid P Therapeutically Attenuates Murine Bleomycin-Induced Pulmonary Fibrosis via Its Effects on Macrophages

    PubMed Central

    Murray, Lynne A.; Rosada, Rogerio; Moreira, Ana Paula; Joshi, Amrita; Kramer, Michael S.; Hesson, David P.; Argentieri, Rochelle L.; Mathai, Susan; Gulati, Mridu; Herzog, Erica L.; Hogaboam, Cory M.

    2010-01-01

    Macrophages promote tissue remodeling but few mechanisms exist to modulate their activity during tissue fibrosis. Serum amyloid P (SAP), a member of the pentraxin family of proteins, signals through Fcγ receptors which are known to affect macrophage activation. We determined that IPF/UIP patients have increased protein levels of several alternatively activated pro-fibrotic (M2) macrophage-associated proteins in the lung and monocytes from these patients show skewing towards an M2 macrophage phenotype. SAP therapeutically inhibits established bleomycin-induced pulmonary fibrosis, when administered systemically or locally to the lungs. The reduction in aberrant collagen deposition was associated with a reduction in M2 macrophages in the lung and increased IP10/CXCL10. These data highlight the role of macrophages in fibrotic lung disease, and demonstrate a therapeutic action of SAP on macrophages which may extend to many fibrotic indications caused by over-exuberant pro-fibrotic macrophage responses. PMID:20300636

  8. Particle-Induced Pulmonary Acute Phase Response Correlates with Neutrophil Influx Linking Inhaled Particles and Cardiovascular Risk

    PubMed Central

    Saber, Anne Thoustrup; Lamson, Jacob Stuart; Jacobsen, Nicklas Raun; Ravn-Haren, Gitte; Hougaard, Karin Sørig; Nyendi, Allen Njimeri; Wahlberg, Pia; Madsen, Anne Mette; Jackson, Petra; Wallin, Håkan; Vogel, Ulla

    2013-01-01

    Background Particulate air pollution is associated with cardiovascular disease. Acute phase response is causally linked to cardiovascular disease. Here, we propose that particle-induced pulmonary acute phase response provides an underlying mechanism for particle-induced cardiovascular risk. Methods We analysed the mRNA expression of Serum Amyloid A (Saa3) in lung tissue from female C57BL/6J mice exposed to different particles including nanomaterials (carbon black and titanium dioxide nanoparticles, multi- and single walled carbon nanotubes), diesel exhaust particles and airborne dust collected at a biofuel plant. Mice were exposed to single or multiple doses of particles by inhalation or intratracheal instillation and pulmonary mRNA expression of Saa3 was determined at different time points of up to 4 weeks after exposure. Also hepatic mRNA expression of Saa3, SAA3 protein levels in broncheoalveolar lavage fluid and in plasma and high density lipoprotein levels in plasma were determined in mice exposed to multiwalled carbon nanotubes. Results Pulmonary exposure to particles strongly increased Saa3 mRNA levels in lung tissue and elevated SAA3 protein levels in broncheoalveolar lavage fluid and plasma, whereas hepatic Saa3 levels were much less affected. Pulmonary Saa3 expression correlated with the number of neutrophils in BAL across different dosing regimens, doses and time points. Conclusions Pulmonary acute phase response may constitute a direct link between particle inhalation and risk of cardiovascular disease. We propose that the particle-induced pulmonary acute phase response may predict risk for cardiovascular disease. PMID:23894396

  9. Cellular localization of transforming growth factor-beta expression in bleomycin-induced pulmonary fibrosis.

    PubMed Central

    Zhang, K.; Flanders, K. C.; Phan, S. H.

    1995-01-01

    Bleomycin-induced pulmonary fibrosis is associated with increased lung transforming growth factor-beta (TGF-beta) gene expression, but cellular localization of the source of this expression has not been unequivocally established. In this study, lung fibrosis was induced in rats by endotracheal bleomycin injection on day 0 and, on selected days afterwards, lungs were harvested for in situ hybridization, immunohistochemical and histochemical analyses for TGF-beta 1 mRNA and protein expression, and cell identification. The results show that control lungs express essentially no detectable TGF-beta 1 mRNA or protein in the parenchyma. Before day 3 after bleomycin treatment, scattered bronchiolar epithelial cells, mononuclear cells, and eosinophils expressed elevated levels of TGF-beta 1. Between days 3 and 14, there was a major increase in the number of eosinophils, myofibroblasts, and fibroblasts strongly expressing TGF-beta 1 mRNA and protein. TGF-beta 1-producing cells were predominantly localized within areas of injury and active fibrosis. After day 14, the intensity and number of TGF-beta 1-expressing cells significantly declined and were predominantly found in fibroblasts in fibrotic areas. The expression of TGF-beta 1 protein was generally coincident with that for mRNA with the exception of bronchiolar epithelial cells in which strong protein expression was unaccompanied by a commensurate increase in mRNA. The study demonstrates that myofibroblasts, fibroblasts, and eosinophils represent the major sources of increased lung TGF-beta 1 expression in this model of pulmonary fibrosis. Images Figure 2 Figure 3 Figure 4 PMID:7543734

  10. Bleomycin-induced pulmonary fibrosis is attenuated in gamma-glutamyl transpeptidase-deficient mice.

    PubMed

    Pardo, Annie; Ruiz, Victor; Arreola, José Luis; Ramírez, Remedios; Cisneros-Lira, José; Gaxiola, Miguel; Barrios, Roberto; Kala, Subbarao V; Lieberman, Michael W; Selman, Moisés

    2003-03-15

    To investigate repair mechanisms in bleomycin-induced pulmonary fibrosis, we used mice deficient in gamma-glutamyl transpeptidase (GGT-/-), a key enzyme in glutathione (GSH) and cysteine metabolism. Seventy-two hours after bleomycin (0.03 U/g), GGT-/- mice displayed a different inflammatory response to wild-type mice as judged by a near absence of neutrophils in lung tissue and bronchoalveolar lavage and a less pronounced rise in matrix metalloproteinase-9. Inflammation in GGT-/- mice consisted mainly of lymphocytes and macrophages. At 1 month, lungs from bleomycin-treated GGT-/- mice exhibited minimal areas of fibrosis compared with wild-type mice(light microscopy fibrosis index: 510 +/- 756 versus 1975 +/- 817, p < 0.01). Lung collagen content revealed a significant increase in bleomycin-treated wild-type (15.1 +/- 3.8 versus 8.5 +/- 0.7 microg hydroxy(OH)-proline/mg dry weight, p < 0.01) but not in GGT-/- (10.4 +/- 1.7 versus 8.8 +/- 0.8). Control lungs from GGT-/- showed a significant reduction of cysteine (0.03 +/- 0.005 versus 0.055 +/- 0.001, p < 0.02) and GSH levels (1.24 +/- 0.055 versus 1.79 +/- 0.065, p < 0.002). These values decreased after 72 hours of bleomycin in both GGT-/- and wild-type but reached their respective control values after 1 month. Supplementation with N-acetyl cysteine partially ameliorated the effects of GGT deficiency. These findings suggest that increased neutrophils and matrix metalloproteinase-9 during the early inflammatory response and adequate thiol reserves are key elements in the fibrotic response after bleomycin-induced pulmonary injury. PMID:12468440

  11. Emission-particle-induced ventilatory abnormalities in a rat model of pulmonary hypertension.

    PubMed Central

    Gardner, Sarah Y; McGee, John K; Kodavanti, Urmila P; Ledbetter, Allen; Everitt, Jeffrey I; Winsett, Darrell W; Doerfler, Donald L; Costa, Daniel L

    2004-01-01

    Preexistent cardiopulmonary disease in humans appears to enhance susceptibility to the adverse effects of ambient particulate matter. Previous studies in this laboratory have demonstrated enhanced inflammation and mortality after intratracheal instillation (IT) and inhalation (INH) of residual oil fly ash (ROFA) in a rat model of pulmonary hypertension induced by monocrotaline (MCT). The present study was conducted to examine the effects of ROFA in this model on ventilatory function in unanesthetized, unrestrained animals. Sixty-day-old male CD rats were injected with MCT (60 mg/kg) or vehicle (VEH) intraperitoneally 10 days before IT of ROFA (8.3 mg/kg) or saline (SAL) (control) or nose-only INH of ROFA [15 mg/m3 for 6 hr on 3 consecutive days or air (control)]. At 24 and 72 hr after exposure, rats were studied individually in a simultaneous gas uptake/whole-body plethysmograph. Lungs were removed at 72 hr for histology. Pulmonary test results showed that tidal volume (VT) decreased 24 hr after IT of ROFA in MCT-treated rats. Breathing frequency, minute volume (VE), and the ventilatory equivalent for oxygen increased in MCT- and VEH-treated rats 24 hr after IT or INH of ROFA and remained elevated 72 hr post-IT. O2 uptake (VO2) decreased after IT of ROFA in MCT-treated rats. Carbon monoxide uptake decreased 24 hr after IT of ROFA, returning to control values in VEH-treated rats but remaining low in MCT-treated rats 72 hr post-IT. ROFA exposure induced histologic changes and abnormalities in several ventilatory parameters, many of which were enhanced by MCT treatment. PMID:15175175

  12. Amplification of TGFβ Induced ITGB6 Gene Transcription May Promote Pulmonary Fibrosis

    PubMed Central

    Tatler, Amanda L.; Goodwin, Amanda T.; Gbolahan, Olumide; Saini, Gauri; Porte, Joanne; John, Alison E.; Clifford, Rachel L.; Violette, Shelia M.; Weinreb, Paul H.; Parfrey, Helen; Wolters, Paul J.; Gauldie, Jack; Kolb, Martin; Jenkins, Gisli

    2016-01-01

    Idiopathic pulmonary fibrosis (IPF) is a devastating, progressive disease with poor survival rates and limited treatment options. Upregulation of αvβ6 integrins within the alveolar epithelial cells is a characteristic feature of IPF and correlates with poor patient survival. The pro-fibrotic cytokine TGFβ1 can upregulate αvβ6 integrin expression but the molecular mechanisms driving this effect have not previously been elucidated. We confirm that stimulation with exogenous TGFβ1 increases expression of the integrin β6 subunit gene (ITGB6) and αvβ6 integrin cell surface expression in a time- and concentration-dependent manner. TGFβ1-induced ITGB6 expression occurs via transcriptional activation of the ITGB6 gene, but does not result from effects on ITGB6 mRNA stability. Basal expression of ITGB6 in, and αvβ6 integrins on, lung epithelial cells occurs via homeostatic αvβ6-mediated TGFβ1 activation in the absence of exogenous stimulation, and can be amplified by TGFβ1 activation. Fundamentally, we show for the first time that TGFβ1-induced ITGB6 expression occurs via canonical Smad signalling since dominant negative constructs directed against Smad3 and 4 inhibit ITGB6 transcriptional activity. Furthermore, disruption of a Smad binding site at -798 in the ITGB6 promoter abolishes TGFβ1-induced ITGB6 transcriptional activity. Using chromatin immunoprecipitation we demonstrate that TGFβ1 stimulation of lung epithelial cells results in direct binding of Smad3, and Smad4, to the ITGB6 gene promoter within this region. Finally, using an adenoviral TGFβ1 over-expression model of pulmonary fibrosis we demonstrate that Smad3 is crucial for TGFβ1-induced αvβ6 integrin expression within the alveolar epithelium in vivo. Together, these data confirm that a homeostatic, autocrine loop of αvβ6 integrin activated TGFβ1-induced ITGB6 gene expression regulates epithelial basal αvβ6 integrin expression, and demonstrates that this occurs via Smad

  13. High-density lipoproteins potentiate α1-antitrypsin therapy in elastase-induced pulmonary emphysema.

    PubMed

    Moreno, Juan-Antonio; Ortega-Gomez, Almudena; Rubio-Navarro, Alfonso; Louedec, Liliane; Ho-Tin-Noé, Benoit; Caligiuri, Giuseppina; Nicoletti, Antonino; Levoye, Angelique; Plantier, Laurent; Meilhac, Olivier

    2014-10-01

    Several studies report that high-density lipoproteins (HDLs) can carry α1-antitrypsin (AAT; an elastase inhibitor). We aimed to determine whether injection of exogenous HDL, enriched or not in AAT, may have protective effects against pulmonary emphysema. After tracheal instillation of saline or elastase, mice were randomly treated intravenously with saline, human plasma HDL (75 mg apolipoprotein A1/kg), HDL-AAT (75 mg apolipoprotein A1-3.75 mg AAT/kg), or AAT alone (3.75 mg/kg) at 2, 24, 48, and 72 hours. We have shown that HDL-AAT reached the lung and prevented the development of pulmonary emphysema by 59.3% at 3 weeks (alveoli mean chord length, 22.9 ± 2.8 μm versus 30.7 ± 4.5 μm; P < 0.001), whereas injection of HDL or AAT alone only showed a moderate, nonsignificant protective effect (28.2 ± 4.2 μm versus 30.7 ± 5 μm [P = 0.23] and 27.3 ± 5.66 μm versus 30.71 ± 4.96 μm [P = 0.18], respectively). Indeed, protection by HDL-AAT was significantly higher than that observed with HDL or AAT (P = 0.006 and P = 0.048, respectively). This protective effect was associated (at 6, 24, and 72 h) with: (1) a reduction in neutrophil and macrophage number in the bronchoalveolar lavage fluid; (2) decreased concentrations of IL-6, monocyte chemoattractant protein-1, and TNF-α in both bronchoalveolar lavage fluid and plasma; (3) a reduction in matrix metalloproteinase-2 and matrix metalloproteinase-9 activities; and (4) a reduction in the degradation of fibronectin, a marker of tissue damage. In addition, HDL-AAT reduced acute cigarette smoke-induced inflammatory response. Intravenous HDL-AAT treatment afforded a better protection against elastase-induced pulmonary emphysema than AAT alone, and may represent a significant development for the management of emphysema associated with AAT deficiency. PMID:24787644

  14. Iron-induced remodeling in cultured rat pulmonary artery endothelial cells.

    PubMed

    Gorbunov, Nikolai V; Atkins, James L; Gurusamy, Narasimman; Pitt, Bruce R

    2012-02-01

    Although iron is known to be a component of the pathogenesis and/or maintenance of acute lung injury (ALI) in experimental animals and human subjects, the majority of these studies have focused on disturbances in iron homeostasis in the airways resulting from exposure to noxious gases and particles. Considerably less is known about the effect of increased plasma levels of redox-reactive non-transferrin bound iron (NTBI) and its impact on pulmonary endothelium. Plasma levels of NTBI can increase under various pathophysiological conditions, including those associated with ALI, and multiple mechanisms are in place to affect the [Fe(2+)]/[Fe(3+)] redox steady state. It is well accepted, however, that intracellular transport of NTBI occurs after reduction of [Fe(3+)] to [Fe(2+)] (and is mediated by divalent metal transporters). Accordingly, as an experimental model to investigate mechanisms mediating vascular effects of redox reactive iron, rat pulmonary artery endothelial cells (RPAECs) were subjected to pulse treatment (10 min) with [Fe(2+)] nitriloacetate (30 μM) in the presence of pyrithione, an iron ionophore, to acutely increase intracellular labile pool of iron. Cellular iron influx and cell shape profile were monitored with time-lapse imaging techniques. Exposure of RPAECs to [Fe(2+)] resulted in: (i) an increase in intracellular iron as detected by the iron sensitive fluorophore, PhenGreen; (ii) depletion of cell glutathione; and (iii) nuclear translocation of stress-response transcriptional factors Nrf2 and NFkB (p65). The resulting iron-induced cell alterations were characterized by cell polarization and formation of membrane cuplike and microvilli-like projections abundant with ICAM-1, caveolin-1, and F-actin. The iron-induced re-arrangements in cytoskeleton, alterations in focal cell-cell interactions, and cell buckling were accompanied by decrease in electrical resistance of RPAEC monolayer. These effects were partially eliminated in the presence of N

  15. Pulmonary surfactant inhibits LPS-induced nitric oxide production by alveolar macrophages.

    PubMed

    Miles, P R; Bowman, L; Rao, K M; Baatz, J E; Huffman, L

    1999-01-01

    The objectives of this investigation were 1) to report that pulmonary surfactant inhibits lipopolysaccharide (LPS)-induced nitric oxide (. NO) production by rat alveolar macrophages, 2) to study possible mechanisms for this effect, and 3) to determine which surfactant component(s) is responsible. NO produced by the cells in response to LPS is due to an inducible. NO synthase (iNOS). Surfactant inhibits LPS-induced. NO formation in a concentration-dependent manner;. NO production is inhibited by approximately 50 and approximately 75% at surfactant levels of 100 and 200 microg phospholipid/ml, respectively. The inhibition is not due to surfactant interference with the interaction of LPS with the cells or to disruption of the formation of iNOS mRNA. Also, surfactant does not seem to reduce. NO formation by directly affecting iNOS activity or by acting as an antioxidant or radical scavenger. However, in the presence of surfactant, there is an approximately 80% reduction in the amount of LPS-induced iNOS protein in the cells. LPS-induced. NO production is inhibited by Survanta, a surfactant preparation used in replacement therapy, as well as by natural surfactant. NO formation is not affected by the major lipid components of surfactant or by two surfactant-associated proteins, surfactant protein (SP) A or SP-C. However, the hydrophobic SP-B inhibits. NO formation in a concentration-dependent manner;. NO production is inhibited by approximately 50 and approximately 90% at SP-B levels of 1-2 and 10 microgram/ml, respectively. These results show that lung surfactant inhibits LPS-induced. NO production by alveolar macrophages, that the effect is due to a reduction in iNOS protein levels, and that the surfactant component responsible for the reduction is SP-B. PMID:9887071

  16. A clinically authentic mouse model of enterovirus 71 (EV-A71)-induced neurogenic pulmonary oedema

    PubMed Central

    Victorio, Carla Bianca Luena; Xu, Yishi; Ng, Qimei; Chua, Beng Hooi; Alonso, Sylvie; Chow, Vincent T. K.; Chua, Kaw Bing

    2016-01-01

    Enterovirus 71 (EV-A71) is a neurotropic virus that sporadically causes fatal neurologic illness among infected children. Animal models of EV-A71 infection exist, but they do not recapitulate in animals the spectrum of disease and pathology observed in fatal human cases. Specifically, neurogenic pulmonary oedema (NPE)—the main cause of EV-A71 infection-related mortality—is not observed in any of these models. This limits their utility in understanding viral pathogenesis of neurologic infections. We report the development of a mouse model of EV-A71 infection displaying NPE in severely affected animals. We inoculated one-week-old BALB/c mice with an adapted EV-A71 strain and identified clinical signs consistent with observations in human cases and other animal models. We also observed respiratory distress in some mice. At necropsy, we found their lungs to be heavier and incompletely collapsed compared to other mice. Serum levels of catecholamines and histopathology of lung and brain tissues of these mice strongly indicated onset of NPE. The localization of virally-induced brain lesions also suggested a potential pathogenic mechanism for EV-A71-induced NPE. This novel mouse model of virally-induced NPE represents a valuable resource for studying viral mechanisms of neuro-pathogenesis and pre-clinical testing of potential therapeutics and prophylactics against EV-A71-related neurologic complications. PMID:27357918

  17. A clinically authentic mouse model of enterovirus 71 (EV-A71)-induced neurogenic pulmonary oedema.

    PubMed

    Victorio, Carla Bianca Luena; Xu, Yishi; Ng, Qimei; Chua, Beng Hooi; Alonso, Sylvie; Chow, Vincent T K; Chua, Kaw Bing

    2016-01-01

    Enterovirus 71 (EV-A71) is a neurotropic virus that sporadically causes fatal neurologic illness among infected children. Animal models of EV-A71 infection exist, but they do not recapitulate in animals the spectrum of disease and pathology observed in fatal human cases. Specifically, neurogenic pulmonary oedema (NPE)-the main cause of EV-A71 infection-related mortality-is not observed in any of these models. This limits their utility in understanding viral pathogenesis of neurologic infections. We report the development of a mouse model of EV-A71 infection displaying NPE in severely affected animals. We inoculated one-week-old BALB/c mice with an adapted EV-A71 strain and identified clinical signs consistent with observations in human cases and other animal models. We also observed respiratory distress in some mice. At necropsy, we found their lungs to be heavier and incompletely collapsed compared to other mice. Serum levels of catecholamines and histopathology of lung and brain tissues of these mice strongly indicated onset of NPE. The localization of virally-induced brain lesions also suggested a potential pathogenic mechanism for EV-A71-induced NPE. This novel mouse model of virally-induced NPE represents a valuable resource for studying viral mechanisms of neuro-pathogenesis and pre-clinical testing of potential therapeutics and prophylactics against EV-A71-related neurologic complications. PMID:27357918

  18. Nitric oxide decreases the sensitivity of pulmonary endothelial cells to LPS-induced apoptosis in a zinc-dependent fashion.

    PubMed

    Tang, Zi-Lue; Wasserloos, Karla J; Liu, Xianghong; Stitt, Molly S; Reynolds, Ian J; Pitt, Bruce R; St Croix, Claudette M

    2002-01-01

    We hypothesized that: (a) S-nitrosylation of metallothionein (MT) is a component of pulmonary endothelial cell nitric oxide (NO) signaling that is associated with an increase in labile zinc; and (b) NO mediated increases in labile zinc in turn reduce the sensitivity of pulmonary endothelium to LPS-induced apoptosis. We used microspectrofluorometric techniques to show that exposing mouse lung endothelial cells (MLEC) to the NO-donor, S-nitrosocysteine, resulted in a 45% increase in fluorescence of the Zn2+-specific fluorophore, Zinquin, that was rapidly reversed by exposure to the Zn2+ chelator, NNN'N'-tetrakis-(2-pyridylmethyl)ethylenediamine; TPEN). The absence of a NO-mediated increase in labile Zn2+ in MLEC from MT-I and -II knockout mice inferred a critical role for MT in the regulation of Zn2+ homeostasis by NO. Furthermore, we found that prior exposure of cultured endothelial cells from sheep pulmonary artery (SPAEC), to the NO-donor, S-nitroso-N-acetylpenicillamine (SNAP) reduced their sensitivity to lipopolysaccharide (LPS) induced apoptosis. The anti-apoptotic effects of NO were significantly inhibited by Zn2+ chelation with low doses of TPEN (10 microM). Collectively, these data suggest that S-nitrosylation of MT is associated with an increase in labile (TPEN chelatable) zinc and NO-mediated MT dependent zinc release is associated with reduced sensitivity to LPS-induced apoptosis in pulmonary endothelium. PMID:12162436

  19. The role of collagen in extralobar pulmonary artery stiffening in response to hypoxia-induced pulmonary hypertension.

    PubMed

    Ooi, Chen Yen; Wang, Zhijie; Tabima, Diana M; Eickhoff, Jens C; Chesler, Naomi C

    2010-12-01

    Hypoxic pulmonary hypertension (HPH) causes extralobar pulmonary artery (PA) stiffening, which potentially impairs right ventricular systolic function. Changes in the extracellular matrix proteins collagen and elastin have been suggested to contribute to this arterial stiffening. We hypothesized that vascular collagen accumulation is a major cause of extralobar PA stiffening in HPH and tested our hypothesis with transgenic mice that synthesize collagen type I resistant to collagenase degradation (Col1a1(R/R)). These mice and littermate controls that have normal collagen degradation (Col1a1(+/+)) were exposed to hypoxia for 10 days; some were allowed to recover for 32 days. In vivo PA pressure and isolated PA mechanical properties and collagen and elastin content were measured for all groups. Vasoactive studies were also performed with U-46619, Y-27632, or calcium- and magnesium-free medium. Pulmonary hypertension occurred in both mouse strains due to chronic hypoxia and resolved with recovery. HPH caused significant PA mechanical changes in both mouse strains: circumferential stretch decreased, and mid-to-high-strain circumferential elastic modulus increased (P < 0.05 for both). Impaired collagen type I degradation prevented a return to baseline mechanical properties with recovery and, in fact, led to an increase in the low and mid-to-high-strain moduli compared with hypoxia (P < 0.05 for both). Significant changes in collagen content were found, which tended to follow changes in mid-to-high-strain elastic modulus. No significant changes in elastin content or vasoactivity were observed. Our results demonstrate that collagen content is important to extralobar PA stiffening caused by chronic hypoxia. PMID:20852040

  20. 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. PMID:26475732

  1. Comparison of Thresholds for Pulmonary Capillary Hemorrhage Induced by Pulsed-wave and B-mode Ultrasound

    NASA Astrophysics Data System (ADS)

    Miller, Douglas L.; Dou, Chunyan; Raghavendran, Krishnan

    Pulsed ultrasound was found to induce pulmonary capillary hemorrhage (PCH) in mice about 25 years ago but remains a poorly understood risk factor for pulmonary diagnostic ultrasound. In early research using laboratory fixed beam ultrasound, thresholds for PCH had frequency variation from 1-4 MHz similar to the Mechanical Index. In recent research, thresholds for B mode diagnostic ultrasound from 1.5-12 MHz had little dependence on frequency. To compare the diagnostic ultrasound method to laboratory pulsed exposure, thresholds for fixed beam ultrasound were determined using comparable methods at 1.5 and 7.5 MHz. PCH thresholds were lower for simple fixed-beam pulse modes than for B mode and in approximate agreement with early research. However, for comparable timing parameters, PCH thresholds had little dependence on ultrasonic frequency. These findings suggest that the MI may not be directly useful as a dosimetric parameter for safety guidance in pulmonary ultrasound.

  2. Non-invasive monitoring of pulmonary artery pressure from timing information by EIT: experimental evaluation during induced hypoxia.

    PubMed

    Proença, Martin; Braun, Fabian; Solà, Josep; Adler, Andy; Lemay, Mathieu; Thiran, Jean-Philippe; Rimoldi, Stefano F

    2016-06-01

    Monitoring of pulmonary artery pressure (PAP) in pulmonary hypertensive patients is currently limited to invasive solutions. We investigate a novel non-invasive approach for continuous monitoring of PAP, based on electrical impedance tomography (EIT), a safe, low-cost and non-invasive imaging technology. EIT recordings were performed in three healthy subjects undergoing hypoxia-induced PAP variations. The pulmonary pulse arrival time (PAT), a timing parameter physiologically linked to the PAP, was automatically calculated from the EIT signals. Values were compared to systolic PAP values from Doppler echocardiography, and yielded strong correlation scores ([Formula: see text]) for all three subjects. Results suggest the feasibility of non-invasive, unsupervised monitoring of PAP. PMID:27212013

  3. Resistin deficiency in mice has no effect on pulmonary responses induced by acute ozone exposure.

    PubMed

    Razvi, Shehla S; Richards, Jeremy B; Malik, Farhan; Cromar, Kevin R; Price, Roger E; Bell, Cynthia S; Weng, Tingting; Atkins, Constance L; Spencer, Chantal Y; Cockerill, Katherine J; Alexander, Amy L; Blackburn, Michael R; Alcorn, Joseph L; Haque, Ikram U; Johnston, Richard A

    2015-11-15

    Acute exposure to ozone (O3), an air pollutant, causes pulmonary inflammation, airway epithelial desquamation, and airway hyperresponsiveness (AHR). Pro-inflammatory cytokines-including IL-6 and ligands of chemokine (C-X-C motif) receptor 2 [keratinocyte chemoattractant (KC) and macrophage inflammatory protein (MIP)-2], TNF receptor 1 and 2 (TNF), and type I IL-1 receptor (IL-1α and IL-1β)-promote these sequelae. Human resistin, a pleiotropic hormone and cytokine, induces expression of IL-1α, IL-1β, IL-6, IL-8 (the human ortholog of murine KC and MIP-2), and TNF. Functional differences exist between human and murine resistin; yet given the aforementioned observations, we hypothesized that murine resistin promotes O3-induced lung pathology by inducing expression of the same inflammatory cytokines as human resistin. Consequently, we examined indexes of O3-induced lung pathology in wild-type and resistin-deficient mice following acute exposure to either filtered room air or O3. In wild-type mice, O3 increased bronchoalveolar lavage fluid (BALF) resistin. Furthermore, O3 increased lung tissue or BALF IL-1α, IL-6, KC, TNF, macrophages, neutrophils, and epithelial cells in wild-type and resistin-deficient mice. With the exception of KC, which was significantly greater in resistin-deficient compared with wild-type mice, no genotype-related differences in the other indexes existed following O3 exposure. O3 caused AHR to acetyl-β-methylcholine chloride (methacholine) in wild-type and resistin-deficient mice. However, genotype-related differences in airway responsiveness to methacholine were nonexistent subsequent to O3 exposure. Taken together, these data demonstrate that murine resistin is increased in the lungs of wild-type mice following acute O3 exposure but does not promote O3-induced lung pathology. PMID:26386120

  4. Electronic properties of tantalum pentoxide polymorphs from first-principles calculations

    NASA Astrophysics Data System (ADS)

    Lee, J.; Lu, W.; Kioupakis, E.

    2014-11-01

    Tantalum pentoxide (Ta2O5) is extensively studied for its attractive properties in dielectric films, anti-reflection coatings, and resistive switching memory. Although various crystalline structures of tantalum pentoxide have been reported, its structural, electronic, and optical properties still remain a subject of research. We investigate the electronic and optical properties of crystalline and amorphous Ta2O5 structures using first-principles calculations based on density functional theory and the GW method. The calculated band gaps of the crystalline structures are too small to explain the experimental measurements, but the amorphous structure exhibits a strong exciton binding energy and an optical band gap (˜4 eV) in agreement with experiment. We determine the atomic orbitals that constitute the conduction band for each polymorph and analyze the dependence of the band gap on the atomic geometry. Our results establish the connection between the underlying structure and the electronic and optical properties of Ta2O5.

  5. Prevention of bleomycin-induced pulmonary fibrosis after adenovirus-mediated transfer of the bacterial bleomycin resistance gene.

    PubMed Central

    Tran, P L; Weinbach, J; Opolon, P; Linares-Cruz, G; Reynes, J P; Grégoire, A; Kremer, E; Durand, H; Perricaudet, M

    1997-01-01

    A serious limitation in the use of the DNA-cleaving, antitumoral-antibiotic, bleomycin during chemotherapy is pulmonary toxicity. Lung injury induced by bleomycin is characterized by an increased deposition of interstitial extracellular matrix proteins in the alveolar wall that compromises respiratory function. Several drugs have been tested in animal models to prevent the pulmonary toxicity of bleomycin, but have not led to a useful clinical treatment because of their adverse effects on other tissues. We have shown that transgenic mice expressing Streptoalloteichus hindustanus (Sh) ble bleomycin resistance protein in pulmonary epithelial cells in the lungs are protected against bleomycin-induced toxicity in lungs. In the present study, we used intranasal administration by adenovirus-mediated gene transfer of the bleomycin resistance Sh ble gene to mouse lung for prevention of bleomycin-induced pulmonary fibrosis. We constructed recombinant adenoviruses Ad.CMVble and Ad.RSVble harboring the bleomycin resistance Sh ble gene under the control of the cytomegalovirus early promoter and the Rous sarcoma virus early promoter, respectively. Transgene expression was detected in epithelia of conducting airways and alveolar septa by immunostaining with a rabbit polyclonal antibody directed against the bleomycin resistance protein and persisted for the duration of drug treatment; i.e., up to 17 d. No toxic effect was seen in adenovirus-treated mice. Pretreatment of mice with Ad.CMVble or Ad.RSVble completely prevented collagen deposition 42-133 d after bleomycin treatment, as measured by lung OH-proline content. Histologic studies indicated that there was little or no lung injury in the adenovirus/bleomycin-treated mice compared with the bleomycin-treated mice. These observations may lead to new approaches for the prevention of bleomycin-induced pulmonary fibrosis. PMID:9045862

  6. Obesity-induced adipokine imbalance impairs mouse pulmonary vascular endothelial function and primes the lung for injury

    PubMed Central

    Shah, Dilip; Romero, Freddy; Duong, Michelle; Wang, Nadan; Paudyal, Bishnuhari; Suratt, Benjamin T.; Kallen, Caleb B.; Sun, Jianxin; Zhu, Ying; Walsh, Kenneth; Summer, Ross

    2015-01-01

    Obesity is a risk factor for the development of acute respiratory distress syndrome (ARDS) but mechanisms mediating this association are unknown. While obesity is known to impair systemic blood vessel function, and predisposes to systemic vascular diseases, its effects on the pulmonary circulation are largely unknown. We hypothesized that the chronic low grade inflammation of obesity impairs pulmonary vascular homeostasis and primes the lung for acute injury. The lung endothelium from obese mice expressed higher levels of leukocyte adhesion markers and lower levels of cell-cell junctional proteins when compared to lean mice. We tested whether systemic factors are responsible for these alterations in the pulmonary endothelium; treatment of primary lung endothelial cells with obese serum enhanced the expression of adhesion proteins and reduced the expression of endothelial junctional proteins when compared to lean serum. Alterations in pulmonary endothelial cells observed in obese mice were associated with enhanced susceptibility to LPS-induced lung injury. Restoring serum adiponectin levels reversed the effects of obesity on the lung endothelium and attenuated susceptibility to acute injury. Our work indicates that obesity impairs pulmonary vascular homeostasis and enhances susceptibility to acute injury and provides mechanistic insight into the increased prevalence of ARDS in obese humans. PMID:26068229

  7. Endothelin-1 receptor antagonist BQ123 prevents pulmonary artery hypertension induced by low ambient temperature in broilers.

    PubMed

    Yang, Ying; Qiao, Jian; Wu, Zhenlong; Chen, Yue; Gao, Mingyu; Ou, Deyuan; Wang, Huiyu

    2005-12-01

    Evidence has indicated that endothelin-1 is related to the pathogenesis of hypertension. To characterize the role of endothelin-1 (ET-1) in the development of pulmonary hypertension syndrome in broilers, the blockade effect of ETA receptor (ET(A)) antagonist, BQ123, on blood pressure in experimental models of pulmonary hypertension was examined. Birds were locally anesthetized and instrumented with venous catheters for pulmonary arterial pressure (PAP) and right ventricular pressure (RVP), followed by packed cell volume (PCV) and Ascites heart index (AHI) measured, after exposed to low ambient temperature for 7 or 14 d. In treated groups, BQ123 (0.4 or 2.0 microg each time, 2 times a day), administered in abdominal cavities for 7 or 14 d during birds kept in low ambient temperature, prevented both PAP and RVP increasing, especially the high dose BQ123 lowered PAP and RVP to normotensive levels as that in control under normal temperature, whereas significant increases (p<0.05) were found in the two parameters of broilers in both untreated and saline treated group under low ambient temperature compared with those of birds in control. Furthermore, there was also a reduction in low ambient temperature-induced right ventricular hypertrophy in the groups administered BQ123. The preventive effect of BQ123 suggests that ET-1 is associated with the development of broilers' pulmonary hypertension, which leads to the development of ascites, and BQ123 can prevent the occurrence of pulmonary hypertension. PMID:16327149

  8. Inhalable delivery of AAV-based MRP4/ABCC4 silencing RNA prevents monocrotaline-induced pulmonary hypertension

    PubMed Central

    Claude, Caroline; Mougenot, Nathalie; Bechaux, Julia; Hadri, Lahouaria; Brockschnieder, Damian; Clergue, Michel; Atassi, Fabrice; Lompré, Anne-Marie; Hulot, Jean-Sébastien

    2015-01-01

    The ATP-binding cassette transporter MRP4 (encoded by ABCC4) regulates membrane cyclic nucleotides concentrations in arterial cells including smooth muscle cells. MRP4/ABCC4 deficient mice display a reduction in smooth muscle cells proliferation and a prevention of pulmonary hypertension in response to hypoxia. We aimed to study gene transfer of a MRP4/ABCC4 silencing RNA via intratracheal delivery of aerosolized adeno-associated virus 1 (AAV1.shMRP4 or AAV1.control) in a monocrotaline-induced model of pulmonary hypertension in rats. Gene transfer was performed at the time of monocrotaline administration and the effect on the development of pulmonary vascular remodeling was assessed 35 days later. AAV1.shMRP4 dose-dependently reduced right ventricular systolic pressure and hypertrophy with a significant reduction with the higher doses (i.e., >1011 DRP/animal) as compared to AAV1.control. The higher dose of AAV1.shMRP4 was also associated with a significant reduction in distal pulmonary arteries remodeling. AAV1.shMRP4 was finally associated with a reduction in the expression of ANF, a marker of cardiac hypertrophy. Collectively, these results support a therapeutic potential for downregulation of MRP4 for the treatment of pulmonary artery hypertension. PMID:26052533

  9. Obesity-induced adipokine imbalance impairs mouse pulmonary vascular endothelial function and primes the lung for injury.

    PubMed

    Shah, Dilip; Romero, Freddy; Duong, Michelle; Wang, Nadan; Paudyal, Bishnuhari; Suratt, Benjamin T; Kallen, Caleb B; Sun, Jianxin; Zhu, Ying; Walsh, Kenneth; Summer, Ross

    2015-01-01

    Obesity is a risk factor for the development of acute respiratory distress syndrome (ARDS) but mechanisms mediating this association are unknown. While obesity is known to impair systemic blood vessel function, and predisposes to systemic vascular diseases, its effects on the pulmonary circulation are largely unknown. We hypothesized that the chronic low grade inflammation of obesity impairs pulmonary vascular homeostasis and primes the lung for acute injury. The lung endothelium from obese mice expressed higher levels of leukocyte adhesion markers and lower levels of cell-cell junctional proteins when compared to lean mice. We tested whether systemic factors are responsible for these alterations in the pulmonary endothelium; treatment of primary lung endothelial cells with obese serum enhanced the expression of adhesion proteins and reduced the expression of endothelial junctional proteins when compared to lean serum. Alterations in pulmonary endothelial cells observed in obese mice were associated with enhanced susceptibility to LPS-induced lung injury. Restoring serum adiponectin levels reversed the effects of obesity on the lung endothelium and attenuated susceptibility to acute injury. Our work indicates that obesity impairs pulmonary vascular homeostasis and enhances susceptibility to acute injury and provides mechanistic insight into the increased prevalence of ARDS in obese humans. PMID:26068229

  10. Picosecond laser structuring of thin film platinum layers covered with tantalum pentoxide isolation

    SciTech Connect

    Heise, Gerhard; Huber, Heinz; Trappendreher, Daniel; Ilchmann, Florian; Weiss, Robin S.; Wolf, Bernhard

    2012-07-01

    A thin film layer system consisting of platinum (Pt) as conductive layer on a glass substrate and tantalum pentoxide as isolating layer on top of the platinum is attractive for designing biocompatible conductor paths and contact pads for bio sensor chips. For the flexible and rapid patterning of the conductive and the isolating layers, both, the complete removal and the selective ablation of the individual thin films were investigated using ultra-short laser pulses with about 10 ps pulse duration and 1064 nm wavelength at low laser fluences. A platinum film covered with tantalum pentoxide shows a significantly lower ablation threshold than a single Pt film on glass alone when illuminated from the front side. Furthermore, we explored that the tantalum pentoxide film can be removed by glass side illumination from the Pt film, without affecting the Pt film and leaving the Pt film on the glass substrate intact. Those ablation phenomena occur at laser fluences of about 0.2 J/cm{sup 2}, far below the evaporation limit of platinum. We present a detailed ablation threshold value examination for the structuring of these layer systems by front side and glass side irradiation for different film thicknesses. Furthermore, we discuss the possible underlying physical mechanisms of these ablation phenomena.

  11. The Pesticide Metabolites Paraoxon and Malaoxon Induce Cellular Death by Different Mechanisms in Cultured Human Pulmonary Cells.

    PubMed

    Angelini, Daniel J; Moyer, Robert A; Cole, Stephanie; Willis, Kristen L; Oyler, Jonathan; Dorsey, Russell M; Salem, Harry

    2015-01-01

    Organophosphorus (OP) pesticides are known to induce pulmonary toxicity in both humans and experimental animals. To elucidate the mechanism of OP-induced cytotoxicity, we examined the effects of parathion and malathion and their respective metabolites, paraoxon and malaoxon, on primary cultured human large and small airway cells. Exposure to paraoxon and malaoxon produced a dose-dependent increase in cytotoxicity following a 24-hour exposure, while treatment with parathion or malathion produced no effects at clinically relevant concentrations. Exposure to paraoxon-induced caspase activation, but malaoxon failed to induce this response. Since caspases have a major role in the regulation of apoptosis and cell death, we evaluated OP-induced cell death in the presence of a caspase inhibitor. Pharmacological caspase inhibition protected against paraoxon-induced cell death but not malaoxon-induced cell death. These data suggest that caspase activation is a key signaling element in paraoxon-induced cell death, but not malaoxon-induced cellular death in the pulmonary epithelium. PMID:26173615

  12. Effect of early treatment with transcutaneous electrical diaphragmatic stimulation (TEDS) on pulmonary inflammation induced by bleomycin

    PubMed Central

    Santos, Laisa A.; Silva, Carlos A.; Polacow, Maria L. O.

    2013-01-01

    Background Bleomycin (B) is an antineoplastic drug that has pulmonary fibrosis as a side effect. There are few experimental studies about the effects of physical therapy treatment in this case. Objective The objective was to study rat lungs treated with B and precocious intervention by transcutaneous electrical diaphragmatic stimulation (TEDS). Method Wistar rats were divided into 4 groups (n=5): a control group (C); a stimulated group (TEDS); a group treated with a single dose of B (intratracheally, 2.5 mg/kg) (B); and a group treated with B and electric stimulation (B + TEDS). After the B instillation, the electrical stimulation was applied for 7 days, for a duration of 20 minutes. Lung fragments were histologically processed with hematoxylin and eosin (HE) and 8-isoprostane-PGF2α (8-iso-PGF2α). The density of the alveolar area was determined by planimetry, the inflammatory profile was defined by the number of cells, and the level of oxidative stress in the pulmonary tissue was evaluated by 8-iso-PGF2α. For statistical analysis of the data, the Shapiro-Wilk test was used, followed by a one-way ANOVA with the post-hoc Bonferroni test (p≤0.05). Results The B group exhibited a significant reduction in the area density, and the acute treatment with B + TEDS prevented this reduction. There were increased numbers of fibroblasts, leukocytes, and macrophages in the B group, as well as increased lipid peroxidation, which was observed only in this group. Conclusion B promoted a reduction in the alveolar density area, thereby inducing the inflammatory process and increasing the production of free radicals. These effects were minimized by the application of TEDS at the initial treatment stage. PMID:24346295

  13. Neutral Lipids Induce Critical Behavior in Interfacial Monolayers of Pulmonary Surfactant†

    PubMed Central

    Discher, Bohdana M.; Maloney, Kevin M.; Grainger, David W.; Sousa, Carolyn A.; Hall, Stephen B.

    2012-01-01

    We have shown previously that lateral compression of pulmonary surfactant monolayers initially induces separation of two phases but that these remix when the films become more dense (1). In the studies reported here, we used fluorescence microscopy to examine the role of the different surfactant constituents in the remixing of the separated phases. Subfractions containing only the purified phospholipids (PPL), the surfactant proteins and phospholipids (SP&PL), and the neutral and phospholipids (N&PL) were obtained by chromatographic separation of the components in extracted calf surfactant (calf lung surfactant extract, CLSE). Compression of the different monolayers produced nonfluorescent domains that emerged for temperatures between 20 and 41 °C at similar surface pressures 6–8 mN/m higher than values observed for dipalmitoyl phosphatidylcholine (DPPC), the most prevalent component of pulmonary surfactant. Comparison of the different preparations showed that the neutral lipid increased the total nonfluorescent area at surface pressures up to 25 mN/m but dispersed that total area among a larger number of smaller domains. The surfactant proteins also produced smaller domains, but they had the opposite effect of decreasing the total nonfluorescent area. Only the neutral lipids caused remixing. In images from static monolayers, the domains for N&PL dropped from a maximum of 26 ± 3% of the interface at 25 mN/m to 4 ± 2% at 30 mN/m, similar to the previously reported behavior for CLSE. During continuous compression through a narrow range of pressure and molecular area, in N&PL, CLSE, and mixtures of PPL with 10% cholesterol, domains became highly distorted immediately prior to remixing. The characteristic transition in shape and abrupt termination of phase coexistence indicate that the remixing caused by the neutral lipids occurs at or close to a critical point. PMID:9890919

  14. Poor Baseline Pulmonary Function May Not Increase the Risk of Radiation-Induced Lung Toxicity

    SciTech Connect

    Wang, Jingbo; Cao, Jianzhong; Yuan, Shuanghu; Arenberg, Douglas; Stanton, Paul; Tatro, Daniel; Ten Haken, Randall K.; Kong, Feng-Ming

    2013-03-01

    Purpose: Poor pulmonary function (PF) is often considered a contraindication to definitive radiation therapy for lung cancer. This study investigated whether baseline PF was associated with radiation-induced lung toxicity (RILT) in patients with non-small cell lung cancer (NSCLC) receiving conformal radiation therapy (CRT). Methods and Materials: NSCLC patients treated with CRT and tested for PF at baseline were eligible. Baseline predicted values of forced expiratory volume in 1 sec (FEV1), forced vital capacity (FVC), and diffusion capacity of lung for carbon monoxide (DLCO) were analyzed. Additional factors included age, gender, smoking status, Karnofsky performance status, coexisting chronic obstructive pulmonary disease (COPD), tumor location, histology, concurrent chemotherapy, radiation dose, and mean lung dose (MLD) were evaluated for RILT. The primary endpoint was symptomatic RILT (SRILT), including grade ≥2 radiation pneumonitis and fibrosis. Results: There was a total of 260 patients, and SRILT occurred in 58 (22.3%) of them. Mean FEV1 values for SRILT and non-SRILT patients were 71.7% and 65.9% (P=.077). Under univariate analysis, risk of SRILT increased with MLD (P=.008), the absence of COPD (P=.047), and FEV1 (P=.077). Age (65 split) and MLD were significantly associated with SRILT in multivariate analysis. The addition of FEV1 and age with the MLD-based model slightly improved the predictability of SRILT (area under curve from 0.63-0.70, P=.088). Conclusions: Poor baseline PF does not increase the risk of SRILT, and combining FEV1, age, and MLD may improve the predictive ability.

  15. Hirsutella sinensis mycelium attenuates bleomycin-induced pulmonary inflammation and fibrosis in vivo.

    PubMed

    Huang, Tsung-Teng; Lai, Hsin-Chih; Ko, Yun-Fei; Ojcius, David M; Lan, Ying-Wei; Martel, Jan; Young, John D; Chong, Kowit-Yu

    2015-01-01

    Hirsutella sinensis mycelium (HSM), the anamorph of Cordyceps sinensis, is a traditional Chinese medicine that has been shown to possess various pharmacological properties. We previously reported that this fungus suppresses interleukin-1β and IL-18 secretion by inhibiting both canonical and non-canonical inflammasomes in human macrophages. However, whether HSM may be used to prevent lung fibrosis and the mechanism underlying this activity remain unclear. Our results show that pretreatment with HSM inhibits TGF-β1-induced expression of fibronectin and α-SMA in lung fibroblasts. HSM also restores superoxide dismutase expression in TGF-β1-treated lung fibroblasts and inhibits reactive oxygen species production in lung epithelial cells. Furthermore, HSM pretreatment markedly reduces bleomycin-induced lung injury and fibrosis in mice. Accordingly, HSM reduces inflammatory cell accumulation in bronchoalveolar lavage fluid and proinflammatory cytokines levels in lung tissues. The HSM extract also significantly reduces TGF-β1 in lung tissues, and this effect is accompanied by decreased collagen 3α1 and α-SMA levels. Moreover, HSM reduces expression of the NLRP3 inflammasome and P2X7R in lung tissues, whereas it enhances expression of superoxide dismutase. These findings suggest that HSM may be used for the treatment of pulmonary inflammation and fibrosis. PMID:26497260

  16. P. falciparum isolate-specific distinct patterns of induced apoptosis in pulmonary and brain endothelial cells.

    PubMed

    N'Dilimabaka, Nadine; Taoufiq, Zacharie; Zougbédé, Sergine; Bonnefoy, Serge; Lorthiois, Audrey; Couraud, Pierre Oliver; Rebollo, Angelita; Snounou, Georges; Mazier, Dominique; Moreno Sabater, Alicia

    2014-01-01

    The factors implicated in the transition from uncomplicated to severe clinical malaria such as pulmonary oedema and cerebral malaria remain unclear. It is known that alterations in vascular integrity due to endothelial cell (EC) activation and death occur during severe malaria. In this study, we assessed the ability of different P. falciparum clinical isolates to induce apoptosis in ECs derived from human lung and brain. We observed that induction of EC apoptosis was sensitive to the environmental pH and required direct contact between the parasite and the cell, though it was not correlated to the ability of the parasite to cytoadhere. Moreover, the extent of induced apoptosis in the two EC types varied with the isolate. Analysis of parasite genes transcript led us to propose that the activation of different pathways, such as Plasmodium apoptosis-linked pathogenicity factors (PALPF), PALPF-2, PALPF-5 and PF11_0521, could be implied in EC death. These observations provide an experimental framework to decipher the molecular mechanism implicated in the genesis of severe malaria. PMID:24686750

  17. P. falciparum Isolate-Specific Distinct Patterns of Induced Apoptosis in Pulmonary and Brain Endothelial Cells

    PubMed Central

    N'Dilimabaka, Nadine; Bonnefoy, Serge; Lorthiois, Audrey; Couraud, Pierre Oliver; Rebollo, Angelita; Snounou, Georges; Mazier, Dominique; Moreno Sabater, Alicia

    2014-01-01

    The factors implicated in the transition from uncomplicated to severe clinical malaria such as pulmonary oedema and cerebral malaria remain unclear. It is known that alterations in vascular integrity due to endothelial cell (EC) activation and death occur during severe malaria. In this study, we assessed the ability of different P. falciparum clinical isolates to induce apoptosis in ECs derived from human lung and brain. We observed that induction of EC apoptosis was sensitive to the environmental pH and required direct contact between the parasite and the cell, though it was not correlated to the ability of the parasite to cytoadhere. Moreover, the extent of induced apoptosis in the two EC types varied with the isolate. Analysis of parasite genes transcript led us to propose that the activation of different pathways, such as Plasmodium apoptosis–linked pathogenicity factors (PALPF), PALPF-2, PALPF-5 and PF11_0521, could be implied in EC death. These observations provide an experimental framework to decipher the molecular mechanism implicated in the genesis of severe malaria. PMID:24686750

  18. Physical exercise is effective in preventing cigarette smoke-induced pulmonary oxidative response in mice

    PubMed Central

    Nesi, Renata Tiscoski; de Souza, Priscila Soares; dos Santos, Giulia Pedroso; Thirupathi, Anand; Menegali, Bruno T; Silveira, Paulo Cesar Lock; da Silva, Luciano Acordi; Valença, Samuel Santos; Pinho, Ricardo Aurino

    2016-01-01

    Reactive oxygen species (ROS) are important in the pathogenesis of pulmonary injury induced by cigarette smoke (CS) exposure, and physical exercise (Ex) is useful in combating impaired oxidative process. We verified the preventive effects of Ex on lung oxidative markers induced by smoking. In this study, 36 mice (C57BL-6, 30–35 g) were split into four groups: control, CS, Ex, and CS plus Ex. Ex groups were given prior physical training in water (2×30 min/d, 5 days/wk, 8 weeks). After training, the CS groups were subjected to passive exposure to four cigarettes, 3 × per day, for 60 consecutive days. After 24 hours from the last exposure, CS animals were sacrificed, and lung samples were collected for further analysis. Left lung sample was prepared for histological analysis, and right lung was used for biochemical analysis (superoxide, hydroxyproline, lipid peroxidation [thiobarbituric acid reactive species], protein carbonylation [carbonyl groups formation], superoxide dismutase [SOD], catalase [CAT], and glutathione peroxidase [GPx] activities). Group comparisons were evaluated by analysis of variance (ANOVA). Results were expressed as mean ± standard deviation, with P<0.05 considered significantly different. Preventive Ex impeded histological changes and increased the enzymatic defense system (SOD and GPx) by reducing oxidative damage in lipids and proteins. This preventive effect of prior physical Ex alleviates damage caused by CS exposure. PMID:27042047

  19. Essential role for the ATG4B protease and autophagy in bleomycin-induced pulmonary fibrosis.

    PubMed

    Cabrera, Sandra; Maciel, Mariana; Herrera, Iliana; Nava, Teresa; Vergara, Fabián; Gaxiola, Miguel; López-Otín, Carlos; Selman, Moisés; Pardo, Annie

    2015-04-01

    Autophagy is a critical cellular homeostatic process that controls the turnover of damaged organelles and proteins. Impaired autophagic activity is involved in a number of diseases, including idiopathic pulmonary fibrosis suggesting that altered autophagy may contribute to fibrogenesis. However, the specific role of autophagy in lung fibrosis is still undefined. In this study, we show for the first time, how autophagy disruption contributes to bleomycin-induced lung fibrosis in vivo using an Atg4b-deficient mouse as a model. Atg4b-deficient mice displayed a significantly higher inflammatory response at 7 d after bleomycin treatment associated with increased neutrophilic infiltration and significant alterations in proinflammatory cytokines. Likewise, we found that Atg4b disruption resulted in augmented apoptosis affecting predominantly alveolar and bronchiolar epithelial cells. At 28 d post-bleomycin instillation Atg4b-deficient mice exhibited more extensive and severe fibrosis with increased collagen accumulation and deregulated extracellular matrix-related gene expression. Together, our findings indicate that the ATG4B protease and autophagy play a crucial role protecting epithelial cells against bleomycin-induced stress and apoptosis, and in the regulation of the inflammatory and fibrotic responses. PMID:25906080

  20. Pyrogallol induces the death of human pulmonary fibroblast cells through ROS increase and GSH depletion.

    PubMed

    Park, Woo Hyun

    2016-08-01

    Pyrogallol (PG) inhibits the growth of various cells via stimulating O2•--mediated death. This study investigated the effects of PG on cell death in human pulmonary fibroblast (HPF) cells in relation to reactive oxygen species (ROS) and glutathione (GSH) levels. PG inhibited the growth of HPF cells with an IC50 of ~50-100 µM at 24 h. PG induced a G1 phase arrest of the cell cycle and also triggered cell death accompanied by the loss of mitochondrial membrane potential (MMP; ∆ψm), Bcl-2 decrease, p53 increase and the activation of caspase-3. PG increased O2•- level in HPF cells and depleted GSH content in these cells. Z-VAD (a pan-caspase inhibitor) did not significantly change cell growth inhibition, death and MMP (∆ψm) loss in PG-treated HPF cells. N-acetylcysteine (NAC) attenuated growth inhibition, death and MMP (∆ψm) loss in PG-treated HPF cells and it decreased O2•- level in these cells as well. However, L-buthionine sulfoximine (BSO) strongly increased ROS level in PG-treated HPF cells and it intensified growth inhibition, cell death, MMP (∆ψm) loss and GSH depletion in these cells. In conclusion, PG-induced HPF cell death was closely related to increases in ROS level and GSH depletion. PMID:27278810

  1. Hirsutella sinensis mycelium attenuates bleomycin-induced pulmonary inflammation and fibrosis in vivo

    PubMed Central

    Huang, Tsung-Teng; Lai, Hsin-Chih; Ko, Yun-Fei; Ojcius, David M.; Lan, Ying-Wei; Martel, Jan; Young, John D.; Chong, Kowit-Yu

    2015-01-01

    Hirsutella sinensis mycelium (HSM), the anamorph of Cordyceps sinensis, is a traditional Chinese medicine that has been shown to possess various pharmacological properties. We previously reported that this fungus suppresses interleukin-1β and IL-18 secretion by inhibiting both canonical and non-canonical inflammasomes in human macrophages. However, whether HSM may be used to prevent lung fibrosis and the mechanism underlying this activity remain unclear. Our results show that pretreatment with HSM inhibits TGF-β1–induced expression of fibronectin and α-SMA in lung fibroblasts. HSM also restores superoxide dismutase expression in TGF-β1–treated lung fibroblasts and inhibits reactive oxygen species production in lung epithelial cells. Furthermore, HSM pretreatment markedly reduces bleomycin–induced lung injury and fibrosis in mice. Accordingly, HSM reduces inflammatory cell accumulation in bronchoalveolar lavage fluid and proinflammatory cytokines levels in lung tissues. The HSM extract also significantly reduces TGF-β1 in lung tissues, and this effect is accompanied by decreased collagen 3α1 and α-SMA levels. Moreover, HSM reduces expression of the NLRP3 inflammasome and P2X7R in lung tissues, whereas it enhances expression of superoxide dismutase. These findings suggest that HSM may be used for the treatment of pulmonary inflammation and fibrosis. PMID:26497260

  2. A Critical Role of the mTOR/eIF2α Pathway in Hypoxia-Induced Pulmonary Hypertension

    PubMed Central

    Wang, Ai-ping; Li, Xiao-hui; Yang, Yong-mei; Li, Wen-qun; Zhang, Wang; Hu, Chang-ping; Zhang, Zheng; Li, Yuan-jian

    2015-01-01

    Enhanced proliferation of pulmonary arterial vascular smooth muscle cells (PASMCs) is a key pathological component of vascular remodeling in hypoxia-induced pulmonary hypertension (HPH). Mammalian targeting of rapamycin (mTOR) signaling has been shown to play a role in protein translation and participate in the progression of pulmonary hypertension. Eukaryotic translation initiation factor-2α (eIF2α) is a key factor in regulation of cell growth and cell cycle, but its role in mTOR signaling and PASMCs proliferation remains unknown. Pulmonary hypertension (PH) rat model was established by hypoxia. Rapamycin was used to treat rats as an mTOR inhibitor. Proliferation of primarily cultured rat PASMCs was induced by hypoxia, rapamycin and siRNA of mTOR and eIF2α were used in loss-of-function studies. The expression and activation of eIF2α, mTOR and c-myc were analyzed. Results showed that mTOR/eIF2α signaling was significantly activated in pulmonary arteries from hypoxia exposed rats and PASMCs cultured under hypoxia condition. Treatment with mTOR inhibitor for 21 days attenuated vascular remodeling, suppressed mTOR and eIF2α activation, inhibited c-myc expression in HPH rats. In hypoxia-induced PASMCs, rapamycin and knockdown of mTOR and eIF2α by siRNA significantly abolished proliferation and increased c-myc expression. These results suggest a critical role of the mTOR/eIF2αpathway in hypoxic vascular remodeling and PASMCs proliferation of HPH. PMID:26120832

  3. PDGF induces SphK1 expression via Egr-1 to promote pulmonary artery smooth muscle cell proliferation.

    PubMed

    Sysol, Justin R; Natarajan, Viswanathan; Machado, Roberto F

    2016-06-01

    Pulmonary arterial hypertension (PAH) is a progressive, life-threatening disease for which there is currently no curative treatment available. Pathologic changes in this disease involve remodeling of the pulmonary vasculature, including marked proliferation of pulmonary artery smooth muscle cells (PASMCs). Recently, the bioactive lipid sphingosine-1-phosphate (S1P) and its activating kinase, sphingosine kinase 1 (SphK1), have been shown to be upregulated in PAH and promote PASMC proliferation. The mechanisms regulating the transcriptional upregulation of SphK1 in PASMCs are unknown. In this study, we investigated the role of platelet-derived growth factor (PDGF), a PAH-relevant stimuli associated with enhanced PASMC proliferation, on SphK1 expression regulation. In human PASMCs (hPASMCs), PDGF significantly increased SphK1 mRNA and protein expression and induced cell proliferation. Selective inhibition of SphK1 attenuated PDGF-induced hPASMC proliferation. In silico promoter analysis for SphK1 identified several binding sites for early growth response protein 1 (Egr-1), a PDGF-associated transcription factor. Luciferase assays demonstrated that PDGF activates the SphK1 promoter in hPASMCs, and truncation of the 5'-promoter reduced PDGF-induced SphK1 expression. Stimulation of hPASMCs with PDGF induced Egr-1 protein expression, and direct binding of Egr-1 to the SphK1 promoter was confirmed by chromatin immunoprecipitation analysis. Inhibition of ERK signaling prevented induction of Egr-1 by PDGF. Silencing of Egr-1 attenuated PDGF-induced SphK1 expression and hPASMC proliferation. These studies demonstrate that SphK1 is regulated by PDGF in hPASMCs via the transcription factor Egr-1, promoting cell proliferation. This novel mechanism of SphK1 regulation may be a therapeutic target in pulmonary vascular remodeling in PAH. PMID:27099350

  4. Inhibitory effect of Bailing capsule on hypoxia-induced proliferation of rat pulmonary arterial smooth muscle cells

    PubMed Central

    Li, Xiaohui; Peng, Kejun; Zhou, Yutian; Deng, Fengmei; Ma, Jiao

    2016-01-01

    Objectives: To investigated the effects of Bailing capsule on hypoxia-induced proliferation of pulmonary arterial smooth muscle cells (PASMCs). Methods: This prospective study was performed at the Central Laboratory, Chengdu Medical College, Chengdu, China between April 2012 and November 2014. Ten healthy adult male Wistar rats were administrated with gastric perfusion of Bailing capsule to obtain serum containing the tested drugs. Proliferation of pulmonary arterial smooth muscle cells proliferation was measured using cell counting kit-8 assay. Production of reactive oxygen species (ROS) in rat PASMCs was determined through a fluorometric assay, whereas production of endothelin-1 (ET-1) was detected by ELISA and quantitative real-time PCR (qRT-PCR). Expression of proliferating cell nuclear antigen (PCNA), c-fos, and c-jun in PASMCs was also determined using immunohistochemistry staining and qRT-PCR. Results: We observed that the medicated serum obviously inhibited hypoxia-induced cell proliferation in a concentration-dependent manner. Moreover, the medicated serum significantly reduced hypoxia-induced production of ROS and ET-1, as well as expression of PCNA, c-fos, and c-jun, in PASMCs. Conclusion: Results demonstrated that Bailing capsule can inhibit hypoxia-induced PASMC proliferation possibly by suppressing ET-1 and ROS production and by inhibiting expression of PCNA, c-fos, and c-jun. These results suggest that Bailing possess antiproliferative property, which is probably one of the underlying mechanisms of Bailing capsule for the clinical treatment of chronic obstructive pulmonary disease. PMID:27146611

  5. Quantification of Kras mutant fraction in the lung DNA of mice exposed to aerosolized particulate vanadium pentoxide by inhalation.

    PubMed

    Banda, Malathi; McKim, Karen L; Haber, Lynne T; MacGregor, Judith A; Gollapudi, B Bhaskar; Parsons, Barbara L

    2015-08-01

    This study investigated whether Kras mutation is an early event in the development of lung tumors induced by inhalation of particulate vanadium pentoxide (VP) aerosols. A National Toxicology Program tumor bioassay of inhaled particulate VP aerosols established that VP-induced alveolar/bronchiolar carcinomas of the B6C3F1 mouse lung carried Kras mutations at a higher frequency than observed in spontaneous mouse lung tumors. Therefore, this study sought to: (1) characterize any Kras mutational response with respect to VP exposure concentration, and (2) investigate the possibility that amplification of preexisting Kras mutation is an early event in VP-induced mouse lung tumorigenesis. Male Big Blue B6C3F1 mice (6 mice/group) were exposed to aerosolized particulate VP by inhalation, 6h/day, 5 days/week for 4 or 8 weeks, using VP exposure concentrations of 0, 0.1, and 1 mg/m(3). The levels of two different Kras codon 12 mutations [GGT → GAT (G12D) and GGT → GTT (G12V)] were measured in lung DNAs by Allele-specific Competitive Blocker PCR (ACB-PCR). For both exposure concentrations (0.1 and 1.0mg/m(3)) and both time points (4 and 8 weeks), the mutant fractions observed in VP-exposed mice were not significantly different from the concurrent controls. Given that 8 weeks of inhalation of a tumorigenic concentration of particulate aerosols of VP did not result in a significant change in levels of lung Kras mutation, the data do not support either a direct genotoxic effect of VP on Kras or early amplification of preexisting mutation as being involved in the genesis of VP-induced mouse lung tumors under the exposure conditions used. Rather, the data suggest that accumulation of Kras mutation occurs later with chronic VP exposure and is likely not an early event in VP-induced mouse lung carcinogenesis. PMID:26232258

  6. Hypoxia, not pulmonary vascular pressure, induces blood flow through intrapulmonary arteriovenous anastomoses

    PubMed Central

    Tremblay, Joshua C; Lovering, Andrew T; Ainslie, Philip N; Stembridge, Mike; Burgess, Keith R; Bakker, Akke; Donnelly, Joseph; Lucas, Samuel JE; Lewis, Nia CS; Dominelli, Paolo B; Henderson, William R; Dominelli, Giulio S; Sheel, A William; Foster, Glen E

    2015-01-01

    Blood flow through intrapulmonary arteriovenous anastomoses (IPAVA) is increased with exposure to acute hypoxia and has been associated with pulmonary artery systolic pressure (PASP). We aimed to determine the direct relationship between blood flow through IPAVA and PASP in 10 participants with no detectable intracardiac shunt by comparing: (1) isocapnic hypoxia (control); (2) isocapnic hypoxia with oral administration of acetazolamide (AZ; 250 mg, three times a day for 48 h) to prevent increases in PASP; and (3) isocapnic hypoxia with AZ and 8.4% NaHCO3 infusion (AZ + HCO3–) to control for AZ-induced acidosis. Isocapnic hypoxia (20 min) was maintained by end-tidal forcing, blood flow through IPAVA was determined by agitated saline contrast echocardiography and PASP was estimated by Doppler ultrasound. Arterial blood samples were collected at rest before each isocapnic–hypoxia condition to determine pH, [HCO3–] and . AZ decreased pH (–0.08 ± 0.01), [HCO3–] (−7.1 ± 0.7 mmol l−1) and (−4.5 ± 1.4 mmHg; P < 0.01), while intravenous NaHCO3 restored arterial blood gas parameters to control levels. Although PASP increased from baseline in all three hypoxic conditions (P < 0.05), a main effect of condition expressed an 11 ± 2% reduction in PASP from control (P < 0.001) following AZ administration while intravenous NaHCO3 partially restored the PASP response to isocapnic hypoxia. Blood flow through IPAVA increased during exposure to isocapnic hypoxia (P < 0.01) and was unrelated to PASP, cardiac output and pulmonary vascular resistance for all conditions. In conclusion, isocapnic hypoxia induces blood flow through IPAVA independent of changes in PASP and the influence of AZ on the PASP response to isocapnic hypoxia is dependent upon the H+ concentration or . PMID:25416621

  7. Novel Peptide for Attenuation of Hyperoxia-induced Disruption of Lung Endothelial Barrier and Pulmonary Edema via Modulating Peroxynitrite Formation*

    PubMed Central

    Kondrikov, Dmitry; Gross, Christine; Black, Stephen M.; Su, Yunchao

    2014-01-01

    Pulmonary damages of oxygen toxicity include vascular leakage and pulmonary edema. We have previously reported that hyperoxia increases the formation of NO and peroxynitrite in lung endothelial cells via increased interaction of endothelial nitric oxide (eNOS) with β-actin. A peptide (P326TAT) with amino acid sequence corresponding to the actin binding region of eNOS residues 326–333 has been shown to reduce the hyperoxia-induced formation of NO and peroxynitrite in lung endothelial cells. In the present study, we found that exposure of pulmonary artery endothelial cells to hyperoxia (95% oxygen and 5% CO2) for 48 h resulted in disruption of monolayer barrier integrity in two phases, and apoptosis occurred in the second phase. NOS inhibitor NG-nitro-l-arginine methyl ester attenuated the endothelial barrier disruption in both phases. Peroxynitrite scavenger uric acid did not affect the first phase but ameliorated the second phase of endothelial barrier disruption and apoptosis. P326TAT inhibited hyperoxia-induced disruption of monolayer barrier integrity in two phases and apoptosis in the second phase. More importantly, injection of P326TAT attenuated vascular leakage, pulmonary edema, and endothelial apoptosis in the lungs of mice exposed to hyperoxia. P326TAT also significantly reduced the increase in eNOS-β-actin association and protein tyrosine nitration. Together, these results indicate that peptide P326TAT ameliorates barrier dysfunction of hyperoxic lung endothelial monolayer and attenuates eNOS-β-actin association, peroxynitrite formation, endothelial apoptosis, and pulmonary edema in lungs of hyperoxic mice. P326TAT can be a novel therapeutic agent to treat or prevent acute lung injury in oxygen toxicity. PMID:25315770

  8. Phosphoinositide 3-kinase γ plays a critical role in bleomycin-induced pulmonary inflammation and fibrosis in mice.

    PubMed

    Russo, Remo C; Garcia, Cristiana C; Barcelos, Lucíola S; Rachid, Milene A; Guabiraba, Rodrigo; Roffê, Ester; Souza, Adriano L S; Sousa, Lirlândia P; Mirolo, Massimiliano; Doni, Andrea; Cassali, Geovanni D; Pinho, Vanessa; Locati, Massimo; Teixeira, Mauro M

    2011-02-01

    PI3Kγ is central in signaling diverse arrays of cellular functions and inflammation. Pulmonary fibrosis is associated with pulmonary inflammation, angiogenesis, and deposition of collagen and is modeled by instillation of bleomycin. The role of PI3Kγ in mediating bleomycin-induced pulmonary inflammation and fibrosis in mice and potential mechanisms involved was investigated here. WT or PI3Kγ KO mice were instilled with bleomycin and leukocyte subtype influx, cytokine and chemokine levels, and angiogenesis and tissue fibrosis evaluated. The activation of lung-derived leukocytes and fibroblasts was evaluated in vitro. The relevance of PI3Kγ for endothelial cell function was evaluated in HUVECs. PI3Kγ KO mice had greater survival and weight recovery and less fibrosis than WT mice after bleomycin instillation. This was associated with decreased production of TGF-β(1) and CCL2 and increased production of IFN-γ and IL-10. There was reduced expression of collagen, fibronectin, α-SMA, and von Willebrand factor and decreased numbers and activation of leukocytes and phosphorylation of AKT and IκB-α. PI3Kγ KO mice had a reduced number and area of blood vessels in the lungs. In vitro, treatment of human endothelial cells with the PI3Kγ inhibitor AS605240 decreased proliferation, migration, and formation of capillary-like structures. AS605240 also decreased production of collagen by murine lung-derived fibroblasts. PI3Kγ deficiency confers protection against bleomycin-induced pulmonary injury, angiogenesis, and fibrosis through the modulation of leukocyte, fibroblast, and endothelial cell functions. Inhibitors of PI3Kγ may be beneficial for the treatment of pulmonary fibrosis. PMID:21048214

  9. Hemorrhagic hypotension-induced hypersensitivity of vagal pulmonary C-fibers to chemical stimulation and lung inflation in anesthetized rats

    PubMed Central

    Lin, Ruei-Lung; Lin, Yu-Jung; Xu, Fadi

    2015-01-01

    This study was carried out to investigate whether hemorrhagic hypotension (HH) altered the sensitivity of vagal pulmonary C-fibers. The fiber activity (FA) of single vagal pulmonary C-fiber was continuously recorded in anesthetized rats before, during, and after HH was induced by bleeding from the femoral arterial catheter into a blood reservoir and lowering the mean systemic arterial pressure (MSAP) to ∼40 mmHg for 20 min. Our results showed the following. First, after MSAP reached a steady state of HH, the peak FA response to intravenous injection of capsaicin was elevated by approximately fivefold. The enhanced C-fiber sensitivity continued to increase during HH and sustained even after MSAP returned to baseline during the recovery, but slowly returned to control ∼20 min later. Second, responses of FA to intravenous injections of other chemical stimulants of pulmonary C-fibers (phenylbiguanide, lactic acid, and adenosine) and a constant-pressure lung hyperinflation were all significantly potentiated by HH. Third, infusion of sodium bicarbonate alleviated the systemic acidosis during HH, and it also attenuated, but did not completely prevent, the HH-induced C-fiber hypersensitivity. In conclusion, the pulmonary C-fiber sensitivity was elevated during HH, probably caused by the endogenous release of chemical substances (e.g., lactic acid) that were produced by tissue ischemia during HH. This enhanced C-fiber sensitivity may heighten the pulmonary protective reflexes mediated through these afferents (e.g., cough, J reflex) during hemorrhage when the body is more susceptible to other hazardous insults and pathophysiological stresses. PMID:25589016

  10. Hemorrhagic hypotension-induced hypersensitivity of vagal pulmonary C-fibers to chemical stimulation and lung inflation in anesthetized rats.

    PubMed

    Lin, Ruei-Lung; Lin, Yu-Jung; Xu, Fadi; Lee, Lu-Yuan

    2015-04-01

    This study was carried out to investigate whether hemorrhagic hypotension (HH) altered the sensitivity of vagal pulmonary C-fibers. The fiber activity (FA) of single vagal pulmonary C-fiber was continuously recorded in anesthetized rats before, during, and after HH was induced by bleeding from the femoral arterial catheter into a blood reservoir and lowering the mean systemic arterial pressure (MSAP) to ∼40 mmHg for 20 min. Our results showed the following. First, after MSAP reached a steady state of HH, the peak FA response to intravenous injection of capsaicin was elevated by approximately fivefold. The enhanced C-fiber sensitivity continued to increase during HH and sustained even after MSAP returned to baseline during the recovery, but slowly returned to control ∼20 min later. Second, responses of FA to intravenous injections of other chemical stimulants of pulmonary C-fibers (phenylbiguanide, lactic acid, and adenosine) and a constant-pressure lung hyperinflation were all significantly potentiated by HH. Third, infusion of sodium bicarbonate alleviated the systemic acidosis during HH, and it also attenuated, but did not completely prevent, the HH-induced C-fiber hypersensitivity. In conclusion, the pulmonary C-fiber sensitivity was elevated during HH, probably caused by the endogenous release of chemical substances (e.g., lactic acid) that were produced by tissue ischemia during HH. This enhanced C-fiber sensitivity may heighten the pulmonary protective reflexes mediated through these afferents (e.g., cough, J reflex) during hemorrhage when the body is more susceptible to other hazardous insults and pathophysiological stresses. PMID:25589016

  11. Ruscogenin exerts beneficial effects on monocrotaline-induced pulmonary hypertension by inhibiting NF-κB expression

    PubMed Central

    Zhu, Rong; Bi, Liqing; Kong, Hui; Xie, Weiping; Hong, Yongqing; Wang, Hong

    2015-01-01

    This study aims to examine the effect of ruscogenin on pulmonary arterial hypertension (PAH) and to determine the mechanism underlying this effect. We isolated pulmonary vascular smooth muscle cells (PVSMCs) from the pulmonary artery of the rats; the PVSMCs were cultured in vitro and then were treated with platelet-derived growth factor (PDGF), PDGF + ruscogenin, or PDGF + ruscogenin + parthenolide. We randomized Sprague-Dawley rats into five groups as follows: control group, PAH group, low-dose group, medium-dose group, and high-dose group; the rats in the low-, medium-, and high-dose groups received the vehicle and ruscogenin 0.1, 0.4, and 0.7 mg/kg, respectively, from day 1 to day 21 after injection of monocrotaline (MCT). We measured the mean pulmonary arterial pressure (mPAP), right ventricular systolic pressure (RVSP), and medial wall thickness of the pulmonary artery (PAWT). We examined the levels of the nuclear factor kappa B (NF-κB) protein by using immunohistochemistry and western blot analysis, and the mRNA levels of NF-κB in PVSMCs were evaluated using real-time polymerase chain reaction (PCR). The mPAP, RVSP, and PAWT and the protein and mRNA levels of NF-κB were significantly higher in the PAH model group than in the control group (P < 0.05). Ruscogenin induced a significant dose-dependent decrease in the mPAP, RVSP, and PAWT and in the NF-κB expression in the PAH group (P < 0.05), which suggests that ruscogenin will also exert dose-dependent effects on MCT-induced PAH through the inhibition of NF-κB. PMID:26722401

  12. Impact of diet on ozone-induced pulmonary and systemic effects in female Brown Norway (BN) rats

    EPA Science Inventory

    Impact of diet on ozone-induced pulmonary and systemic effects in female Brown Norway (BN) ratsV.L. Bass1, M.C. Schladweiler2, S. Snow5, C.J. Gordon4, K.A. Jarema4, P. Phillips4, A.D. Ledbetter2, D.B. Miller3, J.E. Richards2, U.P. Kodavanti2. 1. SPH, UNC, Chapel Hill2. EPHD, NHE...

  13. Usefulness of Intratracheal Instillation Studies for Estimating Nanoparticle-Induced Pulmonary Toxicity

    PubMed Central

    Morimoto, Yasuo; Izumi, Hiroto; Yoshiura, Yukiko; Fujishima, Kei; Yatera, Kazuhiro; Yamamoto, Kazuhiro

    2016-01-01

    Inhalation studies are the gold standard for the estimation of the harmful effects of respirable chemical substances, while there is limited evidence of the harmful effects of chemical substances by intratracheal instillation. We reviewed the effectiveness of intratracheal instillation studies for estimating the hazards of nanoparticles, mainly using papers in which both inhalation and intratracheal instillation studies were performed using the same nanoparticles. Compared to inhalation studies, there is a tendency in intratracheal instillation studies that pulmonary inflammation lasted longer in the lungs. A difference in pulmonary inflammation between high and low toxicity nanoparticles was observed in the intratracheal instillation studies, as in the inhalation studies. Among the endpoints of pulmonary toxicity, the kinetics of neutrophil counts, percentage of neutrophils, and chemokines for neutrophils and macrophages, heme oxygenase-1 (HO-1) in bronchoalveolar lavage fluid (BALF), reflected pulmonary inflammation, suggesting that these markers may be considered the predictive markers of pulmonary toxicity in both types of study. When comparing pulmonary inflammation between intratracheal instillation and inhalation studies under the same initial lung burden, there is a tendency that the inflammatory response following the intratracheal instillation of nanoparticles is greater than or equal to that following the inhalation of nanoparticles. If the difference in clearance in both studies is not large, the estimations of pulmonary toxicity are close. We suggest that intratracheal instillation studies can be useful for ranking the hazard of nanoparticles through pulmonary inflammation. PMID:26828483

  14. Effects of amorphous silica coating on cerium oxide nanoparticles induced pulmonary responses

    PubMed Central

    Ma, Jane; Mercer, Robert R.; Barger, Mark; Schwegler-Berry, Diane; Cohen, Joel M.; Demokritou, Philip; Castranova, Vincent

    2015-01-01

    Recently cerium compounds have been used in a variety of consumer products, including diesel fuel additives, to increase fuel combustion efficiency and decrease diesel soot emissions. However, cerium oxide (CeO2) nanoparticles have been detected in the exhaust, which raises a health concern. Previous studies have shown that exposure of rats to nanoscale CeO2 by intratracheal instillation (IT) induces sustained pulmonary inflammation and fibrosis. In the present study, male Sprague–Dawley rats were exposed to CeO2 or CeO2 coated with a nano layer of amorphous SiO2 (aSiO2/CeO2) by a single IT and sacrificed at various times post-exposure to assess potential protective effects of the aSiO2 coating. The first acellular bronchoalveolar lavage (BAL) fluid and BAL cells were collected and analyzed from all exposed animals. At the low dose (0.15 mg/kg), CeO2 but not aSiO2/CeO2 exposure induced inflammation. However, at the higher doses, both particles induced a dose-related inflammation, cytotoxicity, inflammatory cytokines, matrix metalloproteinase (MMP)-9, and tissue inhibitor of MMP at 1 day post-exposure. Morphological analysis of lung showed an increased inflammation, surfactant and collagen fibers after CeO2 (high dose at 3.5 mg/kg) treatment at 28 days post-exposure. aSiO2 coating significantly reduced CeO2-induced inflammatory responses in the airspace and appeared to attenuate phospholipidosis and fibrosis. Energy dispersive X-ray spectroscopy analysis showed Ce and phosphorous (P) in all particle-exposed lungs, whereas Si was only detected in aSiO2/CeO2-exposed lungs up to 3 days after exposure, suggesting that aSiO2 dissolved off the CeO2 core, and some of the CeO2 was transformed to CePO4 with time. These results demonstrate that aSiO2 coating reduce CeO2-induced inflammation, phospholipidosis and fibrosis. PMID:26210349

  15. Effects of amorphous silica coating on cerium oxide nanoparticles induced pulmonary responses.

    PubMed

    Ma, Jane; Mercer, Robert R; Barger, Mark; Schwegler-Berry, Diane; Cohen, Joel M; Demokritou, Philip; Castranova, Vincent

    2015-10-01

    Recently cerium compounds have been used in a variety of consumer products, including diesel fuel additives, to increase fuel combustion efficiency and decrease diesel soot emissions. However, cerium oxide (CeO2) nanoparticles have been detected in the exhaust, which raises a health concern. Previous studies have shown that exposure of rats to nanoscale CeO2 by intratracheal instillation (IT) induces sustained pulmonary inflammation and fibrosis. In the present study, male Sprague-Dawley rats were exposed to CeO2 or CeO2 coated with a nano layer of amorphous SiO2 (aSiO2/CeO2) by a single IT and sacrificed at various times post-exposure to assess potential protective effects of the aSiO2 coating. The first acellular bronchoalveolar lavage (BAL) fluid and BAL cells were collected and analyzed from all exposed animals. At the low dose (0.15mg/kg), CeO2 but not aSiO2/CeO2 exposure induced inflammation. However, at the higher doses, both particles induced a dose-related inflammation, cytotoxicity, inflammatory cytokines, matrix metalloproteinase (MMP)-9, and tissue inhibitor of MMP at 1day post-exposure. Morphological analysis of lung showed an increased inflammation, surfactant and collagen fibers after CeO2 (high dose at 3.5mg/kg) treatment at 28days post-exposure. aSiO2 coating significantly reduced CeO2-induced inflammatory responses in the airspace and appeared to attenuate phospholipidosis and fibrosis. Energy dispersive X-ray spectroscopy analysis showed Ce and phosphorous (P) in all particle-exposed lungs, whereas Si was only detected in aSiO2/CeO2-exposed lungs up to 3days after exposure, suggesting that aSiO2 dissolved off the CeO2 core, and some of the CeO2 was transformed to CePO4 with time. These results demonstrate that aSiO2 coating reduce CeO2-induced inflammation, phospholipidosis and fibrosis. PMID:26210349

  16. A pathogenic role for tumor necrosis factor-related apoptosis-inducing ligand in chronic obstructive pulmonary disease.

    PubMed

    Haw, T J; Starkey, M R; Nair, P M; Pavlidis, S; Liu, G; Nguyen, D H; Hsu, A C; Hanish, I; Kim, R Y; Collison, A M; Inman, M D; Wark, P A; Foster, P S; Knight, D A; Mattes, J; Yagita, H; Adcock, I M; Horvat, J C; Hansbro, P M

    2016-07-01

    Chronic obstructive pulmonary disease (COPD) is a life-threatening inflammatory respiratory disorder, often induced by cigarette smoke (CS) exposure. The development of effective therapies is impaired by a lack of understanding of the underlining mechanisms. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a cytokine with inflammatory and apoptotic properties. We interrogated a mouse model of CS-induced experimental COPD and human tissues to identify a novel role for TRAIL in COPD pathogenesis. CS exposure of wild-type mice increased TRAIL and its receptor messenger RNA (mRNA) expression and protein levels, as well as the number of TRAIL(+)CD11b(+) monocytes in the lung. TRAIL and its receptor mRNA were also increased in human COPD. CS-exposed TRAIL-deficient mice had decreased pulmonary inflammation, pro-inflammatory mediators, emphysema-like alveolar enlargement, and improved lung function. TRAIL-deficient mice also developed spontaneous small airway changes with increased epithelial cell thickness and collagen deposition, independent of CS exposure. Importantly, therapeutic neutralization of TRAIL, after the establishment of early-stage experimental COPD, reduced pulmonary inflammation, emphysema-like alveolar enlargement, and small airway changes. These data provide further evidence for TRAIL being a pivotal inflammatory factor in respiratory diseases, and the first preclinical evidence to suggest that therapeutic agents that target TRAIL may be effective in COPD therapy. PMID:26555706

  17. Involvement of epithelial-to-mesenchymal transition and associated transforming growth factor-β/Smad signaling in paraquat-induced pulmonary fibrosis.

    PubMed

    Han, Ying-Ying; Shen, Peng; Chang, Wen-Xiu

    2015-12-01

    Paraquat (PQ) is a highly toxic herbicide which is able to induce pulmonary fibrosis in humans and animals. The epithelial‑to‑mesenchymal transition (EMT) was demonstrated to be an important factor in pulmonary fibrosis. However, it has remained elusive whether PQ induces pulmonary fibrosis via EMT, which was therefore investigated in the present study. In addition, the underlying mechanisms of PQ‑induced EMT were examined in vitro. Hematoxylin and eosin staining of rat lung tissues demonstrated that PQ induced pulmonary fibrosis in vivo. Western blot analysis then revealed that the expression of epithelial cell marker E‑cadherin was significantly decreased, while the expression of mesenchymal markers α‑smooth‑muscle actin and vimentin was significantly increased in rat lung tissues and A549 cells following PQ treatment. Transforming growth factor (TGF)‑β/Smad signaling was also induced by PQ as evidenced by increased expression of TGF‑β1 and Smad2. However, PQ‑induced EMT in A549 cells was abolished by transfection with TGF‑β1‑specific small hairpin RNA. In conclusion, the present study demonstrated that PQ induced EMT in vivo and in vitro, which may be an important process in the development of PQ‑induced pulmonary fibrosis. In addition, TGF-β/Smad signaling was involved in PQ-induced EMT. PMID:26499763

  18. Nifuroxazide induces apoptosis and impairs pulmonary metastasis in breast cancer model.

    PubMed

    Yang, F; Hu, M; Lei, Q; Xia, Y; Zhu, Y; Song, X; Li, Y; Jie, H; Liu, C; Xiong, Y; Zuo, Z; Zeng, A; Li, Y; Yu, L; Shen, G; Wang, D; Xie, Y; Ye, T; Wei, Y

    2015-01-01

    Breast carcinoma is the most common female cancer with considerable metastatic potential. Signal transducers and activators of the transcription 3 (Stat3) signaling pathway is constitutively activated in many cancers including breast cancer and has been validated as a novel potential anticancer target. Here, we reported our finding with nifuroxazide, an antidiarrheal agent identified as a potent inhibitor of Stat3. The potency of nifuroxazide on breast cancer was assessed in vitro and in vivo. In this investigation, we found that nifuroxazide decreased the viability of three breast cancer cell lines and induced apoptosis of cancer cells in a dose-dependent manner. In addition, western blot analysis demonstrated that the occurrence of its apoptosis was associated with activation of cleaved caspases-3 and Bax, downregulation of Bcl-2. Moreover, nifuroxazide markedly blocked cancer cell migration and invasion, and the reduction of phosphorylated-Stat3(Tyr705), matrix metalloproteinase (MMP) MMP-2 and MMP-9 expression were also observed. Furthermore, in our animal experiments, intraperitoneal administration of 50 mg/kg/day nifuroxazide suppressed 4T1 tumor growth and blocked formation of pulmonary metastases without detectable toxicity. Meanwhile, histological and immunohistochemical analyses revealed a decrease in Ki-67-positive cells, MMP-9-positive cells and an increase in cleaved caspase-3-positive cells upon nifuroxazide. Notably, nifuroxazide reduced the number of myeloid-derived suppressor cell in the lung. Our data indicated that nifuroxazide may potentially be a therapeutic agent for growth and metastasis of breast cancer. PMID:25811798

  19. Nifuroxazide induces apoptosis and impairs pulmonary metastasis in breast cancer model

    PubMed Central

    Yang, F; Hu, M; Lei, Q; Xia, Y; Zhu, Y; Song, X; Li, Y; Jie, H; Liu, C; Xiong, Y; Zuo, Z; Zeng, A; Li, Y; Yu, L; Shen, G; Wang, D; Xie, Y; Ye, T; Wei, Y

    2015-01-01

    Breast carcinoma is the most common female cancer with considerable metastatic potential. Signal transducers and activators of the transcription 3 (Stat3) signaling pathway is constitutively activated in many cancers including breast cancer and has been validated as a novel potential anticancer target. Here, we reported our finding with nifuroxazide, an antidiarrheal agent identified as a potent inhibitor of Stat3. The potency of nifuroxazide on breast cancer was assessed in vitro and in vivo. In this investigation, we found that nifuroxazide decreased the viability of three breast cancer cell lines and induced apoptosis of cancer cells in a dose-dependent manner. In addition, western blot analysis demonstrated that the occurrence of its apoptosis was associated with activation of cleaved caspases-3 and Bax, downregulation of Bcl-2. Moreover, nifuroxazide markedly blocked cancer cell migration and invasion, and the reduction of phosphorylated-Stat3Tyr705, matrix metalloproteinase (MMP) MMP-2 and MMP-9 expression were also observed. Furthermore, in our animal experiments, intraperitoneal administration of 50 mg/kg/day nifuroxazide suppressed 4T1 tumor growth and blocked formation of pulmonary metastases without detectable toxicity. Meanwhile, histological and immunohistochemical analyses revealed a decrease in Ki-67-positive cells, MMP-9-positive cells and an increase in cleaved caspase-3-positive cells upon nifuroxazide. Notably, nifuroxazide reduced the number of myeloid-derived suppressor cell in the lung. Our data indicated that nifuroxazide may potentially be a therapeutic agent for growth and metastasis of breast cancer. PMID:25811798

  20. Analysis of airway secretions in a model of sulfur dioxide induced chronic obstructive pulmonary disease (COPD)

    PubMed Central

    Wagner, Ulrich; Staats, Petra; Fehmann, Hans-Christoph; Fischer, Axel; Welte, Tobias; Groneberg, David A

    2006-01-01

    Hypersecretion and chronic phlegm are major symptoms of chronic obstructive pulmonary disease (COPD) but animal models of COPD with a defined functional hypersecretion have not been established so far. To identify an animal model of combined morphological signs of airway inflammation and functional hypersecretion, rats were continuously exposed to different levels of sulfur dioxide (SO2, 5 ppm, 10 ppm, 20 ppm, 40 ppm, 80 ppm) for 3 (short-term) or 20–25 (long-term) days. Histology revealed a dose-dependent increase in edema formation and inflammatory cell infiltration in short-term-exposed animals. The submucosal edema was replaced by fibrosis after long-term-exposure. The basal secretory activity was only significantly increased in the 20 ppm group. Also, stimulated secretion was significantly increased only after exposure to 20 ppm. BrdU-assays and AgNOR-analysis demonstrated cellular metaplasia and glandular hypertrophy rather than hyperplasia as the underlying morphological correlate of the hypersecretion. In summary, SO2-exposure can lead to characteristic airway remodeling and changes in mucus secretion in rats. As only long-term exposure to 20 ppm leads to a combination of hypersecretion and airway inflammation, only this mode of exposure should be used to mimic human COPD. Concentrations less or higher than 20 ppm or short term exposure do not induce the respiratory symptom of hypersecretion. The present model may be used to characterize the effects of new compounds on mucus secretion in the background of experimental COPD. PMID:16759388

  1. Influence of Scan Duration on Pulmonary Capillary Hemorrhage Induced by Diagnostic Ultrasound.

    PubMed

    Miller, Douglas L; Dong, Zhihong; Dou, Chunyan; Raghavendran, Krishnan

    2016-08-01

    Diagnostic ultrasound can induce pulmonary capillary hemorrhage (PCH) in rats and display this as "comet tail" artifacts (CTAs) after a time delay. To test the hypothesis that no PCH occurs for brief scans, anesthetized rats were scanned using a 6-MHz linear array for different durations. PCH was characterized by ultrasound CTAs, micro-computed tomography (μCT), and measurements of fixed lung tissue. The μCT images revealed regions of PCH, sometimes penetrating the entire depth of a lobe, which were reflected in the fixed tissue measurements. At -3 dB of power, PCH was substantial for 300-s scans, but not significant for 25-s scans. At 0 dB, PCH was not strongly dependent on scan durations of 300 to 10 s. Contrary to the hypothesis, CTAs were not evident during most 10-s scans (p > 0.05), but PCH was significant (p = 0.02), indicating that PCH could occur without evidence of the injury in the images. PMID:27117631

  2. No protective role for hypoxic pulmonary vasoconstriction in severe hypergravity-induced arterial hypoxemia.

    PubMed

    Karlsson, Lars L; Rohdin, Malin; Nekludov, Michael; Ax, Malin; Petersson, Johan

    2011-09-01

    Supine subjects exposed to hypergravity show a marked arterial desaturation. Previous work from our laboratory has also shown a paradoxical reduction of lung perfusion in dependent lung regions in supine subjects exposed to hypergravity. We reasoned that the increased lung weight during hypergravity caused either direct compression of the blood vessels in the dependent lung tissue or that poor regional ventilation caused reduced perfusion through hypoxic pulmonary vasoconstriction (HPV). The objective of this study was to evaluate the importance of HPV through measurements of arterial oxygenation during exposure to hypergravity with normal and attenuated HPV. A further increased arterial desaturation during hypergravity with attenuated HPV would support the hypothesis that HPV contributes to the paradoxical redistribution of regional perfusion. In a two-phased randomized study we first exposed 12 healthy subjects to 5 G while supine during two single-blinded conditions; control and after 50 mg sildenafil p.o.. In a second phase, 12 supine subjects were exposed to 5 G during three single-blinded conditions; control, after 100 mg sildenafil p.o. and after inhalation of 10 μg iloprost. There was a substantial arterial desaturation by 5-30% units in all subjects with no or only minor differences between conditions. The results speak against HPV as a principal mechanism for the hypergravity-induced reduction of lung perfusion in dependent lung regions in supine humans. PMID:21274557

  3. A human disease model of drug toxicity-induced pulmonary edema in a lung-on-a-chip microdevice.

    PubMed

    Huh, Dongeun; Leslie, Daniel C; Matthews, Benjamin D; Fraser, Jacob P; Jurek, Samuel; Hamilton, Geraldine A; Thorneloe, Kevin S; McAlexander, Michael Allen; Ingber, Donald E

    2012-11-01

    Preclinical drug development studies currently rely on costly and time-consuming animal testing because existing cell culture models fail to recapitulate complex, organ-level disease processes in humans. We provide the proof of principle for using a biomimetic microdevice that reconstitutes organ-level lung functions to create a human disease model-on-a-chip that mimics pulmonary edema. The microfluidic device, which reconstitutes the alveolar-capillary interface of the human lung, consists of channels lined by closely apposed layers of human pulmonary epithelial and endothelial cells that experience air and fluid flow, as well as cyclic mechanical strain to mimic normal breathing motions. This device was used to reproduce drug toxicity-induced pulmonary edema observed in human cancer patients treated with interleukin-2 (IL-2) at similar doses and over the same time frame. Studies using this on-chip disease model revealed that mechanical forces associated with physiological breathing motions play a crucial role in the development of increased vascular leakage that leads to pulmonary edema, and that circulating immune cells are not required for the development of this disease. These studies also led to identification of potential new therapeutics, including angiopoietin-1 (Ang-1) and a new transient receptor potential vanilloid 4 (TRPV4) ion channel inhibitor (GSK2193874), which might prevent this life-threatening toxicity of IL-2 in the future. PMID:23136042

  4. Enalapril Mitigates Radiation-Induced Pneumonitis and Pulmonary Fibrosis if Started 35 Days after Whole-Thorax Irradiation

    PubMed Central

    Gao, Feng; Fish, Brian L.; Moulder, John E.; Jacobs, Elizabeth R.; Medhora, Meetha

    2014-01-01

    Victims of a radiological attack or nuclear accident may receive high-dose, heterogeneous exposures from radiation to the chest that lead to lung damage. Our goal is to develop countermeasures to mitigate such injuries. We used WAG/RijCmcr rats receiving 13 Gy to the whole thorax to induce pulmonary fibrosis within 210 days. The angiotensin converting enzyme (ACE) inhibitor enalapril was evaluated as a mitigator of these injuries at two doses (18 and 36 mg/m2/day) and 8 schedules: starting at 7, 35, 70, 105 and 140 days and continuing to 210 days or starting at 7 days and stopping at 30, 60 or 90 days after whole-thorax irradiation. The earliest start date at 7 days after irradiation would provide an adequate window of time for triage and dosimetry. Survival after 35 days, as permitted by our Institutional Animal Care and Use Committee (IACUC) was also recorded as a primary end point of pneumonitis. Pulmonary fibrosis was evaluated using the Sircol biochemical assay to measure lung collagen. Our results indicated that a short course of either dose of enalapril from 7–90 days improved survival. However, pulmonary fibrosis was only mitigated by the higher dose of enalapril (36 mg/m2/day). The latest effective start date for the drug was 35 days after irradiation. These results indicate that ACE inhibitors can be started at least a month after irradiation for mitigation of pneumonitis and/or pulmonary fibrosis. PMID:24131041

  5. Attenuation of lipopolysaccharide-induced oxidative stress and apoptosis in fetal pulmonary artery endothelial cells by hypoxia.

    PubMed

    Sampath, Venkatesh; Radish, Aaron C; Eis, Annie L; Broniowska, Katarzyna; Hogg, Neil; Konduri, Girija G

    2009-03-01

    Pulmonary vascular endothelial injury resulting from lipopolysaccharide (LPS) and oxygen toxicity contributes to vascular simplification seen in the lungs of premature infants with bronchopulmonary dysplasia. Whether the severity of endotoxin-induced endothelial injury is modulated by ambient oxygen tension (hypoxic intrauterine environment vs. hyperoxic postnatal environment) remains unknown. We posited that ovine fetal pulmonary artery endothelial cells (FPAEC) will be more resistant to LPS toxicity under hypoxic conditions (20-25 Torr) mimicking the fetal milieu. LPS (10 microg/ml) inhibited FPAEC proliferation and induced apoptosis under normoxic conditions (21% O(2)) in vitro. LPS-induced FPAEC apoptosis was attenuated in hypoxia (5% O(2)) and exacerbated by hyperoxia (55% O(2)). LPS increased intracellular superoxide formation, as measured by 2-hydroxyethidium (2-HE) formation, in FPAEC in normoxia and hypoxia. 2-HE formation in LPS-treated FPAEC increased in parallel with the severity of LPS-induced apoptosis in FPAEC, increasing from hypoxia to normoxia to hyperoxia. Differences in LPS-induced apoptosis between hypoxia and normoxia were abolished when LPS-treated FPAEC incubated in hypoxia were pretreated with menadione to increase superoxide production. Apocynin decreased 2-HE formation, and attenuated LPS-induced FPAEC apoptosis under normoxic conditions. We conclude that ambient oxygen concentration modulates the severity of LPS-mediated injury in FPAEC by regulating superoxide levels produced in response to LPS. PMID:19135525

  6. Role of Sialidase in Mycoplasma alligatoris-induced Pulmonary Fibroblast Apoptosis

    PubMed Central

    Hunt, Marguerite E.; Brown, Daniel R.

    2007-01-01

    Mycoplasma alligatoris causes acute lethal cardiopulmonary disease of susceptible hosts. A survey of its genome implicated sialidase and hyaluronidase, synergistic regulators of hyaluronan receptor CD44-mediated signal transduction leading to apoptotic cell death, as virulence factors of M. alligatoris. In this study, after the existence of a CD44 homolog in alligators was established by immunolabeling primary pulmonary fibroblasts with monoclonal antibody IM7 against murine CD44, the sialidase inhibitor 2,3-didehydro-2-deoxy-N-acetylneuraminic acid (DANA) was used to examine the effects of sialidase on fibroblast apoptosis following in vitro infection with M. alligatoris. While their CD44 expression remained constant, infected cells exhibited morphologic changes characteristic of apoptosis including decreased size, rounding, disordered a-tubulin, and nuclear disintegration compared to untreated controls. DANA was a potent, non-toxic inhibitor of the sialidase activity, equivalent to about 1 mU of Clostridium perfringens Type VI sialidase, expressed by M. alligatoris in the inoculum. Although DANA did not measurably reduce the proportion of infected fibroblasts labeled by a specific ligand of activated caspases, co-incubation with DANA protected (P < 0.01) fibroblasts in a concentration-dependent fashion from the M. alligatoris-induced trends toward increased apoptosis receptor CD95 expression, and increased 5-bromo-2′-deoxyuridine incorporation measured in a terminal dUTP nick end-labeling apoptosis assay. In contrast, incubation with 200-fold excess purified C. perfringens sialidase alone did not affect CD95 expression or chromatin integrity, or induce fibroblast apoptosis. From those observations we conclude that interaction of its sialidase with hyaluronidase or another virulence factor(s) is necessary to elicit the pro-apoptotic effects of M. alligatoris infection. PMID:17276629

  7. Pulmonary gallium uptake in rats with granulomatosis induced by complete Freund adjuvant

    SciTech Connect

    Stanislas-Leguern, G.; Masse, R.; Jaubert, F.; Chretien, J.; Huchon, G.

    1988-01-01

    To investigate the mechanism of gallium-67 uptake in lung granulomatosis, we studied 13 rats in which lung granulomatosis was induced by injection of complete Freund adjuvant (CFA) and 14 controls. Gallium uptake was assessed in bronchoalveolar lavage fluid and lavaged lung. The cells responsible for gallium uptake were identified by latent image activation autoradiography. Gallium activity in both lavaged lungs and bronchoalveolar cells (BAC) was higher in CFA-treated animals than in controls (172,205 +/- 134,783 DPM versus 44,456 +/- 14,486 DPM +/- SD (p less than 0.05) and 40,083 +/- 16,350 DPM versus 9100 +/- 4114 DPM (p less than 0.05), respectively). In control rats, about two-thirds of total lung gallium was located in the interstitium, whereas in CFA-treated rats it was found in the mononuclear cells of lung granulomas. Gallium tracks were more numerous in the alveolar macrophages (AM) of CFA-treated rats than in control AM (28.4 +/- 10.0/field versus 8.4 +/- 3.8/field, p less than 0.001) but the number of tracks was proportional to the number of AM (52.4 +/- 18.7 versus 12.2 +/- 4.3, respectively; p less than 0.001). It is concluded that in rats with CFA-induced lung granulomatosis 1) pulmonary gallium uptake increases, 2) mononuclear cells are responsible for this uptake in both granulomas and AM, and 3) the increased uptake is due to the increased number of mononuclear cells.

  8. Combined Tlr2 and Tlr4 Deficiency Increases Radiation-Induced Pulmonary Fibrosis in Mice

    SciTech Connect

    Paun, Alexandra; Fox, Jessica; Balloy, Viviane; Chignard, Michel; Qureshi, Salman T.; Haston, Christina K.

    2010-07-15

    Purpose: To determine whether Toll-like receptor 2 or 4 genotype alters the lung response to irradiation in C57BL/6 mice using a model developing a phenotype that resembles radiotherapy-induced fibrosis in both histological characteristics and onset post-treatment. Methods and Materials: The pulmonary phenotype of C57BL/6 mice deficient in each or both of these genes was assessed after an 18-Gy single dose to the thoracic cavity by survival time postirradiation, bronchoalveolar lavage cell differential, histological evidence of alveolitis and fibrosis, and gene expression levels, and compared with that of wild-type mice. Results: The lung phenotype of Tlr4-deficient and Tlr2-deficient mice did not differ from that of wild-type mice in terms of survival time postirradiation, or by histological evidence of alveolitis or fibrosis. In contrast, mice deficient in both receptors developed respiratory distress at an earlier time than did wild-type mice and presented an enhanced fibrotic response (13.5% vs. 5.8% of the lung by image analysis of histological sections, p < 0.001). No differences in bronchoalveolar cell differential counts, nor in numbers of apoptotic cells in the lung as detected through active caspase-3 staining, were evident among the irradiated mice grouped by Tlr genotype. Gene expression analysis of lung tissue revealed that Tlr2,4-deficient mice have increased levels of hyaluronidase 2 compared with both wild-type mice and mice lacking either Tlr2 or Tlr4. Conclusion: We conclude that a combined deficiency in both Tlr2 and Tlr4, but not Tlr2 or Tlr4 alone, leads to enhanced radiation-induced fibrosis in the C57BL/6 mouse model.

  9. Expression of inducible nitric oxide synthase in rat pulmonary Cryptococcus neoformans granulomas.

    PubMed Central

    Goldman, D.; Cho, Y.; Zhao, M.; Casadevall, A.; Lee, S. C.

    1996-01-01

    Rats, like humans, have extremely effective immune mechanisms for controlling pulmonary Cryptococcus neoformans infection. The mechanism(s) responsible for efficient immunity in rat experimental infection is unknown. Recently, induction of inducible nitric oxide synthase (iNOS) and nitric oxide (NO) have been implicated as an important microbicidal mechanism by which activated macrophages effect cytotoxicity against microbes. In this report, we investigated the expression of iNOS in rat pulmonary cryptococcosis. Localization and regulation of NO production was studied by immunohistochemistry for iNOS in conjunction with immunohistochemistry for cell markers, cytokines, and cryptococcal capsular polysaccharide. iNOS immunoreactivity was detected in macrophages, neutrophils, vascular endothelium, and respiratory epithelium. Double-immunolabeling studies revealed that the most prominent iNOS immunoreactivity was localized to epithelioid macrophages (CD11b/c+) within granulomas; CD4+ and CD8+ T cells were numerous around granulomas but did not express iNOS. iNOS immunoreactivity was detected in a selective population of epithelioid macrophages within some granulomas but not others. iNOS- granulomas were identical to iNOS+ granulomas with respect to morphology and immunohistochemical profiles. Macrophage iNOS immunoreactivity was detected 1 week after infection in one out of four rats and was strongly expressed in all rats at 2 weeks (in up to 50 percent of the granulomas) but declined considerably by 25 days. iNOS expression coincided with granuloma formation and preceded a decrease in lung fungal burden, suggesting an anticryptococcal role for NO. By double labeling, cytokines that have been shown to promote (interferon-gamma, granulocyte/macrophage colony-stimulating factor) and inhibit (transforming growth factor-beta) macrophage iNOS expression were detected around iNOS+ granuloma. iNOS immunoreactivity was expressed in selected neutrophils (1 and 2 weeks) and

  10. Folic Acid Promotes Recycling of Tetrahydrobiopterin and Protects Against Hypoxia-Induced Pulmonary Hypertension by Recoupling Endothelial Nitric Oxide Synthase

    PubMed Central

    Chalupsky, Karel; Kračun, Damir; Kanchev, Ivan; Bertram, Katharina

    2015-01-01

    Abstract Aims: Nitric oxide (NO) derived from endothelial NO synthase (eNOS) has been implicated in the adaptive response to hypoxia. An imbalance between 5,6,7,8-tetrahydrobiopterin (BH4) and 7,8-dihydrobiopterin (BH2) can result in eNOS uncoupling and the generation of superoxide instead of NO. Dihydrofolate reductase (DHFR) can recycle BH2 to BH4, leading to eNOS recoupling. However, the role of DHFR and eNOS recoupling in the response to hypoxia is not well understood. We hypothesized that increasing the capacity to recycle BH4 from BH2 would improve NO bioavailability as well as pulmonary vascular remodeling (PVR) and right ventricular hypertrophy (RVH) as indicators of pulmonary hypertension (PH) under hypoxic conditions. Results: In human pulmonary artery endothelial cells and murine pulmonary arteries exposed to hypoxia, eNOS was uncoupled as indicated by reduced superoxide production in the presence of the nitric oxide synthase inhibitor, L-(G)-nitro-L-arginine methyl ester (L-NAME). Concomitantly, NO levels, BH4 availability, and expression of DHFR were diminished under hypoxia. Application of folic acid (FA) restored DHFR levels, NO bioavailability, and BH4 levels under hypoxia. Importantly, FA prevented the development of hypoxia-induced PVR, right ventricular pressure increase, and RVH. Innovation: FA-induced upregulation of DHFR recouples eNOS under hypoxia by improving BH4 recycling, thus preventing hypoxia-induced PH. Conclusion: FA might serve as a novel therapeutic option combating PH. Antioxid. Redox Signal. 23, 1076–1091. PMID:26414244

  11. Preventive Effects of Rhodiola rosea L. on Bleomycin-Induced Pulmonary Fibrosis in Rats

    PubMed Central

    Zhang, Ke; Si, Xiao-Ping; Huang, Jian; Han, Jian; Liang, Xu; Xu, Xiao-Bo; Wang, Yi-Ting; Li, Guo-Yu; Wang, Hang-Yu; Wang, Jin-Hui

    2016-01-01

    Rhodiola rosea L. (RRL) possesses a wide range of pharmacological properties, including lung-protective activity, and has been utilized in folk medicine for several 100 years. However, the lung-protective mechanism remains unclear. This study investigated the possible lung-protective activity mechanism of RRL in a pulmonary fibrosis (PF) rat model. Lung fibrotic injury was induced in Sprague–Dawley rats by single intratracheal instillation of saline containing bleomycin (BLM; 5 mg/kg). The rats were administered 125, 250, or 500 mg/kg of a 95% ethanol extract of RRL for 28 days. The animals were killed to detect changes in body weight, serum levels of glutathione (GSH) and total superoxide dismutase (T-SOD), as well as lung tissue hydroxyproline (HYP) content. Tumor necrosis factor-α (TNF-α), transforming growth factor-β1 (TGF-β1), and interleukin 6 (IL-6) levels were measured in bronchoalveolar lavage fluid (BALF) by enzyme-linked immunosorbent assay. Hematoxylin and eosin, Masson’s trichrome, and immunohistochemical staining were performed to observe the histopathological changes in lung tissues. Additionally, target-related proteins were measured by Western blotting. RRL alleviated the loss of body weight induced by instilling BLM in PF rats, particularly at the 500 mg/kg per day dose. RRL reduced HYP (p < 0.01) and increased GSH and T-SOD contents. BALF levels of TNF-α, TGF-β1, and IL-6 decreased significantly in the RRL-treated groups. Expression levels of matrix metalloproteinase-9 (MMP-9) and α-smooth muscle actin decreased significantly in a dose-dependent manner in response to RRL. Moreover, the levels of TGF-β1 and tissue inhibitor of metalloproteinase-1 in lung tissues also decreased in the RRL-treated groups. RRL alleviated BLM-induced PF in rats. Our results reveal that the protective effects of RRL against fibrotic lung injury in rats are correlated with its anti-inflammatory, antioxidative, and anti-fibrotic properties. MMP-9 may play

  12. Preventive Effects of Rhodiola rosea L. on Bleomycin-Induced Pulmonary Fibrosis in Rats.

    PubMed

    Zhang, Ke; Si, Xiao-Ping; Huang, Jian; Han, Jian; Liang, Xu; Xu, Xiao-Bo; Wang, Yi-Ting; Li, Guo-Yu; Wang, Hang-Yu; Wang, Jin-Hui

    2016-01-01

    Rhodiola rosea L. (RRL) possesses a wide range of pharmacological properties, including lung-protective activity, and has been utilized in folk medicine for several 100 years. However, the lung-protective mechanism remains unclear. This study investigated the possible lung-protective activity mechanism of RRL in a pulmonary fibrosis (PF) rat model. Lung fibrotic injury was induced in Sprague-Dawley rats by single intratracheal instillation of saline containing bleomycin (BLM; 5 mg/kg). The rats were administered 125, 250, or 500 mg/kg of a 95% ethanol extract of RRL for 28 days. The animals were killed to detect changes in body weight, serum levels of glutathione (GSH) and total superoxide dismutase (T-SOD), as well as lung tissue hydroxyproline (HYP) content. Tumor necrosis factor-α (TNF-α), transforming growth factor-β1 (TGF-β1), and interleukin 6 (IL-6) levels were measured in bronchoalveolar lavage fluid (BALF) by enzyme-linked immunosorbent assay. Hematoxylin and eosin, Masson's trichrome, and immunohistochemical staining were performed to observe the histopathological changes in lung tissues. Additionally, target-related proteins were measured by Western blotting. RRL alleviated the loss of body weight induced by instilling BLM in PF rats, particularly at the 500 mg/kg per day dose. RRL reduced HYP (p < 0.01) and increased GSH and T-SOD contents. BALF levels of TNF-α, TGF-β1, and IL-6 decreased significantly in the RRL-treated groups. Expression levels of matrix metalloproteinase-9 (MMP-9) and α-smooth muscle actin decreased significantly in a dose-dependent manner in response to RRL. Moreover, the levels of TGF-β1 and tissue inhibitor of metalloproteinase-1 in lung tissues also decreased in the RRL-treated groups. RRL alleviated BLM-induced PF in rats. Our results reveal that the protective effects of RRL against fibrotic lung injury in rats are correlated with its anti-inflammatory, antioxidative, and anti-fibrotic properties. MMP-9 may play

  13. Tobacco smoke induced lung granulomas and tumors: association with pulmonary Langerhans cells.

    PubMed

    Zeid, N A; Muller, H K

    1995-07-01

    The density of zinc-iodide-osmium (ZIO) positive pulmonary Langerhans dendritic cells (LC) was increased about 20-fold in mice after passive exposure to tobacco smoke. This was associated with pulmonary changes consistent with the cigarette smoking-related clinical syndrome in humans, pulmonary Langerhans cell granulomatosis. The major feature was an interstitial peribronchial granuloma. The cellular infiltrate of the granuloma (lymphocytes, plasma cells, eosinophils, clusters of large histiocyte-like cells and macrophages) extended into the adjacent alveolar septum forming a star-shaped lesion. The histiocyte-like cells were large with pale acidophilic cytoplasm and many ill-defined short dendrites extending from the cell membrane. Bronchial epithelial metaplasia also developed. The interstitial changes were followed by the development of proliferative alveolar and bronchial lesions in 2 mice. The zinc-iodide-osmium positive cells were consistent with la positive pulmonary dendritic cells and their ultrastructure was similar to that of pulmonary Langerhans cells. After ceasing exposure to tobacco smoke the density of pulmonary Langerhans cells returned to that of the control level; interstitial granulomatous lesions disappeared, but the bronchial epithelial metaplasia did not reverse. Tobacco smoke exposure of mice produces interstitial granulomatous inflammation similar to Langerhans cell granulomatosis in humans. The elevated level of pulmonary Langerhans cells implicate these cells in the pathogenesis of these lesions. PMID:8532391

  14. Development and Characterization of an Inducible Rat Model of Chronic Thromboembolic Pulmonary Hypertension.

    PubMed

    Arias-Loza, Paula-Anahi; Jung, Pius; Abeßer, Marco; Umbenhauer, Sandra; Williams, Tatjana; Frantz, Stefan; Schuh, Kai; Pelzer, Theo

    2016-05-01

    Chronic thromboembolic pulmonary hypertension (CTEPH) is an entity of PH that not only limits patients quality of life but also causes significant morbidity and mortality. The treatment of choice is pulmonary endarterectomy. However numerous patients do not qualify for pulmonary endarterectomy or present with residual vasculopathy post pulmonary endarterectomy and require specific vasodilator treatment. Currently, there is no available specific small animal model of CTEPH that could serve as tool to identify targetable molecular pathways and to test new treatment options. Thus, we generated and standardized a rat model that not only resembles functional and histological features of CTEPH but also emulates thrombi fibrosis. The pulmonary embolism protocol consisted of 3 sequential tail vein injections of fibrinogen/collagen-covered polystyrene microspheres combined with thrombin and administered to 10-week-old male Wistar rats. After the third embolism, rats developed characteristic features of CTEPH including elevated right ventricular systolic pressure, right ventricular cardiomyocyte hypertrophy, pulmonary artery remodeling, increased serum brain natriuretic peptide levels, thrombi fibrosis, and formation of pulmonary cellular-fibrotic lesions. The current animal model seems suitable for detailed study of CTEPH pathophysiology and permits preclinical testing of new pharmacological therapies against CTEPH. PMID:27045032

  15. AVP-induced pulmonary vasodilation during specific V1 receptor block in conscious dogs.

    PubMed

    Nyhan, D P; Clougherty, P W; Murray, P A

    1987-09-01

    Our objectives were 1) to determine whether exogenously administered arginine vasopressin (AVP) can exert a vasoactive influence on the pulmonary circulation of conscious dogs during specific vasopressinergic-1 (V1) receptor block, and 2) to assess the extent to which the pulmonary vascular response to AVP during V1 receptor block is mediated by either sympathetic beta-adrenergic or cholinergic receptor activation or by cyclooxygenase pathway activation. Multipoint pulmonary vascular pressure-cardiac index (P/Q) plots were constructed during normoxia in conscious dogs by stepwise constriction of the thoracic inferior vena cava to reduce Q. In dogs pretreated with a specific V1 receptor antagonist [d(CH2)5 AVP, 10 micrograms/kg iv], AVP infusion (7.6 ng.kg-1 X min-1 iv) increased (P less than 0.01) Q from 139 +/- 6 to 175 +/- 8 ml.min-1 X kg-1, and decreased (P less than 0.01) the pulmonary vascular pressure gradient (pulmonary arterial pressure-pulmonary capillary wedge pressure: PAP-PCWP) over the entire range of Q studied (140 to 80 ml.min-1 X kg-1). This pulmonary vasodilator response to AVP during V1 block was also observed following sympathetic beta-adrenergic block alone, following combined sympathetic beta-adrenergic and cholinergic block, and following cyclooxygenase pathway inhibition. Thus exogenous administration of AVP during specific V1 receptor block results in active, nonflow-dependent pulmonary vasodilation. This pulmonary vasodilator response is not mediated by reflex activation of sympathetic beta-adrenergic or cholinergic receptors or by metabolites of the cyclooxygenase pathway over a broad range of Q. PMID:2888317

  16. Inhalative Exposure to Vanadium Pentoxide Causes DNA Damage in Workers: Results of a Multiple End Point Study

    PubMed Central

    Ehrlich, Veronika A.; Nersesyan, Armen K.; Hoelzl, Christine; Ferk, Franziska; Bichler, Julia; Valic, Eva; Schaffer, Andreas; Schulte-Hermann, Rolf; Fenech, Michael; Wagner, Karl-Heinz; Knasmüller, Siegfried

    2008-01-01

    Background Inhalative exposure to vanadium pentoxide (V2O5) causes lung cancer in rodents. Objective The aim of the study was to investigate the impact of V2O5 on DNA stability in workers from a V2O5 factory. Methods We determined DNA strand breaks in leukocytes of 52 workers and controls using the alkaline comet assay. We also investigated different parameters of chromosomal instability in lymphocytes of 23 workers and 24 controls using the cytokinesis-block micronucleus (MN) cytome method. Results Seven of eight biomarkers were increased in blood cells of the workers, and vanadium plasma concentrations in plasma were 7-fold higher than in the controls (0.31 μg/L). We observed no difference in DNA migration under standard conditions, but we found increased tail lengths due to formation of oxidized purines (7%) and pyrimidines (30%) with lesion-specific enzymes (formamidopyrimidine glycosylase and endonuclease III) in the workers. Bleomycin-induced DNA migration was higher in the exposed group (25%), whereas the repair of bleomycin-induced lesions was reduced. Workers had a 2.5-fold higher MN frequency, and nucleoplasmic bridges (NPBs) and nuclear buds (Nbuds) were increased 7-fold and 3-fold, respectively. Also, apoptosis and necrosis rates were higher, but only the latter parameter reached statistical significance. Conclusions V2O5 causes oxidation of DNA bases, affects DNA repair, and induces formation of MNs, NPBs, and Nbuds in blood cells, suggesting that the workers are at increased risk for cancer and other diseases that are related to DNA instability. PMID:19079721

  17. Up-regulation of the mammalian target of rapamycin complex 1 subunit Raptor by aldosterone induces abnormal pulmonary artery smooth muscle cell survival patterns to promote pulmonary arterial hypertension.

    PubMed

    Aghamohammadzadeh, Reza; Zhang, Ying-Yi; Stephens, Thomas E; Arons, Elena; Zaman, Paula; Polach, Kevin J; Matar, Majed; Yung, Lai-Ming; Yu, Paul B; Bowman, Frederick P; Opotowsky, Alexander R; Waxman, Aaron B; Loscalzo, Joseph; Leopold, Jane A; Maron, Bradley A

    2016-07-01

    Activation of the mammalian target of rapamycin complex 1 (mTORC1) subunit Raptor induces cell growth and is a downstream target of Akt. Elevated levels of aldosterone activate Akt, and, in pulmonary arterial hypertension (PAH), correlate with pulmonary arteriole thickening, which suggests that mTORC1 regulation by aldosterone may mediate adverse pulmonary vascular remodeling. We hypothesized that aldosterone-Raptor signaling induces abnormal pulmonary artery smooth muscle cell (PASMC) survival patterns to promote PAH. Remodeled pulmonary arterioles from SU-5416/hypoxia-PAH rats and monocrotaline-PAH rats with hyperaldosteronism expressed increased levels of the Raptor target, p70S6K, which provided a basis for investigating aldosterone-Raptor signaling in human PASMCs. Aldosterone (10(-9) to 10(-7) M) increased Akt/mTOR/Raptor to activate p70S6K and increase proliferation, viability, and apoptosis resistance in PASMCs. In PASMCs transfected with Raptor-small interfering RNA or treated with spironolactone/eplerenone, aldosterone or pulmonary arterial plasma from patients with PAH failed to increase p70S6K activation or to induce cell survival in vitro Optimal inhibition of pulmonary arteriole Raptor was achieved by treatment with Staramine-monomethoxy polyethylene glycol that was formulated with Raptor-small interfering RNA plus spironolactone in vivo, which decreased arteriole muscularization and pulmonary hypertension in 2 experimental animal models of PAH in vivo Up-regulation of mTORC1 by aldosterone is a critical pathobiologic mechanism that controls PASMC survival to promote hypertrophic vascular remodeling and PAH.-Aghamohammadzadeh, R., Zhang, Y.-Y., Stephens, T. E., Arons, E., Zaman, P., Polach, K. J., Matar, M., Yung, L.-M., Yu, P. B., Bowman, F. P., Opotowsky, A. R., Waxman, A. B., Loscalzo, J., Leopold, J. A., Maron, B. A. Up-regulation of the mammalian target of rapamycin complex 1 subunit Raptor by aldosterone induces abnormal pulmonary artery smooth

  18. Blood volume increase in salt-induced pulmonary hypertension, heart failure and ascites in broiler and White Leghorn chickens.

    PubMed Central

    Mirsalimi, S M; O'Brien, P J; Julian, R J

    1993-01-01

    In this study we tested the hypothesis that excess dietary salt produces an expansion of extracellular fluid volume which may be associated with pulmonary hypertension-induced right ventricular failure in chickens with rapid growth rates. One-week-old broiler and White Leghorn chickens were given 0.5% salt in their drinking water for three weeks. Saline water had a minimal effect on White Leghorns. The hypothesis appears to be correct since salt-treatment in broilers resulted in up to 30% expansion in blood volume and there was 50% mortality from pulmonary hypertension-induced right ventricular failure and ascites. There was marked (up to 88% in some broilers) right ventricular hypertrophy, an indicator of pulmonary hypertension. There was less left ventricular hypertrophy as shown by an increase in the ratio of the right to total ventricle weight. There was up to 32% decrease in growth rate. There was renal hypertrophy in the salt-treated birds as shown by a higher kidney to body weight ratio. PMID:8490804

  19. Role of oxidative stress, inflammation, nitric oxide and transforming growth factor-beta in the protective effect of diosgenin in monocrotaline-induced pulmonary hypertension in rats.

    PubMed

    Ahmed, Lamiaa A; Obaid, Al Arqam Z; Zaki, Hala F; Agha, Azza M

    2014-10-01

    Pulmonary hypertension is a progressive disease of various origins that is associated with right ventricular dysfunction. In the present study, the protective effect of diosgenin was investigated in monocrotaline-induced pulmonary hypertension in rats. Pulmonary hypertension was induced by a single subcutaneous injection of monocrotaline (60 mg/kg). Diosgenin (100 mg/kg) was given by oral administration once daily for 3 weeks. At the end of the experiment, mean arterial blood pressure, electrocardiography and echocardiography were recorded. Rats were then sacrificed and serum was separated for determination of total nitrate/nitrite level. Right ventricles and lungs were isolated for estimation of oxidative stress markers, tumor necrosis factor-alpha, total nitrate/nitrite and transforming growth factor-beta contents. Myeloperoxidase and caspase-3 activities in addition to endothelial and inducible nitric oxide synthase protein expression were also determined. Moreover, histological analysis of pulmonary arteries and cardiomyocyte cross-sectional area was performed. Diosgenin treatment provided a significant improvement toward preserving hemodynamic changes and alleviating oxidative stress, inflammatory and apoptotic markers induced by monocrotaline in rats. Furthermore, diosgenin therapy prevented monocrotaline-induced changes in nitric oxide production, endothelial and inducible nitric oxide synthase protein expression as well as histological analysis. These findings support the beneficial effect of diosgenin in pulmonary hypertension induced by monocrotaline in rats. PMID:25062790

  20. Evanescent field Sensors Based on Tantalum Pentoxide Waveguides – A Review

    PubMed Central

    Schmitt, Katrin; Oehse, Kerstin; Sulz, Gerd; Hoffmann, Christian

    2008-01-01

    Evanescent field sensors based on waveguide surfaces play an important role where high sensitivity is required. Particularly tantalum pentoxide (Ta2O5) is a suitable material for thin-film waveguides due to its high refractive index and low attenuation. Many label-free biosensor systems such as grating couplers and interferometric sensors as well as fluorescence-based systems benefit from this waveguide material leading to extremely high sensitivity. Some biosensor systems based on Ta2O5 waveguides already took the step into commercialization. This report reviews the various detection systems in terms of limit of detection, the applications, and the suitable surface chemistry.

  1. Pneumomediastinum, subcutaneous emphysema, and pneumothorax after a pulmonary function testing in a patient with bleomycin-induced interstitial pneumonitis*

    PubMed Central

    Araujo, Mariana Sponholz; Fernandes, Frederico Leon Arrabal; Kay, Fernando Uliana; Carvalho, Carlos Roberto Ribeiro

    2013-01-01

    Spontaneous pneumomediastinum is an uncommon event, the clinical picture of which includes retrosternal chest pain, subcutaneous emphysema, dyspnea, and dysphonia. The pathophysiological mechanism involved is the emergence of a pressure gradient between the alveoli and surrounding structures, causing alveolar rupture with subsequent dissection of the peribronchovascular sheath and infiltration of the mediastinum and subcutaneous tissue with air. Known triggers include acute exacerbations of asthma and situations that require the Valsalva maneuver. We described and documented with HRCT scans the occurrence of pneumomediastinum after a patient with bleomycin-induced interstitial lung disease underwent pulmonary function testing. Although uncommon, the association between pulmonary function testing and air leak syndromes has been increasingly reported in the literature, and lung diseases, such as interstitial lung diseases, include structural changes that facilitate the occurrence of this complication. PMID:24310635

  2. New models of pulmonary hypertension based on VEGF receptor blockade-induced endothelial cell apoptosis

    PubMed Central

    Nicolls, Mark R.; Mizuno, Shiro; Taraseviciene-Stewart, Laima; Farkas, Laszlo; Drake, Jennnifer I.; Al Husseini, Aysar; Gomez-Arroyo, Jose G.; Voelkel, Norbert F.; Bogaard, Herman J.

    2012-01-01

    In spite of treatment, severe angioproliferative pulmonary arterial hypertension (PAH) remains a disease characterized by great morbidity and shortened survival. New treatment strategies for patients with PAH are needed, and after drug development, preclinical studies are best conducted in animal models which present with pulmonary angio-obliterative disease and right heart failure. A rat model of severe pulmonary hypertension and right heart failure, described a decade ago, continues to be investigated and provide insight into the nature of the lung vascular lesions and mechanisms of cardiac adaptation to an altered lung circulation. This rat model is based on the combination of VEGF receptor blockade with Su5416 and chronic hypoxia; use of this pulmonary hypertension induction strategy led to developing the concept of apoptosis-dependent compensatory vascular cell growth. Although, often employed in experimental designs, chronic hypoxia is not necessary for the development of angio-obliterative pulmonary hypertension. Left pneumonectomy combined with Su5416 also results in severe pulmonary hypertension in normoxic conditions. Similarly, the immune insufficiency component of severe PAH can be modeled in athymic rats (lacking T-lymphocytes). In these rats housed under normoxic conditions, treatment with the VEGFR receptor blocker results in angioproliferative pulmonary hypertension; cardiopulmonary disease in these animals can be prevented by immune reconstitution of regulatory T-cells (Tregs). Finally, chronic hypoxia can be replaced with another stimulator of HIF-1α: Ovalbumin (Ova). Immunization of rats with Ova increases lung tissue HIF-1α protein expression, and in Su5416-treated rats causes lethal pulmonary hypertension. Finally, we postulate that these models may also be useful for “reverse translation”; that is, the mechanisms of lung vascular cell death and growth and the modifying influences of immune and bone marrow cells that have been identified

  3. [A case of pulmonary tumor thrombotic microangiopathy induced by early gastric cancer].

    PubMed

    Yasui, Hideki; Akamatsu, Taisuke; Nakamura, Yutarou; Inui, Naoki; Suda, Takafumi; Chida, Kingo; Meguro, Shiori; Baba, Satoshi

    2011-02-01

    A 56-year-old man with chief complaints of dry cough and dyspnea was admitted. He had severe hypoxemia, and his chest radiographs showed enhancement of pulmonary artery opacities with multiple defects on pulmonary blood flow scintigraphy. Enhanced computed tomography (CT) revealed swelling of the mediastinum and hilar lymph nodes, but no apparent thrombi in the pulmonary arteries was seen. A biopsy specimen of a left neck lymph node showed poorly differentiated adenocarcinoma, including signet-ring cell carcinoma components, but the origin was unclear. Despite receiving chemotherapy, his respiratory condition worsened, and he died 3 days after admission. Routine autopsy failed to clarify the tumor origin, but a detailed dissection of specimens confirmed early gastric cancer. Additionally, pathology of the pulmonary arteries was compatible with pulmonary tumor thrombotic microangiopathy (PTTM). PTTM is a rare condition characterized by the presence of diffuse thrombotic microthrombi and fibrocellular intimal proliferation in the pulmonary vasculature. Accompanied with early gastric cancer, this is an extremely rare but important case of PTTM. PMID:21400909

  4. Cell- and isoform-specific increases in arginase expression in acute silica-induced pulmonary inflammation.

    PubMed

    Poljakovic, Mirjana; Porter, Dale W; Millecchia, Lyndell; Kepka-Lenhart, Diane; Beighley, Christopher; Wolfarth, Michael G; Castranova, Vincent; Morris, Sidney M

    2007-01-15

    Arginase induction was reported in several inflammatory lung diseases, suggesting that this may be a common feature underlying the pathophysiology of such diseases. As little is known regarding arginase expression in silicosis, the induction and cellular localization of arginase were elucidated in lungs of Sprague-Dawley rats 24 h following exposure to varying doses of silica by intratracheal instillation. Arginase expression was evaluated by activity assay, quantification of arginase I and arginase II mRNA levels using real-time polymerase chain reaction (PCR), and immunohistochemistry. Analyses of cells and fluid obtained by bronchoalveolar lavage (BAL) showed that markers of pulmonary inflammation, tissue damage, activation of alveolar macrophages (AM) and NO production were significantly increased by all silica doses. Arginase activity was increased also in AMs isolated from BAL fluid of silica-treated rats. Silica produced two- and three-fold increases in arginase activity of whole lung at doses of 1 and 5 mg/100 g body weight, respectively. Levels of arginase I mRNA, but not of arginase II mRNA, were similarly elevated. In control lungs, arginase I immunoreactivity was observed only in AMs sparsely dispersed throughout the lung; no inducible nitric oxide synthase (iNOS) immunoreactivity was detected. In silica-treated lungs, arginase I and iNOS were co-expressed in most AMs that were abundantly clustered at inflammatory foci. The rapid induction of arginase I expression in inflammatory lung cells, similar to induction of arginase in other inflammatory lung diseases, implicates elevated arginase activity as a factor in the development of lung damage following exposure to silica. PMID:17365572

  5. Tiotropium Attenuates Virus-Induced Pulmonary Inflammation in Cigarette Smoke-Exposed Mice.

    PubMed

    Bucher, Hannes; Duechs, Matthias J; Tilp, Cornelia; Jung, Birgit; Erb, Klaus J

    2016-06-01

    Viral infections trigger exacerbations in chronic obstructive pulmonary disease (COPD), and tiotropium, a M3 receptor antagonist, reduces exacerbations in patients by unknown mechanisms. In this report, we investigated whether tiotropium has anti-inflammatory effects in mice exposed to cigarette smoke (CS) and infected with influenza virus A/PR/8/34 (H1N1) or respiratory syncytial virus (RSV) and compared these effects with those of steroid fluticasone and PDE4-inhibitor roflumilast. Mice were exposed to CS; infected with H1N1 or RSV; and treated with tiotropium, fluticasone, or roflumilast. The amount of cells and cytokine levels in the airways, lung function, and viral load was determined. NCI-H292 cells were infected with H1N1 or RSV and treated with the drugs. In CS/H1N1-exposed mice, tiotropium reduced neutrophil and macrophage numbers and levels of interleukin-6 (IL-6) and interferon-γ (IFN-γ) in the airways and improved lung function. In contrast, fluticasone increased the loss of body weight; failed to reduce neutrophil or macrophage numbers; increased IL-6, KC, and tumor necrosis factor-α (TNF-α) in the lungs; and worsened lung function. Treatment with roflumilast reduced macrophage numbers, IL-6, and KC in the lungs but had no effect on neutrophil numbers or lung function. In CS/RSV-exposed mice, treatment with tiotropium, but not fluticasone or roflumilast, reduced neutrophil numbers and IL-6 and TNF-α levels in the lungs. Viral load of H1N1 and RSV was significantly elevated in CS/virus-exposed mice and NCI-H292 cells after fluticasone treatment, whereas tiotropium and roflumilast had no effect. In conclusion, tiotropium has anti-inflammatory effects on CS/virus-induced inflammation in mice that are superior to the effects of roflumilast and fluticasone. This finding might help to explain the observed reduction of exacerbation rates in COPD patients. PMID:27016458

  6. The effects of physical exercise on the cigarette smoke-induced pulmonary oxidative response.

    PubMed

    Menegali, Bruno T; Nesi, Renata T; Souza, Priscila S; Silva, Luciano A; Silveira, Paulo C L; Valença, Samuel S; Pinho, Ricardo A

    2009-12-01

    Studies have shown that the oxidative power of cigarettes is related to the pathogenesis of several pulmonary diseases and that regular physical exercise contributes significantly to reducing the deleterious effects of cigarettes. The objective of the present study was to investigate the therapeutic effects of physical exercise on histological and oxidative stress markers in animals exposed to cigarette smoke. Thirty-six male, eight-week-old C57BL-6 mice were divided into four groups (n = 9 for each group): control, exercise, cigarette smoke, and cigarette smoke plus exercise. The cigarette smoke (CS) groups were exposed to cigarette smoke 3 times/day (4 cigarettes/session) for 60 consecutive days. The exercise groups were submitted to swimming physical training 5 days/week for eight weeks. Forty-eight hours after the last exercise and cigarette exposure, the animals were sacrificed using cervical traction. The right lung was removed, processed, and stored for future analysis. In addition to the analysis of collagen content (hydroxyproline), oxidant production (anion superoxide), antioxidant enzyme activity (SOD and CAT), and lipid and protein oxidative damage (TBARS and Carbonylation), histological and morphological studies were performed. The results revealed that the animals exposed to cigarette smoke showed enlargement and destruction of the alveolar septum and increases in the numbers of macrophages and neutrophils, as well as in the amount of collagen. Our results also showed a decrease in the volume density of elastic fibers and an increase in the volume density of airspaces. However, physical exercise partially improved these markers. Additionally, physical exercise decreased oxidant production and increased the activity of the enzymatic antioxidant defense system, but did not reverse lipid and protein oxidative damage induced by cigarette smoke. These results suggest that physical training partially improves histological and oxidative stress parameters in

  7. IL-6 receptor-mediated lung Th2 cytokine networking in silica-induced pulmonary fibrosis.

    PubMed

    Tripathi, Shambhoo Sharan; Mishra, Vani; Shukla, Mamta; Verma, Mukesh; Chaudhury, Bhushan Pradosh; Kumar, Pradeep; Chhabra, Jasmeet Kaur; Pandey, Haushila Prasad; Paul, Bholanath

    2010-12-01

    Pulmonary silicosis is a deadly disease which kills thousands of people every year worldwide. The disease initially develops as an inflammatory response with recruitment of inflammatory cells into the lung controlled by multiple cytokines. The question whether these cytokines exert biological functions through signal transducing pathway remains unanswered along with the potential role of interleukin-6 receptor α (IL-6Rα) in regulating inflammatory cytokines. We aimed to assess the status of signal transducers and activator of transcription (Stat3), suppressor of cytokine signalling 3(Socs3) and inflammatory cytokines in airways of silica-exposed mice, and their relationship with IL-6Rα. Silica-exposed and silica-exposed IL-6Rα gene knockdown Balb/c mice were used in the study. Lung function was measured by plethysmography, mRNA expression of cytokines and signal molecules by qRT(2)-PCR and lung architecture by histopathology; T helper cell-type 2 (Th2) cytokines in broncho-alveolar lavage fluids were evaluated by ELISA and hydroxyproline in lung by colorimetry. Elevated levels of collagen deposition, signs of lung fibrosis, infiltration of inflammatory cells and presence of exfoliated mucosa in the lung of silica-exposed mice with concurrent increase in methacholine-induced specific resistance of airways were observed on day 60 post-exposure. In parallel, heightened expression of Th2 cytokines (IL-4, IL-5, IL-6) and signal molecules (Stat3 and Socs3) were observed in the airways of silica-exposed mice. Th1 (IL-1β and TNF-α) cytokines are underexpressed in majority of the airways tissues of silica-exposed mice. Silencing IL-6Rα in lung of silica-exposed mice down regulated the hypermorphic mRNA pool of potential Th2 cytokines and signal molecules. Hypermorphic expression of Th2 cytokines and signal molecules in airways of silica-exposed mice are mediated through IL-6Rα. PMID:20490462

  8. Tiotropium Attenuates Virus-Induced Pulmonary Inflammation in Cigarette Smoke–Exposed Mice

    PubMed Central

    Bucher, Hannes; Duechs, Matthias J.; Tilp, Cornelia; Jung, Birgit

    2016-01-01

    Viral infections trigger exacerbations in chronic obstructive pulmonary disease (COPD), and tiotropium, a M3 receptor antagonist, reduces exacerbations in patients by unknown mechanisms. In this report, we investigated whether tiotropium has anti-inflammatory effects in mice exposed to cigarette smoke (CS) and infected with influenza virus A/PR/8/34 (H1N1) or respiratory syncytial virus (RSV) and compared these effects with those of steroid fluticasone and PDE4-inhibitor roflumilast. Mice were exposed to CS; infected with H1N1 or RSV; and treated with tiotropium, fluticasone, or roflumilast. The amount of cells and cytokine levels in the airways, lung function, and viral load was determined. NCI-H292 cells were infected with H1N1 or RSV and treated with the drugs. In CS/H1N1-exposed mice, tiotropium reduced neutrophil and macrophage numbers and levels of interleukin-6 (IL-6) and interferon-γ (IFN-γ) in the airways and improved lung function. In contrast, fluticasone increased the loss of body weight; failed to reduce neutrophil or macrophage numbers; increased IL-6, KC, and tumor necrosis factor-α (TNF-α) in the lungs; and worsened lung function. Treatment with roflumilast reduced macrophage numbers, IL-6, and KC in the lungs but had no effect on neutrophil numbers or lung function. In CS/RSV-exposed mice, treatment with tiotropium, but not fluticasone or roflumilast, reduced neutrophil numbers and IL-6 and TNF-α levels in the lungs. Viral load of H1N1 and RSV was significantly elevated in CS/virus-exposed mice and NCI-H292 cells after fluticasone treatment, whereas tiotropium and roflumilast had no effect. In conclusion, tiotropium has anti-inflammatory effects on CS/virus-induced inflammation in mice that are superior to the effects of roflumilast and fluticasone. This finding might help to explain the observed reduction of exacerbation rates in COPD patients. PMID:27016458

  9. Impact of Olmesartan Medoxomil on Amiodarone-Induced Pulmonary Toxicity in Rats: Focus on Transforming Growth Factor-ß1.

    PubMed

    Sharaf El-Din, Abeer A I; Abd Allah, Omaima M

    2016-07-01

    Amiodarone (AD) is one of the most frequently prescribed anti-arrhythmic agents worldwide, but its effectiveness is limited due to the development of pulmonary toxicity. Several lines of evidence have suggested that AT1 receptor antagonists can attenuate pulmonary fibrosis in different animal models. This study was performed to evaluate the effect of olmesartan medoxomil (OM) on lung injury induced in rats by AD which was assessed biochemically (hydroxyproline content, MDA level and SOD activity), histologically (Ashcroft criteria and Masson's trichrome stain) and immunohistochemically (TGF-β1 expression in lung tissue). The expression levels of TGF-β1 and type I collagen mRNA were also determined by quantitative real-time polymerase chain reaction. Forty-eight adult male rats were randomized into six equal groups: control group, OM control groups, AD group received 40 mg/kg/day, p.o. for 4 weeks to induce pulmonary injury in rats and OM-treated groups received 0.6 and 6 mg/kg/day, p.o. concomitantly with AD for the same period. The results indicated that OM significantly decreased collagen deposition and hydroxyproline content, ameliorated pathological score and decreased the elevation in type I collagen and TGF-ß1 mRNA expression in lung tissue. Furthermore, it attenuated the AD-induced increase in the MDA level and increased SOD activity in lung tissue. It can be concluded that OM exerts a protective effect against AD-induced lung damage in rats which is attributed to modulation of pro-fibrogenic cytokine (TGF-β1) and antioxidant effect. PMID:26781185

  10. Intercellular Adhesion Molecule-1–Dependent Neutrophil Adhesion to Endothelial Cells Induces Caveolae-Mediated Pulmonary Vascular Hyperpermeability

    PubMed Central

    Hu, Guochang; Vogel, Stephen M.; Schwartz, David E.; Malik, Asrar B.; Minshall, Richard D.

    2009-01-01

    We investigated the role of caveolae in the mechanism of increased pulmonary vascular permeability and edema formation induced by the activation of polymorphonuclear neutrophils (PMNs). We observed that the increase in lung vascular permeability induced by the activation of PMNs required caveolin-1, the caveolae scaffold protein. The permeability increase induced by PMN activation was blocked in caveolin-1 knockout mice and by suppressing caveolin-1 expression in rats. The response was also dependent on Src phosphorylation of caveolin-1 known to activate caveolae-mediated endocytosis in endothelial cells. To address the role of PMN interaction with endothelial cells, we used an intercellular adhesion molecule (ICAM)-1 blocking monoclonal antibody. Preventing the ICAM-1–mediated PMN binding to endothelial cells abrogated Src phosphorylation of caveolin-1, as well as the increase in endothelial permeability. Direct ICAM-1 activation by crosslinking recapitulated these responses, suggesting that ICAM-1 activates caveolin-1 signaling responsible for caveolae-mediated endothelial hyperpermeability. Our results provide support for the novel concept that a large component of pulmonary vascular hyperpermeability induced by activation of PMNs adherent to the vessel wall is dependent on signaling via caveolin-1 and increased caveolae-mediated transcytosis. Thus, it is important to consider the role of the transendothelial vesicular permeability pathway that contributes to edema formation in developing therapeutic interventions against PMN-mediated inflammatory diseases such as acute lung injury. PMID:18511851

  11. Granulomatous interstitial pneumonia induced by the intake of rice bran pickles: a rare subtype of pulmonary manifestation associated with food allergy.

    PubMed

    Kinoshita, Yoshiaki; Sakamoto, Atsuhiko; Aishima, Shinichi; Hidaka, Kouko

    2015-01-01

    Pulmonary manifestations associated with food allergy are rich in variety. We report the first case of food-induced granulomatous interstitial pneumonia mimicking hypersensitivity pneumonitis (HP). A 77-year-old woman with respiratory symptoms was referred to our hospital. We performed a surgical lung biopsy, which showed the features of granulomatous interstitial pneumonia. Her clinical history resembled those observed in HP. However, avoidance of exposure to the causative antigens did not improve her symptoms. Moreover, the patient had some features inconsistent with HP, such as elevated serum IgE levels, blood eosinophilia, intrathoracic lymphadenopathies and pleural effusion. Therefore, we pursued another extrinsic non-inhaled antigen as the cause of pulmonary involvements. We noted that she had been eating homemade rice bran pickles, and pulmonary involvements were induced by an ingestion challenge test. We suggest that granulomatous interstitial pneumonia may be a rare subtype of the pulmonary manifestations associated with food allergy. PMID:25858927

  12. Pulmonary administration of 1,25-dihydroxyvitamin D3 to the lungs induces alveolar regeneration in a mouse model of chronic obstructive pulmonary disease.

    PubMed

    Horiguchi, Michiko; Hirokawa, Mai; Abe, Kaori; Kumagai, Harumi; Yamashita, Chikamasa

    2016-07-10

    Chronic obstructive pulmonary disease (COPD) is a progressive respiratory disease with several causes, including smoking, and no curative therapeutic agent is available, particularly for destructive alveolar lesions. In this study, we investigated the differentiation-inducing effect on undifferentiated lung cells (Calu-6) and the alveolar regenerative effect of the active vitamin 1,25-dihydroxy vitamin D3 (VD3) with the ultimate goal of developing a novel curative drug for COPD. First, the differentiation-inducing effect of VD3 on Calu-6 cells was evaluated. Treatment with VD3 increased the proportions of type I alveolar epithelial (AT-I) and type II alveolar epithelial (AT-II) cells constituting alveoli in a concentration- and treatment time-dependent manner, demonstrating the potent differentiation-inducing activity of VD3 on Calu-6 cells. We thus administered VD3 topically to the mice lung using a previously developed intrapulmonary administration via self-inhalation method. To evaluate the alveolus-repairing effect of VD3, we administered VD3 intrapulmonarily to elastase-induced COPD model mice and computed the mean distance between the alveolar walls as an index of the extent of alveolar injury. Results showed significant decreases in the alveolar wall distance in groups of mice that received 0.01, 0.1, and 1μg/kg of intrapulmonary VD3, revealing excellent alveolus-regenerating effect of VD3. Furthermore, we evaluated the effect of VD3 on improving respiratory function using a respiratory function analyzer. Lung elasticity and respiratory competence [forced expiratory volume (FEV) 1 s %] are reduced in COPD, reflecting advanced emphysematous changes. In elastase-induced COPD model mice, although lung elasticity and respiratory competence were reduced, VD3 administered intrapulmonarily twice weekly for 2weeks recovered tissue elastance and forced expiratory volume in 0.05s to the forced vital capacity, which are indicators of lung elasticity and respiratory

  13. Ginsenoside Rg1 attenuates hypoxia and hypercapnia-induced vasoconstriction in isolated rat pulmonary arterial rings by reducing the expression of p38

    PubMed Central

    Zheng, Mengxiao; Zhao, Meiping; Tang, Lanlan; Zhang, Congcong; Song, Longsheng

    2016-01-01

    Background Pulmonary arterial hypertension (PAH) is a fatal disease characterized by increased pulmonary arteriolar resistance. Pulmonary vasoconstriction has been proved to play a significant role in PAH. We previously reported that Panax notoginseng saponins (PNS) might attenuate hypoxia and hypercapnia-induced pulmonary vasoconstriction (HHPV). Methods In the present study, our specific objective was to investigate the role of ginsenoside Rg1, a major component of PNS, in this process and the possible underlying mechanism. The second order pulmonary rings isolated from the Sprague-Dawley rats were treated with different dosage of ginsenoside Rg1 at 8, 40, or 100 mg/L respectively, both before and during the conditions of hypoxia and hypercapnia. Contractile force changes of the rings were detected. Furthermore, SB203580, the selective inhibitor for p38 activation was applied to the rings. Pulmonary arterial smooth muscle cells (PASMCs) were cultured under hypoxic and hypercapnic conditions, and ginsenoside Rg1 was administered to detect the changes induced by p38. Results Under the hypoxic and hypercapnic conditions, we observed a biphasic pulmonary artery contractile response to the second pulmonary artery rings. It is hypothesized that the observed attenuation of vasoconstriction and the production of vasodilation could have been induced by ginsenoside Rg1. This effect was significantly reinforced by SB203580 (P<0.05 or P<0.01). The expression of p38 in the PASMCs under hypoxic and hypercapnic conditions was significantly activated (P<0.05 or P<0.01) and the observed activation was attenuated by ginsenoside Rg1 (P<0.05 or P<0.01). Conclusions Our findings strongly support the significant role of ginsenoside Rg1 in the inhibition of hypoxia and hypercapnia-induced vasoconstriction by the p38 pathway. PMID:27499938

  14. Pulmonary edema

    MedlinePlus

    ... congestion; Lung water; Pulmonary congestion; Heart failure - pulmonary edema ... Pulmonary edema is often caused by congestive heart failure . When the heart is not able to pump efficiently, blood ...

  15. Beneficial effects of a novel agonist of the adenosine A2A receptor on monocrotaline-induced pulmonary hypertension in rats

    PubMed Central

    Alencar, Allan K N; Pereira, Sharlene L; Montagnoli, Tadeu L; Maia, Rodolfo C; Kümmerle, Arthur E; Landgraf, Sharon S; Caruso-Neves, Celso; Ferraz, Emanuelle B; Tesch, Roberta; Nascimento, José H M; de Sant'Anna, Carlos M R; Fraga, Carlos A M; Barreiro, Eliezer J; Sudo, Roberto T; Zapata-Sudo, Gisele

    2013-01-01

    Background and Purpose Pulmonary arterial hypertension (PAH) is characterized by enhanced pulmonary vascular resistance, right ventricular hypertrophy and increased right ventricular systolic pressure. Here, we investigated the effects of a N-acylhydrazone derivative, 3,4-dimethoxyphenyl-N-methyl-benzoylhydrazide (LASSBio-1359), on monocrotaline (MCT)-induced pulmonary hypertension in rats. Experimental Approach PAH was induced in male Wistar rats by a single i.p. injection of MCT (60 mg·kg−1) and 2 weeks later, oral LASSBio-1359 (50 mg·kg−1) or vehicle was given once daily for 14 days. Echocardiography was used to measure cardiac function and pulmonary artery dimensions, with histological assay of vascular collagen. Studies of binding to human recombinant adenosine receptors (A1, A2A, A3) and of docking with A2A receptors were also performed. Key Results MCT administration induced changes in vascular and ventricular structure and function, characteristic of PAH. These changes were reversed by treatment with LASSBio-1359. MCT also induced endothelial dysfunction in pulmonary artery, as measured by diminished relaxation of pre-contracted arterial rings, and this dysfunction was reversed by LASSBio-1359. In pulmonary artery rings from normal Wistar rats, LASSBio-1359 induced relaxation, which was decreased by the adenosine A2A receptor antagonist, ZM 241385. In adenosine receptor binding studies, LASSBio-1359 showed most affinity for the A2A receptor and in the docking analyses, binding modes of LASSBio-1359 and the A2A receptor agonist, CGS21680, were very similar. Conclusion and Implications In rats with MCT-induced PAH, structural and functional changes in heart and pulmonary artery were reversed by treatment with oral LASSBio-1359, most probably through the activation of adenosine A2A receptors. PMID:23530610

  16. TDPAC study of complex structure semiconductor compounds; The case of niobium pentoxide

    SciTech Connect

    Shitu, J.; Renteria, M.; Massolo, C.P.; Bibiloni, A.G.; Desimonni, J. )

    1992-07-20

    In this paper, a new method for analyzing Time-Differential Perturbed Angular Correlation spectra is presented and applied to study the hyperfine interaction of {sup 100}Rh in the high temperature modification of niobium pentoxide. The measured quadrupole interactions are assigned to about 80% of the radioactive probes replacing niobium atoms in the lattice and about 20% located in perturbed sites. The origin of this perturbation, producing a high frequency component in the measured spectra is discussed and temptatively assigned to remaining radiation damage in the compound. The hyperfine interaction of {sup 111}Cd probes, introduced through thermal diffusion into niobium pentoxide, is also presented. The temperature dependence of the hyperfine parameters in this case is studied in the temperature range RT-800{degrees} C. The spectral analyzing method employed allows a direct comparison of experimental data with point charge model calculations and a simultaneous evaluation of the antishielding factor {beta}. The obtained values (27 for {sup 100}Rh and 15 for {sup 111}Cd) are discussed in terms of the compound and probe's characteristics.

  17. TDPAC study of complex structure semiconductor compounds; The case niobium pentoxide

    SciTech Connect

    Shitu, J.; Renteria, M.; Massolo, C.P.; Bibiloni, A.G.; Desimoni, J. )

    1992-07-10

    In this paper, a new method for analyzing Time-Differential Perturbed Angular Correlation spectra is presented and applied to study the hyperfine interaction of {sup 100}Rh in the high temperature modification of niobium pentoxide. The measured quadrupole interactions are assigned to about 80% of the radioactive probes replacing niobium atoms in the lattice and about 20% located in perturbed sites. The origin of this perturbation, producing a high frequency component in the measured spectra is discussed and temptatively assigned to remaining radiation damage in the compound. The hyperfine interaction of {sup 111}Cd probes, introduced through thermal diffusion into niobium pentoxide, is also presented. The temperature dependence of the hyperfine parameters in this case is studied in the temperature range RT-800{degrees}C. The spectral analyzing method employed allows a direct comparison of experimental data with point charge model calculations and a simultaneous evaluation of the anti-shielding factor {beta}. The obtained values (27 for {sup 100}Rh and 15 for {sup 111}Cd) are discussed in terms of the compound and probe's characteristics.

  18. Synthesis and thermal evolution of structure in alkoxide-derived niobium pentoxide gels

    NASA Technical Reports Server (NTRS)

    Bansal, Narottam P.

    1993-01-01

    Niobium pentoxide gels in the form of transparent monoliths and powder have been synthesized from the controlled hydrolysis and polycondensation of niobium pentaethoxide under different experimental conditions using various mole ratios of Nb(OC2H5)5:H2O:C2H5OH:HCl. Alcohol acted as the mutual solvent and HCl as the deflocculating agent. In the absence of HCl, precipitation of colloidal particles was encountered on the addition of any water to the alkoxide. The gels were subjected to various thermal treatments and characterized by differential thermal analysis, thermogravimetric analysis, x-ray diffraction, and infrared spectroscopy. After drying at 400 C, the gels were amorphous to x-rays. The amorphous powder crystallized into the low-temperature orthorhombic form of Nb2O5 at approximately 500 C, which transformed irreversibly into the high-temperature monoclinic alpha-Nb2O5 between 900 to 1000 C. The kinetics of crystallization of the amorphous niobium pentoxide have been investigated by non-isothermal differential scanning calorimetry. The crystallization activation energy was determined to be 399 kJ/mol.

  19. Electronic structure of crystalline phosphorus pentoxide and the effect of an Ag impurity

    NASA Astrophysics Data System (ADS)

    Abarenkov, I. V.; Tupitsyn, I. I.; Kuznetsov, V. G.; Payne, M. C.

    1999-09-01

    The phosphorus pentoxide crystal with Pnam symmetry containing four P2O5 molecules in the unit cell was calculated by ab initio density-functional theory in the local-density approximation with a plane-wave basis set using the CASTEP code. The calculated optimized geometry is in good agreement with experiment. The population analysis made in terms of Löwdin and Mulliken charges and Wiberg indexes showed that this crystal has a mixed chemical bonding, partly ionic, partly covalent. An Ag atom impurity in the phosphorus pentoxide crystal was investigated within the periodic model. The distortion of the lattice around the impurity was analyzed in terms of PO4 tetrahedra. The calculations showed that in spite of considerable deformation of the lattice, the Ag impurity does not break the P-O bonding network and changes the P-O bond order only a little. The Ag impurity atom is bound to the crystal with an almost pure ionic bond, the Ag atomic charge being 0.6 (Löwdin charge).

  20. Electronic properties of tantalum pentoxide polymorphs from first-principles calculations

    SciTech Connect

    Lee, J.; Lu, W.; Kioupakis, E.

    2014-11-17

    Tantalum pentoxide (Ta{sub 2}O{sub 5}) is extensively studied for its attractive properties in dielectric films, anti-reflection coatings, and resistive switching memory. Although various crystalline structures of tantalum pentoxide have been reported, its structural, electronic, and optical properties still remain a subject of research. We investigate the electronic and optical properties of crystalline and amorphous Ta{sub 2}O{sub 5} structures using first-principles calculations based on density functional theory and the GW method. The calculated band gaps of the crystalline structures are too small to explain the experimental measurements, but the amorphous structure exhibits a strong exciton binding energy and an optical band gap (∼4 eV) in agreement with experiment. We determine the atomic orbitals that constitute the conduction band for each polymorph and analyze the dependence of the band gap on the atomic geometry. Our results establish the connection between the underlying structure and the electronic and optical properties of Ta{sub 2}O{sub 5}.

  1. N-acetylcysteine improves established monocrotaline-induced pulmonary hypertension in rats

    PubMed Central

    2014-01-01

    Background The outcome of patients suffering from pulmonary arterial hypertension (PAH) are predominantly determined by the response of the right ventricle to the increase afterload secondary to high vascular pulmonary resistance. However, little is known about the effects of the current available or experimental PAH treatments on the heart. Recently, inflammation has been implicated in the pathophysiology of PAH. N-acetylcysteine (NAC), a well-known safe anti-oxidant drug, has immuno-modulatory and cardioprotective properties. We therefore hypothesized that NAC could reduce the severity of pulmonary hypertension (PH) in rats exposed to monocrotaline (MCT), lowering inflammation and preserving pulmonary vascular system and right heart function. Methods Saline-treated control, MCT-exposed, MCT-exposed and NAC treated rats (day 14–28) were evaluated at day 28 following MCT for hemodynamic parameters (right ventricular systolic pressure, mean pulmonary arterial pressure and cardiac output), right ventricular hypertrophy, pulmonary vascular morphometry, lung inflammatory cells immunohistochemistry (monocyte/macrophages and dendritic cells), IL-6 expression, cardiomyocyte hypertrophy and cardiac fibrosis. Results The treatment with NAC significantly decreased pulmonary vascular remodeling, lung inflammation, and improved total pulmonary resistance (from 0.71 ± 0.05 for MCT group to 0.50 ± 0.06 for MCT + NAC group, p < 0.05). Right ventricular function was also improved with NAC treatment associated with a significant decrease in cardiomyocyte hypertrophy (625 ± 69 vs. 439 ± 21 μm2 for MCT and MCT + NAC group respectively, p < 0.001) and heart fibrosis (14.1 ± 0.8 vs. 8.8 ± 0.1% for MCT and MCT + NAC group respectively, p < 0.001). Conclusions Through its immuno-modulatory and cardioprotective properties, NAC has beneficial effect on pulmonary vascular and right heart function in experimental PH. PMID:24929652

  2. Bone marrow mesenchymal stem cells protect against bleomycin-induced pulmonary fibrosis in rat by activating Nrf2 signaling

    PubMed Central

    Ni, Shirong; Wang, Dexuan; Qiu, Xiaoxiao; Pang, Lingxia; Song, Zhangjuan; Guo, Kunyuan

    2015-01-01

    Pulmonary fibrosis is a progressive and lethal disorder. Although the precise mechanisms of pulmonary fibrosis are not fully understood, oxidant/antioxidant may play an important role in many of the processes of inflammation and fibrosis. Keap1-Nrf2-ARE pathway represents one of the most important cellular defense mechanisms against oxidative stress. Mesenchymal stem cells (MSC) are in clinical trials for widespread indications including musculoskeletal, neurological, cardiac and haematological disorders. One emerging concept is that MSCs may have paracrine, rather than a functional, roles in lung injury repair and regeneration. In the present study, we investigated bone marrow mesenchymal stem cells (BMSCs) for the treatment of bleomycin-induced pulmonary fibrosis. Our results showed that BMSCs administration significantly ameliorated the bleomycin mediated histological alterations and blocked collagen deposition with parallel reduction in the hydroxyproline level. The gene expression levels of NAD(P)H: quinine oxidoreductase 1 (NQO1), gama-glutamylcysteine synthetase (γ-GCS), heme oxygenase-1 (HO-1) and nuclear factor erythroid 2-related factor 2 (Nrf2), attenuated by bleomycin, were increased up to basal levels after BMSCs transplantation. BMSCs significantly increased superoxide dismutase (SOD) activity and inhibited malondialdehyde (MDA) production in the injured lung. The present study provides evidence that BMSCs may be a potential therapeutic reagent for the treatment of lung fibrosis. PMID:26339340

  3. Surfactant proteins A and D protect mice against pulmonary hypersensitivity induced by Aspergillus fumigatus antigens and allergens.

    PubMed

    Madan, T; Kishore, U; Singh, M; Strong, P; Clark, H; Hussain, E M; Reid, K B; Sarma, P U

    2001-02-01

    Allergic bronchopulmonary aspergillosis (ABPA) is an allergic disorder caused by an opportunistic fungal pathogen, Aspergillus fumigatus (AFU:). Lung surfactant proteins SP-A and SP-D can interact with the glycosylated antigens and allergens of AFU:, inhibit specific IgE binding to these allergens, and block histamine release from sensitized basophils. We have now examined the therapeutic effect of exogenous administration of human SP-A, SP-D, and a recombinant fragment of SP-D (rSP-D), in a murine model of pulmonary hypersensitivity induced by AFU: antigens and allergens, which resembles human ABPA immunologically. The ABPA mice exhibited high levels of AFU:-specific IgG and IgE, blood eosinophilia, extensive infiltration of lymphocytes and eosinophils in the lung sections, and a Th2 cytokine response. Treatment with SP-A, SP-D, and rSP-D lowered blood eosinophilia, pulmonary infiltration, and specific Ab levels considerably, which persisted up to 4 days in the SP-A-treated ABPA mice, and up to 16 days in the SP-D- or rSP-D-treated ABPA mice. The levels of IL-2, IL-4, and IL-5 were decreased, while the level of IFN-gamma was raised in the splenic supernatants of the treated mice, indicating a marked shift from Th2 to Th1 response. These results clearly implicate pulmonary SP-A and SP-D in the modulation of allergic reactions. PMID:11181646

  4. Inactivated Pseudomonas aeruginosa inhibits hypoxia-induced pulmonary hypertension by preventing TGF-β1/Smad signaling

    PubMed Central

    Chai, S.D.; Liu, T.; Dong, M.F.; Li, Z.K.; Tang, P.Z.; Wang, J.T.; Ma, S.J.

    2016-01-01

    Pseudomonas aeruginosa is one of the common colonizing bacteria of the human body and is an opportunistic pathogen frequently associated with respiratory infections. Inactivated P. aeruginosa (IPA) have a variety of biological effects against inflammation and allergy. Transforming growth factor-β (TGF-β) signaling plays a critical role in the regulation of cell growth, differentiation, and development in a wide range of biological systems. The present study was designed to investigate the effects of IPA on TGF-β/Smad signaling in vivo, using a hypoxia-induced pulmonary hypertension (PH) rat model. Sprague Dawley rats (n=40) were exposed to 10% oxygen for 21 days to induce PH. At the same time, IPA was administered intravenously from day 1 to day 14. Mean pulmonary artery pressure (mPAP) and the right ventricle (RV) to left ventricle plus the interventricular septum (LV+S) mass ratio were used to evaluate the development of PH. Vessel thickness and density were measured using immunohistochemistry. Primary arterial smooth muscle cells (PASMCs) were isolated and the proliferation of PASMCs was assayed by flow cytometry. The production of TGF-β1 in cultured supernatant of PASMCs was assayed by ELISA. The expression levels of α-smooth muscle actin (α-SMA), TGF-β1 and phospho-Smad 2/3 in PASMCs were assayed by western blot. Our data indicated that IPA attenuated PH, RV hypertrophy and pulmonary vascular remodeling in rats, which was probably mediated by restraining the hypoxia-induced overactive TGF-β1/Smad signaling. In conclusion, IPA is a promising protective treatment in PH due to the inhibiting effects on TGF-β1/Smad 2/3 signaling. PMID:27580007

  5. Inactivated Pseudomonas aeruginosa inhibits hypoxia-induced pulmonary hypertension by preventing TGF-β1/Smad signaling.

    PubMed

    Chai, S D; Liu, T; Dong, M F; Li, Z K; Tang, P Z; Wang, J T; Ma, S J

    2016-01-01

    Pseudomonas aeruginosa is one of the common colonizing bacteria of the human body and is an opportunistic pathogen frequently associated with respiratory infections. Inactivated P. aeruginosa (IPA) have a variety of biological effects against inflammation and allergy. Transforming growth factor-β (TGF-β) signaling plays a critical role in the regulation of cell growth, differentiation, and development in a wide range of biological systems. The present study was designed to investigate the effects of IPA on TGF-β/Smad signaling in vivo, using a hypoxia-induced pulmonary hypertension (PH) rat model. Sprague Dawley rats (n=40) were exposed to 10% oxygen for 21 days to induce PH. At the same time, IPA was administered intravenously from day 1 to day 14. Mean pulmonary artery pressure (mPAP) and the right ventricle (RV) to left ventricle plus the interventricular septum (LV+S) mass ratio were used to evaluate the development of PH. Vessel thickness and density were measured using immunohistochemistry. Primary arterial smooth muscle cells (PASMCs) were isolated and the proliferation of PASMCs was assayed by flow cytometry. The production of TGF-β1 in cultured supernatant of PASMCs was assayed by ELISA. The expression levels of α-smooth muscle actin (α-SMA), TGF-β1 and phospho-Smad 2/3 in PASMCs were assayed by western blot. Our data indicated that IPA attenuated PH, RV hypertrophy and pulmonary vascular remodeling in rats, which was probably mediated by restraining the hypoxia-induced overactive TGF-β1/Smad signaling. In conclusion, IPA is a promising protective treatment in PH due to the inhibiting effects on TGF-β1/Smad 2/3 signaling. PMID:27580007

  6. Vascular endothelial-cadherin downregulation as a feature of endothelial transdifferentiation in monocrotaline-induced pulmonary hypertension.

    PubMed

    Nikitopoulou, Ioanna; Orfanos, Stylianos E; Kotanidou, Anastasia; Maltabe, Violetta; Manitsopoulos, Nikolaos; Karras, Panagiotis; Kouklis, Panos; Armaganidis, Apostolos; Maniatis, Nikolaos A

    2016-08-01

    Increased pulmonary vascular resistance in pulmonary hypertension (PH) is caused by vasoconstriction and obstruction of small pulmonary arteries by proliferating vascular cells. In analogy to cancer, subsets of proliferating cells may be derived from endothelial cells transitioning into a mesenchymal phenotype. To understand phenotypic shifts transpiring within endothelial cells in PH, we injected rats with alkaloid monocrotaline to induce PH and measured lung tissue levels of endothelial-specific protein and critical differentiation marker vascular endothelial (VE)-cadherin. VE-cadherin expression by immonoblotting declined significantly 24 h and 15 days postinjection to rebound to baseline at 30 days. There was a concomitant increase in transcriptional repressors Snail and Slug, along with a reduction in VE-cadherin mRNA. Mesenchymal markers α-smooth muscle actin and vimentin were upregulated by immunohistochemistry and immunoblotting, and α-smooth muscle actin was colocalized with endothelial marker platelet endothelial cell adhesion molecule-1 by confocal microscopy. Apoptosis was limited in this model, especially in the 24-h time point. In addition, monocrotaline resulted in activation of protein kinase B/Akt, endothelial nitric oxide synthase (eNOS), nuclear factor (NF)-κB, and increased lung tissue nitrotyrosine staining. To understand the etiological relationship between nitrosative stress and VE-cadherin suppression, we incubated cultured rat lung endothelial cells with endothelin-1, a vasoconstrictor and pro-proliferative agent in pulmonary arterial hypertension. This resulted in activation of eNOS, NF-κB, and Akt, in addition to induction of Snail, downregulation of VE-cadherin, and synthesis of vimentin. These effects were blocked by eNOS inhibitor N(ω)-nitro-l-arginine methyl ester. We propose that transcriptional repression of VE-cadherin by nitrosative stress is involved in endothelial-mesenchymal transdifferentiation in experimental PH. PMID

  7. Trans-bronchoscopy with implantation of 125I radioactive seeds in patients with pulmonary atelectasis induced by lung cancer

    PubMed Central

    LU, MINGJIAN; PU, DELI; ZHANG, WEIDONG; LIAO, JIANGRONG; ZHANG, TAO; YANG, GUANG; LIU, ZHENYIN; SINGH, SRISTI; GAO, FEI; ZHANG, FUJUN

    2015-01-01

    To evaluate the role of low-dose-rate interstitial brachytherapy using trans-bronchoscope 125I radioactive seeds implantation in patients with pulmonary atelectasis induced by lung cancer, in terms of feasibility, safety, quality of life (QOL), and survival time. Between April 2008 and June 2011, 15 patients from two medical institutions that had obstructive pulmonary atelectasis caused by inoperable lung cancer were assigned to receive 125I implantation endoluminal brachytherapy by bronchoscopy. Subsequent to the implantation of 125I seeds, the outcomes were measured in terms of procedure success rate, reopening of atelectasis, complications associated with the procedure, Karnofsky performance status (KPS) scores and survival time. The surgical procedure was successfully performed in all 15 patients. No procedure-associated mortality occurred and the complications were mild and considered acceptable. Irritable cough and temporary increase of hemoptysis occurred in 11 (73.3%) and 10 (66.7%) patients respectively, and were the most common complications. The pulmonary atelectasis reopening rate subsequent to the procedure was 86.7, 76.9, 80.0, 75.0 and 50.0% at 2, 6, 12, 18 and 24 months, respectively. The KPS score significantly improved following the implantation of 125I seeds and the duration of improvement ranged between 3 and 27 months. The median and mean survival times were 15.6 and 16 months, respectively. Actuarial survival rates at 6, 12 and 24 months after the procedure were 86.7, 66.7 and 13.3%, respectively. In patients with advanced lung cancer and those presenting with obstructive pulmonary atelectasis, treatment with intraluminal implantation of 125I seeds is a safe and effective therapy option with easy accessibility. PMID:26171002

  8. NADPH oxidases and reactive oxygen species at different stages of chronic hypoxia-induced pulmonary hypertension in newborn piglets

    PubMed Central

    Dennis, Kathleen E.; Aschner, J. L.; Milatovic, D.; Schmidt, J. W.; Aschner, M.; Kaplowitz, M. R.; Zhang, Y.

    2009-01-01

    Recently, we reported that reactive oxygen species (ROS) generated by NADPH oxidase (NOX) contribute to aberrant responses in pulmonary resistance arteries (PRAs) of piglets exposed to 3 days of hypoxia (Am J Physiol Lung Cell Mol Physiol 295: L881–L888, 2008). An objective of the present study was to determine whether NOX-derived ROS also contribute to altered PRA responses at a more advanced stage of pulmonary hypertension, after 10 days of hypoxia. We further wished to advance knowledge about the specific NOX and antioxidant enzymes that are altered at early and later stages of pulmonary hypertension. Piglets were raised in room air (control) or hypoxia for 3 or 10 days. Using a cannulated artery technique, we found that treatments with agents that inhibit NOX (apocynin) or remove ROS [an SOD mimetic (M40403) + polyethylene glycol-catalase] diminished responses to ACh in PRAs from piglets exposed to 10 days of hypoxia. Western blot analysis showed an increase in expression of NOX1 and the membrane fraction of p67phox. Expression of NOX4, SOD2, and catalase were unchanged, whereas expression of SOD1 was reduced, in arteries from piglets raised in hypoxia for 3 or 10 days. Markers of oxidant stress, F2-isoprostanes, measured by gas chromatography-mass spectrometry, were increased in PRAs from piglets raised in hypoxia for 3 days, but not 10 days. We conclude that ROS derived from some, but not all, NOX family members, as well as alterations in the antioxidant enzyme SOD1, contribute to aberrant PRA responses at an early and a more progressive stage of chronic hypoxia-induced pulmonary hypertension in newborn piglets. PMID:19592458

  9. Long-term exposure to high-altitude chronic hypoxia during gestation induces neonatal pulmonary hypertension at sea level

    PubMed Central

    Herrera, Emilio A.; Riquelme, Raquel A.; Ebensperger, Germán; Reyes, Roberto V.; Ulloa, César E.; Cabello, Gertrudis; Krause, Bernardo J.; Parer, Julian T.; Giussani, Dino A.

    2010-01-01

    We determined whether postnatal pulmonary hypertension induced by 70% of pregnancy at high altitude (HA) persists once the offspring return to sea level and investigated pulmonary vascular mechanisms operating under these circumstances. Pregnant ewes were divided into two groups: conception, pregnancy, and delivery at low altitude (580 m, LLL) and conception at low altitude, pregnancy at HA (3,600 m) from 30% of gestation until delivery, and return to lowland (LHL). Pulmonary arterial pressure (PAP) was measured in vivo. Vascular reactivity and morphometry were assessed in small pulmonary arteries (SPA). Protein expression of vascular mediators was determined. LHL lambs had higher basal PAP and a greater increment in PAP after NG-nitro-l-arginine methyl ester (20.9 ± 1.1 vs. 13.7 ± 0.5 mmHg; 39.9 ± 5.0 vs. 18.3 ± 1.3 mmHg, respectively). SPA from LHL had a greater maximal contraction to K+ (1.34 ± 0.05 vs. 1.16 ± 0.05 N/m), higher sensitivity to endothelin-1 and nitroprusside, and persistence of dilatation following blockade of soluble guanylate cyclase. The heart ratio of the right ventricle-to-left ventricle plus septum was higher in the LHL relative to LLL. The muscle area of SPA (29.3 ± 2.9 vs. 21.1 ± 1.7%) and the protein expression of endothelial nitric oxide synthase (1.7 ± 0.1 vs. 1.1 ± 0.2), phosphodiesterase (1.4 ± 0.1 vs. 0.7 ± 0.1), and Ca2+-activated K+ channel (0.76 ± 0.16 vs. 0.30 ± 0.01) were greater in LHL compared with LLL lambs. In contrast, LHL had decreased heme oxygenase-1 expression (0.82 ± 0.26 vs. 2.22 ± 0.44) and carbon monoxide production (all P < 0.05). Postnatal pulmonary hypertension induced by 70% of pregnancy at HA promotes cardiopulmonary remodeling that persists at sea level. PMID:20881096

  10. Nano zerovalent iron particles induce pulmonary and cardiovascular toxicity in an in vitro human co-culture model.

    PubMed

    Sun, Zhelin; Yang, Lingyan; Chen, Ku-Fan; Chen, Guan-Wen; Peng, Yen-Ping; Chen, Jen-Kun; Suo, Guangli; Yu, Jiantao; Wang, Wen-Cheng; Lin, Chia-Hua

    2016-09-01

    Despite promising environmental applications for nano zerovalent iron (nZVI), concerns remain about the potential accumulation and toxic effects of nZVI particles. Here, we use an alveolar-capillary co-culture model to investigate a possible link between low-level epithelial exposure to nZVI and pulmonary and cardiovascular toxicity. While nZVI was unable to pass through the epithelial barrier into the endothelium, nZVI exposure did cause oxidative and inflammatory responses in both epithelial and endothelial cells. Therefore, toxic effects induced by nZVI are not restricted to epithelial cells but can be transferred into the endothelium. Communication between A549 and EA.hy926 cells is responsible for amplification of nZVI-induced toxic responses. Decreases in transepithelial electrical resistance and zonula occludens proteins after epithelial exposure to nZVI impaired epithelial barrier integrity. Increases in oxidized α1-antitrypsin and oxidized low-density lipoprotein in the co-culture model suggest that nZVI exposure increases the risk of chronic obstructive pulmonary disease and atherosclerosis. Therefore, inhalation of nZVI has the potential to induce cardiovascular disease through oxidative and inflammatory mediators produced from the damaged lung epithelium in chronic lung diseases. PMID:26694701

  11. TRPV4 inhibition counteracts edema and inflammation and improves pulmonary function and oxygen saturation in chemically induced acute lung injury

    PubMed Central

    Balakrishna, Shrilatha; Song, Weifeng; Achanta, Satyanarayana; Doran, Stephen F.; Liu, Boyi; Kaelberer, Melanie M.; Yu, Zhihong; Sui, Aiwei; Cheung, Mui; Leishman, Emma; Eidam, Hilary S.; Ye, Guosen; Willette, Robert N.; Thorneloe, Kevin S.; Bradshaw, Heather B.; Matalon, Sadis

    2014-01-01

    The treatment of acute lung injury caused by exposure to reactive chemicals remains challenging because of the lack of mechanism-based therapeutic approaches. Recent studies have shown that transient receptor potential vanilloid 4 (TRPV4), an ion channel expressed in pulmonary tissues, is a crucial mediator of pressure-induced damage associated with ventilator-induced lung injury, heart failure, and infarction. Here, we examined the effects of two novel TRPV4 inhibitors in mice exposed to hydrochloric acid, mimicking acid exposure and acid aspiration injury, and to chlorine gas, a severe chemical threat with frequent exposures in domestic and occupational environments and in transportation accidents. Postexposure treatment with a TRPV4 inhibitor suppressed acid-induced pulmonary inflammation by diminishing neutrophils, macrophages, and associated chemokines and cytokines, while improving tissue pathology. These effects were recapitulated in TRPV4-deficient mice. TRPV4 inhibitors had similar anti-inflammatory effects in chlorine-exposed mice and inhibited vascular leakage, airway hyperreactivity, and increase in elastance, while improving blood oxygen saturation. In both models of lung injury we detected increased concentrations of N-acylamides, a class of endogenous TRP channel agonists. Taken together, we demonstrate that TRPV4 inhibitors are potent and efficacious countermeasures against severe chemical exposures, acting against exaggerated inflammatory responses, and protecting tissue barriers and cardiovascular function. PMID:24838754

  12. TRPV4 inhibition counteracts edema and inflammation and improves pulmonary function and oxygen saturation in chemically induced acute lung injury.

    PubMed

    Balakrishna, Shrilatha; Song, Weifeng; Achanta, Satyanarayana; Doran, Stephen F; Liu, Boyi; Kaelberer, Melanie M; Yu, Zhihong; Sui, Aiwei; Cheung, Mui; Leishman, Emma; Eidam, Hilary S; Ye, Guosen; Willette, Robert N; Thorneloe, Kevin S; Bradshaw, Heather B; Matalon, Sadis; Jordt, Sven-Eric

    2014-07-15

    The treatment of acute lung injury caused by exposure to reactive chemicals remains challenging because of the lack of mechanism-based therapeutic approaches. Recent studies have shown that transient receptor potential vanilloid 4 (TRPV4), an ion channel expressed in pulmonary tissues, is a crucial mediator of pressure-induced damage associated with ventilator-induced lung injury, heart failure, and infarction. Here, we examined the effects of two novel TRPV4 inhibitors in mice exposed to hydrochloric acid, mimicking acid exposure and acid aspiration injury, and to chlorine gas, a severe chemical threat with frequent exposures in domestic and occupational environments and in transportation accidents. Postexposure treatment with a TRPV4 inhibitor suppressed acid-induced pulmonary inflammation by diminishing neutrophils, macrophages, and associated chemokines and cytokines, while improving tissue pathology. These effects were recapitulated in TRPV4-deficient mice. TRPV4 inhibitors had similar anti-inflammatory effects in chlorine-exposed mice and inhibited vascular leakage, airway hyperreactivity, and increase in elastance, while improving blood oxygen saturation. In both models of lung injury we detected increased concentrations of N-acylamides, a class of endogenous TRP channel agonists. Taken together, we demonstrate that TRPV4 inhibitors are potent and efficacious countermeasures against severe chemical exposures, acting against exaggerated inflammatory responses, and protecting tissue barriers and cardiovascular function. PMID:24838754

  13. Postnatally Induced Inactivation of gp130 in Mice Results in Neurological, Cardiac, Hematopoietic, Immunological, Hepatic, and Pulmonary Defects

    PubMed Central

    Betz, Ulrich A.K.; Bloch, Wilhelm; van den Broek, Maries; Yoshida, Kanji; Taga, Tetsuya; Kishimoto, Tadamitsu; Addicks, Klaus; Rajewsky, Klaus; Müller, Werner

    1998-01-01

    The pleiotrophic but overlapping functions of the cytokine family that includes interleukin (IL)-6, IL-11, leukemia inhibitory factor, oncostatin M, ciliary neurotrophic factor, and cardiotrophin 1 are mediated by the cytokine receptor subunit gp130 as the common signal transducer. Although mice lacking individual members of this family display only mild phenotypes, animals lacking gp130 are not viable. To assess the collective role of this cytokine family, we inducibly inactivated gp130 via Cre-loxP–mediated recombination in vivo. Such conditional mutant mice exhibited neurological, cardiac, hematopoietic, immunological, hepatic, and pulmonary defects, demonstrating the widespread importance of gp130-dependent cytokines. PMID:9815272

  14. Cardiomyopathy Induced by Pulmonary Sequestration in a 50-Year-Old Man

    PubMed Central

    Chatelain, Shaun; Comp, Robert A.; Grace, R. Randal

    2015-01-01

    A 50-year-old black man presented at the emergency department with midsternal, nonradiating chest pressure and chronic dyspnea on exertion. Four years before the current admission, he had been diagnosed with nonischemic cardiomyopathy at another facility. After our complete evaluation, we suspected that his symptoms arose from left-to-left shunting in association with pulmonary sequestration, a congenital malformation. Our preliminary diagnosis of secondary dilated cardiomyopathy was confirmed by normalization of the patient's ventricular size and function after lobectomy. To our knowledge, this patient is the oldest on record to present with cardiomyopathy consequent to pulmonary sequestration. His case is highly unusual because of his age and the rapid resolution of his symptoms after lobectomy. We believe that pulmonary sequestration should be included in the differential diagnosis of dilated cardiomyopathy. PMID:25873803

  15. Cetrimide-chlorhexidine-induced multiorgan failure in surgery of pulmonary hydatid cyst

    PubMed Central

    Tripathy, Swagata; Sasmal, Prakash; Rao, P. Bhaskar; Mishra, Tushar S.; Nayak, Sukdev

    2016-01-01

    Savlon (0.5% cetrimide/0.05% chlorhexidine) is used as a scolicidal during surgery of hydatid cysts. It is considered a safe and effective agent. However, there are no recommendations for the appropriate concentration or dosage of these agents. Previously reported to cause severe metabolic acidosis, its effects on the pulmonary system have not been explored. We present a case of acute lung injury and respiratory distress along with acute cardiopulmonary distress, severe metabolic acidosis, and renal failure following its use during surgical removal of pulmonary hydatid cyst. The agent may act as a chemical sclerosant causing pulmonary parenchymal damage through bronchial openings present in the pericyst. Till safe dose limits are known, use of this agent should be limited, especially in large or multiple cyst surgery. PMID:27397471

  16. Cetrimide-chlorhexidine-induced multiorgan failure in surgery of pulmonary hydatid cyst.

    PubMed

    Tripathy, Swagata; Sasmal, Prakash; Rao, P Bhaskar; Mishra, Tushar S; Nayak, Sukdev

    2016-01-01

    Savlon (0.5% cetrimide/0.05% chlorhexidine) is used as a scolicidal during surgery of hydatid cysts. It is considered a safe and effective agent. However, there are no recommendations for the appropriate concentration or dosage of these agents. Previously reported to cause severe metabolic acidosis, its effects on the pulmonary system have not been explored. We present a case of acute lung injury and respiratory distress along with acute cardiopulmonary distress, severe metabolic acidosis, and renal failure following its use during surgical removal of pulmonary hydatid cyst. The agent may act as a chemical sclerosant causing pulmonary parenchymal damage through bronchial openings present in the pericyst. Till safe dose limits are known, use of this agent should be limited, especially in large or multiple cyst surgery. PMID:27397471

  17. Pulmonary embolus

    MedlinePlus

    ... blood clot; Blood clot - lung; Embolus; Tumor embolus; Embolism - pulmonary; DVT-pulmonary embolism; Thrombosis - pulmonary embolism ... x-ray CT angiogram of the chest Pulmonary ventilation/perfusion scan, also called a V/Q scan ...

  18. HIF-1α regulates EMT via the Snail and β-catenin pathways in paraquat poisoning-induced early pulmonary fibrosis.

    PubMed

    Zhu, Yong; Tan, Jiuting; Xie, Hui; Wang, Jinfeng; Meng, Xiaoxiao; Wang, Ruilan

    2016-04-01

    Paraquat (PQ) poisoning-induced pulmonary fibrosis is one of the primary causes of death in patients with PQ poisoning. Hypoxia-inducible factor-1α (HIF-1α) and epithelial-mesenchymal transition (EMT) are involved in the progression of pulmonary fibrosis. Snail and β-catenin are two other factors involved in promoting EMT. However, the relationship among HIF-1α, Snail and β-catenin in PQ poisoning-induced pulmonary fibrosis is not clear. Our research aimed to determine whether the regulation of HIF-1α in EMT occurs via the Snail and β-catenin pathways in PQ poisoning-induced pulmonary fibrosis. Sixty-six Sprague-Dawley rats were randomly and evenly divided into a control group and a PQ group. The PQ group was treated with an intragastric infusion of a 20% PQ solution (50 mg/kg) for 2, 6, 12, 24, 48 and 72 hrs. A549 and RLE-6TN cell lines were transfected with HIF-1α siRNA for 48 hrs before being exposed to PQ. Western blotting, real-time quantitative PCR, immunofluorescence, immunohistochemistry and other assays were used in our research. In vivo, the protein levels of HIF-1α and α-SMA were increased at 2 hrs and the level of ZO-1 (Zonula Occluden-1) was reduced at 12 hrs. In vitro, the transient transfection of HIF-1α siRNA resulted in a decrease in the degree of EMT. The expression levels of Snail and β-catenin were significantly reduced when HIF-α was silenced. These data demonstrate that EMT may be involved in PQ poisoning-induced pulmonary fibrosis and regulated by HIF-1α via the Snail and β-catenin pathways. Hypoxia-inducible factor-1α may be a therapeutic target for the treatment of PQ poisoning-induced pulmonary fibrosis. PMID:26781174

  19. Naringenin adds to the protective effect of L-arginine in monocrotaline-induced pulmonary hypertension in rats: favorable modulation of oxidative stress, inflammation and nitric oxide.

    PubMed

    Ahmed, Lamiaa A; Obaid, Al Arqam Z; Zaki, Hala F; Agha, Azza M

    2014-10-01

    The present study was directed to investigate the possible modulatory effect of naringenin when co-administered with L-arginine in monocrotaline-induced pulmonary hypertension in rats. Pulmonary hypertension was induced by a single subcutaneous injection of monocrotaline (60 mg/kg). L-arginine (500 mg/kg) and naringenin (50 mg/kg) were orally administered daily, alone and in combination, for 3 weeks. Mean arterial blood pressure, electrocardiography and echocardiography were then recorded and rats were sacrificed and serum was separated for determination of total nitrate/nitrite level. Right ventricles and lungs were isolated for estimation of oxidative stress markers, tumor necrosis factor-alpha, total nitrate/nitrite and transforming growth factor-beta. Myeloperoxidase and caspase-3 activities in addition to endothelial and inducible nitric oxide synthase protein expression were also determined. Moreover, histological analysis of pulmonary arteries and cardiomyocyte cross-sectional area was performed. Combined therapy provided a significant improvement in L-arginine protective effect toward preserving hemodynamic changes and alleviating oxidative stress, inflammatory and apoptotic markers induced by monocrotaline treatment. Furthermore, combined therapy prevented monocrotaline-induced changes in endothelial and inducible nitric oxide synthase protein expression as well as histological analysis compared with either treatment alone. In conclusion, naringenin significantly adds to the protective effect of L-arginine in pulmonary hypertension induced by monocrotaline in rats. PMID:24878387

  20. Evaluation of pulmonary dysfunctions and acid–base imbalances induced by Chlamydia psittaci in a bovine model of respiratory infection

    PubMed Central

    2014-01-01

    Background Chlamydia psittaci (Cp) is a respiratory pathogen capable of inducing acute pulmonary zoonotic disease (psittacosis) or persistent infection. To elucidate the pathogenesis of this infection, a translational large animal model was recently introduced by our group. This study aims at quantifying and differentiating pulmonary dysfunction and acid–base imbalances induced by Cp. Methods Forty-two calves were grouped in (i) animals inoculated with Cp (n = 21) and (ii) controls sham-inoculated with uninfected cell culture (n = 21). For pulmonary function testing, impulse oscillometry, capnography, and FRC (functional residual capacity) measurement were applied to spontaneously breathing animals. Variables of acid–base status were assessed in venous blood using both (i) traditional Henderson-Hasselbalch and (ii) strong ion approach. Results Both obstructive and restrictive pulmonary disorders were induced in calves experimentally inoculated with Cp. Although disorders in respiratory mechanics lasted for 8–11 days, the pattern of spontaneous breathing was mainly altered in the period of acute illness (until 4 days post inoculation, dpi). Expiration was more impaired than inspiration, resulting in elevated FRC. Ventilation was characterised by a reduction in tidal volume (−25%) combined with an increased percentage of dead space volume and a significant reduction of alveolar volume by 10%. Minute ventilation increased significantly (+50%) due to a compensatory doubling of respiratory rate. Hyperventilatory hypocapnia at 2–3 dpi resulted in slightly increased blood pH at 2 dpi. However, the acid–base equilibrium was additionally influenced by metabolic components, i.e. the systemic inflammatory response, all of which were detected with help of the strong ion theory. Decreased concentrations of albumin (2–10 dpi), a negative acute-phase marker, resulted in a decrease in the sum of non-volatile weak acids (Atot), revealing an alkalotic effect

  1. Mechanisms of surface-tension-induced epithelial cell damage in a model of pulmonary airway reopening.

    PubMed

    Bilek, Anastacia M; Dee, Kay C; Gaver, Donald P

    2003-02-01

    Airway collapse and reopening due to mechanical ventilation exerts mechanical stress on airway walls and injures surfactant-compromised lungs. The reopening of a collapsed airway was modeled experimentally and computationally by the progression of a semi-infinite bubble in a narrow fluid-occluded channel. The extent of injury caused by bubble progression to pulmonary epithelial cells lining the channel was evaluated. Counterintuitively, cell damage increased with decreasing opening velocity. The presence of pulmonary surfactant, Infasurf, completely abated the injury. These results support the hypotheses that mechanical stresses associated with airway reopening injure pulmonary epithelial cells and that pulmonary surfactant protects the epithelium from this injury. Computational simulations identified the magnitudes of components of the stress cycle associated with airway reopening (shear stress, pressure, shear stress gradient, or pressure gradient) that may be injurious to the epithelial cells. By comparing these magnitudes to the observed damage, we conclude that the steep pressure gradient near the bubble front was the most likely cause of the observed cellular damage. PMID:12433851

  2. Aryl radical involvement in amiodarone-induced pulmonary toxicity: Investigation of protection by spin-trapping nitrones

    SciTech Connect

    Nicolescu, Adrian C.; Comeau, Jeannette L.; Hill, Bruce C.; Bedard, Leanne L.; Takahashi, Takashi; Brien, James F.; Racz, William J.; Massey, Thomas E. . E-mail: masseyt@post.queensu.ca

    2007-04-01

    Amiodarone (AM), an antidysrrhythmic drug, can produce serious adverse effects, including potentially fatal AM-induced pulmonary toxicity (AIPT). AM-induced cytotoxicity and pulmonary fibrosis are well recognized, but poorly understood mechanistically. The hypothesis of aryl radical involvement in AM toxicity was tested in non-biological and biological systems. Photolysis of anaerobic aqueous solutions of AM, or N-desethylamiodarone (DEA) resulted in the formation of an aryl radical, as determined by spin-trapping and electron paramagnetic resonance (EPR) spectroscopy experiments. The non-iodinated AM analogue, didesiodoamiodarone (DDIA), did not form aryl radicals under identical conditions. The toxic susceptibility of human lung epithelioid HPL1A cells to AM, DEA, and DDIA showed time- and concentration-dependence. DEA had a more rapid and potent toxic effect (LC{sub 50} = 8 {mu}M) than AM (LC{sub 50} = 146 {mu}M), whereas DDIA cytotoxicity was intermediate (LC{sub 50} = 26 {mu}M) suggesting a minor contribution of the iodine atoms. Incubation of human lung epithelial cells with the spin-trapping nitrones {alpha}-phenyl-N-t-butylnitrone (PBN, 10 mM) or {alpha}-(4-pyridyl N-oxide)-N-t-butylnitrone (POBN, 5.0 mM) did not significantly protect against AM, DEA, or DDIA cytotoxicity. Intratracheal administration of AM to hamsters produced pulmonary fibrosis at day 21, which was not prevented by 4 days of treatment with 150 mg/kg/day PBN or 164 mg/kg/day POBN. However, the body weight loss in AM-treated animals was counteracted by PBN. These results suggest that, although AM can generate an aryl radical photochemically, its in vivo formation may not be a major contributor to AM toxicity, and that spin-trapping reagents do not halt the onset of AM toxicity.

  3. Systemic interleukin-2 administration improves lung function and modulates chorioamnionitis-induced pulmonary inflammation in the ovine fetus.

    PubMed

    Willems, Monique G M; Ophelders, Daan R M G; Nikiforou, Maria; Jellema, Reint K; Butz, Anke; Delhaas, Tammo; Kramer, Boris W; Wolfs, Tim G A M

    2016-01-01

    Chorioamnionitis, an inflammatory reaction of the fetal membranes to microbes, is an important cause of preterm birth and associated with inflammation-driven lung injury. However, inflammation in utero overcomes immaturity of the premature lung by inducing surfactant lipids and lung gas volume. Previously, we found that lipopolysaccharide (LPS)-induced chorioamnionitis resulted in pulmonary inflammation with increased effector T cells and decreased regulatory T cell (Treg) numbers. Because Tregs are crucial for immune regulation, we assessed the effects of interleukin (IL)-2-driven selective Treg expansion on the fetal lung in an ovine chorioamnionitis model. Instrumented fetuses received systemic prophylactic IL-2 treatment [118 days gestational age (dGA)] with or without subsequent exposure to intra-amniotic LPS (122 dGA). Following delivery at 129 dGA (term 147 dGA), pulmonary and systemic inflammation, morphological changes, lung gas volume, and phospholipid concentration were assessed. IL-2 pretreatment increased the FoxP3(+)/CD3(+) ratio, which was associated with reduced CD3-positive cells in the fetal lungs of LPS-exposed animals. Prophylactic IL-2 treatment did not prevent pulmonary accumulation of myeloperoxidase- and PU.1-positive cells or elevation of bronchoalveolar lavage fluid IL-8 and systemic IL-6 concentrations in LPS-exposed animals. Unexpectedly, IL-2 treatment improved fetal lung function of control lambs as indicated by increased disaturated phospholipids and improved lung gas volume. In conclusion, systemic IL-2 treatment in utero preferentially expanded Tregs and improved lung gas volume and disaturated phospholipids. These beneficial effects on lung function were maintained despite the moderate immunomodulatory effects of prophylactic IL-2 in the course of chorioamnionitis. PMID:26519206

  4. Reversal of elastase-induced pulmonary emphysema and promotion of alveolar epithelial cell proliferation by simvastatin in mice.

    PubMed

    Takahashi, Saeko; Nakamura, Hidetoshi; Seki, Makoto; Shiraishi, Yoshiki; Yamamoto, Miyuki; Furuuchi, Momoyo; Nakajima, Takahiro; Tsujimura, Shuko; Shirahata, Toru; Nakamura, Miho; Minematsu, Naoto; Yamasaki, Motohiro; Tateno, Hiroki; Ishizaka, Akitoshi

    2008-05-01

    Besides lowering cholesterol, statins exert multiple effects, such as anti-inflammatory activity and improvement of endothelial cell function. We examined whether simvastatin (SS) protects against the development of elastase-induced pulmonary emphysema in mice by using mean linear intercepts of alveoli (Lm) as a morphometric parameter of emphysema. After injection of intratracheal elastase on day 0, C57BL/6 mice were treated daily with SS (SS+ group) or PBS (SS- group) for 2 wk. A 21% decrease in Lm on day 7 was observed in the SS+ group vs. the SS- group. Anti-inflammatory effects of SS were observed as a decrease in percentage of neutrophils up to day 3, and in hydroxyproline concentration on day 3, in bronchoalveolar lavage fluid (BALF). SS also increased the number of proliferating cell nuclear antigen (PCNA)-positive alveolar epithelial cells between days 3 and 14. To confirm the role of statins in promoting proliferation of alveolar cells, mice were treated with SS (SS+) vs. PBS (SS-) for 12 days, starting 3 wk after elastase administration. After SS treatment, Lm decreased by 52% and PCNA-positive alveolar epithelial cells increased compared with the SS- group. Concentrations of vascular endothelial growth factor in BALF and endothelial nitric oxide synthase protein expression in pulmonary vessels tended to be higher in the SS+ group vs. the SS- group in this protocol. In conclusion, SS inhibited the development of elastase-induced pulmonary emphysema in mice. This therapeutic effect was due not only to anti-inflammation but also to the promotion of alveolar epithelial cell regeneration, partly mediated by restoring endothelial cell functions. PMID:18310229

  5. Acute pulmonary toxicity and inflammation induced by combined exposure to didecyldimethylammonium chloride and ethylene glycol in rats.

    PubMed

    Kwon, Do Young; Kim, Hyun-Mi; Kim, Eunji; Lim, Yeon-Mi; Kim, Pilje; Choi, Kyunghee; Kwon, Jung-Taek

    2016-02-01

    Didecyldimethylammonium chloride (DDAC), an antimicrobial agent, has been reported to induce pulmonary toxicity in animal studies. DDAC is frequently used in spray-form household products in combination with ethylene glycol (EG). The purpose of this study was to evaluate the toxic interaction between DDAC and EG in the lung. DDAC at a sub-toxic dose (100 μg/kg body weight) was mixed with a non-toxic dose of EG (100 or 200 μg/kg body weight), and was administrated to rats via intratracheal instillation. Lactate dehydrogenase activity and total protein content in the bronchoalveolar lavage fluid (BALF) were not changed by singly treated DDAC or EG, but significantly enhanced at 1 d after treatment with the mixture, with the effect dependent on the dose of EG. Total cell count in BALF was largely increased and polymorphonuclear leukocytes were predominantly recruited to the lung in rats administrated with the mixture. Inflammatory cytokines, tumor necrosis factor-alpha and interleukin-6 also appeared to be increased by the mixture of DDAC and EG (200 μg/kg body weight) at 1 d post-exposure, which might be associated with the increase in inflammatory cells in lung. BALF protein content and inflammatory cell recruitment in the lung still remained elevated at 7 d after the administration of DDAC with the higher dose of EG. These results suggest that the combination of DDAC and EG can synergistically induce pulmonary cytotoxicity and inflammation, and EG appears to amplify the harmful effects of DDAC on the lung. Therefore pulmonary exposure to these two chemicals commonly found in commercial products can be a potential hazard to human health. PMID:26763389

  6. Involvement of mast cells in monocrotaline-induced pulmonary hypertension in rats

    PubMed Central

    2011-01-01

    Background Mast cells (MCs) are implicated in inflammation and tissue remodeling. Accumulation of lung MCs is described in pulmonary hypertension (PH); however, whether MC degranulation and c-kit, a tyrosine kinase receptor critically involved in MC biology, contribute to the pathogenesis and progression of PH has not been fully explored. Methods Pulmonary MCs of idiopathic pulmonary arterial hypertension (IPAH) patients and monocrotaline-injected rats (MCT-rats) were examined by histochemistry and morphometry. Effects of the specific c-kit inhibitor PLX and MC stabilizer cromolyn sodium salt (CSS) were investigated in MCT-rats both by the preventive and therapeutic approaches. Hemodynamic and right ventricular hypertrophy measurements, pulmonary vascular morphometry and analysis of pulmonary MC localization/counts/activation were performed in animal model studies. Results There was a prevalence of pulmonary MCs in IPAH patients and MCT-rats as compared to the donors and healthy rats, respectively. Notably, the perivascular MCs were increased and a majority of them were degranulated in lungs of IPAH patients and MCT-rats (p < 0.05 versus donor and control, respectively). In MCT-rats, the pharmacological inhibitions of MC degranulation and c-kit with CSS and PLX, respectively by a preventive approach (treatment from day 1 to 21 of MCT-injection) significantly attenuated right ventricular systolic pressure (RVSP) and right ventricular hypertrophy (RVH). Moreover, vascular remodeling, as evident from the significantly decreased muscularization and medial wall thickness of distal pulmonary vessels, was improved. However, treatments with CSS and PLX by a therapeutic approach (from day 21 to 35 of MCT-injection) neither improved hemodynamics and RVH nor vascular remodeling. Conclusions The accumulation and activation of perivascular MCs in the lungs are the histopathological features present in clinical (IPAH patients) and experimental (MCT-rats) PH. Moreover, the

  7. Comparison of Serum Adiponectin in Smoke-induced Pulmonary Emphysema Rats Fed Different Diets

    PubMed Central

    Wang, Rui-Ying; Liu, Hu; Ma, Li-Juan; Xu, Jian-Ying

    2016-01-01

    Background: Smoking and body mass index (BMI) are the key risk factors for chronic obstructive pulmonary disease (COPD). Adiponectin with both anti-inflammatory and pro-inflammatory properties is a vital modulator of inflammatory processes, which is expressed in epithelial cells in the airway in COPD-emphysema. The aim of this study was to examine the effects of adiponectin on tobacco smoke-induced emphysema in rats, which were fed different diets. Methods: Seventy-six adult (6–8 weeks old) male Sprague-Dawley rats (average weight 220 ± 20 g) were exposed to smoke or smoke-free room atmosphere and fed different diets (regular, high-fat, or low-fat diets) for 6 months. The rats were randomly divided into six groups. They are nonsmoke-exposed regular diet (n = 10), nonsmoke-exposed high-fat diet (n = 14), nonsmoke-exposed low-fat diet (n = 14), smoke-exposed regular diet (n = 10), smoke-exposed high-fat diet (n = 14), and smoke-exposed low-fat diet groups (n = 14). A full 23 factorial design was used to evaluate the effect of independent variables on smoke exposure and different rearing methods. Serum adiponectin and inflammatory cytokines were measured by the enzyme-linked immunosorbent assay (ELISA). Results: Serum adiponectin levels in rats fed low-fat and regular diets exposed to smoke exposure were remarkably higher than that of rats exposed to room air while serum adiponectin levels of fat-rich diet rats exposed to tobacco smoke were lower than that of rats exposed to room air. Compared with regular diet or low-fat diet group, serum adiponectin levels in high-fat diet rats exposed to tobacco smoke were lower (t = 6.932, 11.026; all P < 0.001). BMI was inversely correlated with serum adiponectin levels (r = −0.751, P = 0.012). Serum interleukin 6 (IL-6), tumor necrosis factor-α (TNF-α), and 4-hydroxy 2-nonenal (HNE) levels in rats exposed to low-fat or fat-rich diets were remarkably higher than that of rats exposed to normal diets (IL-6, t = 4.196, 3

  8. Epstein-Barr virus-induced gene 3 (EBI3) polymorphisms and expression are associated with susceptibility to pulmonary tuberculosis.

    PubMed

    Zheng, Ruijuan; Liu, Haipeng; Song, Peng; Feng, Yonghong; Qin, Lianhua; Huang, Xiaochen; Chen, Jianxia; Yang, Hua; Liu, Zhonghua; Cui, Zhenglin; Hu, Zhongyi; Ge, Baoxue

    2015-07-01

    Tuberculosis (TB) remains a major global health problem and host genetic factors play a critical role in susceptibility and resistance to TB. The aim of this study was to identify novel candidate genes associated with TB susceptibility. We performed a population-based case-control study to genotype 13 tag SNPs spanning Epstein-Barr virus-induced gene 3 (EBI3), colony stimulating factor 2 (CSF2), IL-4, interferon beta 1 (IFNB1), chemokine (C-X-C motif) ligand 14 (CXCL14) and myeloid differentiation primary response gene 88 (Myd88) genes in 435 pulmonary TB patients and 375 health donors from China. We observed that EBI3 gene rs4740 polymorphism was associated with susceptibility to pulmonary tuberculosis (PTB) and the allele G was associated with a protective effect against PTB. Furthermore, EBI3 deficiency led to reduced bacterial burden and histopathological impairment in the lung of mice infected with Mycobacterium bovis BCG. Meanwhile, higher abundance of EBI3 was observed in the granuloma of PTB patients and in the lung tissue of BCG-infected mice. Of note, the expression of EBI3 in macrophages was remarkably induced by mycobacteria infection at both mRNA and protein level. In conclusion, EBI3 gene rs4740 polymorphism is closely associated with susceptibility to PTB and the elevation and enrichment of EBI3 in the lung which at least partially derived from macrophages may contribute to the exacerbation of mycobacterial infection. PMID:25937126

  9. Pulmonary transcriptome analysis in the surgically induced rabbit model of diaphragmatic hernia treated with fetal tracheal occlusion

    PubMed Central

    Engels, Alexander C.; Brady, Paul D.; Kammoun, Molka; Finalet Ferreiro, Julio; DeKoninck, Philip; Endo, Masayuki; Toelen, Jaan; Vermeesch, Joris R.; Deprest, Jan

    2016-01-01

    ABSTRACT Congenital diaphragmatic hernia (CDH) is a malformation leading to pulmonary hypoplasia, which can be treated in utero by fetal tracheal occlusion (TO). However, the changes of gene expression induced by TO remain largely unknown but could be used to further improve the clinically used prenatal treatment of this devastating malformation. Therefore, we aimed to investigate the pulmonary transcriptome changes caused by surgical induction of diaphragmatic hernia (DH) and additional TO in the fetal rabbit model. Induction of DH was associated with 378 upregulated genes compared to controls when allowing a false-discovery rate (FDR) of 0.1 and a fold change (FC) of 2. Those genes were again downregulated by consecutive TO. But DH+TO was associated with an upregulation of 157 genes compared to DH and controls. When being compared to control lungs, 106 genes were downregulated in the DH group and were not changed by TO. Therefore, the overall pattern of gene expression in DH+TO is more similar to the control group than to the DH group. In this study, we further provide a database of gene expression changes induced by surgical creation of DH and consecutive TO in the rabbit model. Future treatment strategies could be developed using this dataset. We also discuss the most relevant genes that are involved in CDH. PMID:26744354

  10. Adipose-derived stromal cell autologous transplantation ameliorates pulmonary arterial hypertension induced by shunt flow in rat models.

    PubMed

    Liu, Kai; Liu, Ruifang; Cao, Guangqing; Sun, Hourong; Wang, Xuping; Wu, Shuming

    2011-06-01

    Hyperkinetic pulmonary arterial hypertension (PAH) severely influences the success of operation for congenital heart disease and deteriorates the prognosis of disease. Adipose-derived stromal cell (ADSC) is a good alternative multipotent stem cell for regeneration medicine. PAH rat models were established by arteriovenous shunt and ADSCs were isolated, cultured, and labeled in vitro. Twelve weeks after shunt operation, rats received an injection of 5 × 10(7) ADSCs. Two weeks after transplantation, hemodynamic abnormality induced by the shunt flow and the hypertrophy of right ventricle were reversed, which was confirmed by invasive measurement and echocardiography examination. The PAH rats receiving cell transplantation demonstrated decreased remodeling of small arteries in the lung; immunohistochemistry analysis showed augmented expression of hepatocyte growth factor (HGF) and increased number of pulmonary small arteries. Western blot and real-time reverse transcriptase-polymerase chain reaction indicated that the protein and mRNA levels of HGF and endothelial nitric oxide synthase increased, respectively, in the lung after cell transplantation. Our results suggested that ADSC transplantation can ameliorate PAH induced by shunt flow by enhancing the expression of HGF and subsequently promoting angiogenesis in the injured lung tissue. PMID:20828291

  11. The regulatory role of interferon-γ producing gamma delta T cells via the suppression of T helper 17 cell activity in bleomycin-induced pulmonary fibrosis.

    PubMed

    Segawa, S; Goto, D; Iizuka, A; Kaneko, S; Yokosawa, M; Kondo, Y; Matsumoto, I; Sumida, T

    2016-09-01

    Interstitial pneumonia (IP) is a chronic progressive interstitial lung disease associated with poor prognosis and high mortality. However, the pathogenesis of IP remains to be elucidated. The aim of this study was to clarify the role of pulmonary γδT cells in IP. In wild-type (WT) mice exposed to bleomycin, pulmonary γδT cells were expanded and produced large amounts of interferon (IFN)-γ and interleukin (IL)-17A. Histological and biochemical analyses showed that bleomycin-induced IP was more severe in T cell receptor (TCR-δ-deficient (TCRδ(-/-) ) mice than WT mice. In TCRδ(-/-) mice, pulmonary IL-17A(+) CD4(+) Τ cells expanded at days 7 and 14 after bleomycin exposure. In TCRδ(-/-) mice infused with γδT cells from WT mice, the number of pulmonary IL-17A(+) CD4(+) T cells was lower than in TCRδ(-/-) mice. The examination of IL-17A(-/-) TCRδ(-/-) mice indicated that γδT cells suppressed pulmonary fibrosis through the suppression of IL-17A(+) CD4(+) T cells. The differentiation of T helper (Th)17 cells was determined in vitro, and CD4(+) cells isolated from TCRδ(-/-) mice showed normal differentiation of Th17 cells compared with WT mice. Th17 cell differentiation was suppressed in the presence of IFN-γ producing γδT cells in vitro. Pulmonary fibrosis was attenuated by IFN-γ-producing γδT cells through the suppression of pulmonary IL-17A(+) CD4(+) T cells. These results suggested that pulmonary γδT cells seem to play a regulatory role in the development of bleomycin-induced IP mouse model via the suppression of IL-17A production. PMID:27083148

  12. A mathematical model of the unidirectional block caused by the pulmonary veins for anatomically induced atrial reentry.

    PubMed

    Chun, Sehun

    2014-06-01

    It is widely believed that the pulmonary veins (PVs) of the left atrium play the central role in the generation of anatomically induced atrial reentry but its mechanism has not been analytically explained. To understand this mechanism, a new analytic approach is proposed by adapting the geometric relative acceleration analysis from spacetime physics based on the hypothesis that a large relative acceleration can translate to a dramatic increase in the curvature of a wavefront and subsequently to conduction failure. By verifying the strong dependency of the propagational direction and the magnitude of anisotropy for conduction failure, this analytic method reveals that a unidirectional block can be generated by asymmetric propagation toward the PVs. This model is validated by computational tests in a T-shaped domain, computational simulations for three-dimensional atrial reentry and previous in-silico reports for anatomically induced atrial reentry. PMID:24789612

  13. Expression profiling of genes regulated by Fra-1/AP-1 transcription factor during bleomycin-induced pulmonary fibrosis

    PubMed Central

    2013-01-01

    Background The Fra-1/AP-1 transcription factor regulates the expression of genes controlling various processes including migration, invasion, and survival as well as extracellular remodeling. We recently demonstrated that loss of Fra-1 leads to exacerbated bleomycin-induced pulmonary fibrosis, accompanied by enhanced expression of various inflammatory and fibrotic genes. To better understand the molecular mechanisms by which Fra-1 confers protection during bleomycin-induced lung injury, genome-wide mRNA expression profiling was performed. Results We found that Fra-1 regulates gene expression programs that include: 1) several cytokines and chemokines involved in inflammation, 2) several genes involved in the extracellular remodeling and cell adhesion, and 3) several genes involved in programmed cell death. Conclusion Loss of Fra-1 leads to the enhanced expression of genes regulating inflammation and immune responses and decreased the expression of genes involved in apoptosis, suggesting that this transcription factor distinctly modulates early pro-fibrotic cellular responses. PMID:23758685

  14. Cigarette Smoke-Induced Emphysema and Pulmonary Hypertension Can Be Prevented by Phosphodiesterase 4 and 5 Inhibition in Mice

    PubMed Central

    Pichl, Alexandra; Bednorz, Mariola; Ghofrani, Hossein Ardeschir; Schermuly, Ralph Theo; Seeger, Werner; Grimminger, Friedrich; Weissmann, Norbert

    2015-01-01

    Rationale Chronic obstructive pulmonary disease (COPD) is a widespread disease, with no curative therapies available. Recent findings suggest a key role of NO and sGC-cGMP signaling for the pathogenesis of the disease. Previous data suggest a downregulation/inactivation of the cGMP producing soluble guanylate cyclase, and sGC stimulation prevented cigarette smoke-induced emphysema and pulmonary hypertension (PH) in mice. We thus aimed to investigate if the inhibition of the cGMP degrading phosphodiesterase (PDE)5 has similar effects. Results were compared to the effects of a PDE 4 inhibitor (cAMP elevating) and a combination of both. Methods C57BL6/J mice were chronically exposed to cigarette smoke and in parallel either treated with Tadalafil (PDE5 inhibitor), Piclamilast (PDE4 inhibitor) or both. Functional measurements (lung compliance, hemodynamics) and structural investigations (alveolar and vascular morphometry) as well as the heart ratio were determined after 6 months of tobacco smoke exposure. In addition, the number of alveolar macrophages in the respective lungs was counted. Results Preventive treatment with Tadalafil, Piclamilast or a combination of both almost completely prevented the development of emphysema, the increase in lung compliance, tidal volume, structural remodeling of the lung vasculature, right ventricular systolic pressure, and right ventricular hypertrophy induced by cigarette smoke exposure. Single, but not combination treatment prevented or reduced smoke-induced increase in alveolar macrophages. Conclusion Cigarette smoke-induced emphysema and PH could be prevented by inhibition of the phosphodiesterases 4 and 5 in mice. PMID:26058042

  15. Bone morphogenic protein-2 regulates the myogenic differentiation of PMVECs in CBDL rat serum-induced pulmonary microvascular remodeling.

    PubMed

    Liu, Chang; Chen, Lin; Zeng, Jing; Cui, Jian; Ning, Jiao-Nin; Wang, Guan-Song; Belguise, Karine; Wang, Xiaobo; Qian, Gui-Sheng; Lu, Kai-Zhi; Yi, Bin

    2015-08-01

    Hepatopulmonary syndrome (HPS) is characterized by an arterial oxygenation defect induced by intrapulmonary vasodilation (IPVD) that increases morbidity and mortality. In our previous study, it was determined that both the proliferation and the myogenic differentiation of pulmonary microvascular endothelial cells (PMVECs) play a key role in the development of IPVD. However, the molecular mechanism underlying the relationship between IPVD and the myogenic differentiation of PMVECs remains unknown. Additionally, it has been shown that bone morphogenic protein-2 (BMP2), via the control of protein expression, may regulate cell differentiation including cardiomyocyte differentiation, neuronal differentiation and odontoblastic differentiation. In this study, we observed that common bile duct ligation (CBDL)-rat serum induced the upregulation of the expression of several myogenic proteins (SM-α-actin, calponin, SM-MHC) and enhanced the expression levels of BMP2 mRNA and protein in PMVECs. We also observed that both the expression levels of Smad1/5 and the activation of phosphorylated Smad1/5 were significantly elevated in PMVECs following exposure to CBDL-rat serum, which was accompanied by the down-regulation of Smurf1. The blockage of the BMP2/Smad signaling pathway with Noggin inhibited the myogenic differentiation of PMVECs, a process that was associated with relatively low expression levels of both SM-α-actin and calponin in the setting of CBDL-rat serum exposure, although SM-MHC expression was not affected. These findings suggested that the BMP2/Smad signaling pathway is involved in the myogenic differentiation of the PMVECs. In conclusion, our data highlight the pivotal role of BMP2 in the CBDL-rat serum-induced myogenic differentiation of PMVECs via the activation of both Smad1 and Smad5 and the down-regulation of Smurf1, which may represent a potential therapy for HPS-induced pulmonary vascular remodeling. PMID:26071935

  16. Administration of antioxidant peptide SS-31 attenuates transverse aortic constriction-induced pulmonary arterial hypertension in mice

    PubMed Central

    Lu, Hung-i; Huang, Tien-hung; Sung, Pei-hsun; Chen, Yung-lung; Chua, Sarah; Chai, Han-yan; Chung, Sheng-ying; Liu, Chu-feng; Sun, Cheuk-kwan; Chang, Hsueh-wen; Zhen, Yen-yi; Lee, Fan-yen; Yip, Hon-kan

    2016-01-01

    Aim: Antioxidant peptide SS-31 is a class of cell-permeable small peptides, which selectively resides on the inner mitochondrial membrane and possesses intrinsic mitochondrial protective capacities. In this study we investigated the therapeutic effects of antioxidant peptide SS-31 on transverse aortic constriction (TAC)-induced pulmonary arterial hypertension (PAH) in a murine model. Methods: Adult male mice were divided into 3 groups: sham-operated mice, TAC mice, and TAC+SS-31 mice that underwent TAC surgery and received SS-31 (2 mg/d, ip) for 60 d. The right ventricular systolic blood pressure (RVSBP) was measured on d 60 prior to sacrificing the mice; then their right heart and lung tissues were collected for histological and biochemical examinations. Lung injury scores were defined by the increased crowded area and decreased number of alveolar sacs. Results: TAC mice showed significantly higher RVSBP compared with sham-operated mice, the elevation was substantially suppressed in TAC+SS-31 mice. The same pattern of changes was found in pulmonary levels of oxidative stress proteins (NOX-1/NOX-2/oxidized proteins), cytosolic cytochrome c, biomarkers related to inflammation (MMP-9/TNF-α/iNOS), calcium overload index (TRPC1, 2, 4, 6), apoptosis (mitochondrial BAX, cleaved caspase 3/PARP), fibrosis (Smad3/TGF-β), hypoxic (HIF-1α), DNA damage (γ-H2AX) and endothelial function (eNOS/ET-1R), as well as in lung injury score, number of muscularized vessels in lungs, number of TRPC1+ and HIF-1α+ cells in pulmonary artery, and number of γ-H2AX+ and Ki-67+ cells in lung parenchyma. An opposite pattern of changes was observed in pulmonary anti-fibrotic markers (Smad1/5, BMP-2), number of small vessels, and number of alveolar sacs. In contrast, the levels of antioxidant proteins (HO-1/NQO-1/GR/GPx) in lung parenchyma were progressively and significantly increased from sham-operated mice, TAC mice to TAC+SS-31 mice. Conclusion: Antioxidant peptide SS-31 administration

  17. Synthesis and electrochemical properties of niobium pentoxide deposited on layered carbide-derived carbon

    NASA Astrophysics Data System (ADS)

    Zhang, Chuanfang (John); Maloney, Ryan; Lukatskaya, Maria R.; Beidaghi, Majid; Dyatkin, Boris; Perre, Emilie; Long, Donghui; Qiao, Wenming; Dunn, Bruce; Gogotsi, Yury

    2015-01-01

    Herein we report on the hydrothermal synthesis of niobium pentoxide on carbide-derived carbon (Nb2O5/CDC) with a layered structure. The presence of phenylphosphonic acid guides the deposition during preparation, leading to the formation of amorphous Nb2O5 particles which are 4-10 nm in diameter and homogeneously distributed on the CDC framework. Electrochemical testing of the Nb2O5/CDC electrode indicated that the highest capacitance and Coulombic efficiency occurred using an electrolyte comprised of 1 M lithium perchlorate in ethylene carbonate/dimethyl carbonate. Subsequent heat treatment of Nb2O5/CDC in CO2 environment led to crystallization of the Nb2O5, allowing reversible Li+ intercalation/de-intercalation. For sweep rates corresponding to charging and discharging in under 3 min, a volumetric charge of 180 C cm-3 and Coulombic efficiency of 99.2% were attained.

  18. Production of large-scale, freestanding vanadium pentoxide nanobelt porous structures.

    PubMed

    Yun, Yong Ju; Kim, Byung Hoon; Hong, Won G; Kim, Chang Hee; Kim, Yark Yeon; Jeong, Eun-ju; Jang, Won Ick; Yu, Han Young

    2012-03-01

    Large-scale, freestanding, porous structures of vanadium pentoxide nanobelts (VPNs) were successfully prepared using the template-free freeze-drying method. The porous and multi-layered VPN macrostructures are composed of randomly oriented long nanobelts (over 100 μm) and their side length can be controlled up to a few tens of centimetres. Also, the bulk density and surface area of these macrostructures are 3-5 mg cm(-3) and 40-80 m(2) g(-1), respectively, which are similar to those of the excellent adsorbents. In addition, the removal efficiency measurements of ammonia molecules revealed that the VPN porous structures can adsorb the ammonia molecules with the combinations of van der Waals forces and strong chemical bonding by functional groups on the VPN surface. PMID:22293666

  19. Production of large-scale, freestanding vanadium pentoxide nanobelt porous structures

    NASA Astrophysics Data System (ADS)

    Yun, Yong Ju; Kim, Byung Hoon; Hong, Won G.; Kim, Chang Hee; Kim, Yark Yeon; Jeong, Eun-Ju; Jang, Won Ick; Yu, Han Young

    2012-02-01

    Large-scale, freestanding, porous structures of vanadium pentoxide nanobelts (VPNs) were successfully prepared using the template-free freeze-drying method. The porous and multi-layered VPN macrostructures are composed of randomly oriented long nanobelts (over 100 μm) and their side length can be controlled up to a few tens of centimetres. Also, the bulk density and surface area of these macrostructures are 3-5 mg cm-3 and 40-80 m2 g-1, respectively, which are similar to those of the excellent adsorbents. In addition, the removal efficiency measurements of ammonia molecules revealed that the VPN porous structures can adsorb the ammonia molecules with the combinations of van der Waals forces and strong chemical bonding by functional groups on the VPN surface.

  20. Synthesis, characterization and reactivity of early transition metal neo-pentoxides

    SciTech Connect

    Boyle, T.J.; Alam, T.M.; Scott, B.; Ziller, J.W.

    1997-12-31

    Titanium neo-pentoxide was isolated by the alcoholysis exchange between Ti(OCHMe{sub 2}){sub 4} and ONep. The molecule, [Ti(ONep){sub 4}]{sub 2}, was characterized using X-ray analysis and solution {sup 17}O, and {sup 47},{sup 49}Ti NMR spectroscopy. This dinuclear complex is the smallest Ti(OR){sub 4} isolated wherein each metal center is 5-coordinated. The molecule is highly soluble in standard solvents and volatile. The reactivity of this compound has been undertaken to compare with the ubiquitous Ti(O-I-Pr){sub 4}. The various compounds isolated and further NMR studies will be reported. Analogous routes to other M(ONep){sub n} will be reported as well.

  1. Nicardipine-induced acute pulmonary edema: a rare but severe complication of tocolysis.

    PubMed

    Serena, Claire; Begot, Emmanuelle; Cros, Jérôme; Hodler, Charles; Fedou, Anne Laure; Nathan-Denizot, Nathalie; Clavel, Marc

    2014-01-01

    We report four cases of acute pulmonary edema that occurred during treatment by intravenous tocolysis using nicardipine in pregnancy patients with no previous heart problems. Clinical severity justified hospitalization in intensive care unit (ICU) each time. Acute dyspnea has begun at an average of 63 hours after initiation of treatment. For all patients, the first diagnosis suspected was pulmonary embolism. The patients' condition improved rapidly with appropriate diuretic treatment and by modifying the tocolysis. The use of intravenous nicardipine is widely used for tocolysis in France even if its prescription does not have a marketing authorization. The pathophysiological mechanisms of this complication remain unclear. The main reported risk factors are spontaneous preterm labor, multiple pregnancy, concomitant obstetrical disease, association with beta-agonists, and fetal lung maturation corticotherapy. A better knowledge of this rare but serious adverse event should improve the management of patients. Nifedipine or atosiban, the efficiency of which tocolysis was also studied, could be an alternative. PMID:25215245

  2. [Drug-induced alteration of the alveolar content of pulmonary surfactant ].

    PubMed

    Alcindor, L G

    1982-05-01

    Pulmonary surfactant is a lipoprotein made up mostly of tensio-active phospholipids. It is synthesized by type II pneumocytes and accumulates as lamellar bodies before being excreted into pulmonary alveoli where it fills intercellular spaces and results in a liquid film (about 1 micron thick) covering the alveolar wall. Surfactant turnover occurs through the action of phospholipases from the alveolus or pneumocytes. Level of alveolar surfactant dependents on the ratio of synthesis and degradation of its principal constituent, dipalmitoyl-phosphatidylcholine. Many substances are known to be able of alter this ratio. Among these, synthetic glucocorticosteroids appear to be the most active in increasing alveolar surfactant. The multiple possible sites of action of these steroids explain their relative efficacy in the prevention of respiratory distress in humans. Studies in progress should increase the number and the quality of drugs available for this purpose. PMID:6896976

  3. Nicardipine-Induced Acute Pulmonary Edema: A Rare but Severe Complication of Tocolysis

    PubMed Central

    Serena, Claire; Begot, Emmanuelle; Cros, Jérôme; Hodler, Charles; Fedou, Anne Laure; Nathan-Denizot, Nathalie; Clavel, Marc

    2014-01-01

    We report four cases of acute pulmonary edema that occurred during treatment by intravenous tocolysis using nicardipine in pregnancy patients with no previous heart problems. Clinical severity justified hospitalization in intensive care unit (ICU) each time. Acute dyspnea has begun at an average of 63 hours after initiation of treatment. For all patients, the first diagnosis suspected was pulmonary embolism. The patients' condition improved rapidly with appropriate diuretic treatment and by modifying the tocolysis. The use of intravenous nicardipine is widely used for tocolysis in France even if its prescription does not have a marketing authorization. The pathophysiological mechanisms of this complication remain unclear. The main reported risk factors are spontaneous preterm labor, multiple pregnancy, concomitant obstetrical disease, association with beta-agonists, and fetal lung maturation corticotherapy. A better knowledge of this rare but serious adverse event should improve the management of patients. Nifedipine or atosiban, the efficiency of which tocolysis was also studied, could be an alternative. PMID:25215245

  4. Inhibition of Nitro-Oxidative Stress Attenuates Pulmonary and Systemic Injury Induced by High-Tidal Volume Mechanical Ventilation.

    PubMed

    Martínez-Caro, Leticia; Nin, Nicolás; Sánchez-Rodríguez, Carolina; Ferruelo, Antonio; El Assar, Mariam; de Paula, Marta; Fernández-Segoviano, Pilar; Esteban, Andrés; Lorente, José A

    2015-07-01

    Mechanisms contributing to pulmonary and systemic injury induced by high tidal volume (VT) mechanical ventilation are not well known. We tested the hypothesis that increased peroxynitrite formation is involved in organ injury and dysfunction induced by mechanical ventilation. Male Sprague-Dawley rats were subject to low- (VT, 9 mL/kg; positive end-expiratory pressure, 5 cmH2O) or high- (VT, 25 mL/kg; positive end-expiratory pressure, 0 cmH2O) VT mechanical ventilation for 120 min, and received 1 of 3 treatments: 3-aminobenzamide (3-AB, 10 mg/kg, intravenous, a poly adenosine diphosphate ribose polymerase [PARP] inhibitor), or the metalloporphyrin manganese(III) tetrakis(1-methyl-4-pyridyl)porphyrin (MnTMPyP, 5 mg/kg intravenous, a peroxynitrite scavenger), or no treatment (control group), 30 min before starting the mechanical ventilation protocol (n = 8 per group, 6 treatment groups). We measured mean arterial pressure, peak inspiratory airway pressure, blood chemistry, and gas exchange. Oxidation (fluorescence for oxidized dihydroethidium), protein nitration (immunofluorescence and Western blot for 3-nitrotyrosine), PARP protein (Western blot) and gene expression of the nitric oxide (NO) synthase (NOS) isoforms (quantitative real-time reverse transcription polymerase chain reaction) were measured in lung and vascular tissue. Lung injury was quantified by light microscopy. High-VT mechanical ventilation was associated with hypotension, increased peak inspiratory airway pressure, worsened oxygenation; oxidation and protein nitration in lung and aortic tissue; increased PARP protein in lung; up-regulation of NOS isoforms in lung tissue; signs of diffuse alveolar damage at histological examination. Treatment with 3AB or MnTMPyP attenuated the high-VT mechanical ventilation-induced changes in pulmonary and cardiovascular function; down-regulated the expression of NOS1, NOS2, and NOS3; decreased oxidation and nitration in lung and aortic tissue; and attenuated

  5. Broiler pulmonary hypertensive responses during lipopolysaccharide-induced tolerance and cyclooxygenase inhibition.

    PubMed

    Wideman, R F; Bowen, O T; Erf, G F

    2009-01-01

    Bacterial lipopolysaccharide (LPS, endotoxin) triggers pulmonary hypertension (PH) characterized by an increase in pulmonary arterial pressure (PAP) that reaches a peak value within 20 to 25 min and then gradually subsides within 60 min. As the PAP subsides PH cannot be reinitiated, signifying the onset of a period of tolerance (refractoriness) to repeated LPS exposure. The present study was conducted to determine the duration of this tolerance, and to evaluate key mediators thought to contribute to LPS-mediated PH in broilers. Tolerance was shown to persist for 4 to 5 d after the initial exposure to LPS. In tolerant broilers supramaximal i.v. injections of LPS did not reinitiate PH, nor was a significant modulatory role for nitric oxide demonstrated. The pulmonary vasculature of tolerant broilers remains responsive to the thromboxane A(2) (TxA(2)) mimetic U44069, 5-hydroxytryptamine (5-HT, serotonin), and constitutive nitric oxide. Meclofenamate successfully blocked the conversion of arachidonic acid to vasoconstrictive eicosanoids such as TxA(2); nevertheless, meclofenamate failed to inhibit PH in response to LPS. Therefore, TxA(2) does not appear to be the primary vasoconstrictor involved in the PH response to LPS and neither does 5-HT. Broilers emerging from tolerance 5 d after the initial exposure to LPS exhibited interindividual variation in their PH responsiveness to a second LPS injection, ranging from zero response (individuals that remain fully tolerant) to large increases in PAP (post-tolerant individuals). Tolerance might be an important compensatory or protective mechanism for broilers whose pulmonary vascular capacity is marginally adequate under optimal conditions, and whose respiratory systems are chronically challenged with LPS in commercial production facilities. The key vasoconstrictors responsible for the PH elicited by LPS remain to be determined. PMID:19096060

  6. Rattus model utilizing selective pulmonary ischemia induces bronchiolitis obliterans organizing pneumonia.

    PubMed

    Densmore, John C; Jeziorczak, Paul M; Clough, Anne V; Pritchard, Kirkwood A; Cummens, Breana; Medhora, Meetha; Rao, Arjun; Jacobs, Elizabeth R

    2013-03-01

    Bronchiolitis obliterans organizing pneumonia (BOOP), a morbid condition when associated with lung transplant and chronic lung disease, is believed to be a complication of ischemia. Our goal was to develop a simple and reliable model of lung ischemia in the Sprague-Dawley rat that would produce BOOP. Unilateral ischemia without airway occlusion was produced by an occlusive slipknot placed around the left main pulmonary artery. Studies were performed 7 days later. Relative pulmonary and systemic flow to each lung was measured by injection of technetium Tc 99m macroaggregated albumin. Histological sections were examined for structure and necrosis and scored for BOOP. Apoptosis was detected by immunohistochemistry with an antibody against cleaved caspase 3. Pulmonary artery blood flow to left lungs was less than 0.1% of the cardiac output, and bronchial artery circulation was ∼2% of aortic artery flow. Histological sections from ischemic left lungs consistently showed Masson bodies, inflammation, and young fibroblasts filling the distal airways and alveoli, consistent with BOOP. In quantitative evaluation of BOOP using epithelial changes, inflammation and fibrosis were higher in ischemic left lungs than right or sham-operated left lungs. Apoptosis was increased in areas exhibiting histological BOOP, but there was no histological evidence of necrosis. Toll-like receptor 4 expression was increased in ischemic left lungs over right. An occlusive slipknot around the main left pulmonary artery in rats produces BOOP, providing direct evidence that ischemia without immunomodulation or coinfection is sufficient to initiate this injury. It also affords an excellent model to study signaling and genetic mechanisms underlying BOOP. PMID:23364425

  7. TRP channels and traffic-related environmental pollution-induced pulmonary disease

    PubMed Central

    Akopian, Armen N.; Fanick, E. Robert

    2016-01-01

    Environmental pollutant exposures are major risk factors for adverse health outcomes, with increased morbidity and mortality in humans. Diesel exhaust (DE) is one of the major harmful components of traffic-related air pollution. Exposure to DE affects several physiological systems, including the airways, and pulmonary diseases are increased in highly populated urban areas. Hence, there are urgent needs to (1) create newer and lesser polluting fuels, (2) improve exhaust aftertreatments and reduce emissions, and (3) understand mechanisms of actions for toxic effects of both conventional and cleaner diesel fuels on the lungs. These steps could aid the development of diagnostics and interventions to prevent the negative impact of traffic-related air pollution on the pulmonary system. Exhaust from conventional, and to a lesser extent, clean fuels, contains particulate matter (PM) and more than 400 additional chemical constituents. The major toxic constituents are nitrogen oxides (NOx) and polycyclic aromatic hydrocarbons (PAHs). PM and PAHs could potentially act via transient receptor potential (TRP) channels. In this review, we will first discuss the associations between DE from conventional as well as clean fuel technologies and acute and chronic airway inflammation. We will then review possible activation and/or potentiation of TRP vanilloid type 1 (TRPV1) and ankyrin 1 (TRPA1) channels by PM and PAHs. Finally, we will discuss and summarize recent findings on the mechanisms whereby TRPs could control the link between DE and airway inflammation, which is a primary determinant leading to pulmonary disease. PMID:26837756

  8. TRP channels and traffic-related environmental pollution-induced pulmonary disease.

    PubMed

    Akopian, Armen N; Fanick, E Robert; Brooks, Edward G

    2016-05-01

    Environmental pollutant exposures are major risk factors for adverse health outcomes, with increased morbidity and mortality in humans. Diesel exhaust (DE) is one of the major harmful components of traffic-related air pollution. Exposure to DE affects several physiological systems, including the airways, and pulmonary diseases are increased in highly populated urban areas. Hence, there are urgent needs to (1) create newer and lesser polluting fuels, (2) improve exhaust aftertreatments and reduce emissions, and (3) understand mechanisms of actions for toxic effects of both conventional and cleaner diesel fuels on the lungs. These steps could aid the development of diagnostics and interventions to prevent the negative impact of traffic-related air pollution on the pulmonary system. Exhaust from conventional, and to a lesser extent, clean fuels, contains particulate matter (PM) and more than 400 additional chemical constituents. The major toxic constituents are nitrogen oxides (NOx) and polycyclic aromatic hydrocarbons (PAHs). PM and PAHs could potentially act via transient receptor potential (TRP) channels. In this review, we will first discuss the associations between DE from conventional as well as clean fuel technologies and acute and chronic airway inflammation. We will then review possible activation and/or potentiation of TRP vanilloid type 1 (TRPV1) and ankyrin 1 (TRPA1) channels by PM and PAHs. Finally, we will discuss and summarize recent findings on the mechanisms whereby TRPs could control the link between DE and airway inflammation, which is a primary determinant leading to pulmonary disease. PMID:26837756

  9. Amiodarone-induced pulmonary toxicity--a fatal case report and literature review.

    PubMed

    Range, Felix T; Hilker, Ekkehard; Breithardt, Günter; Buerke, Boris; Lebiedz, Pia

    2013-06-01

    Amiodarone is a widely used and very potent antiarrhythmic substance. Among its adverse effects, pulmonary toxicity is the most dangerous without a causal treatment option. Due to a very long half-life, accumulation can only be prevented by strict adherence to certain dosage patterns. In this review, we outline different safe and proven dosing schemes of amiodarone and compare the incidence and description of pulmonary toxicity. Reason for this is a case of fatal pulmonary toxicity due to a subacute iatrogenic overdosing of amiodarone in a 74-year-old male patient with known severe coronary artery disease, congestive heart failure and ectopic atrial tachycardia with reduced function of kidneys and liver but without preexisting lung disease. Within 30 days, the patient received 32.2 g of amiodarone instead of 15.6 g as planned. Despite early corticosteroid treatment after fast exclusion of all other differential diagnoses, the patient died another month later in our intensive care unit from respiratory failure due to bipulmonal pneumonitis. PMID:23397327

  10. Allergic pulmonary inflammation in mice is dependent on eosinophil-induced recruitment of effector T cells

    PubMed Central

    Jacobsen, Elizabeth A.; Ochkur, Sergei I.; Pero, Ralph S.; Taranova, Anna G.; Protheroe, Cheryl A.; Colbert, Dana C.; Lee, Nancy A.; Lee, James J.

    2008-01-01

    The current paradigm surrounding allergen-mediated T helper type 2 (Th2) immune responses in the lung suggests an almost hegemonic role for T cells. Our studies propose an alternative hypothesis implicating eosinophils in the regulation of pulmonary T cell responses. In particular, ovalbumin (OVA)-sensitized/challenged mice devoid of eosinophils (the transgenic line PHIL) have reduced airway levels of Th2 cytokines relative to the OVA-treated wild type that correlated with a reduced ability to recruit effector T cells to the lung. Adoptive transfer of Th2-polarized OVA-specific transgenic T cells (OT-II) alone into OVA-challenged PHIL recipient mice failed to restore Th2 cytokines, airway histopathologies, and, most importantly, the recruitment of pulmonary effector T cells. In contrast, the combined transfer of OT-II cells and eosinophils into PHIL mice resulted in the accumulation of effector T cells and a concomitant increase in both airway Th2 immune responses and histopathologies. Moreover, we show that eosinophils elicit the expression of the Th2 chemokines thymus- and activation-regulated chemokine/CCL17 and macrophage-derived chemokine/CCL22 in the lung after allergen challenge, and blockade of these chemokines inhibited the recruitment of effector T cells. In summary, the data suggest that pulmonary eosinophils are required for the localized recruitment of effector T cells. PMID:18316417

  11. p53 mediates cigarette smoke-induced apoptosis of pulmonary endothelial cells: inhibitory effects of macrophage migration inhibitor factor.

    PubMed

    Damico, Rachel; Simms, Tiffany; Kim, Bo S; Tekeste, Zenar; Amankwan, Henry; Damarla, Mahendra; Hassoun, Paul M

    2011-03-01

    Exposure to cigarette smoke (CS) is the most common cause of emphysema, a debilitating pulmonary disease histopathologically characterized by the irreversible destruction of lung architecture. Mounting evidence links enhanced endothelial apoptosis causally to the development of emphysema. However, the molecular determinants of human endothelial cell apoptosis and survival in response to CS are not fully defined. Such determinants could represent clinically relevant targets for intervention. We show here that CS extract (CSE) triggers the death of human pulmonary macrovascular endothelial cells (HPAECs) through a caspase 9-dependent apoptotic pathway. Exposure to CSE results in the increased expression of p53 in HPAECs. Using the p53 inhibitor, pifithrin-α (PFT-α), and RNA interference (RNAi) directed at p53, we demonstrate that p53 function and expression are required for CSE-mediated apoptosis. The expression of macrophage migration inhibitory factor (MIF), an antiapoptotic cytokine produced by HPAECs, also increases in response to CSE exposure. The addition of recombinant human MIF prevents cell death from exposure to CSE. Further, the suppression of MIF or its receptor/binding partner, Jun activation domain-binding protein 1 (Jab-1), with RNAi enhances the sensitivity of human pulmonary endothelial cells to CSE via a p53-dependent (PFT-α-inhibitable) pathway. Finally, we demonstrate that MIF is a negative regulator of p53 expression in response to CSE, placing MIF upstream of p53 as an antagonist of CSE-induced apoptosis. We conclude that MIF can protect human vascular endothelium from the toxic effects of CSE via the antagonism of p53-mediated apoptosis. PMID:20448056

  12. Experimental extrinsic allergic alveolitis and pulmonary angiitis induced by intratracheal or intravenous challenge with Corynebacterium parvum in sensitized rats.

    PubMed Central

    Yi, E. S.; Lee, H.; Suh, Y. K.; Tang, W.; Qi, M.; Yin, S.; Remick, D. G.; Ulich, T. R.

    1996-01-01

    Extrinsic allergic alveolitis and pulmonary sarcoidosis are granulomatous diseases of the lung for which clinical presentation and anatomic site of granuloma formation differ. Extrinsic allergic alveolitis is caused by inhaled antigens, whereas the nature and source of the inciting antigen in sarcoidosis is unknown. To test the hypothesis that the route via which antigen is introduced to the lung contributes to the clinicopathological presentation of pulmonary granulomatous disease, rats immunized with intravenous (i.v.) Corynebacterium parvum were challenged after 2 weeks with either intratracheal (i.t.) or i.v. C. parvum. The granulomatous inflammation elicited by i.t. challenge predominantly involved alveolar spaces and histologically simulated extrinsic allergic alveolitis. In contrast, the inflammation induced by i.v. challenge was characterized by granulomatous angiitis and interstitial inflammation simulating sarcoidosis. Elevations of leukocyte counts and TNF levels in bronchoalveolar fluid, which reflect inflammation in the intra-alveolar compartment, were much more pronounced after i.t. than after i.v. challenge. Tumor necrosis factor, interleukin-6, CC chemokine, CXC chemokine, and adhesion molecule mRNA and protein expression occurred in each model. In conclusion, i.t. or i.v. challenge with C. parvum in sensitized rats caused pulmonary granulomatous inflammation that was histologically similar to human extrinsic allergic alveolitis and sarcoidosis, respectively. Although the soluble and cellular mediators of granulomatous inflammation were qualitatively similar in both disease models, the differing anatomic source of the same antigenic challenge was responsible for differing clinicopathological presentations. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 11 Figure 13 Figure 12 Figure 14 PMID:8863677

  13. Effect of ultrafine carbon black particles on lipoteichoic acid-induced early pulmonary inflammation in BALB/c mice

    SciTech Connect

    Yamamoto, Shoji . E-mail: snyamamo@nies.go.jp; Tin-Tin-Win-Shwe; Ahmed, Sohel; Kobayashi, Takahiro; Fujimaki, Hidekazu

    2006-06-15

    We studied the interaction effects of a single intratracheal instillation of ultrafine carbon black (CB) particles and staphylococcal lipoteichoic acid (LTA) on early pulmonary inflammation in male BALB/c mice. We examined the cellular profile, cytokine and chemokine levels in the bronchoalveolar lavage (BAL) fluid, and expression of chemokine and toll-like receptor (TLR) mRNAs in lungs. LTA produced a dose-related increase in early pulmonary inflammation, which was characterized by (1) influx of polymorphonuclear neutrophils (PMNs) and (2) induction of interleukin (IL)-6, tumor necrosis factor (TNF)-{alpha}, macrophage inflammatory protein (MIP)-1{alpha}/CCL3, but no effect on monocyte chemoattractant protein (MCP)-1/CCL2 at 24 h after instillation. Levels of some proinflammatory indicators and TLR2-mRNA expression were significantly increased by 14 nm or 95 nm CB (125 {mu}g) and low-dose LTA (10 {mu}g) treatment compared to CB or LTA alone at 4 h after instillation. Notably, PMN levels and production of IL-6 and CCL2 in the 14 nm CB + LTA were significantly higher than that of 95 nm CB + LTA at 4 h after instillation. However, at 24 h after instillation, only PMN levels were significantly higher in the 14 nm CB + LTA than 95 nm CB + LTA but not the cytokines and chemokines. These data show additive as well as synergistic interaction effects of 14 nm or 95 nm ultrafine CB particles and LTA. We suggest that early pulmonary inflammatory responses in male BALB/c mice may be induced in a size-specific manner of the CB particles used in our study.

  14. Normal pulmonary gas exchange efficiency and absence of exercise-induced arterial hypoxemia in adults with bronchopulmonary dysplasia.

    PubMed

    Lovering, Andrew T; Laurie, Steven S; Elliott, Jonathan E; Beasley, Kara M; Yang, Ximeng; Gust, Caitlyn E; Mangum, Tyler S; Goodman, Randall D; Hawn, Jerold A; Gladstone, Igor M

    2013-10-01

    Cardiopulmonary function is reduced in adults born very preterm, but it is unknown if this results in reduced pulmonary gas exchange efficiency during exercise and, consequently, leads to reduced aerobic capacity in subjects with and without bronchopulmonary dysplasia (BPD). We hypothesized that an excessively large alveolar to arterial oxygen difference (AaDO2) and resulting exercise-induced arterial hypoxemia (EIAH) would contribute to reduced aerobic fitness in adults born very preterm with and without BPD. Measurements of pulmonary function, lung volumes and diffusion capacity for carbon monoxide (DLco) were made at rest. Measurements of maximal oxygen consumption, peak workload, temperature- and tonometry-corrected arterial blood gases, and direct measure of hemoglobin saturation with oxygen (SaO2) were made preexercise and during cycle ergometer exercise in ex-preterm subjects ≤32-wk gestational age, with BPD (n = 12), without BPD (PRE; n = 12), and full term controls (CONT; n = 12) breathing room air. Both BPD and PRE had reduced pulmonary function and reduced DLco compared with CONT. The AaDO2 was not significantly different between groups, and there was no evidence of EIAH (SaO2 < 95% and/or AaDO2 ≥ 40 Torr) in any subject group preexercise or at any workload. Arterial O2 content was not significantly different between the groups preexercise or during exercise. However, peak power output was decreased in BPD and PRE subjects compared with CONT. We conclude that EIAH in adult subjects born very preterm with and without BPD does not likely contribute to the reduction in aerobic exercise capacity observed in these subjects. PMID:23869070

  15. Caveolin-1 Deficiency Induces Spontaneous Endothelial-to-Mesenchymal Transition in Murine Pulmonary Endothelial Cells in Vitro

    PubMed Central

    Li, Zhaodong; Wermuth, Peter J.; Benn, Bryan S.; Lisanti, Michael P.; Jimenez, Sergio A.

    2014-01-01

    It was previously demonstrated that transforming growth factor β (TGF-β) induces endothelial-to-mesenchymal transition (EndoMT) in murine lung endothelial cells (ECs) in vitro. Owing to the important role of caveolin-1 (CAV1) in TGF-β receptor internalization and TGF-β signaling, the participation of CAV1 in the induction of EndoMT in murine lung ECs was investigated. Pulmonary ECs were isolated from wild-type and Cav1 knockout mice using immunomagnetic methods with sequential anti-CD31 and anti-CD102 antibody selection followed by in vitro culture and treatment with TGF-β1. EndoMT was assessed by semiquantitative RT-PCR for Acta2, Col1a1, Snai1, and Snai2; by immunofluorescence for α-smooth muscle actin; and by Western blot analysis for α-smooth muscle actin, SNAIL1, SNAIL2, and the α2 chain of type I collagen. The same studies were performed in Cav1−/− pulmonary ECs after restoration of functional CAV1 domains using a cell-permeable CAV1 scaffolding domain peptide. Pulmonary ECs from Cav1 knockout mice displayed high levels of spontaneous Acta2, Col1A, Snai1, and Snai2 expression, which increased after TGF-β treatment. Spontaneous and TGF-β1–stimulated EndoMT were abrogated by the restoration of functional CAV1 domains using a cell-permeable peptide. The findings suggest that CAV1 regulation of EndoMT may play a role in the development of fibroproliferative vasculopathies. PMID:23195429

  16. Use of bivalirudin for heparin-induced thrombocytopaenia after thrombolysis in massive pulmonary embolism: a case report

    PubMed Central

    Fasullo, Sergio; Scalzo, Sebastiano; Maringhini, Giorgio; Ganci, Filippo; Giubilato, Alfonso; Cannizzaro, Sergio; Baglini, Roberto; Cangemi, Debora; Terrazzino, Gabriella; Paterna, Salvatore

    2010-01-01

    A 68-year-old man was referred to the emergency department 6 h after onset of sudden acute dyspnoea. Immediate ECG showed sinus tachycardia with the typical S1-Q3-T3 pattern and incomplete right bundle branch block. The echocardiogram showed the presence of mobile thrombus in the right atrium, a distended right ventricle with free wall hypokinesia and displacement of the interventricular septum towards the left ventricle. Lung spiral computed tomography (CT) showed bilateral pulmonary involvement and confirmed the picture of a thrombotic system in the right atrium and caval vein. Thrombolytic treatment with recombinant tissue plasminogen activator (rt-PA) and heparin (alteplase 10 mg bolus, then 90 mg over 2 h) was administered. Six hours after thrombolysis bleeding gums and significant reduction in platelet count (around 50,000) were observed. Heparin was discontinued and bivalirudin (0.1 mg/kg bolus and 1.75 mg/kg per h infusion) plus warfarin was initiated and continued for 5 days until the international normalised ratio (INR) was within the therapeutic range (2.0–3.0) for 2 consecutive days, with concomitant platelet count normalisation. Lung spiral and lower abdominal CT before discharge did not show the presence of clots in the pulmonary arteries of the right and left lung. This case suggests that bivalirudin could offer promise for use in patients with heparin-induced thrombocytopaenia (HIT) after thrombolysis for massive pulmonary embolism. PMID:21031046

  17. Decreased creatine kinase is linked to diastolic dysfunction in rats with right heart failure induced by pulmonary artery hypertension

    PubMed Central

    Fowler, Ewan D.; Benoist, David; Drinkhill, Mark J.; Stones, Rachel; Helmes, Michiel; Wüst, Rob C.I.; Stienen, Ger J.M.; Steele, Derek S.; White, Ed

    2015-01-01

    Our objective was to investigate the role of creatine kinase in the contractile dysfunction of right ventricular failure caused by pulmonary artery hypertension. Pulmonary artery hypertension and right ventricular failure were induced in rats by monocrotaline and compared to saline-injected control animals. In vivo right ventricular diastolic pressure–volume relationships were measured in anesthetized animals; diastolic force–length relationships in single enzymatically dissociated myocytes and myocardial creatine kinase levels by Western blot. We observed diastolic dysfunction in right ventricular failure indicated by significantly steeper diastolic pressure–volume relationships in vivo and diastolic force–length relationships in single myocytes. There was a significant reduction in creatine kinase protein expression in failing right ventricle. Dysfunction also manifested as a shorter diastolic sarcomere length in failing myocytes. This was associated with a Ca2 +-independent mechanism that was sensitive to cross-bridge cycling inhibition. In saponin-skinned failing myocytes, addition of exogenous creatine kinase significantly lengthened sarcomeres, while in intact healthy myocytes, inhibition of creatine kinase significantly shortened sarcomeres. Creatine kinase inhibition also changed the relatively flat contraction amplitude–stimulation frequency relationship of healthy myocytes into a steeply negative, failing phenotype. Decreased creatine kinase expression leads to diastolic dysfunction. We propose that this is via local reduction in ATP:ADP ratio and thus to Ca2 +-independent force production and diastolic sarcomere shortening. Creatine kinase inhibition also mimics a definitive characteristic of heart failure, the inability to respond to increased demand. Novel therapies for pulmonary artery hypertension are needed. Our data suggest that cardiac energetics would be a potential ventricular therapeutic target. PMID:26116865

  18. Pentoxifylline inhibits pulmonary inflammation induced by infrarenal aorticcross-clamping dependent of adenosine receptor A2A

    PubMed Central

    Li, Hali; Tan, Gang; Tong, Liquan; Han, Peng; Zhang, Feng; Liu, Bing; Sun, Xueying

    2016-01-01

    Infrarenal aortic cross-clamping (IAC) is commonly used during infrarenal vascular operations. Prolonged IAC causes ischemia-reperfusion injury to local tissues, resulting in the release of inflammatory cytokines and acute lung injury (ALI). Pentoxifylline (PTX) is a clinically used drug for chronic occlusive arterial diseases and exerts protective effects against ALI induced by various factors in experimental models. In this study, we evaluated the protective effects of PTX in a rat model of IAC. Wistar rats underwent IAC for 2 h, followed by 4 h reperfusion. PTX alone, or in combination with ZM-241385 (an adenosine receptor A2A antagonist) or CGS-21680 (an A2A agonist), was pre-administered to rats 1 h prior to IAC, and the severity of lung injury and inflammation were examined. Administration of PTX significantly attenuated ALI induced by IAC, evidenced by reduced histological scores and wet lung contents, improved blood gas parameters, decreased cell counts and protein amounts in bronchoalveolar lavage fluids, and inhibition of MPO activity and ICAM-1 expression in lung tissues, and lower plasma levels of TNF-α, IL-6, IL-1β and soluble ICAM-1. ZM-241385 significantly abrogated, while CGS-21680 slightly enhanced, the effects of PTX in ameliorating ALI and inhibiting pulmonary inflammation. In exploration of the mechanisms, we found that PTX stimulated IL-10 production through the phosphorylation of STAT3, and A2A receptor participated in this regulation. The study indicates PTX plays a protective role in IAC-induced ALI in rats by inhibiting pulmonary inflammation through A2A signaling pathways. PMID:27347328

  19. Early Macrophage Recruitment and Alternative Activation Are Critical for the Later Development of Hypoxia-induced Pulmonary Hypertension

    PubMed Central

    Vergadi, Eleni; Chang, Mun Seog; Lee, Changjin; Liang, Olin; Liu, Xianlan; Fernandez-Gonzalez, Angeles; Mitsialis, S. Alex; Kourembanas, Stella

    2011-01-01

    Background Lung inflammation precedes the development of hypoxia-induced pulmonary hypertension (HPH); however its role in the pathogenesis of HPH is poorly understood. We sought to characterize the hypoxic inflammatory response and elucidate its role in the development of HPH. We also aimed to investigate the mechanisms by which heme oxygenase-1 (HO-1), an anti-inflammatory enzyme, is protective in HPH. Methods and Results We generated bitransgenic mice that overexpress human HO-1 under doxycycline (dox) control in an inducible, lung-specific manner. Hypoxic exposure of mice in the absence of dox resulted in early transient accumulation of monocytes/macrophages in the bronchoalveolar lavage. Alveolar macrophages acquired an alternatively activated phenotype (M2) in response to hypoxia, characterized by