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Sample records for detectable pulmonary inflammation

  1. Pulmonary magnetic resonance imaging is similar to chest tomography in detecting inflammation in patients with systemic sclerosis.

    PubMed

    Müller, Carolina de Souza; Warszawiak, Danny; Paiva, Eduardo Dos Santos; Escuissato, Dante Luiz

    2017-02-20

    Interstitial lung disease (ILD) and pulmonary arterial hypertension (PAH) are prevalent complications of systemic sclerosis (SS) and are currently the leading causes of death related to the disease. The accurate recognition of these conditions is therefore of utmost importance for patient management. A study was carried out with 24 SS patients being followed at the Rheumatology Department of the Hospital de Clínicas of Universidade Federal do Paraná (UFPR) and 14 healthy volunteers, with the objective of evaluating the usefulness of lung magnetic resonance imaging (MRI) when assessing ILD in SS patients. The results obtained with lung MRI were compared to those obtained by computed tomography (CT) of the chest, currently considered the examination of choice when investigating ILD in SS patients. The assessed population was predominantly composed of women with a mean age of 50 years, limited cutaneous SS, and a disease duration of approximately 7 years. In most cases, there was agreement between the findings on chest CT and lung MRI. Considering it is a radiation-free examination and capable of accurately identifying areas of lung tissue inflammatory involvement, lung MRI showed to be a useful examination, and further studies are needed to assess whether there is an advantage in using lung MRI instead of chest CT when assessing ILD activity in SS patients.

  2. Systemic inflammation in chronic obstructive pulmonary disease and lung cancer: common driver of pulmonary cachexia?

    PubMed

    Ceelen, Judith J M; Langen, Ramon C J; Schols, Annemie M W J

    2014-12-01

    In this article, a putative role of systemic inflammation as a driver of pulmonary cachexia induced by either chronic obstructive pulmonary disease or nonsmall cell lung cancer is reviewed. Gaps in current translational research approaches are discussed and alternative strategies are proposed to provide new insights. Activation of the ubiquitin proteasome system has generally been considered a cause of pulmonary cachexia, but current animal models lack specificity and evidence is lacking in nonsmall cell lung cancer and conflicting in chronic obstructive pulmonary disease patients. Recent studies have shown activation of the autophagy-lysosome pathway in both nonsmall cell lung cancer and chronic obstructive pulmonary disease. Myonuclear loss, as a consequence of increased apoptotic events in myofibers, has been suggested in cancer-cachexia-associated muscle atrophy. Plasma transfer on myotube cultures can be used to detect early inflammatory signals in patients and presence of atrophy-inducing activity within the circulation. Comparative clinical research between nonsmall cell lung cancer and chronic obstructive pulmonary disease in different disease stages is useful to unravel disease-specific versus common denominators of pulmonary cachexia.

  3. Physicochemical characteristics of nanomaterials that affect pulmonary inflammation

    PubMed Central

    2014-01-01

    The increasing manufacture and use of products based on nanotechnology raises concerns for both workers and consumers. Various studies report induction of pulmonary inflammation after inhalation exposure to nanoparticles, which can vary in aspects such as size, shape, charge, crystallinity, chemical composition, and dissolution rate. Each of these aspects can affect their toxicity, although it is largely unknown to what extent. The aim of the current review is to analyse published data on inhalation of nanoparticles to identify and evaluate the contribution of their physicochemical characteristics to the onset and development of pulmonary inflammation. Many physicochemical characteristics of nanoparticles affect their lung deposition, clearance, and pulmonary response that, in combination, ultimately determine whether pulmonary inflammation will occur and to what extent. Lung deposition is mainly determined by the physical properties of the aerosol (size, density, shape, hygroscopicity) in relation to airflow and the anatomy of the respiratory system, whereas clearance and translocation of nanoparticles are mainly determined by their geometry and surface characteristics. Besides size and chemical composition, other physicochemical characteristics influence the induction of pulmonary inflammation after inhalation. As some nanoparticles dissolve, they can release toxic ions that can damage the lung tissue, making dissolution rate an important characteristic that affects lung inflammation. Fibre-shaped materials are more toxic to the lungs compared to spherical shaped nanoparticles of the same chemical composition. In general, cationic nanoparticles are more cytotoxic than neutral or anionic nanoparticles. Finally, surface reactivity correlates well with observed pulmonary inflammation. With all these characteristics affecting different stages of the events leading to pulmonary inflammation, no unifying dose metric could be identified to describe pulmonary

  4. Carbon dioxide inhalation causes pulmonary inflammation.

    PubMed

    Abolhassani, Mohammad; Guais, Adeline; Chaumet-Riffaud, Philippe; Sasco, Annie J; Schwartz, Laurent

    2009-04-01

    The aim of this study was to assess whether one of the most common poisons of cellular respiration, i.e., carbon dioxide, is proinflammatory. CO(2) is naturally present in the atmosphere at the level of 0.038% and involved in numerous cellular biochemical reactions. We analyzed in vitro the inflammation response induced by exposure to CO(2) for 48 h (0-20% with a constant O(2) concentration of 21%). In vivo mice were submitted to increasing concentrations of CO(2) (0, 5, 10, and 15% with a constant O(2) concentration of 21%) for 1 h. The exposure to concentrations above 5% of CO(2) resulted in the increased transcription (RNase protection assay) and secretion (ELISA) of proinflammatory cytokines [macrophage inflammatory protein-1alpha (MIP-1alpha), MIP-1beta, MIP-2, IL-8, IL-6, monocyte chemoattractant protein-1, and regulated upon activation, normal T cell expressed, and, presumably, secreted (RANTES)] by epithelial cell lines HT-29 or A549 and primary pulmonary cells retrieved from the exposed mice. Lung inflammation was also demonstrated in vivo by mucin 5AC-enhanced production and airway hyperreactivity induction. This response was mostly mediated by the nuclear translocation of p65 NF-kappaB, itself a consequence of protein phosphatase 2A (PP2A) activation. Short inhibiting RNAs (siRNAs) targeted toward PP2Ac reversed the effect of carbon dioxide, i.e., disrupted the NF-kappaB activation and the proinflammatory cytokine secretion. In conclusion, this study strongly suggests that exposure to carbon dioxide may be more toxic than previously thought. This may be relevant for carcinogenic effects of combustion products.

  5. Persistent inactivation of macrophage cyclooxygenase-2 in mycobacterial pulmonary inflammation.

    PubMed

    Shinohara, Tsutomu; Pantuso, Traci; Shinohara, Shizuka; Kogiso, Mari; Myrvik, Quentin N; Henriksen, Ruth Ann; Shibata, Yoshimi

    2009-08-01

    The induction of cyclooxygenase-2 (COX-2) in tissue macrophages (MØ) increases prostaglandin E(2) (PGE(2)) release, potentially down-regulating granulomatous inflammation. In response to Mycobacteria, local MØ express COX-2, which is either nuclear envelope (NE)-associated or NE-dissociated. Persistent mycobacterial pulmonary inflammation is characterized by alveolar MØ expressing NE-dissociated (inactive) COX-2 without release of PGE(2). In this study, we examined COX-2 in alveolar MØ after intranasal exposure to heat-killed Mycobacterium bovis BCG (HK-BCG). After administration, whole lungs of C57Bl/6 mice were lavaged with saline; COX-2 expression and PGE(2) release by alveolar MØ and tumor necrosis factor (TNF)-alpha and nitric oxide levels in the lung lavage were monitored. Normal alveolar MØ had undetectable levels of COX-2 on Western blots. However, 1 day after intranasal administration, almost all alveolar MØ had phagocytosed HK-BCG and expressed NE-dissociated COX-2 without any increase in the release of PGE(2). At 28 days after intranasal administration, 68% of alveolar MØ still contained both BCG and the NE-dissociated form of COX-2. NE-associated (active) COX-2 was not observed in alveolar MØ. In contrast, 7 days after intraperitoneal injection of HK-BCG, peritoneal MØ containing HK-BCG were no longer detected. At 28 days after intranasal administration, TNF-alpha and nitrite levels in the lung lavage fluid were significantly higher than those in controls. Our results indicate that mycobacterial pulmonary inflammation is associated with suppressed PGE(2) production by alveolar MØ, with expression of COX-2 dissociated from the NE.

  6. [TLR-4 involvement in pyroptosis of mice with pulmonary inflammation infected by Actinobacillus pleuropneumoniae].

    PubMed

    Hu, Peipei; Huang, Fushen; Niu, Junchao; Tang, Zhaoshan

    2015-05-04

    Pyroptosis is a caspase-1 dependent programmed cell death and involves pathogenesis of infectious diseases by releasing many pro-inflammatory cytokines to induced inflammation. TLR-4 plays an important role in mediating pathogenesis of some infectious diseases. In this study, we detected the expression of TLR-4 and some molecules (e. g caspase-1, TNF-α, IL-1β, IL-6, IL-18 ) related with pyroptosis to determine its involvement and mechanisms of pulmonary inflammation in mice infected by A. pleuropneumoniae. Mice were intranasally infected by A. pleuropneumoniae and killed 48 hours post infection. Pulmonary gross lesion and histological pathology by H-E were observed. Expression levels of caspase-1 , caspase-3, TNF-α, IL-1β, IL-6, IL-18, and TLR-4 in lung of mice were detected by RT-PCR and qPCR. Serious pulmonary hemorrhage and inflammation in infected mice were observed. Expression levels of caspase-1, caspase-3, TNF-α, IL-1β, IL-6, IL-18 and TLR-4 increased, and expression levels of caspase-3 were not changed in lung of infected mice. TLR-4 might be involved in pulmonary inflammation of mice infected by A. pleuropneumoniae. After induced by activated TLR-4 some cells in this lesion expressed pro-inflammatory cytokines. These cytokines would induce pulmonary inflammation. This lesion might involve pyroptosis with caspase-1 expression.

  7. H2S inhibits pulmonary arterial endothelial cell inflammation in rats with monocrotaline-induced pulmonary hypertension.

    PubMed

    Feng, Shasha; Chen, Siyao; Yu, Wen; Zhang, Da; Zhang, Chunyu; Tang, Chaoshu; Du, Junbao; Jin, Hongfang

    2017-03-01

    This study aimed to determine whether hydrogen sulfide (H2S) inhibits pulmonary arterial endothelial inflammation in rats with monocrotaline (MCT)-induced pulmonary hypertension and its possible mechanisms. Twenty-four male Wistar rats were divided randomly into control, MCT, and MCT+H2S treatment groups. Human pulmonary arterial endothelial cells (HPAEC) were cultured and divided into four groups: control, MCT, MCT+H2S, and H2S. Pulmonary artery pressure was determined using a right cardiac catheterization procedure 3 weeks after MCT administration. Pulmonary vascular morphological changes and inflammatory infiltration were measured. Endogenous H2S levels, cystathionine-γ-lyase (CSE) expression, and inflammatory cytokines were determined both in vivo and in vitro. In addition, phosphorylation of NF-κB p65 and IκBα was detected by western blotting, and NF-κB p65 nuclear translocation, as well as its DNA-binding activity, was determined. Pulmonary hypertension and vascular remolding developed 3 wks after MCT administration, with elevated lung tissue inflammatory infiltration and cytokine level associated with activation of the NF-κB pathway, both in vivo and in vitro. However, the endogenous H2S/CSE pathway was downregulated in MCT rats. By contrast, an H2S donor markedly reduced pulmonary artery pressure, pulmonary vascular structural remolding, and increased lung inflammatory infiltration and cytokine levels of MCT-treated rats. Meanwhile, H2S reversed the activation of the NF-κB pathway successfully. The downregulated pulmonary arterial endothelial H2S/CSE pathway is involved in the pulmonary inflammatory response in MCT-treated pulmonary hypertensive rats. H2S attenuated endothelial inflammation by inhibiting the NF-κB pathway.

  8. [Measurement of pulmonary inflammation in cystic fibrosis].

    PubMed

    Fayon, M; Chiron, R; Abely, M

    2008-06-01

    Lung inflammation is a pivotal phenomenon in the pathogenesis of cystic fibrosis. Inflammation can be measured and quantified within a research perspective, as well as in daily clinical practice. In this review paper, the "Inflammation Task Force" of the "Société Française de Mucoviscidose" has reviewed the literature regarding the various techniques currently available (bronchoalveolar lavage, sputum analysis, nasal wash and brushing, exhaled breath condensates, carbon monoxide and nitric oxide, and systemic measurements (plasma and urine)). The interpretation of all these determinations in children and adults is also discussed.

  9. Inflammation and repair processes in chronic obstructive pulmonary disease.

    PubMed

    Rennard, S I

    1999-11-01

    COPD is characterized by chronic inflammation and injury of both the airways and the parenchymal structures of the lung. These processes are associated with ongoing repair. Whether repair leads to restoration of normal tissue architecture or to altered tissue structure with loss of function depends on complex interrelationships of a variety of interacting mediators. The possibility that repair processes can be modulated by exogenous agents raises the possibility that therapeutic strategies aimed at repair can be effective. Such strategies offer tremendous promise both for slowing the relentlessly progressive natural history which most often characterizes COPD and, possibly, for restoring lung function. Rennard SI. Inflammation and repair processes in chronic obstructive pulmonary disease.

  10. Multi-walled carbon nanotube physicochemical properties predict pulmonary inflammation and genotoxicity

    PubMed Central

    Poulsen, Sarah S.; Jackson, Petra; Kling, Kirsten; Knudsen, Kristina B.; Skaug, Vidar; Kyjovska, Zdenka O.; Thomsen, Birthe L.; Clausen, Per Axel; Atluri, Rambabu; Berthing, Trine; Bengtson, Stefan; Wolff, Henrik; Jensen, Keld A.; Wallin, Håkan; Vogel, Ulla

    2016-01-01

    Abstract Lung deposition of multi-walled carbon nanotubes (MWCNT) induces pulmonary toxicity. Commercial MWCNT vary greatly in physicochemical properties and consequently in biological effects. To identify determinants of MWCNT-induced toxicity, we analyzed the effects of pulmonary exposure to 10 commercial MWCNT (supplied in three groups of different dimensions, with one pristine and two/three surface modified in each group). We characterized morphology, chemical composition, surface area and functionalization levels. MWCNT were deposited in lungs of female C57BL/6J mice by intratracheal instillation of 0, 6, 18 or 54 μg/mouse. Pulmonary inflammation (neutrophil influx in bronchoalveolar lavage (BAL)) and genotoxicity were determined on day 1, 28 or 92. Histopathology of the lungs was performed on day 28 and 92. All MWCNT induced similar histological changes. Lymphocytic aggregates were detected for all MWCNT on day 28 and 92. Using adjusted, multiple regression analyses, inflammation and genotoxicity were related to dose, time and physicochemical properties. The specific surface area (BET) was identified as a positive predictor of pulmonary inflammation on all post-exposure days. In addition, length significantly predicted pulmonary inflammation, whereas surface oxidation (–OH and –COOH) was predictor of lowered inflammation on day 28. BET surface area, and therefore diameter, significantly predicted genotoxicity in BAL fluid cells and lung tissue such that lower BET surface area or correspondingly larger diameter was associated with increased genotoxicity. This study provides information on possible toxicity-driving physicochemical properties of MWCNT. The results may contribute to safe-by-design manufacturing of MWCNT, thereby minimizing adverse effects. PMID:27323647

  11. Distal airway dysfunction identifies pulmonary inflammation in asymptomatic smokers.

    PubMed

    Berger, Kenneth I; Pradhan, Deepak R; Goldring, Roberta M; Oppenheimer, Beno W; Rom, William N; Segal, Leopoldo N

    2016-10-01

    Smoking induced inflammation leads to distal airway destruction. However, the relationship between distal airway dysfunction and inflammation remains unclear, particularly in smokers prior to the development of airway obstruction. Seven normal controls and 16 smokers without chronic obstructive pulmonary disease (COPD) were studied. Respiratory function was assessed using the forced oscillation technique (FOT). Abnormal FOT was defined as elevated resistance at 5 Hz (R5). Parameters reflecting distal lung function included frequency dependence of resistance (R5-20) and dynamic elastance (X5). Inflammation was quantified in concentrated bronchoalveolar lavage utilising cell count differential and cytokines expressed as concentration per mL epithelial lining fluid. All control subjects and seven smokers had normal R5. Nine smokers had elevated R5 with abnormal R5-20 and X5, indicating distal lung dysfunction. The presence of abnormal FOT was associated with two-fold higher lymphocyte and neutrophil counts (p<0.025) and with higher interleukin (IL)-8, eotaxin and fractalkine levels (p<0.01). Reactivity of R5-20 and X5 correlated with levels of IL-8, eotaxin, fractalkine, IL-12p70 and transforming growth factor-α (r>0.47, p<0.01). Distal airway dysfunction in smokers without COPD identifies the presence of distal lung inflammation that parallel reported observations in established COPD. These findings were not evident on routine pulmonary function testing and may allow the identification of smokers at risk of progression to COPD.

  12. Distal airway dysfunction identifies pulmonary inflammation in asymptomatic smokers

    PubMed Central

    Berger, Kenneth I.; Pradhan, Deepak R.; Goldring, Roberta M.; Oppenheimer, Beno W.; Rom, William N.

    2016-01-01

    Smoking induced inflammation leads to distal airway destruction. However, the relationship between distal airway dysfunction and inflammation remains unclear, particularly in smokers prior to the development of airway obstruction. Seven normal controls and 16 smokers without chronic obstructive pulmonary disease (COPD) were studied. Respiratory function was assessed using the forced oscillation technique (FOT). Abnormal FOT was defined as elevated resistance at 5 Hz (R5). Parameters reflecting distal lung function included frequency dependence of resistance (R5–20) and dynamic elastance (X5). Inflammation was quantified in concentrated bronchoalveolar lavage utilising cell count differential and cytokines expressed as concentration per mL epithelial lining fluid. All control subjects and seven smokers had normal R5. Nine smokers had elevated R5 with abnormal R5–20 and X5, indicating distal lung dysfunction. The presence of abnormal FOT was associated with two-fold higher lymphocyte and neutrophil counts (p<0.025) and with higher interleukin (IL)-8, eotaxin and fractalkine levels (p<0.01). Reactivity of R5–20 and X5 correlated with levels of IL-8, eotaxin, fractalkine, IL-12p70 and transforming growth factor-α (r>0.47, p<0.01). Distal airway dysfunction in smokers without COPD identifies the presence of distal lung inflammation that parallel reported observations in established COPD. These findings were not evident on routine pulmonary function testing and may allow the identification of smokers at risk of progression to COPD. PMID:27995132

  13. Interleukin-23-Mediated Inflammation in Pseudomonas aeruginosa Pulmonary Infection

    PubMed Central

    Martz, Ashley; Eisenstatt, Jessica R.; Fox, Michael D.; Logar, Alison; Kolls, Jay K.

    2012-01-01

    Pseudomonas aeruginosa is an opportunistic pathogen that is capable of causing acute and chronic pulmonary infection in the immunocompromised host. In the case of cystic fibrosis (CF), chronic P. aeruginosa infection causes increased mortality by promoting overly exuberant airway inflammation and cumulative lung damage. Identifying the key regulators of this inflammation may lead to the development of new therapies that improve P. aeruginosa-related mortality. We report here that interleukin-23 (IL-23), the cytokine most clearly tied to IL-17-mediated inflammation, also promotes IL-17-independent inflammation during P. aeruginosa pulmonary infection. During the early innate immune response, prior to IL-17 induction, IL-23 acts synergistically with IL-1β to promote early neutrophil (polymorphonuclear leukocyte [PMN]) recruitment. However, at later time points, IL-23 also promoted IL-17 production by lung γδ T cells, which was greatly augmented in the presence of IL-1β. These studies show that IL-23 controls two independent phases of neutrophil recruitment in response to P. aeruginosa infection: early PMN emigration that is IL-17 independent and later PMN emigration regulated by IL-17. PMID:22025517

  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. Chronic Thromboembolic Pulmonary Hypertension Associated with Chronic Inflammation.

    PubMed

    Kuse, Naoyuki; Abe, Shinji; Kuribayashi, Hidehiko; Fukuda, Asami; Kusunoki, Yuji; Narato, Ritsuko; Saito, Hitoshi; Gemma, Akihiko

    2016-01-01

    Chronic thromboembolic pulmonary hypertension (CTEPH) is one of the leading causes of severe pulmonary hypertension. According to previously reported studies in the pertinent literature, chronic inflammatory conditions may be implicated in the development of CTEPH. We herein describe the case of a 56-year-old woman who was diagnosed with CTEPH in association with chronic infection. The patient had experienced five episodes of pneumonia in the five years prior to the diagnosis of CTEPH. Blood tests from the previous five years of outpatient follow-up demonstrated that the C-reactive protein level was slightly elevated. This case suggests that a relationship exists between chronic inflammation and CTEPH, and furthermore, may contribute towards elucidating the pathophysiology of CTEPH.

  16. Pulmonary Inflammation Disrupts Surfactant Function during Pneumocystis carinii Pneumonia

    PubMed Central

    Wright, Terry W.; Notter, Robert H.; Wang, Zhengdong; Harmsen, Allen G.; Gigliotti, Francis

    2001-01-01

    During Pneumocystis carinii pneumonia (PCP) in mice, the degree of pulmonary inflammation correlates directly with the severity of lung function deficits. Therefore, studies were undertaken to determine whether the host inflammatory response contributes to PCP-related respiratory impairment, at least in part, by disrupting the pulmonary surfactant system. Protein and phospholipid content and surfactant activity were measured in the lavage fluid of infected mice in either the absence or presence of an inflammatory response. At 9 weeks postinfection with P. carinii, nonreconstituted SCID mice exhibited no signs of pulmonary inflammation, respiratory impairment, or surfactant dysfunction. Lavage fluid obtained from these mice had protein/phospholipid (Pr/PL) ratios (64% ± 4.7%) and minimum surface tension values (4.0 ± 0.9 mN/m) similar to those of P. carinii-free control mice. However, when infected SCID mice were immunologically reconstituted, an intense inflammatory response ensued. Pr/PL ratios (218% ± 42%) and minimum surface tension values (27.2 ± 2.7 mN/m) of the lavage fluid were significantly elevated compared to those of the lavage fluid from infected, nonreconstituted mice (P < 0.05). To examine the specific role of CD8+ T-cell-mediated inflammation in surfactant dysfunction during PCP, mice with defined T-cell populations were studied. P. carinii-infected, CD4+-depleted mice had elevated lavage fluid Pr/PL ratios (126% ± 20%) and elevated minimum surface tension values (16.3 ± 1.0 mN/m) compared to normal mice (P < 0.05). However, when infected mice were additionally depleted of CD8+ cells, Pr/PL ratios were normal and surfactant activity was improved. These findings demonstrate that the surfactant pathology associated with PCP is related to the inflammatory process rather than being a direct effect of P. carinii. Moreover, CD8+ lymphocytes are involved in the mechanism leading to surfactant dysfunction. PMID:11159965

  17. Systemic inflammation after inspiratory loading in chronic obstructive pulmonary disease

    PubMed Central

    Fuster, Antonia; Sauleda, Jaume; Sala, Ernest; Barceló, Bernardí; Pons, Jaume; Carrera, Miguel; Noguera, Aina; Togores, Bernat; Agustí, Alvar GN

    2008-01-01

    Objective Patients with chronic obstructive pulmonary disease (COPD) present systemic inflammation. Strenuous resistive breathing induces systemic inflammation in healthy subjects. We hypothesized that the increased respiratory load that characterizes COPD can contribute to systemic inflammation in these patients. Patients and methods To test this hypothesis, we compared leukocyte numbers and levels of circulating cytokines (tumor necrosis factor alpha [TNFα], interleukin-1β [IL-1β], IL-6, IL-8, and IL-10), before and 1 hour after maximal incremental inspiratory loading in 13 patients with stable COPD (forced expiratory volume in one second [FEV1] 29 ± 2.5% ref) and in 8 healthy sedentary subjects (FEV1 98 ± 5% ref). Results We found that: (1) at baseline, patients with COPD showed higher leukocyte counts and IL-8 levels than controls (p < 0.01); and, (2) one hour after maximal inspiratory loading these values were unchanged, except for IL-10, which increased in controls (p < 0.05) but not in patients with COPD. Conclusions This study confirms the presence of systemic inflammation in COPD, shows that maximal inspiratory loading does not increase the levels of pro-inflammatory cytokines (IL-1β, IL-8) in COPD patients or controls, but suggests that the former may be unable to mount an appropriate systemic anti-inflammatory response to exercise. PMID:18488438

  18. 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.

  19. CFTR-regulated MAPK/NF-κB signaling in pulmonary inflammation in thermal inhalation injury

    PubMed Central

    Dong, Zhi Wei; Chen, Jing; Ruan, Ye Chun; Zhou, Tao; Chen, Yu; Chen, YaJie; Tsang, Lai Ling; Chan, Hsiao Chang; Peng, Yi Zhi

    2015-01-01

    The mechanism underlying pulmonary inflammation in thermal inhalation injury remains elusive. Cystic fibrosis, also hallmarked with pulmonary inflammation, is caused by mutations in CFTR, the expression of which is temperature-sensitive. We investigated whether CFTR is involved in heat-induced pulmonary inflammation. We applied heat-treatment in 16HBE14o- cells with CFTR knockdown or overexpression and heat-inhalation in rats in vivo. Heat-treatment caused significant reduction in CFTR and, reciprocally, increase in COX-2 at early stages both in vitro and in vivo. Activation of ERK/JNK, NF-κB and COX-2/PGE2 were detected in heat-treated cells, which were mimicked by knockdown, and reversed by overexpression of CFTR or VX-809, a reported CFTR mutation corrector. JNK/ERK inhibition reversed heat-/CFTR-knockdown-induced NF-κB activation, whereas NF-κB inhibitor showed no effect on JNK/ERK. IL-8 was augmented by heat-treatment or CFTR-knockdown, which was abolished by inhibition of NF-κB, JNK/ERK or COX-2. Moreover, in vitro or in vivo treatment with curcumin, a natural phenolic compound, significantly enhanced CFTR expression and reversed the heat-induced increases in COX-2/PGE2/IL-8, neutrophil infiltration and tissue damage in the airway. These results have revealed a CFTR-regulated MAPK/NF-κB pathway leading to COX-2/PGE2/IL-8 activation in thermal inhalation injury, and demonstrated therapeutic potential of curcumin for alleviating heat-induced pulmonary inflammation. PMID:26515683

  20. Inhalation of Respirable Crystalline Rifapentine Particles Induces Pulmonary Inflammation.

    PubMed

    Parumasivam, Thaigarajan; Ashhurst, Anneliese S; Nagalingam, Gayathri; Britton, Warwick J; Chan, Hak-Kim

    2017-01-03

    Rifapentine is an anti-tuberculosis (anti-TB) drug with a prolonged half-life, but oral delivery results in low concentrations in the lungs because of its high binding (98%) to plasma proteins. We have shown that inhalation of crystalline rifapentine overcomes the limitations of oral delivery by significantly enhancing and prolonging the drug concentration in the lungs. The delivery of crystalline particles to the lungs may promote inflammation. This in vivo study characterizes the inflammatory response caused by pulmonary deposition of the rifapentine particles. The rifapentine powder was delivered to BALB/c mice by intratracheal insufflation at a dose of 20 mg/kg. The inflammatory response in the lungs and bronchoalveolar lavage (BAL) was examined at 12 h, 24 h, and 7 days post-treatment by flow cytometry and histopathology. At 12 and 24 h post-treatment, there was a significant influx of neutrophils into the lungs, and this returned to normal by day 7. A significant recruitment of macrophages occurred in the BAL at 24 h. Consistent with these findings, histopathological analysis demonstrated pulmonary vascular congestion and significant macrophage recruitment at 12 and 24 h post-treatment. In conclusion, the pulmonary delivery of crystalline rifapentine caused a transient neutrophil-associated inflammatory response in the lungs that resolved over 7 days. This observation may limit pulmonary delivery of rifapentine to once a week at a dose of 20 mg/kg or less. The effectiveness of weekly dosing with inhalable rifapentine will be assessed in murine Mycobacterium tuberculosis infection.

  1. Immune Inflammation and Disease Progression in Idiopathic Pulmonary Fibrosis

    PubMed Central

    Balestro, Elisabetta; Calabrese, Fiorella; Turato, Graziella; Lunardi, Francesca; Bazzan, Erica; Marulli, Giuseppe; Biondini, Davide; Rossi, Emanuela; Sanduzzi, Alessandro; Rea, Federico; Rigobello, Chiara; Gregori, Dario; Baraldo, Simonetta; Spagnolo, Paolo

    2016-01-01

    The clinical course in idiopathic pulmonary fibrosis (IPF) is highly heterogeneous, with some patients having a slow progression and others an accelerated clinical and functional decline. This study aims to clinically characterize the type of progression in IPF and to investigate the pathological basis that might account for the observed differences in disease behavior. Clinical and functional data were analyzed in 73 IPF patients, followed long-time as candidates for lung transplantation. The forced vital capacity (FVC) change/year (< or ≥10% predicted) was used to define “slow” or “rapid” disease progression. Pathological abnormalities were quantified in the explanted lung of 41 out of 73 patients undergoing lung transplantation. At diagnosis, slow progressors (n = 48) showed longer duration of symptoms and lower FVC than rapid progressors (n = 25). Eleven slow and 3 rapid progressors developed an acute exacerbation (AE) during follow-up. Quantitative lung pathology showed a severe innate and adaptive inflammatory infiltrate in rapid progressors, markedly increased compared to slow progressors and similar to that observed in patients experiencing AE. The extent of inflammation was correlated with the yearly FVC decline (r = 0.52, p = 0.005). In conclusion an innate and adaptive inflammation appears to be a prominent feature in the lung of patients with IPF and could contribute to determining of the rate of disease progression. PMID:27159038

  2. Mycoplasma pneumoniae CARDS Toxin Induces Pulmonary Eosinophilic and Lymphocytic Inflammation

    PubMed Central

    Medina, Jorge L.; Coalson, Jacqueline J.; Brooks, Edward G.; Winter, Vicki T.; Chaparro, Adriana; Principe, Molly F. R.; Kannan, Thirumalai R.; Baseman, Joel B.

    2012-01-01

    Mycoplasma pneumoniae causes acute and chronic lung infections in humans, leading to a variety of pulmonary and extrapulmonary sequelae. Of the airway complications of M. pneumoniae infection, M. pneumoniae–associated exacerbation of asthma and pediatric wheezing are emerging as significant sources of human morbidity. However, M. pneumoniae products capable of promoting allergic inflammation are unknown. Recently, we reported that M. pneumoniae produces an ADP-ribosylating and vacuolating toxin termed the community-acquired respiratory distress syndrome (CARDS) toxin. Here we report that naive mice exposed to a single dose of recombinant CARDS (rCARDS) toxin respond with a robust inflammatory response consistent with allergic disease. rCARDS toxin induced 30-fold increased expression of the Th-2 cytokines IL-4 and IL-13 and 70- to 80-fold increased expression of the Th-2 chemokines CCL17 and CCL22, corresponding to a mixed cellular inflammatory response comprised of a robust eosinophilia, accumulation of T cells and B cells, and mucus metaplasia. The inflammatory responses correlate temporally with toxin-dependent increases in airway hyperreactivity characterized by increases in airway restriction and decreases in lung compliance. Furthermore, CARDS toxin–mediated changes in lung function and histopathology are dependent on CD4+ T cells. Altogether, the data suggest that rCARDS toxin is capable of inducing allergic-type inflammation in naive animals and may represent a causal factor in M. pneumoniae–associated asthma. PMID:22281984

  3. Inhalation of Carbon Black Nanoparticles Aggravates Pulmonary Inflammation in Mice

    PubMed Central

    Saputra, Devina; Yoon, Jin-ha; Park, Hyunju; Heo, Yongju; Yang, Hyoseon; Lee, Eun Ji; Lee, Sangjin; Song, Chang-Woo; Lee, Kyuhong

    2014-01-01

    An increasing number of recent studies have focused on the impact of particulate matter on human health. As a model for atmospheric particulate inhalation, we investigated the effects of inhaled carbon black nanoparticles (CBNP) on mice with bleomycin-induced pulmonary fibrosis. The CNBPs were generated by a novel aerosolization process, and the mice were exposed to the aerosol for 4 hours. We found that CBNP inhalation exacerbated lung inflammation, as evidenced by histopathology analysis and by the expression levels of interleukin-6 protein, fibronectin, and interferon-γ mRNAs in lung tissues. Notably, fibronectin mRNA expression showed a statistically significant increase in expression after CBNP exposure. These data suggest that the concentration of CBNPs delivered (calculated to be 12.5 μg/m3) can aggravate lung inflammation in mice. Our results also suggest that the inhalation of ultrafine particles like PM 2.5 is an impactful environmental risk factor for humans, particularly in susceptible populations with predisposing lung conditions. PMID:25071917

  4. Immune Inflammation and Disease Progression in Idiopathic Pulmonary Fibrosis.

    PubMed

    Balestro, Elisabetta; Calabrese, Fiorella; Turato, Graziella; Lunardi, Francesca; Bazzan, Erica; Marulli, Giuseppe; Biondini, Davide; Rossi, Emanuela; Sanduzzi, Alessandro; Rea, Federico; Rigobello, Chiara; Gregori, Dario; Baraldo, Simonetta; Spagnolo, Paolo; Cosio, Manuel G; Saetta, Marina

    2016-01-01

    The clinical course in idiopathic pulmonary fibrosis (IPF) is highly heterogeneous, with some patients having a slow progression and others an accelerated clinical and functional decline. This study aims to clinically characterize the type of progression in IPF and to investigate the pathological basis that might account for the observed differences in disease behavior. Clinical and functional data were analyzed in 73 IPF patients, followed long-time as candidates for lung transplantation. The forced vital capacity (FVC) change/year (< or ≥10% predicted) was used to define "slow" or "rapid" disease progression. Pathological abnormalities were quantified in the explanted lung of 41 out of 73 patients undergoing lung transplantation. At diagnosis, slow progressors (n = 48) showed longer duration of symptoms and lower FVC than rapid progressors (n = 25). Eleven slow and 3 rapid progressors developed an acute exacerbation (AE) during follow-up. Quantitative lung pathology showed a severe innate and adaptive inflammatory infiltrate in rapid progressors, markedly increased compared to slow progressors and similar to that observed in patients experiencing AE. The extent of inflammation was correlated with the yearly FVC decline (r = 0.52, p = 0.005). In conclusion an innate and adaptive inflammation appears to be a prominent feature in the lung of patients with IPF and could contribute to determining of the rate of disease progression.

  5. Establishment of a mouse model for pulmonary inflammation and fibrosis by intratracheal instillation of polyhexamethyleneguanidine phosphate.

    PubMed

    Lee, Sang Jin; Park, Jong-Hwan; Lee, Jun-Young; Jeong, Yu-Jin; Song, Jeong Ah; Lee, Kyuhong; Kim, Dong-Jae

    2016-04-01

    Although several animal models have been developed to study human pulmonary fibrosis, lack of a perfect model has raised the need for various animal models of pulmonary fibrosis. In this study, we evaluated the pulmonary effect of polyhexamethyleneguanidine phosphate instillation into the lungs of mice to determine the potential of these mice as a murine model of pulmonary fibrosis. Intratracheal instillation of polyhexamethyleneguanidine phosphate induced severe lung inflammation manifested by the infiltration of mononuclear cells and neutrophils and increased production of IL-6, TNF-α, CCL2 and CXCL1. The lung inflammation gradually increased until 28 days after polyhexamethyleneguanidine phosphate exposure, and increases of collagen deposition and TGF-β production, which are indicators of pulmonary fibrosis, were seen. Our study showed that intratracheal instillation of polyhexamethyleneguanidine phosphate induces pulmonary inflammation and fibrosis in mice.

  6. Establishment of a mouse model for pulmonary inflammation and fibrosis by intratracheal instillation of polyhexamethyleneguanidine phosphate

    PubMed Central

    Lee, Sang Jin; Park, Jong-Hwan; Lee, Jun-Young; Jeong, Yu-Jin; Song, Jeong Ah; Lee, Kyuhong; Kim, Dong-Jae

    2016-01-01

    Although several animal models have been developed to study human pulmonary fibrosis, lack of a perfect model has raised the need for various animal models of pulmonary fibrosis. In this study, we evaluated the pulmonary effect of polyhexamethyleneguanidine phosphate instillation into the lungs of mice to determine the potential of these mice as a murine model of pulmonary fibrosis. Intratracheal instillation of polyhexamethyleneguanidine phosphate induced severe lung inflammation manifested by the infiltration of mononuclear cells and neutrophils and increased production of IL-6, TNF-α, CCL2 and CXCL1. The lung inflammation gradually increased until 28 days after polyhexamethyleneguanidine phosphate exposure, and increases of collagen deposition and TGF-β production, which are indicators of pulmonary fibrosis, were seen. Our study showed that intratracheal instillation of polyhexamethyleneguanidine phosphate induces pulmonary inflammation and fibrosis in mice. PMID:27182113

  7. Role of A2B adenosine receptor signaling in adenosine-dependent pulmonary inflammation and injury

    PubMed Central

    Sun, Chun-Xiao; Zhong, Hongyan; Mohsenin, Amir; Morschl, Eva; Chunn, Janci L.; Molina, Jose G.; Belardinelli, Luiz; Zeng, Dewan; Blackburn, Michael R.

    2006-01-01

    Adenosine has been implicated in the pathogenesis of chronic lung diseases such as asthma and chronic obstructive pulmonary disease. In vitro studies suggest that activation of the A2B adenosine receptor (A2BAR) results in proinflammatory and profibrotic effects relevant to the progression of lung diseases; however, in vivo data supporting these observations are lacking. Adenosine deaminase–deficient (ADA-deficient) mice develop pulmonary inflammation and injury that are dependent on increased lung adenosine levels. To investigate the role of the A2BAR in vivo, ADA-deficient mice were treated with the selective A2BAR antagonist CVT-6883, and pulmonary inflammation, fibrosis, and airspace integrity were assessed. Untreated and vehicle-treated ADA-deficient mice developed pulmonary inflammation, fibrosis, and enlargement of alveolar airspaces; conversely, CVT-6883–treated ADA-deficient mice showed less pulmonary inflammation, fibrosis, and alveolar airspace enlargement. A2BAR antagonism significantly reduced elevations in proinflammatory cytokines and chemokines as well as mediators of fibrosis and airway destruction. In addition, treatment with CVT-6883 attenuated pulmonary inflammation and fibrosis in wild-type mice subjected to bleomycin-induced lung injury. These findings suggest that A2BAR signaling influences pathways critical for pulmonary inflammation and injury in vivo. Thus in chronic lung diseases associated with increased adenosine, antagonism of A2BAR-mediated responses may prove to be a beneficial therapy. PMID:16841096

  8. Familial idiopathic pulmonary fibrosis. Evidence of lung inflammation in unaffected family members

    SciTech Connect

    Bitterman, P.B.; Rennard, S.I.; Keogh, B.A.; Wewers, M.D.; Adelberg, S.; Crystal, R.G.

    1986-05-22

    We evaluated 17 clinically unaffected members of three families with an autosomal dominant form of idiopathic pulmonary fibrosis for evidence of alveolar inflammation. Each person in the study was examined by gallium-67 scanning for a general estimate of pulmonary inflammation, and by bronchoalveolar lavage for characterization of the types of recovered cells and their state of activation. Eight of the 17 subjects had evidence of alveolar inflammation on the lavage studies. Supporting data included increased numbers of neutrophils and activated macrophages that released one or more neutrophil chemoattractants, and growth factors for lung fibroblasts--findings similar to those observed in patients with overt idiopathic pulmonary fibrosis. Four of these eight also had a positive gallium scan; in all the other clinically unaffected subjects the scan was normal. During a follow-up of two to four years in seven of the eight subjects who had evidence of inflammation, no clinical evidence of pulmonary fibrosis has appeared. These results indicate that alveolar inflammation occurs in approximately half the clinically unaffected family members at risk of inheriting autosomal dominant idiopathic pulmonary fibrosis. Whether these persons with evidence of pulmonary inflammation but no fibrosis will proceed to have clinically evident pulmonary fibrosis is not yet known.

  9. 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...

  10. Pulmonary oxidative stress, inflammation and dysregulated iron homeostatis in rat models of cardiovascular disease

    EPA Science Inventory

    Underlying cardiovascular disease (CVD) is considered a risk factor for the exacerbation of air pollution health effects. Therefore, rodent models of CVD are increasingly used to examine mechanisms ofvariation in susceptibility. Pulmonary oxidative stress, inflammation and altere...

  11. Pulmonary oxidative stress, inflammation and dysregulated iron homeostatis in rat models of cardiovascular disease

    EPA Science Inventory

    Underlying cardiovascular disease (CVD) is considered a risk factor for the exacerbation of air pollution health effects. Therefore, rodent models of CVD are increasingly used to examine mechanisms ofvariation in susceptibility. Pulmonary oxidative stress, inflammation and altere...

  12. 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...

  13. 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...

  14. 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...

  15. Inhibitory Effects of Astragaloside IV on Bleomycin-Induced Pulmonary Fibrosis in Rats Via Attenuation of Oxidative Stress and Inflammation.

    PubMed

    Yu, Wei-Na; Sun, Li-Feng; Yang, Hua

    2016-10-01

    In this study, we investigated the effects of astragaloside IV (As-IV) on pulmonary fibrosis and its mechanisms of action. Sprague-Dawley rats were used in a model of pulmonary fibrosis induced by an intratracheal instillation of bleomycin (BLM). Rats were intraperitoneally injected with As-IV (10, 20, 50 mg/kg) daily for 28 days, while the rats in control and BLM groups were injected with a saline solution. The effects of As-IV treatment on pulmonary injury were evaluated with the lung wet/dry weight ratios, cell counts, and histopathologic. Oxidative stress was evaluated by detecting the levels of malondialdehyde (MDA), superoxide dismutase (SOD), total antioxidant capacity (T-AOC), and reactive oxygen species (ROS) in lung tissue. Inflammation was assessed by measuring the levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 in bronchoalveolar lavage fluid (BALF). The results indicated that As-IV treatment remarkably ameliorated BLM-induced pulmonary fibrosis and attenuated BLM-induced oxidative stress and inflammation. Our findings indicate that As-IV-mediated suppression of fibroproliferation may contribute to the anti-fibrotic effect against BLM-induced pulmonary fibrosis. Its mechanisms of action are associated with inhibiting oxidative stress and inflammatory response. In summary, our study suggests a therapeutic potential of As-IV in the treatment of pulmonary fibrosis.

  16. 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

  17. Dermatophagoides-farinae-induced pulmonary eosinophilic inflammation in mice.

    PubMed

    Yu, C K; Yang, B C; Lee, S C; Wang, J Y; Hsiue, T R; Lei, H Y

    1997-01-01

    a mixed granulocytic, monocytic pulmonary inflammation with a large number of eosinophils accumulating within the submucosa of the airways and blood vessels of sensitized mice after challenge. Der f challenge induced a sequential expression pattern of eight cytokine genes in BAL cells. The mRNA of interleukin (IL)-1 beta and tumor necrosis factor (TNF)-alpha strongly expressed throughout the course of the experiment. The IL-6 mRNA expression peaked at 0.5-72 h, IL-10 at 1-6 and 48-72 h, IL-4 at 6-72 h, IL-2 at 6-96 h, IL-5 at 24-72 h, and interferon-gamma at 24-96 h. Intraperitoneal injection of sensitized mice with monoclonal antibody (mAb) to murine IL-5 (TRFK5, 300 micrograms/mouse) 1 h before challenge caused 62% suppression of eosinophils in the BAL fluids. The concomitant accumulation of neutrophils and mononuclear cells, however, was not affected by this treatment. On the other hand, intranasal administration of mAb to murine TNF-alpha (MP6-XT3, 20 micrograms/ mouse), but not IL-5, 1 h before challenge and 24 h AC significantly reduced the numbers of eosinophils, neutrophils, and lymphocytes in the BAL fluids. The intraperitoneal injection of dexamethasone (50 mg/kg) for a total of four times resulted in total inhibition of the Der-f-induced cellular responses, whereas vasoactive amine antagonists (diphenhydramine, ketanserin and cyprohepatidine) did not show any effect.

  18. 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

  19. Systemic and pulmonary inflammation is independent of skeletal muscle changes in patients with chronic obstructive pulmonary disease.

    PubMed

    Barker, Bethan L; McKenna, Susan; Mistry, Vijay; Pancholi, Mitesh; Patel, Hemu; Haldar, Koirobi; Barer, Michael R; Pavord, Ian D; Steiner, Michael C; Brightling, Christopher E; Bafadhel, Mona

    2014-01-01

    Nutritional depletion is an important manifestation of chronic obstructive pulmonary disease (COPD), which has been related to systemic inflammation. It remains unclear to what degree airway inflammation contributes to the presence or progression of nutritional depletion. To determine whether airway inflammation and lung bacterial colonization are related to nutritional status or predict progressive weight loss and muscle atrophy in patients with COPD. Body composition using dual energy X-ray absorptiometry, indices of airway inflammation, and bacterial colonization were measured in 234 COPD patients. Systemic inflammation was assessed from serum C reactive protein (CRP) and circulating total and differential leukocyte counts. Nutritional depletion was defined as a body mass index (BMI) less than 21 kg/m(2) and/or fat-free mass index (FFMI) less than 15 or 17 kg/m(2) in women and men, respectively. FFMI was calculated as the fat-free mass (FFM) corrected for body surface area. Measurements were repeated in 94 patients after a median 16-month follow-up. Regression analysis was used to assess the relationships of weight change and FFM change with indices of bacterial colonization and airway and systemic inflammation. Nutritional depletion occurred in 37% of patients. Lung function was worsened in patients with nutritional depletion compared to those without (forced expiratory volume in 1 second 1.17 L versus 1.41 L, mean difference 0.24, 95% confidence interval 0.10 to 0.38, P<0.01). There were no differences in airway inflammation and bacterial colonization in patients with and without nutritional depletion. At baseline, BMI correlated positively with serum CRP (rs=0.14, P=0.04). Change in weight and change in FFM over time could not be predicted from baseline patient characteristics. Nutritional depletion and progressive muscle atrophy are not related to airway inflammation or bacterial colonization. Overspill of pulmonary inflammation is not a key driver of muscle

  20. Rosiglitazone dampens pulmonary inflammation in a porcine model of acute lung injury.

    PubMed

    Mirakaj, Valbona; Mutz, Christian; Vagts, Dierk; Henes, Janek; Haeberle, Helene A; Husung, Susanne; König, Tony; Nöldge-Schomburg, Gabriele; Rosenberger, Peter

    2014-08-01

    The hallmarks of acute lung injury (ALI) are the compromised alveolar-capillary barrier and the extravasation of leukocytes into the alveolar space. Given the fact that the peroxisome proliferator-activated receptor-γ agonist rosiglitazone holds significant anti-inflammatory properties, we aimed to evaluate whether rosiglitazone could dampen these hallmarks of local pulmonary inflammation in a porcine model of lung injury. For this purpose, we used a model of lipopolysaccharide (LPS, 50 μg/kg)-induced ALI. One hundred twenty minutes following the infusion of LPS, we started the exposure to rosiglitazone through inhalation or infusion. We found that intravenous rosiglitazone significantly controlled local pulmonary inflammation as determined through the expression of cytokines within the alveolar compartment. Furthermore, we found a significant reduction of the protein concentration and neutrophil activity within the alveolar space. In summary, we therefore conclude that the treatment with rosiglitazone might dampen local pulmonary inflammation during the initial stages of ALI.

  1. Lung inflammation and genotoxicity following pulmonary exposure to nanoparticles in ApoE-/- mice

    PubMed Central

    Jacobsen, Nicklas Raun; Møller, Peter; Jensen, Keld Alstrup; Vogel, Ulla; Ladefoged, Ole; Loft, Steffen; Wallin, Håkan

    2009-01-01

    Background The toxic and inflammatory potential of 5 different types of nanoparticles were studied in a sensitive model for pulmonary effects in apolipoprotein E knockout mice (ApoE-/-). We studied the effects instillation or inhalation Printex 90 of carbon black (CB) and compared CB instillation in ApoE-/- and C57 mice. Three and 24 h after pulmonary exposure, inflammation was assessed by mRNA levels of cytokines in lung tissue, cell composition, genotoxicity, protein and lactate dehydrogenase activity in broncho-alveolar lavage (BAL) fluid. Results Firstly, we found that intratracheal instillation of CB caused far more pulmonary toxicity in ApoE-/- mice than in C57 mice. Secondly, we showed that instillation of CB was more toxic than inhalation of a presumed similar dose with respect to inflammation in the lungs of ApoE-/- mice. Thirdly, we compared effects of instillation in ApoE-/- mice of three carbonaceous particles; CB, fullerenes C60 (C60) and single walled carbon nanotubes (SWCNT) as well as gold particles and quantum dots (QDs). Characterization of the instillation media revealed that all particles were delivered as agglomerates and aggregates. Significant increases in Il-6, Mip-2 and Mcp-1 mRNA were detected in lung tissue, 3 h and 24 h following instillation of SWCNT, CB and QDs. DNA damage in BAL cells, the fraction of neutrophils in BAL cells and protein in BAL fluid increased statistically significantly. Gold and C60 particles caused much weaker inflammatory responses. Conclusion Our data suggest that ApoE-/- model is sensitive for evaluating particle induced inflammation. Overall QDs had greatest effects followed by CB and SWCNT with C60 and gold being least inflammatory and DNA-damaging. However the gold was used at a much lower mass dose than the other particles. The strong effects of QDs were likely due to Cd release. The surface area of the instilled dose correlated well the inflammatory response for low toxicity particles. PMID:19138394

  2. The role of inflammation and autoimmunity in the pathophysiology of pulmonary arterial hypertension.

    PubMed

    Kherbeck, Nada; Tamby, Mathieu C; Bussone, Guillaume; Dib, Hanadi; Perros, Frederic; Humbert, Marc; Mouthon, Luc

    2013-02-01

    Pulmonary arterial hypertension is characterized by a remodeling of pulmonary arteries with endothelial cell, fibroblast, and vascular smooth muscle cell activation and proliferation. Since pulmonary arterial hypertension occurs frequently in autoimmune conditions such as systemic sclerosis, inflammation and autoimmunity have been suspected to play a critical role in both idiopathic pulmonary arterial hypertension and systemic sclerosis-associated pulmonary arterial hypertension. High levels of pro-inflammatory cytokines such as interleukin-1 and interleukin-6, platelet-derived growth factor, or macrophage inflammatory protein 1 have been found in lung samples of patients with pulmonary arterial hypertension, along with inflammatory cell infiltrates mainly composed of macrophages and dendritic cells, T and B lymphocytes. In addition, circulating autoantibodies are found in the peripheral blood of patients. Thus, autoimmunity and inflammation probably play a role in the development of pulmonary arterial hypertension. In this setting, it would be important to set-up new experimental models of pulmonary arterial hypertension, in order to define novel therapeutics that specifically target immune disturbances in this devastating condition.

  3. Home-based pulmonary rehabilitation improves clinical features and systemic inflammation in chronic obstructive pulmonary disease patients.

    PubMed

    do Nascimento, Eloisa Sanches Pereira; Sampaio, Luciana Maria Malosá; Peixoto-Souza, Fabiana Sobral; Dias, Fernanda Dultra; Gomes, Evelim Leal Freitas Dantas; Greiffo, Flavia Regina; Ligeiro de Oliveira, Ana Paula; Stirbulov, Roberto; Vieira, Rodolfo Paula; Costa, Dirceu

    2015-01-01

    Chronic obstructive pulmonary disease (COPD) is a respiratory disease characterized by chronic airflow limitation that leads beyond the pulmonary changes to important systemic effects. COPD is characterized by pulmonary and systemic inflammation. However, increases in the levels of inflammatory cytokines in plasma are found even when the disease is stable. Pulmonary rehabilitation improves physical exercise capacity and quality of life and decreases dyspnea. The aim of this study was to evaluate whether a home-based pulmonary rehabilitation (HBPR) program improves exercise tolerance in COPD patients, as well as health-related quality of life and systemic inflammation. This prospective study was conducted at the Laboratory of Functional Respiratory Evaluation, Nove de Julho University, São Paulo, Brazil. After anamnesis, patients were subjected to evaluations of health-related quality of life and dyspnea, spirometry, respiratory muscle strength, upper limbs incremental test, incremental shuttle walk test, and blood test for quantification of systemic inflammatory markers (interleukin [IL]-6 and IL-8). At the end of the evaluations, patients received a booklet containing the physical exercises to be performed at home, three times per week for 8 consecutive weeks. Around 25 patients were enrolled, and 14 completed the pre- and post-HBPR ratings. There was a significant increase in the walked distance and the maximal inspiratory pressure, improvements on two components from the health-related quality-of-life questionnaire, and a decrease in plasma IL-8 levels after the intervention. The HBPR is an important and viable alternative to pulmonary rehabilitation for the treatment of patients with COPD; it improves exercise tolerance, inspiratory muscle strength, quality of life, and systemic inflammation in COPD patients.

  4. Home-based pulmonary rehabilitation improves clinical features and systemic inflammation in chronic obstructive pulmonary disease patients

    PubMed Central

    do Nascimento, Eloisa Sanches Pereira; Sampaio, Luciana Maria Malosá; Peixoto-Souza, Fabiana Sobral; Dias, Fernanda Dultra; Gomes, Evelim Leal Freitas Dantas; Greiffo, Flavia Regina; Ligeiro de Oliveira, Ana Paula; Stirbulov, Roberto; Vieira, Rodolfo Paula; Costa, Dirceu

    2015-01-01

    Chronic obstructive pulmonary disease (COPD) is a respiratory disease characterized by chronic airflow limitation that leads beyond the pulmonary changes to important systemic effects. COPD is characterized by pulmonary and systemic inflammation. However, increases in the levels of inflammatory cytokines in plasma are found even when the disease is stable. Pulmonary rehabilitation improves physical exercise capacity and quality of life and decreases dyspnea. The aim of this study was to evaluate whether a home-based pulmonary rehabilitation (HBPR) program improves exercise tolerance in COPD patients, as well as health-related quality of life and systemic inflammation. This prospective study was conducted at the Laboratory of Functional Respiratory Evaluation, Nove de Julho University, São Paulo, Brazil. After anamnesis, patients were subjected to evaluations of health-related quality of life and dyspnea, spirometry, respiratory muscle strength, upper limbs incremental test, incremental shuttle walk test, and blood test for quantification of systemic inflammatory markers (interleukin [IL]-6 and IL-8). At the end of the evaluations, patients received a booklet containing the physical exercises to be performed at home, three times per week for 8 consecutive weeks. Around 25 patients were enrolled, and 14 completed the pre- and post-HBPR ratings. There was a significant increase in the walked distance and the maximal inspiratory pressure, improvements on two components from the health-related quality-of-life questionnaire, and a decrease in plasma IL-8 levels after the intervention. The HBPR is an important and viable alternative to pulmonary rehabilitation for the treatment of patients with COPD; it improves exercise tolerance, inspiratory muscle strength, quality of life, and systemic inflammation in COPD patients. PMID:25848241

  5. Reducing hypoxia and inflammation during invasive pulmonary aspergillosis by targeting the Interleukin-1 receptor

    PubMed Central

    Gresnigt, Mark S.; Rekiki, Abdessalem; Rasid, Orhan; Savers, Amélie; Jouvion, Grégory; Dannaoui, Eric; Parlato, Marianna; Fitting, Catherine; Brock, Matthias; Cavaillon, Jean-Marc; van de Veerdonk, Frank L.; Ibrahim-Granet, Oumaïma

    2016-01-01

    Hypoxia as a result of pulmonary tissue damage due to unresolved inflammation during invasive pulmonary aspergillosis (IPA) is associated with a poor outcome. Aspergillus fumigatus can exploit the hypoxic microenvironment in the lung, but the inflammatory response required for fungal clearance can become severely disregulated as a result of hypoxia. Since severe inflammation can be detrimental to the host, we investigated whether targeting the interleukin IL-1 pathway could reduce inflammation and tissue hypoxia, improving the outcome of IPA. The interplay between hypoxia and inflammation was investigated by in vivo imaging of hypoxia and measurement of cytokines in the lungs in a model of corticosteroid immunocompromised and in Cxcr2 deficient mice. Severe hypoxia was observed following Aspergillus infection in both models and correlated with development of pulmonary inflammation and expression of hypoxia specific transcripts. Treatment with IL-1 receptor antagonist reduced hypoxia and slightly, but significantly reduced mortality in immunosuppressed mice, but was unable to reduce hypoxia in Cxcr2−/− mice. Our data provides evidence that the inflammatory response during invasive pulmonary aspergillosis, and in particular the IL-1 axis, drives the development of hypoxia. Targeting the inflammatory IL-1 response could be used as a potential immunomodulatory therapy to improve the outcome of aspergillosis. PMID:27215684

  6. Skeletal muscle response to inflammation--lessons for chronic obstructive pulmonary disease.

    PubMed

    Reid, W Darlene; Rurak, Jennifer; Harris, R Luke

    2009-10-01

    To describe how inflammation affects muscle adaptation and performance in people with chronic obstructive pulmonary disease. In chronic obstructive pulmonary disease, an increasingly sedentary lifestyle is a primary contributor to muscle dysfunction that results in a loss of mobility and independence and, ultimately, mortality. Given the systemic chronic inflammation and profound limb muscle atrophy in chronic obstructive pulmonary disease, it is tempting to speculate that the inflammatory process is deleterious to skeletal muscle. In healthy people, however, the inflammatory process initially is dominated by a destructive phase that is tightly regulated and modulates a reparative, regenerative phase. Although the inflammatory process and associated oxidative stress is more closely connected to muscle wasting in animal models of chronic obstructive pulmonary disease, the causative role of inflammation toward muscle atrophy and weakness in people with chronic obstructive pulmonary disease has not been definitively shown. Anti-inflammatory interventions aimed toward tempering muscle wasting and weakness in chronic obstructive pulmonary disease may not prove to be beneficial because of longer-term disruption of the regeneration of muscle tissue. Temporally and spatially targeted interventions aimed toward ameliorating oxidative stress, such as antioxidants, nutritional supplements, and chronic exercise training, may optimize outcomes toward maintaining muscle mass and performance.

  7. Fas ligand-expressing lymphocytes enhance alveolar macrophage apoptosis in the resolution of acute pulmonary inflammation

    PubMed Central

    Barthel, Lea; Bednarek, Joseph M.; Yunt, Zulma X.; Henson, Peter M.; Janssen, William J.

    2014-01-01

    Apoptosis of alveolar macrophages and their subsequent clearance by neighboring phagocytes are necessary steps in the resolution of acute pulmonary inflammation. We have recently identified that activation of the Fas death receptor on the cell surface of macrophages drives macrophage apoptosis. However, the source of the cognate ligand for Fas (FasL) responsible for induction of alveolar macrophage apoptosis is not defined. Given their known role in the resolution of inflammation and ability to induce macrophage apoptosis ex vivo, we hypothesized that T lymphocytes represented a critical source of FasL. To address this hypothesis, C57BL/6J and lymphocyte-deficient (Rag-1−/−) mice were exposed to intratracheal lipopolysaccharide to induce pulmonary inflammation. Furthermore, utilizing mice expressing nonfunctional FasL, we adoptively transferred donor lymphocytes into inflamed lymphocyte-deficient mice to characterize the effect of lymphocyte-derived FasL on alveolar macrophage apoptosis in the resolution of inflammation. Herein, evidence is presented that lymphocytes expressing FasL enhance alveolar macrophage apoptosis during the resolution of LPS-induced inflammation. Moreover, lymphocyte induction of alveolar macrophage apoptosis results in contraction of the alveolar macrophage pool, which occurs in a FasL-dependent manner. Specifically, FasL-expressing CD8+ T lymphocytes potently induce alveolar macrophage apoptosis and contraction of the alveolar macrophage pool. Together, these studies identify a novel role for CD8+ T lymphocytes in the resolution of acute pulmonary inflammation. PMID:24838751

  8. Inhibitory effects of hydrogen sulphide on pulmonary fibrosis in smoking rats via attenuation of oxidative stress and inflammation.

    PubMed

    Zhou, Xiang; An, Guoyin; Chen, Jianchang

    2014-06-01

    Accumulating evidence has demonstrated that hydrogen sulphide (H2 S) is involved in the pathogenesis of various respiratory diseases. In the present study, we established a rat model of passive smoking and investigated whether or not H2 S has protective effects against pulmonary fibrosis induced by chronic cigarette smoke exposure. Rat lung tissues were stained with haematoxylin-eosin and Masson's trichrome. The expression of type I collagen was detected by immunohistochemistry. Oxidative stress was evaluated by detecting serum levels of malondialdehyde, superoxide dismutase and glutathione peroxidase and measuring reactive oxygen species generation in lung tissue. Inflammation was assessed by measuring serum levels of inflammatory cytokines, including high-sensitivity C-reactive protein, tumour necrosis factor-α, interleukin (IL)-1β and IL-6. The protein expression of Nrf2, NF-κB and phosphorylated mitogen-activated protein kinases (MAPKs) in the pulmonary tissue was determined by Western blotting. Our findings indicated that administration of NaHS (a donor of H2 S) could protect against pulmonary fibrosis in the smoking rats. H2 S was found to induce the nuclear accumulation of Nrf2 in lung tissue and consequently up-regulate the expression of antioxidant genes HO-1 and Trx-1 in the smoking rats. Moreover, H2 S could also reduce cigarette smoking-induced inflammation by inhibiting the phosphorylation of ERK 1/2, JNK and p38 MAPKs and negatively regulating NF-κB activation. In conclusion, our study suggests that H2 S has protective effects against pulmonary fibrosis in the smoking rats by attenuating oxidative stress and inflammation.

  9. Role of inflammation in the lung disease of systemic sclerosis: comparison with idiopathic pulmonary fibrosis.

    PubMed

    Owens, G R; Paradis, I L; Gryzan, S; Medsger, T A; Follansbee, W P; Klein, H A; Dauber, J H

    1986-03-01

    Alveolar inflammation is thought to underlie the development of pulmonary fibrosis in several forms of diffuse lung disease including the connective tissue diseases. The relationship between inflammation and the clinical manifestations of systemic sclerosis (scleroderma), such as skin and lung involvement, is less clear. We therefore evaluated 14 never-smoking patients with systemic sclerosis with pulmonary involvement by bronchoalveolar lavage (BAL) and compared the results with those found in eight nonsmoking patients with idiopathic pulmonary fibrosis (IPF) and eight normal subjects. The patients with scleroderma also underwent gallium citrate Ga 67 scanning. We found that patients with scleroderma and pulmonary involvement have alveolitis that appears to wane with time. In addition, patients with systemic sclerosis have a cellular profile in lavage fluid that appears to differ from that of patients with IPF. Finally, we found a significant correlation between BAL cellular recovery and the single-breath carbon monoxide diffusing capacity in patients with systemic sclerosis but not in patients with IPF. We conclude that inflammation may play an important role in the pathogenesis of the pulmonary disease of scleroderma and that different mechanisms may lead to fibrosis in IPF and scleroderma.

  10. Global analysis of gene expression in pulmonary fibrosis reveals distinct programs regulating lung inflammation and fibrosis

    NASA Astrophysics Data System (ADS)

    Kaminski, Naftali; Allard, John D.; Pittet, Jean F.; Zuo, Fengrong; Griffiths, Mark J. D.; Morris, David; Huang, Xiaozhu; Sheppard, Dean; Heller, Renu A.

    2000-02-01

    The molecular mechanisms of pulmonary fibrosis are poorly understood. We have used oligonucleotide arrays to analyze the gene expression programs that underlie pulmonary fibrosis in response to bleomycin, a drug that causes lung inflammation and fibrosis, in two strains of susceptible mice (129 and C57BL/6). We then compared the gene expression patterns in these mice with 129 mice carrying a null mutation in the epithelial-restricted integrin 6 subunit (6/-), which develop inflammation but are protected from pulmonary fibrosis. Cluster analysis identified two distinct groups of genes involved in the inflammatory and fibrotic responses. Analysis of gene expression at multiple time points after bleomycin administration revealed sequential induction of subsets of genes that characterize each response. The availability of this comprehensive data set should accelerate the development of more effective strategies for intervention at the various stages in the development of fibrotic diseases of the lungs and other organs.

  11. The role of inflammation in hypoxic pulmonary hypertension: from cellular mechanisms to clinical phenotypes

    PubMed Central

    Poth, Jens M.; Fini, Mehdi A.; Olschewski, Andrea; El Kasmi, Karim C.; Stenmark, Kurt R.

    2014-01-01

    Hypoxic pulmonary hypertension (PH) comprises a heterogeneous group of diseases sharing the common feature of chronic hypoxia-induced pulmonary vascular remodeling. The disease is usually characterized by mild to moderate pulmonary vascular remodeling that is largely thought to be reversible compared with the progressive irreversible disease seen in World Health Organization (WHO) group I disease. However, in these patients, the presence of PH significantly worsens morbidity and mortality. In addition, a small subset of patients with hypoxic PH develop “out-of-proportion” severe pulmonary hypertension characterized by pulmonary vascular remodeling that is irreversible and similar to that in WHO group I disease. In all cases of hypoxia-related vascular remodeling and PH, inflammation, particularly persistent inflammation, is thought to play a role. This review focuses on the effects of hypoxia on pulmonary vascular cells and the signaling pathways involved in the initiation and perpetuation of vascular inflammation, especially as they relate to vascular remodeling and transition to chronic irreversible PH. We hypothesize that the combination of hypoxia and local tissue factors/cytokines (“second hit”) antagonizes tissue homeostatic cellular interactions between mesenchymal cells (fibroblasts and/or smooth muscle cells) and macrophages and arrests these cells in an epigenetically locked and permanently activated proremodeling and proinflammatory phenotype. This aberrant cellular cross-talk between mesenchymal cells and macrophages promotes transition to chronic nonresolving inflammation and vascular remodeling, perpetuating PH. A better understanding of these signaling pathways may lead to the development of specific therapeutic targets, as none are currently available for WHO group III disease. PMID:25416383

  12. Pulmonary epithelial CCR3 promotes LPS-induced lung inflammation by mediating release of IL-8.

    PubMed

    Li, Bo; Dong, Chunling; Wang, Guifang; Zheng, Huiru; Wang, Xiangdong; Bai, Chunxue

    2011-09-01

    Interleukin (IL)-8 from pulmonary epithelial cells has been suggested to play an important role in the airway inflammation, although the mechanism remains unclear. We envisioned a possibility that pulmonary epithelial CCR3 could be involved in secretion and regulation of IL-8 and promote lipopolysaccharide (LPS)-induced lung inflammation. Human bronchial epithelial cell line NCI-H292 and alveolar type II epithelial cell line A549 were used to test role of CCR3 in production of IL-8 at cellular level. In vivo studies were performed on C57/BL6 mice instilled intratracheally with LPS in a model of acute lung injury (ALI). The activity of a CCR3-specific inhibitor (SB-328437) was measured in both in vitro and in vivo systems. We found that expression of CCR3 in NCI-H292 and A549 cells were increased by 23% and 16%, respectively, 24 h after the challenge with LPS. LPS increased the expression of CCR3 in NCI-H292 and A549 cells in a time-dependent manner, which was inhibited significantly by SB-328437. SB-328437 also diminished neutrophil recruitment in alveolar airspaces and improved LPS-induced ALI and production of IL-8 in bronchoalveolar lavage fluid. These results suggest that pulmonary epithelial CCR3 be involved in progression of LPS-induced lung inflammation by mediating release of IL-8. CCR3 in pulmonary epithelia may be an attractive target for development of therapies for ALI.

  13. Muscle wasting and impaired muscle regeneration in a murine model of chronic pulmonary inflammation.

    PubMed

    Langen, Ramon C J; Schols, Annemie M W J; Kelders, Marco C J M; van der Velden, Jos L J; Wouters, Emiel F M; Janssen-Heininger, Yvonne M W

    2006-12-01

    Muscle wasting and increased circulating levels of inflammatory cytokines, including TNF-alpha, are common features of chronic obstructive pulmonary disease. To investigate whether inflammation of the lung is responsible for systemic inflammation and muscle wasting, we adopted a mouse model of pulmonary inflammation resulting from directed overexpression of a TNF-alpha transgene controlled by the surfactant protein C (SP-C) promoter. Compared with wild-type mice, SP-C/TNF-alpha mice exhibited increased levels of TNF-alpha in the circulation and increased endogenous TNF-alpha expression in skeletal muscle, potentially reflecting an amplificatory response to circulating TNF-alpha. Decreased muscle and body weights observed in SP-C/TNF-alpha mice were indicative of muscle wasting. Further evaluation of the SP-C/TNF-alpha mouse musculature revealed a decreased muscle regenerative capacity, shown by attenuated myoblast proliferation and differentiation in response to reloading of disuse-atrophied muscle, which may contribute to skeletal muscle wasting. Importantly, incubation of cultured myoblasts with TNF-alpha also resulted in elevated TNF-alpha mRNA levels and inhibition of myoblast differentiation. Collectively, our results demonstrate that chronic pulmonary inflammation results in muscle wasting and impaired muscle regeneration in SP-C/TNF-alpha mice, possibly as a consequence of an amplificatory TNF-alpha expression circuit extending from the lung to skeletal muscle.

  14. ALLERGIC PULMONARY INFLAMMATION PROMOTES THE RECRUITMENT OF CIRCULATING TUMOR CELLS TO THE LUNG

    PubMed Central

    Taranova, Anna G.; Maldonado, David; Vachon, Celine M.; Jacobsen, Elizabeth A.; Abdala-Valencia, Hiam; McGarry, Michael P.; Ochkur, Sergei I.; Protheroe, Cheryl A.; Doyle, Alfred; Grant, Clive S.; Cook-Mills, Joan; Birnbaumer, Lutz; Lee, Nancy A.; Lee, James J.

    2010-01-01

    Allergen-induced respiratory inflammation facilitates and/or elicits the extravasation of proinflammatory leukocytes by well understood mechanisms that mediate the movement of multiple cell types. The non-specific character of these pathways led us to hypothesize that circulating cancer cells use similar mechanisms, promoting secondary tumor formation at distal sites. To test this hypothesis, the frequency of metastasis to the lung as a function of allergic pulmonary inflammation was assessed following the intravenous injection of B16-F10 melanoma cells in mice. These studies demonstrated that allergen-induced pulmonary inflammation resulted in a >3-fold increase in lung metastases. This increase was dependent on CD4+ T cell activities; however, it occurred independent of the induced eosinophilia associated with allergen provocation. Interventional strategies showed that existing therapeutic modalities for asthma, such as inhaled corticosteroids, were sufficient to block the enhanced pulmonary recruitment of cancer cells from circulation. Additional mechanistic studies further suggested that the ability of circulating cancer cells to extravasate to surrounding lung tissues was linked to the activation of the vascular endothelium via one or more Gαi-coupled receptors. Interestingly, a survey of a clinical breast cancer surgical database showed that the incidence of asthma was higher among patients with lung metastases. Thus, our data demonstrate that allergic respiratory inflammation may represent a risk factor for the development of lung metastases and suggests that amelioration of the pulmonary inflammation associated with asthma will have a direct and immediate benefit to the 7–8% of breast cancer patients with this lung disease. PMID:18922934

  15. [Detection and characterization of pulmonary nodules using multislice computed tomography].

    PubMed

    Bastarrika, G; Cano, D; Hernández, C; Alonso-Burgos, A; González, I; Villanueva, A; Vivas, I; Zulueta, J

    2007-01-01

    Pulmonary nodules are a common finding in routine chest studies. Although there are no pathognomic clinical or radiological signs that enable the exact nature of a pulmonary nodule to be determined, the clinical context and the appropriate characterization of the pulmonary nodule make it possible to reach the correct diagnosis in most cases. This article discusses the most important aspects involved in the use of multislice computed tomography in the noninvasive detection and characterization of pulmonary nodules.

  16. Kallistatin protects against bleomycin-induced idiopathic pulmonary fibrosis by inhibiting angiogenesis and inflammation

    PubMed Central

    Huang, Xiaoping; Wang, Xiao; Xie, Xiaolan; Zeng, Shulan; Li, Zhaofa; Xu, Xianxiang; Yang, Huiyong; Qiu, Fei; Lin, Junsheng; Diao, Yong

    2017-01-01

    Aberrant angiogenesis and vascular remodeling are the main features of idiopathic pulmonary fibrosis. Kallistatin is an anti-angiogenic peptide with known effects on endothelial cells. This study aimed to demonstrate that kallistatin has beneficial effects on bleomycin (BLM)-induced pulmonary fibrosis in a rat model by inhibiting angiogenesis. Twenty-five rats were randomly divided into five experimental groups: (A) Saline only (SA)-as the negative control, (B) BLM only (BLM)-as the model group, (C) BLM and 0.1 mg/kg kallistatin (L-Kal), (D) BLM and 0.5 mg/kg kallistatin (M-Kal), and (E) BLM and 2.5 mg/kg kallistatin (H-Kal). Fibrillar collagen was quantified by Masson’s trichrome and hematoxylin-eosin staining. Transforming growth factor-β1 (TGF-β1), α-smooth-muscle-actin (α-SMA) and microvascular density (MVD) were measured by immunohistochemistry. Vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor (VEGFR), and tumor necrosis factor-α (TNF-α) were assayed by Western immunoblotting or ELISA. Daily administration of kallistatin attenuated fibrosis in BLM-induced pulmonary fibrosis, as shown by histology. During inflammation from BLM-induced pulmonary fibrosis, kallistatin reduced the number of inflammatory cells infiltrating the bronchoalveolar lavage fluid. Kallistatin also inhibited VEGF expression and phosphorylation of VEGFR2 (Flk-1). In vitro, kallistatin blocked tube formation by inhibiting Flk-1 and GSK-3β phosphorylation. The results demonstrated that continuous administration of kallistatin attenuated BLM-induced pulmonary fibrosis and improved survival of BLM rats. Reducing pulmonary fibrosis was achieved by partial inhibition of pulmonary inflammation and angiogenesis. PMID:28386328

  17. Manganese (II) induces chemical hypoxia by inhibiting HIF-prolyl hydroxylase: Implication in manganese-induced pulmonary inflammation

    SciTech Connect

    Han, Jeongoh; Lee, Jong-Suk; Choi, Daekyu; Lee, Youna; Hong, Sungchae; Choi, Jungyun; Han, Songyi; Ko, Yujin; Kim, Jung-Ae; Mi Kim, Young; Jung, Yunjin

    2009-03-15

    Manganese (II), a transition metal, causes pulmonary inflammation upon environmental or occupational inhalation in excess. We investigated a potential molecular mechanism underlying manganese-induced pulmonary inflammation. Manganese (II) delayed HIF-1{alpha} protein disappearance, which occurred by inhibiting HIF-prolyl hydroxylase (HPH), the key enzyme for HIF-1{alpha} hydroxylation and subsequent von Hippel-Lindau(VHL)-dependent HIF-1{alpha} degradation. HPH inhibition by manganese (II) was neutralized significantly by elevated dose of iron. Consistent with this, the induction of cellular HIF-1{alpha} protein by manganese (II) was abolished by pretreatment with iron. Manganese (II) induced the HIF-1 target gene involved in pulmonary inflammation, vascular endothelial growth factor (VEGF), in lung carcinoma cell lines. The induction of VEGF was dependent on HIF-1. Manganese-induced VEGF promoted tube formation of HUVEC. Taken together, these data suggest that HIF-1 may be a potential mediator of manganese-induced pulmonary inflammation.

  18. Protection against fine particle-induced pulmonary and systemic inflammation by omega-3 polyunsaturated fatty acids.

    PubMed

    Li, Xiang-Yong; Hao, Lei; Liu, Ying-Hua; Chen, Chih-Yu; Pai, Victor J; Kang, Jing X

    2017-03-01

    Exposure to fine particulate matter, such as through air pollution, has been linked to the increased incidence of chronic diseases. However, few measures have been taken to reduce the health risks associated with fine particle exposure. The identification of safe and effective methods to protect against fine particle exposure-related damage is urgently needed. We used synthetic, non-toxic, fluorescent fine particles to investigate the physical distribution of inhaled fine particles and their effects on pulmonary and systemic inflammation in mice. Tissue levels of omega-3 fatty acids were elevated via dietary supplementation or the fat-1 transgenic mouse model. Markers of pulmonary and systemic inflammation were assessed. We discovered that fine particulate matter not only accumulates in the lungs but can also penetrate the pulmonary barrier and travel into other organs, including the brain, liver, spleen, kidney, and testis. These particles induced both pulmonary and systemic inflammation and increased oxidative stress. We also show that elevating tissue levels of omega-3 fatty acids was effective in reducing fine particle-induced inflammation, whether as a preventive method (prior to exposure) or as an intervention (after exposure). These results advance our understanding of how fine particles contribute to disease development and suggest that increasing tissue omega-3 levels may be a promising nutritional means for reducing the risk of diseases induced by particle exposure. Our findings demonstrate that elevating tissue omega-3 levels can prevent and treat fine particle-induced health problems and thereby present an immediate, practical solution for reducing the disease burden of air pollution. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

  19. Microbiota Promotes Chronic Pulmonary Inflammation by Enhancing IL-17A and Autoantibodies.

    PubMed

    Yadava, Koshika; Pattaroni, Céline; Sichelstiel, Anke K; Trompette, Aurélien; Gollwitzer, Eva S; Salami, Olawale; von Garnier, Christophe; Nicod, Laurent P; Marsland, Benjamin J

    2016-05-01

    Changes in the pulmonary microbiota are associated with progressive respiratory diseases including chronic obstructive pulmonary disease (COPD). Whether there is a causal relationship between these changes and disease progression remains unknown. To investigate the link between an altered microbiota and disease, we used a murine model of chronic lung inflammation that is characterized by key pathological features found in COPD and compared responses in specific pathogen-free (SPF) mice and mice depleted of microbiota by antibiotic treatment or devoid of a microbiota (axenic). Mice were challenged with LPS/elastase intranasally over 4 weeks, resulting in a chronically inflamed and damaged lung. The ensuing cellular infiltration, histological damage, and decline in lung function were quantified. Similar to human disease, the composition of the pulmonary microbiota was altered in diseased animals. We found that the microbiota richness and diversity were decreased in LPS/elastase-treated mice, with an increased representation of the genera Pseudomonas and Lactobacillus and a reduction in Prevotella. Moreover, the microbiota was implicated in disease development as mice depleted, or devoid, of microbiota exhibited an improvement in lung function, reduced inflammation, and lymphoid neogenesis. The absence of microbial cues markedly decreased the production of IL-17A, whereas intranasal transfer of fluid enriched with the pulmonary microbiota isolated from diseased mice enhanced IL-17A production in the lungs of antibiotic-treated or axenic recipients. Finally, in mice harboring a microbiota, neutralizing IL-17A dampened inflammation and restored lung function. Collectively, our data indicate that host-microbial cross-talk promotes inflammation and could underlie the chronicity of inflammatory lung diseases.

  20. Bufei Huoxue Capsule Attenuates PM2.5-Induced Pulmonary Inflammation in Mice

    PubMed Central

    Jing, Yue; Cai, Zhe; Zhao, Yukun; Wu, Ye; Zheng, Xuan; Liu, Ying; Qin, Yuying; Gu, Mingjie; Jin, Jin

    2017-01-01

    Atmospheric fine particulate matter 2.5 (PM 2.5) may carry many toxic substances on its surface and this may pose a public health threat. Epidemiological research indicates that cumulative ambient PM2.5 is correlated to morbidity and mortality due to pulmonary and cardiovascular diseases and cancer. Mitigating the toxic effects of PM2.5 is therefore highly desired. Bufei Huoxue (BFHX) capsules have been used in China to treat pulmonary heart disease (cor pulmonale). Thus, we assessed the effects of BFHX capsules on PM2.5-induced pulmonary inflammation and the underlying mechanisms of action. Using Polysearch and Cytoscape 3.2.1 software, pharmacological targets of BFHX capsules in atmospheric PM2.5-related respiratory disorders were predicted and found to be related to biological pathways of inflammation and immune function. In a mouse model of PM2.5-induced inflammation established with intranasal instillation of PM2.5 suspension, BFHX significantly reduced pathological response and inflammatory mediators including IL-4, IL-6, IL-10, IL-8, TNF-α, and IL-1β. BFHX also reduced keratinocyte growth factor (KGF), secretory immunoglobulin A (sIgA), and collagen fibers deposition in lung and improved lung function. Thus, BFHX reduced pathological responses induced by PM2.5, possibly via regulation of inflammatory mediators in mouse lungs. PMID:28337225

  1. Diabetic Microvascular Disease and Pulmonary Fibrosis: The Contribution of Platelets and Systemic Inflammation

    PubMed Central

    Jagadapillai, Rekha; Rane, Madhavi J.; Lin, Xingyu; Roberts, Andrew M.; Hoyle, Gary W.; Cai, Lu; Gozal, Evelyne

    2016-01-01

    Diabetes is strongly associated with systemic inflammation and oxidative stress, but its effect on pulmonary vascular disease and lung function has often been disregarded. Several studies identified restrictive lung disease and fibrotic changes in diabetic patients and in animal models of diabetes. While microvascular dysfunction is a well-known complication of diabetes, the mechanisms leading to diabetes-induced lung injury have largely been disregarded. We described the potential involvement of diabetes-induced platelet-endothelial interactions in perpetuating vascular inflammation and oxidative injury leading to fibrotic changes in the lung. Changes in nitric oxide synthase (NOS) activation and decreased NO bioavailability in the diabetic lung increase platelet activation and vascular injury and may account for platelet hyperreactivity reported in diabetic patients. Additionally, the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway has been reported to mediate pancreatic islet damage, and is implicated in the onset of diabetes, inflammation and vascular injury. Many growth factors and diabetes-induced agonists act via the JAK/STAT pathway. Other studies reported the contribution of the JAK/STAT pathway to the regulation of the pulmonary fibrotic process but the role of this pathway in the development of diabetic lung fibrosis has not been considered. These observations may open new therapeutic perspectives for modulating multiple pathways to mitigate diabetes onset or its pulmonary consequences. PMID:27834824

  2. Inflammation in pulmonary hypertension: what we know and what we could logically and safely target first.

    PubMed

    Cohen-Kaminsky, Sylvia; Hautefort, Aurélie; Price, Laura; Humbert, Marc; Perros, Frédéric

    2014-08-01

    Inflammation is important for the initiation and the maintenance of vascular remodeling in most of the animal models of pulmonary arterial hypertension (PAH), and therapeutic targeting of inflammation in these models blocks PAH development. In humans, pulmonary vascular lesions of PAH are the source of cytokine and chemokine production, related to inflammatory cell recruitment and lymphoid neogenesis. Circulating autoantibodies to endothelial cells and to fibroblasts have been reported in 10-40% of patients with idiopathic PAH, suggesting a possible role for autoimmunity in the pathogenesis of pulmonary vascular lesions. Current specific PAH treatments have immunomodulatory properties, and some studies have demonstrated a correlation between levels of circulating inflammatory mediators and patient survival. New immunopathological approaches to PAH should enable the development of innovative treatments for this severe condition.

  3. Carbocisteine reduces virus-induced pulmonary inflammation in mice exposed to cigarette smoke.

    PubMed

    Yageta, Yuichi; Ishii, Yukio; Morishima, Yuko; Ano, Satoshi; Ohtsuka, Shigeo; Matsuyama, Masashi; Takeuchi, Kaoru; Itoh, Ken; Yamamoto, Masayuki; Hizawa, Nobuyuki

    2014-05-01

    Carbocisteine (S-CMC) inhibits viral infection and prevents acute exacerbation of chronic obstructive pulmonary disease. We recently demonstrated the protective effects of NF-E2-related factor (Nrf) 2 against influenza virus (FluV)-induced pulmonary inflammation in mice exposed to cigarette smoke (CS). In our current study, we investigated the effects of S-CMC on Nrf2 activation in cultured macrophages, and in mice infected with influenza after exposure to CS. Nuclear translocation of Nrf2 and the expression of Nrf2-targeted antioxidant genes, such as heavy and light subunits of γ glutamyl cysteine synthetase and heme oxigenase-1, were enhanced in a dose-dependent manner after treatment with S-CMC in peritoneal and alveolar macrophages of wild-type mice, but not in those of Nrf2-deficient mice. Nuclear translocation of Nrf2 in macrophages was inhibited by the phosphatidylinositol 3-kinase inhibitor, LY294002. Phosphorylated Akt, Nrf2, and heme oxigenase-1 were induced in the alveolar macrophages of the lungs in wild-type mice after S-CMC administration. The extent of oxidative stress, inflammatory cell infiltration, pulmonary edema, and goblet cell hyperplasia was suppressed by S-CMC administration in the lungs of wild-type mice after exposure to both CS and FluV. Our findings suggest that S-CMC reduces pulmonary inflammation and mucus overproduction in mice exposed to CS after infection with FluV via the activation of Nrf2.

  4. Prostaglandin D2 Attenuates Bleomycin-Induced Lung Inflammation and Pulmonary Fibrosis

    PubMed Central

    Omori, Keisuke; Nakamura, Tatsuro; Maehara, Toko; Aritake, Kosuke; Urade, Yoshihiro; Murata, Takahisa

    2016-01-01

    Pulmonary fibrosis is a progressive and fatal lung disease with limited therapeutic options. Although it is well known that lipid mediator prostaglandins are involved in the development of pulmonary fibrosis, the role of prostaglandin D2 (PGD2) remains unknown. Here, we investigated whether genetic disruption of hematopoietic PGD synthase (H-PGDS) affects the bleomycin-induced lung inflammation and pulmonary fibrosis in mouse. Compared with H-PGDS naïve (WT) mice, H-PGDS-deficient mice (H-PGDS-/-) represented increased collagen deposition in lungs 14 days after the bleomycin injection. The enhanced fibrotic response was accompanied by an increased mRNA expression of inflammatory mediators, including tumor necrosis factor-α, monocyte chemoattractant protein-1, and cyclooxygenase-2 on day 3. H-PGDS deficiency also increased vascular permeability on day 3 and infiltration of neutrophils and macrophages in lungs on day 3 and 7. Immunostaining showed that the neutrophils and macrophages expressed H-PGDS, and its mRNA expression was increased on day 3and 7 in WT lungs. These observations suggest that H-PGDS-derived PGD2 plays a protective role in bleomycin-induced lung inflammation and pulmonary fibrosis. PMID:27992456

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

    PubMed

    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 1h 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 6h 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.

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

    PubMed Central

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

    2013-01-01

    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. PMID:23800689

  7. Local delivery of siRNA-loaded calcium phosphate nanoparticles abates pulmonary inflammation.

    PubMed

    Frede, Annika; Neuhaus, Bernhard; Knuschke, Torben; Wadwa, Munisch; Kollenda, Sebastian; Klopfleisch, Robert; Hansen, Wiebke; Buer, Jan; Bruder, Dunja; Epple, Matthias; Westendorf, Astrid M

    2017-08-08

    The local interference of cytokine signaling mediated by siRNA-loaded nanoparticles might be a promising new therapeutic approach to dampen inflammation during pulmonary diseases. For the local therapeutic treatment of pulmonary inflammation, we produced multi-shell nanoparticles consisting of a calcium phosphate core, coated with siRNAs directed against pro-inflammatory mediators, encapsulated into poly(lactic-co-glycolic acid), and coated with a final outer layer of polyethylenimine. Nasal instillation of nanoparticles loaded with a mixture of siRNAs directed against different cytokines to mice suffering from TH1 cell-mediated lung inflammation, or of siRNA directed against NS-1 in an influenza infection model led to a significant reduction of target gene expression which was accompanied by distinct amelioration of lung inflammation in both models. Thus, this study provides strong evidence that the specific and local modulation of the inflammatory response by CaP/PLGA nanoparticle-mediated siRNA delivery could be a promising approach for the treatment of inflammatory disorders of the lung. Copyright © 2017 Elsevier Inc. All rights reserved.

  8. Pulmonary and pleural inflammation after intratracheal instillation of short single-walled and multi-walled carbon nanotubes.

    PubMed

    Fujita, Katsuhide; Fukuda, Makiko; Endoh, Shigehisa; Maru, Junko; Kato, Haruhisa; Nakamura, Ayako; Shinohara, Naohide; Uchino, Kanako; Honda, Kazumasa

    2016-08-22

    Relationships between the physical properties of carbon nanotubes (CNTs) and their toxicities have been studied. However, little research has been conducted to investigate the pulmonary and pleural inflammation caused by short-fiber single-walled CNTs (SWCNTs) and multi-walled CNTs (MWCNTs). This study was performed to characterize differences in rat pulmonary and pleural inflammation caused by intratracheal instillation with doses of 0.15 or 1.5mg/kg of either short-sized SWCNTs or MWCNTs. Data from bronchoalveolar lavage fluid analysis, histopathological findings, and transcriptional profiling of rat lungs obtained over a 90-day period indicated that short SWCNTs caused persistent pulmonary inflammation. In addition, the short MWCNTs markedly impacted alveoli immediately after instillation, with the levels of pulmonary inflammation following MWCNT instillation being reduced in a time-dependent manner. MWCNT instillation induced greater levels of pleural inflammation than did short SWCNTs. SWCNTs and MWCNTs translocated in mediastinal lymph nodes were observed, suggesting that SWCNTs and MWCNTs underwent lymphatic drainage to the mediastinal lymph nodes after pleural penetration. Our results suggest that short SWCNTs and MWCNTs induced pulmonary and pleural inflammation and that they might be transported throughout the body after intratracheal instillation. The extent of changes in inflammation differed following SWCNT and MWCNT instillation in a time-dependent manner. Copyright © 2016 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

  9. Resveratrol alleviate hypoxic pulmonary hypertension via anti-inflammation and anti-oxidant pathways in rats.

    PubMed

    Xu, Dunquan; Li, Yan; Zhang, Bo; Wang, Yanxia; Liu, Yi; Luo, Ying; Niu, Wen; Dong, Mingqing; Liu, Manling; Dong, Haiying; Zhao, Pengtao; Li, Zhichao

    2016-01-01

    Resveratrol, a plant-derived polyphenolic compound and a phytoestrogen, was shown to possess multiple protective effects including anti-inflammatory response and anti-oxidative stress. Hypoxic pulmonary hypertension (HPH) is a progressive disease characterized by sustained vascular resistance and marked pulmonary vascular remodeling. The exact mechanisms of HPH are still unclear, but inflammatory response and oxidative stress was demonstrated to participate in the progression of HPH. The present study was designed to investigate the effects of resveratrol on HPH development. Sprague-Dawley rats were challenged by hypoxia exposure for 28 days to mimic hypoxic pulmonary hypertension along with treating resveratrol (40 mg/kg/day). Hemodynamic and pulmonary pathomorphology data were then obtained, and the anti-proliferation effect of resveratrol was determined by in vitro assays. The anti-inflammation and anti-oxidative effects of resveratrol were investigated in vivo and in vitro. The present study showed that resveratrol treatment alleviated right ventricular systolic pressure and pulmonary arterial remodeling induced by hypoxia. In vitro experiments showed that resveratrol notably inhibited proliferation of pulmonary arterial smooth muscle cells in an ER-independent manner. Data showed that resveratrol administration inhibited HIF-1 α expression in vivo and in vitro, suppressed inflammatory cells infiltration around the pulmonary arteries, and decreased ROS production induced by hypoxia in PAMSCs. The inflammatory cytokines' mRNA levels of tumor necrosis factor α, interleukin 6, and interleukin 1β were all suppressed by resveratrol treatment. The in vitro assays showed that resveratrol inhibited the expression of HIF-1 α via suppressing the MAPK/ERK1 and PI3K/AKT pathways. The antioxidant axis of Nuclear factor erythroid-2 related factor 2/ Thioredoxin 1 (Nrf-2/Trx-1) was up-regulated both in lung tissues and in cultured PASMCs. In general, the current study

  10. Resveratrol alleviate hypoxic pulmonary hypertension via anti-inflammation and anti-oxidant pathways in rats

    PubMed Central

    Xu, Dunquan; Li, Yan; Zhang, Bo; Wang, Yanxia; Liu, Yi; Luo, Ying; Niu, Wen; Dong, Mingqing; Liu, Manling; Dong, Haiying; Zhao, Pengtao; Li, Zhichao

    2016-01-01

    Resveratrol, a plant-derived polyphenolic compound and a phytoestrogen, was shown to possess multiple protective effects including anti-inflammatory response and anti-oxidative stress. Hypoxic pulmonary hypertension (HPH) is a progressive disease characterized by sustained vascular resistance and marked pulmonary vascular remodeling. The exact mechanisms of HPH are still unclear, but inflammatory response and oxidative stress was demonstrated to participate in the progression of HPH. The present study was designed to investigate the effects of resveratrol on HPH development. Sprague-Dawley rats were challenged by hypoxia exposure for 28 days to mimic hypoxic pulmonary hypertension along with treating resveratrol (40 mg/kg/day). Hemodynamic and pulmonary pathomorphology data were then obtained, and the anti-proliferation effect of resveratrol was determined by in vitro assays. The anti-inflammation and anti-oxidative effects of resveratrol were investigated in vivo and in vitro. The present study showed that resveratrol treatment alleviated right ventricular systolic pressure and pulmonary arterial remodeling induced by hypoxia. In vitro experiments showed that resveratrol notably inhibited proliferation of pulmonary arterial smooth muscle cells in an ER-independent manner. Data showed that resveratrol administration inhibited HIF-1 α expression in vivo and in vitro, suppressed inflammatory cells infiltration around the pulmonary arteries, and decreased ROS production induced by hypoxia in PAMSCs. The inflammatory cytokines' mRNA levels of tumor necrosis factor α, interleukin 6, and interleukin 1β were all suppressed by resveratrol treatment. The in vitro assays showed that resveratrol inhibited the expression of HIF-1 α via suppressing the MAPK/ERK1 and PI3K/AKT pathways. The antioxidant axis of Nuclear factor erythroid-2 related factor 2/ Thioredoxin 1 (Nrf-2/Trx-1) was up-regulated both in lung tissues and in cultured PASMCs. In general, the current study

  11. Clinical application of autologous technetium-99m-labelled eosinophils to detect focal eosinophilic inflammation in the lung.

    PubMed

    Loutsios, Chrystalla; Farahi, Neda; Simmonds, Rosalind; Cullum, Ian; Gillett, Daniel; Solanki, Chandra; Solanki, Kishor; Buscombe, John; Condliffe, Alison M; Peters, A Mike; Chilvers, Edwin R

    2015-11-01

    The detection of focal eosinophilic inflammation by non-invasive means may aid the diagnosis and follow-up of a variety of pulmonary pathologies. All current methods of detection involve invasive sampling, which may be contraindicated or too high-risk to be performed safely. The use of injected autologous technetium-99m (Tc-99m)-labelled eosinophils coupled to single-photon emission computed tomography (SPECT) has been demonstrated to localise eosinophilic inflammation in the lungs of a patient with antineutrophil cytoplasmic antibody-positive vasculitis. Here, we report on the utility of this technique to detect active eosinophilic inflammation in a patient with focal lung inflammation where a biopsy was contraindicated.

  12. Sequential Exposure to Carbon Nanotubes and Bacteria Enhances Pulmonary Inflammation and Infectivity

    PubMed Central

    Shvedova, Anna A.; Fabisiak, James P.; Kisin, Elena R.; Murray, Ashley R.; Roberts, Jenny R.; Tyurina, Yulia Y.; Antonini, James M.; Feng, Wei Hong; Kommineni, Choudari; Reynolds, Jeffrey; Barchowsky, Aaron; Castranova, Vince; Kagan, Valerian E.

    2008-01-01

    Carbon nanotubes (CNT), with their applications in industry and medicine, may lead to new risks to human health. CNT induce a robust pulmonary inflammation and oxidative stress in rodents. Realistic exposures to CNT may occur in conjunction with other pathogenic impacts (microbial infections) and trigger enhanced responses. We evaluated interactions between pharyngeal aspiration of single-walled CNT (SWCNT) and bacterial pulmonary infection of C57BL/6 mice with Listeria monocytogenes (LM). Mice were given SWCNT (0, 10, and 40 μg/mouse) and 3 days later were exposed to LM (103 bacteria/mouse). Sequential exposure to SWCNT/LM amplified lung inflammation and collagen formation. Despite this robust inflammatory response, SWCNT pre-exposure significantly decreased the pulmonary clearance of LM-exposed mice measured 3 to 7 days after microbial infection versus PBS/LM-treated mice. Decreased bacterial clearance in SWCNT-pre-exposed mice was associated with decreased phagocytosis of bacteria by macrophages and a decrease in nitric oxide production by these phagocytes. Pre-incubation of naïve alveolar macrophages with SWCNT in vitro also resulted in decreased nitric oxide generation and suppressed phagocytizing activity toward LM. Failure of SWCNT-exposed mice to clear LM led to a continued elevation in nearly all major chemokines and acute phase cytokines into the later course of infection. In SWCNT/LM-exposed mice, bronchoalveolar lavage neutrophils, alveolar macrophages, and lymphocytes, as well as lactate dehydrogenase level, were increased compared with mice exposed to SWCNT or LM alone. In conclusion, enhanced acute inflammation and pulmonary injury with delayed bacterial clearance after SWCNT exposure may lead to increased susceptibility to lung infection in exposed populations. PMID:18096873

  13. Non-invasive biomarkers of pulmonary damage and inflammation: Application to children exposed to ozone and trichloramine

    SciTech Connect

    Bernard, Alfred . E-mail: bernard@toxi.ucl.ac.be; Carbonnelle, Sylviane; Nickmilder, Marc; Burbure, Claire de

    2005-08-07

    To date, airways injury or inflammation caused by air pollutants has been evaluated mainly by analysis of bronchoalveolar lavage, an invasive technique totally unsuitable to children. The assessment of respiratory risks in this particularly vulnerable population has thus for a long time relied on spirometric tests and self-reported symptoms which are relatively late and inaccurate indicators of lung damage. Research in the field of biomarkers is now opening new perspectives with the development of non-invasive tests allowing to monitor inflammation and damage in the deep lung. Blood tests measuring lung-specific proteins (pneumoproteins) such as Clara cell protein (CC16) and surfactant-associated proteins (A, B or D) are now available to evaluate the permeability and/or the cellular integrity of the pulmonary epithelium. The application of these tests to children has recently led to the discovery of a lung epithelium hyperpermeability caused by trichloramine (nitrogen trichloride), an irritant gas contaminating the air of indoor-chlorinated pools. Serum CC16 can also serve to detect increases of airway permeability during short-term exposures to ambient ozone. Indicators measurable in exhaled air such as nitric oxide (NO) appear more useful to detect airway inflammation. By applying the exhaled NO test to children attending summer camps, we recently found that ambient ozone produces an acute inflammatory response in children from levels slightly lower than current air quality guidelines. In a study exploring the links between atopy, asthma, and exposure to chlorination products in indoor pools, we also found that the exhaled NO test can serve to detect the chronic airway inflammation associated with excessive exposure to trichloramine. Lung-specific proteins measurable in serum and markers in exhaled air represent sensitive tools that can be used to assess non-invasively the effects of air pollutants on the respiratory tract of children.

  14. 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.

  15. Inhibitory effects of Cnidium monnieri fruit extract on pulmonary inflammation in mice induced by cigarette smoke condensate and lipopolysaccharide.

    PubMed

    Kwak, Ho-Geun; Lim, Heung-Bin

    2014-09-01

    The aim of this study was to investigate the inhibitory effect of Cnidium monnieri fruit (CM) extracts on pulmonary inflammation induced in mice by cigarette smoke condensate (CSC) and lipopolysaccharide (LPS). Pulmonary inflammation was induced by intratracheal instillation of LPS and CSC five times within 12 days. CM extract was administered orally at a dose of 50 or 200 mg·kg(-1). The number of inflammatory cells in the bronchoalveolar lavage fluid was counted using a fluorescence activated cell sorter. Inflammatory mediator levels were determined by enzyme-linked immunosorbent assay. The administration of LPS and CSC exacerbated airway hyper-responsiveness (AHR) and induced an accumulation of inflammatory cells and mediators, and led to histological changes. However, these responses are modulated by treatment with CM, and the treatment with CM extract produces similar or more extensive results than the treatment with cyclosporin A (CSA). CM extract may have an inhibitory effect on pulmonary inflammation related with chronic obstructive pulmonary disease.

  16. Matrikines are key regulators in modulating the amplitude of lung inflammation in acute pulmonary infection

    PubMed Central

    Akthar, Samia; Patel, Dhiren F.; Beale, Rebecca C.; Peiró, Teresa; Xu, Xin; Gaggar, Amit; Jackson, Patricia L.; Blalock, J. Edwin; Lloyd, Clare M.; Snelgrove, Robert J.

    2015-01-01

    Bioactive matrix fragments (matrikines) have been identified in a myriad of disorders, but their impact on the evolution of airway inflammation has not been demonstrated. We recently described a pathway where the matrikine and neutrophil chemoattractant proline–glycine–proline (PGP) could be degraded by the enzyme leukotriene A4 hydrolase (LTA4H). LTA4H classically functions in the generation of pro-inflammatory leukotriene B4, thus LTA4H exhibits opposing pro- and anti-inflammatory activities. The physiological significance of this secondary anti-inflammatory activity remains unknown. Here we show, using readily resolving pulmonary inflammation models, that loss of this secondary activity leads to more pronounced and sustained inflammation and illness owing to PGP accumulation. PGP elicits an exacerbated neutrophilic inflammation and protease imbalance that further degrades the extracellular matrix, generating fragments that perpetuate inflammation. This highlights a critical role for the secondary anti-inflammatory activity of LTA4H and thus has consequences for the generation of global LTA4H inhibitors currently being developed. PMID:26400771

  17. Effect of Naturally Occurring Ozone Air Pollution Episodes on Pulmonary Oxidative Stress and Inflammation

    PubMed Central

    Pirozzi, Cheryl; Sturrock, Anne; Weng, Hsin-Yi; Greene, Tom; Scholand, Mary Beth; Kanner, Richard; Paine, Robert

    2015-01-01

    This study aimed to determine if naturally occurring episodes of ozone air pollution in the Salt Lake Valley in Utah, USA, during the summer are associated with increased pulmonary inflammation and oxidative stress, increased respiratory symptoms, and decreased lung function in individuals with chronic obstructive pulmonary disease (COPD) compared to controls. We measured biomarkers (nitrite/nitrate (NOx), 8-isoprostane) in exhaled breath condensate (EBC), spirometry, and respiratory symptoms in 11 former smokers with moderate-to-severe COPD and nine former smokers without airflow obstruction during periods of low and high ozone air pollution. High ozone levels were associated with increased NOx in EBC in both COPD (8.7 (±8.5) vs. 28.6 (±17.6) μmol/L on clean air vs. pollution days, respectively, p < 0.01) and control participants (7.6 (±16.5) vs. 28.5 (±15.6) μmol/L on clean air vs. pollution days, respectively, p = 0.02). There was no difference in pollution effect between COPD and control groups, and no difference in EBC 8-isoprostane, pulmonary function, or respiratory symptoms between clean air and pollution days in either group. Former smokers both with and without airflow obstruction developed airway oxidative stress and inflammation in association with ozone air pollution episodes. PMID:25985308

  18. Effect of naturally occurring ozone air pollution episodes on pulmonary oxidative stress and inflammation.

    PubMed

    Pirozzi, Cheryl; Sturrock, Anne; Weng, Hsin-Yi; Greene, Tom; Scholand, Mary Beth; Kanner, Richard; Paine, Robert

    2015-05-12

    This study aimed to determine if naturally occurring episodes of ozone air pollution in the Salt Lake Valley in Utah, USA, during the summer are associated with increased pulmonary inflammation and oxidative stress, increased respiratory symptoms, and decreased lung function in individuals with chronic obstructive pulmonary disease (COPD) compared to controls. We measured biomarkers (nitrite/nitrate (NOx), 8-isoprostane) in exhaled breath condensate (EBC), spirometry, and respiratory symptoms in 11 former smokers with moderate-to-severe COPD and nine former smokers without airflow obstruction during periods of low and high ozone air pollution. High ozone levels were associated with increased NOx in EBC in both COPD (8.7 (±8.5) vs. 28.6 (±17.6) μmol/L on clean air vs. pollution days, respectively, p < 0.01) and control participants (7.6 (±16.5) vs. 28.5 (±15.6) μmol/L on clean air vs. pollution days, respectively, p = 0.02). There was no difference in pollution effect between COPD and control groups, and no difference in EBC 8-isoprostane, pulmonary function, or respiratory symptoms between clean air and pollution days in either group. Former smokers both with and without airflow obstruction developed airway oxidative stress and inflammation in association with ozone air pollution episodes.

  19. Lung inflammation and genotoxicity in mice lungs after pulmonary exposure to candle light combustion particles.

    PubMed

    Skovmand, Astrid; Damiao Gouveia, Ana Cecilia; Koponen, Ismo Kalevi; Møller, Peter; Loft, Steffen; Roursgaard, Martin

    2017-07-05

    Candle burning produces a large amount of particles that contribute substantially to the exposure to indoor particulate matter. The exposures to various types of combustion particles, such as diesel exhaust particles, have been associated with increased risk of lung cancer by mechanisms that involve oxidative stress, inflammation and genotoxicity. The aim of this study was to compare pulmonary effects of candle light combustion particles (CP) with two benchmark diesel exhaust particles (A-DEP and SRM2975). Intratracheal (i.t.) instillation of CP (5mg/kg bodyweight) in C57BL/6n mice produced a significant influx of alveolar macrophages and polymorphonuclear leukocytes and increased concentrations of proteins and lactate dehydrogenase activity in bronchoalveolar fluid. Lower levels of these markers of inflammation and cytotoxicity were observed after i.t. instillation of the same dose of A-DEP or SRM2975. The i.t. instillation of CP did not generate oxidative damage to DNA in lung tissue, measured as DNA strand breaks and human 8-oxoguanine glycosylase-sensitive sites by the comet assay. The lack of genotoxic response was confirmed in lung epithelial (A549) cells, although the exposure to CP increased intracellular levels of reactive oxygen species. In conclusion, pulmonary exposure to particles from burning candles is associated with inflammation and cytotoxicity in the lungs. Copyright © 2017 Elsevier B.V. All rights reserved.

  20. Acute secondhand smoke-induced pulmonary inflammation is diminished in RAGE knockout mice.

    PubMed

    Wood, Tyler T; Winden, Duane R; Marlor, Derek R; Wright, Alex J; Jones, Cameron M; Chavarria, Michael; Rogers, Geraldine D; Reynolds, Paul R

    2014-11-15

    The receptor for advanced glycation end-products (RAGE) has increasingly been demonstrated to be an important modulator of inflammation in cases of pulmonary disease. Published reports involving tobacco smoke exposure have demonstrated increased expression of RAGE, its participation in proinflammatory signaling, and its role in irreversible pulmonary remodeling. The current research evaluated the in vivo effects of short-term secondhand smoke (SHS) exposure in RAGE knockout and control mice compared with identical animals exposed to room air only. Quantitative PCR, immunoblotting, and immunohistochemistry revealed elevated RAGE expression in controls after 4 wk of SHS exposure and an anticipated absence of RAGE expression in RAGE knockout mice regardless of smoke exposure. Ras activation, NF-κB activity, and cytokine elaboration were assessed to characterize the molecular basis of SHS-induced inflammation in the mouse lung. Furthermore, bronchoalveolar lavage fluid was procured from RAGE knockout and control animals for the assessment of inflammatory cells and molecules. As a general theme, inflammation coincident with leukocyte recruitment was induced by SHS exposure and significantly influenced by the availability of RAGE. These data reveal captivating information suggesting a role for RAGE signaling in lungs exposed to SHS. However, ongoing research is still warranted to fully explain roles for RAGE and other receptors in cells coping with involuntary smoke exposure for prolonged periods of time. Copyright © 2014 the American Physiological Society.

  1. Fresh frozen plasma lessens pulmonary endothelial inflammation and hyperpermeability after hemorrhagic shock and is associated with loss of syndecan-1

    PubMed Central

    Peng, Zhanglong; Pati, Shibani; Potter, Daniel; Brown, Ryan; Holcomb, John B; Grill, Raymond; Wataha, Kathryn; Park, Pyong Woo; Xue, Hasen; Kozar, Rosemary A

    2013-01-01

    BACKGROUND We have recently demonstrated that injured patients in hemorrhagic shock shed syndecan-1 and that the early use of fresh frozen plasma (FFP) in these patients is correlated with improved clinical outcomes. As the lungs are frequently injured after trauma, we hypothesized that hemorrhagic shock-induced shedding of syndecan-1 exposes the underlying pulmonary vascular endothelium to injury resulting in inflammation and hyperpermeability, and that these effects would be mitigated by FFP. METHODS In vitro, pulmonary endothelial permeability, endothelial monolayer flux, transendothelial electrical resistance (TER), and leukocyte-endothelial binding were measured in pulmonary endothelial cells after incubation with equal volumes of FFP or lactated Ringers (LR). In vivo, using a coagulopathic mouse model of trauma and hemorrhagic shock, pulmonary hyperpermeability, neutrophil infiltration, and syndecan-1 expression and systemic shedding were assessed after three hours of resuscitation with either 1XFFP or 3XLR and compared to shock alone and shams. RESULTS In vitro, endothelial permeability and flux were decreased, TER was increased, and leukocyte-endothelial binding was inhibited by FFP compared to LR treated endothelial cells. In vivo, hemorrhagic shock was associated with systemic shedding of syndecan-1 which correlated with decreased pulmonary sydnecan-1 and increased pulmonary vascular hyperpermeability and inflammation. FFP resuscitation, compared to LR resuscitation, abrogated these injurious effects. CONCLUSIONS After hemorrhagic shock, FFP resuscitation inhibits endothelial cell hyperpermeability and inflammation and restores pulmonary syndecan-1 expression. Modulation of pulmonary syndecan-1 expression may mechanistically contribute to the beneficial effects FFP. PMID:23807246

  2. Fresh frozen plasma lessens pulmonary endothelial inflammation and hyperpermeability after hemorrhagic shock and is associated with loss of syndecan 1.

    PubMed

    Peng, Zhanglong; Pati, Shibani; Potter, Daniel; Brown, Ryan; Holcomb, John B; Grill, Raymond; Wataha, Kathryn; Park, Pyong Woo; Xue, Hasen; Kozar, Rosemary A

    2013-09-01

    We have recently demonstrated that injured patients in hemorrhagic shock shed syndecan 1 and that the early use of fresh frozen plasma (FFP) in these patients is correlated with improved clinical outcomes. As the lungs are frequently injured after trauma, we hypothesized that hemorrhagic shock-induced shedding of syndecan 1 exposes the underlying pulmonary vascular endothelium to injury resulting in inflammation and hyperpermeability and that these effects would be mitigated by FFP. In vitro, pulmonary endothelial permeability, endothelial monolayer flux, transendothelial electrical resistance, and leukocyte-endothelial binding were measured in pulmonary endothelial cells after incubation with equal volumes of FFP or lactated Ringer's (LR). In vivo, using a coagulopathic mouse model of trauma and hemorrhagic shock, pulmonary hyperpermeability, neutrophil infiltration, and syndecan 1 expression and systemic shedding were assessed after 3 h of resuscitation with either 1× FFP or 3× LR and compared with shock alone and shams. In vitro, endothelial permeability and flux were decreased, transendothelial electrical resistance was increased, and leukocyte-endothelial binding was inhibited by FFP compared with LR-treated endothelial cells. In vivo, hemorrhagic shock was associated with systemic shedding of syndecan 1, which correlated with decreased pulmonary syndecan 1 and increased pulmonary vascular hyperpermeability and inflammation. Fresh frozen plasma resuscitation, compared with LR resuscitation, abrogated these injurious effects. After hemorrhagic shock, FFP resuscitation inhibits endothelial cell hyperpermeability and inflammation and restores pulmonary syndecan 1 expression. Modulation of pulmonary syndecan 1 expression may mechanistically contribute to the beneficial effects FFP.

  3. Attenuation of pulmonary inflammation after exposure to blast overpressure by N-acetylcysteine amide.

    PubMed

    Chavko, Mikulas; Adeeb, Saleena; Ahlers, Stephen T; McCarron, Richard M

    2009-09-01

    Lung contusion is a common problem from blunt chest trauma caused by mechanical forces and by exposure to blast overpressure, often with fatal consequences. Lung contusion is also a risk factor for the development of pneumonia, severe clinical acute lung injury (ALI), and acute respiratory distress syndrome (ARDS). Infiltrating neutrophils are considered to be central mediators of lung injuries after blunt trauma. Recent studies have demonstrated that antioxidants reduced pulmonary inflammation in different models of lung damage. This study examined the effect of antioxidant N-acetylcysteine amide (NACA) on the progression of lung inflammation after exposure to a moderate level of blast overpressure (140 kPa). Rats were administered with NACA (i.p. 100 mg/kg) or placebo (PBS) 30, 60 min and 24 h after exposure. Nonblasted sham-injected animals served as controls. Neutrophil infiltration measured by myeloperoxidase (MPO) activity in the lung was significantly increased at 2 days after blast and returned to controls at 8 days. This increase corresponded with activation of integrin CD11b mRNA and lung inflammatory chemokine mRNA expression; macrophage inflammatory protein-1 (MIP-1), monocyte chemotactic peptide-1 (MCP-1), and cytokine-induced neutrophil chemoattractant-1 (CINC-1). At 8 days, all inflammatory mediators returned to control levels. In addition, expression of heme oxygenase-1 (HO-1) mRNA increased at 2 days after exposure. No changes were detected in the lung manganase superoxide dismutase (MnSOD) or glutathione reductase (GR) mRNA expression after blast. N-Acetylcysteine amide significantly reduced infiltration of neutrophils and CD11b mRNA activation in lungs, and completely blocked activation of MIP-1, MCP-1 and CINC-1 mRNA. The relatively higher inhibition of chemokine mRNAs compared with reduction in MPO activity and CD11b is in accordance with an antioxidant effect of NACA on reactive oxygen species (ROS) accumulation, rather than by an effect on

  4. Serum amyloid A opposes lipoxin A₄ to mediate glucocorticoid refractory lung inflammation in chronic obstructive pulmonary disease.

    PubMed

    Bozinovski, Steven; Uddin, Mohib; Vlahos, Ross; Thompson, Michelle; McQualter, Jonathan L; Merritt, Anne-Sophie; Wark, Peter A B; Hutchinson, Anastasia; Irving, Louis B; Levy, Bruce D; Anderson, Gary P

    2012-01-17

    Chronic obstructive pulmonary disease (COPD) will soon be the third most common cause of death globally. Despite smoking cessation, neutrophilic mucosal inflammation persistently damages the airways and fails to protect from recurrent infections. This maladaptive and excess inflammation is also refractory to glucocorticosteroids (GC). Here, we identify serum amyloid A (SAA) as a candidate mediator of GC refractory inflammation in COPD. Extrahepatic SAA was detected locally in COPD bronchoalveolar lavage fluid, which correlated with IL-8 and neutrophil elastase, consistent with neutrophil recruitment and activation. Immunohistochemistry detected SAA was in close proximity to airway epithelium, and in vitro SAA triggered release of IL-8 and other proinflammatory mediators by airway epithelial cells in an ALX/FPR2 (formyl peptide receptor 2) receptor-dependent manner. Lipoxin A(4) (LXA(4)) can also interact with ALX/FPR2 receptors and lead to allosteric inhibition of SAA-initiated epithelial responses (pA(2) 13 nM). During acute exacerbation, peripheral blood SAA levels increased dramatically and were disproportionately increased relative to LXA(4). Human lung macrophages (CD68(+)) colocalized with SAA and GCs markedly increased SAA in vitro (THP-1, pEC(50) 43 nM). To determine its direct actions, SAA was administered into murine lung, leading to induction of CXC chemokine ligand 1/2 and a neutrophilic response that was inhibited by 15-epi-LXA(4) but not dexamethasone. Taken together, these findings identify SAA as a therapeutic target for inhibition and implicate SAA as a mediator of GC-resistant lung inflammation that can overwhelm organ protective signaling by lipoxins at ALX/FPR2 receptors.

  5. Silver Nanoparticles: A study of dissolution, kinetics, and factors affecting pulmonary inflammation

    NASA Astrophysics Data System (ADS)

    Saunders, Eric L.

    The growing use of silver (Ag) nanoparticles (NP) in consumer and industrial goods has led to an increase in interest in the health effects associated with exposure, both occupationally and environmentally. The aim of this research is to examine the contribution of size, shape, and dissolution of AgNP, with its corresponding effect on pulmonary inflammation and clearance. In addition this study looks at metallothionein (MT) and the role it plays as an inflammatory modulator. A nose only exposure method was used to expose three strains of mouse (two inbred, one knockout) to two different sizes of AgNP (˜25 nm and ˜100 nm). This research demonstrates that size, chemistry, and dissolution play key roles in NP deposition and inflammatory response, while no conclusions could be drawn about shape. Additionally, this study found that the main factors affecting the deposition of NP in mice both acutely and sub-chronically are particle size and mouse strain. The results of this study also indicate a relationship between MT2 and inflammation. It was found that the mRNA levels of MT2 were greatly up-regulated in the livers and lungs of mice exposed to AgNP, while MT protein levels were not significantly altered to correlate with the altered regulation of mRNA. Finally, this study showed that, for AgNP, the mechanisms of pulmonary clearance and dissolution happened rapidly and that they, combined, likely represent a major pathway of AgNP transport out of the lung. Taken as a whole, the data in this study show that dissolution, coupled with protein interaction, is a significant mediator of pulmonary inflammation and translocation of AgNP.

  6. Tissue heme oxygenase-1 exerts anti-inflammatory effects on LPS-induced pulmonary inflammation.

    PubMed

    Konrad, F M; Knausberg, U; Höne, R; Ngamsri, K-C; Reutershan, J

    2016-01-01

    Heme oxygenase-1 (HO-1) has been shown to display anti-inflammatory properties in models of acute pulmonary inflammation. For the first time, we investigated the role of leukocytic HO-1 using a model of HO-1(flox/flox) mice lacking leukocytic HO-1 that were subjected to lipopolysaccharide (LPS)-induced acute pulmonary inflammation. Immunohistology and flow cytometry demonstrated that activation of HO-1 using hemin decreased migration of polymorphonuclear leukocytes (PMNs) to the lung interstitium and bronchoalveolar lavage (BAL) in the wild-type and, surprisingly, also in HO-1(flox/flox) mice, emphasizing the anti-inflammatory potential of nonmyeloid HO-1. Nevertheless, hemin reduced the CXCL1, CXCL2/3, tumor necrosis factor-α (TNFα), and interleukin 6 (IL6) levels in both animal strains. Microvascular permeability was attenuated by hemin in wild-type and HO-1(flox/flox) mice, indicating a crucial role of non-myeloid HO-1 in endothelial integrity. The determination of the activity of HO-1 in mouse lungs revealed no compensatory increase in the HO-1(flox/flox) mice. Topical administration of hemin via inhalation reduced the dose required to attenuate PMN migration and microvascular permeability by a factor of 40, emphasizing its clinical potential. In addition, HO-1 stimulation was protective against pulmonary inflammation when initiated after the inflammatory stimulus. In conclusion, nonmyeloid HO-1 is crucial for the anti-inflammatory effect of this enzyme on PMN migration to different compartments of the lung and on microvascular permeability.

  7. Herbal Formula, PM014, Attenuates Lung Inflammation in a Murine Model of Chronic Obstructive Pulmonary Disease

    PubMed Central

    Lee, Hyojung; Kim, Youngeun; Kim, Hye Jin; Park, Soojin; Jang, Young Pyo; Jung, Sungki; Jung, Heejae; Bae, Hyunsu

    2012-01-01

    Chronic obstructive pulmonary disease (COPD), which is characterized by airway obstruction, leads to, as the two major forms of COPD, chronic bronchitis and emphysema. This study was conducted to evaluate the effects of herbal formula, PM014, in a murine model of COPD. Balb/c mice were treated once with each herb extract in PM014 or PM014 mixture via an oral injection. Lipopolysaccharide (LPS) or elastase/LPS were administrated to the mice to induce a disease that resembles COPD. PM014 treatment significantly attenuated the increased accumulation of immune cells in bronchoalveolar lavage fluid (BALF) compared to control mice. In addition, the TNF-α and IL-6 levels in BALF were decreased in the PM014 mice. Furthermore, histological analysis demonstrated that PM014 attenuated the hazardous effects of lung inflammation. These data suggest that PM014 exerts beneficial effects against forms of COPD such as lung inflammation. PMID:22778777

  8. Neutrophil restraint by green tea: inhibition of inflammation, associated angiogenesis, and pulmonary fibrosis.

    PubMed

    Donà, Massimo; Dell'Aica, Isabella; Calabrese, Fiorella; Benelli, Roberto; Morini, Monica; Albini, Adriana; Garbisa, Spiridione

    2003-04-15

    Neutrophils play an essential role in host defense and inflammation, but the latter may trigger and sustain the pathogenesis of a range of acute and chronic diseases. Green tea has been claimed to exert anti-inflammatory properties through unknown molecular mechanisms. We have previously shown that the most abundant catechin of green tea, (-)epigallocatechin-3-gallate (EGCG), strongly inhibits neutrophil elastase. Here we show that 1) micromolar EGCG represses reactive oxygen species activity and inhibits apoptosis of activated neutrophils, and 2) dramatically inhibits chemokine-induced neutrophil chemotaxis in vitro; 3) both oral EGCG and green tea extract block neutrophil-mediated angiogenesis in vivo in an inflammatory angiogenesis model, and 4) oral administration of green tea extract enhances resolution in a pulmonary inflammation model, significantly reducing consequent fibrosis. These results provide molecular and cellular insights into the claimed beneficial properties of green tea and indicate that EGCG is a potent anti-inflammatory compound with therapeutic potential.

  9. Enrichment of lung microbiome with supraglottic taxa is associated with increased pulmonary inflammation

    PubMed Central

    2013-01-01

    Background The lung microbiome of healthy individuals frequently harbors oral organisms. Despite evidence that microaspiration is commonly associated with smoking-related lung diseases, the effects of lung microbiome enrichment with upper airway taxa on inflammation has not been studied. We hypothesize that the presence of oral microorganisms in the lung microbiome is associated with enhanced pulmonary inflammation. To test this, we sampled bronchoalveolar lavage (BAL) from the lower airways of 29 asymptomatic subjects (nine never-smokers, 14 former-smokers, and six current-smokers). We quantified, amplified, and sequenced 16S rRNA genes from BAL samples by qPCR and 454 sequencing. Pulmonary inflammation was assessed by exhaled nitric oxide (eNO), BAL lymphocytes, and neutrophils. Results BAL had lower total 16S than supraglottic samples and higher than saline background. Bacterial communities in the lower airway clustered in two distinct groups that we designated as pneumotypes. The rRNA gene concentration and microbial community of the first pneumotype was similar to that of the saline background. The second pneumotype had higher rRNA gene concentration and higher relative abundance of supraglottic-characteristic taxa (SCT), such as Veillonella and Prevotella, and we called it pneumotypeSCT. Smoking had no effect on pneumotype allocation, α, or β diversity. PneumotypeSCT was associated with higher BAL lymphocyte-count (P= 0.007), BAL neutrophil-count (P= 0.034), and eNO (P= 0.022). Conclusion A pneumotype with high relative abundance of supraglottic-characteristic taxa is associated with enhanced subclinical lung inflammation. PMID:24450871

  10. Airway inflammation in chronic obstructive pulmonary disease (COPD): a true paradox.

    PubMed

    Eapen, Mathew Suji; Myers, Stephen; Walters, Eugene Haydn; Sohal, Sukhwinder Singh

    2017-08-02

    Chronic obstructive pulmonary disease (COPD) is primarily an airway condition, which mainly affects cigarette smokers and presents with shortness of breath that is progressive and poorly reversible. In COPD research, there has been a long held belief that airway disease progression is due to inflammation. Although this may be true in the airway lumen with innate immunity activated by the effect of smoke or secondary to infection, the accurate picture of inflammatory cells in the airway wall, where the pathophysiological COPD remodeling occurs, is uncertain and debatable. Areas covered: The current review provides a comprehensive literature survey of the changes in the main inflammatory cells in human COPD patients and focuses on contrarian views that affect the prevailing dogma on inflammation. The review also delves into the role of oxidative stress and inflammasomes in modulating the immune response in COPD. Further, the effects of inflammation in affecting the epithelium, fibroblasts, and airway remodeling are discussed. Expert commentary: Inflammation as a driving force for airway wall damage and remodelling in early COPD is at the very least 'oversimplified' and is likely to be misleading. This has serious implications for rational thinking about the illness, including pathogenesis and designing therapy.

  11. Pulmonary Remodeling in Equine Asthma: What Do We Know about Mediators of Inflammation in the Horse?

    PubMed Central

    Gehlen, Heidrun

    2016-01-01

    Equine inflammatory airway disease (IAD) and recurrent airway obstruction (RAO) represent a spectrum of chronic inflammatory disease of the airways in horses resembling human asthma in many aspects. Therefore, both are now described as severity grades of equine asthma. Increasing evidence in horses and humans suggests that local pulmonary inflammation is influenced by systemic inflammatory processes and the other way around. Inflammation, coagulation, and fibrinolysis as well as extracellular remodeling show close interactions. Cytology of bronchoalveolar lavage fluid and tracheal wash is commonly used to evaluate the severity of local inflammation in the lung. Other mediators of inflammation, like interleukins involved in the chemotaxis of neutrophils, have been studied. Chronic obstructive pneumopathies lead to remodeling of bronchial walls and lung parenchyma, ultimately causing fibrosis. Matrix metalloproteinases (MMPs) are discussed as the most important proteolytic enzymes during remodeling in human medicine and increasing evidence exists for the horse as well. A systemic involvement has been shown for severe equine asthma by increased acute phase proteins like serum amyloid A and haptoglobin in peripheral blood during exacerbation. Studies focusing on these and further possible inflammatory markers for chronic respiratory disease in the horse are discussed in this review of the literature. PMID:28053371

  12. Eosinophilic airway inflammation: role in asthma and chronic obstructive pulmonary disease

    PubMed Central

    George, Leena; Brightling, Christopher E.

    2016-01-01

    The chronic lung diseases, asthma and chronic obstructive pulmonary disease (COPD), are common affecting over 500 million people worldwide and causing substantial morbidity and mortality. Asthma is typically associated with Th2-mediated eosinophilic airway inflammation, in contrast to neutrophilic inflammation observed commonly in COPD. However, there is increasing evidence that the eosinophil might play an important role in 10–40% of patients with COPD. Consistently in both asthma and COPD a sputum eosinophilia is associated with a good response to corticosteroid therapy and tailored strategies aimed to normalize sputum eosinophils reduce exacerbation frequency and severity. Advances in our understanding of the multistep paradigm of eosinophil recruitment to the airway, and the consequence of eosinophilic inflammation, has led to the development of new therapies to target these molecular pathways. In this article we discuss the mechanisms of eosinophilic trafficking, the tools to assess eosinophilic airway inflammation in asthma and COPD during stable disease and exacerbations and review current and novel anti-eosinophilic treatments. PMID:26770668

  13. Machine learning-based automatic detection of pulmonary trunk

    NASA Astrophysics Data System (ADS)

    Wu, Hong; Deng, Kun; Liang, Jianming

    2011-03-01

    Pulmonary embolism is a common cardiovascular emergency with about 600,000 cases occurring annually and causing approximately 200,000 deaths in the US. CT pulmonary angiography (CTPA) has become the reference standard for PE diagnosis, but the interpretation of these large image datasets is made complex and time consuming by the intricate branching structure of the pulmonary vessels, a myriad of artifacts that may obscure or mimic PEs, and suboptimal bolus of contrast and inhomogeneities with the pulmonary arterial blood pool. To meet this challenge, several approaches for computer aided diagnosis of PE in CTPA have been proposed. However, none of these approaches is capable of detecting central PEs, distinguishing the pulmonary artery from the vein to effectively remove any false positives from the veins, and dynamically adapting to suboptimal contrast conditions associated the CTPA scans. To overcome these shortcomings, it requires highly efficient and accurate identification of the pulmonary trunk. For this very purpose, in this paper, we present a machine learning based approach for automatically detecting the pulmonary trunk. Our idea is to train a cascaded AdaBoost classifier with a large number of Haar features extracted from CTPA image samples, so that the pulmonary trunk can be automatically identified by sequentially scanning the CTPA images and classifying each encountered sub-image with the trained classifier. Our approach outperforms an existing anatomy-based approach, requiring no explicit representation of anatomical knowledge and achieving a nearly 100% accuracy tested on a large number of cases.

  14. Cannabidiol (CBD) Enhances Lipopolysaccharide (LPS)-Induced Pulmonary Inflammation in C57BL/6 Mice

    PubMed Central

    Karmaus, Peer W. F.; Wagner, James G.; Harkema, Jack R.; Kaminski, Norbert E.; Kaplan, Barbara L.F.

    2012-01-01

    Cannabidiol (CBD) is a plant-derived cannabinoid that has been predominantly characterized as anti-inflammatory. However, it is clear that immune effects of cannabinoids can vary with cannabinoid concentration, or type or magnitude of immune stimulus. The present studies demonstrate that oral administration of CBD enhanced lipopolysaccharide (LPS)-induced pulmonary inflammation in C57BL/6 mice. The enhanced inflammatory cell infiltrate as observed in bronchoalveolar lavage fluid (BALF) was comprised mainly of neutrophils, with some monocytes. Concomitantly, CBD enhanced pro-inflammatory cytokine mRNA production, including tumor necrosis factor-α (Tnfa), interleukins (IL) 6 and 23 (Il6, Il23), and granulocyte colony stimulating factor (Gcsf). These results demonstrate that the CBD-mediated enhancement of LPS-induced pulmonary inflammation is mediated at the level of transcription of a variety of pro-inflammatory genes. The significance of these studies is that CBD is part of a therapeutic currently in use for spasticity and pain in multiple sclerosis patients, and therefore it is important to further understand mechanisms by which CBD alters immune function. PMID:23173851

  15. The P2Y6 Receptor Inhibits Effector T Cell Activation in Allergic Pulmonary Inflammation1

    PubMed Central

    Giannattasio, Giorgio; Ohta, Shin; Boyce, Joshua R.; Xing, Wei; Balestrieri, Barbara; Boyce, Joshua A.

    2011-01-01

    We show that the P2Y6 receptor, a G-protein-coupled receptor with high affinity for the nucleotide uridine diphosphate, is an important endogenous inhibitor of T cell function in allergic pulmonary inflammation. Mice conditionally deficient in P2Y6 receptors [p2ry6 (flox/flox);cre/+ mice] exhibited severe airway and tissue pathology relative to P2Y6-sufficient [p2ry6 (flox/flox)] littermates (+/+ mice) when treated intranasally with an extract (Df) of the dust mite Dermatophagoides farinae. P2Y6 receptors were inducibly expressed by lung, lymph node and splenic CD4+ and CD8+ T cells of Df-treated +/+ mice. Df-restimulated P2Y6-deficient lymph node cells produced higher levels of Th1 and Th2 cytokines, and polyclonally-stimulated P2Y6-deficient CD4+ T cells proliferated faster than comparably stimulated P2Y6-sufficient cells. The absence of P2Y6 receptors on CD4+ cells, but not antigen presenting cells, was sufficient to amplify cytokine generation. Thus, P2Y6 receptors protect the lung against exuberant allergen-induced pulmonary inflammation by inhibiting the activation of effector T cells. PMID:21724990

  16. Cannabidiol (CBD) enhances lipopolysaccharide (LPS)-induced pulmonary inflammation in C57BL/6 mice.

    PubMed

    Karmaus, Peer W F; Wagner, James G; Harkema, Jack R; Kaminski, Norbert E; Kaplan, Barbara L F

    2013-01-01

    Cannabidiol (CBD) is a plant-derived cannabinoid that has been predominantly characterized as anti-inflammatory. However, it is clear that immune effects of cannabinoids can vary with cannabinoid concentration, or type or magnitude of immune stimulus. The present studies demonstrate that oral administration of CBD enhanced lipopolysaccharide (LPS)-induced pulmonary inflammation in C57BL/6 mice. The enhanced inflammatory cell infiltrate as observed in bronchoalveolar lavage fluid (BALF) was comprised mainly of neutrophils, with some monocytes. Concomitantly, CBD enhanced pro-inflammatory cytokine mRNA production, including tumor necrosis factor-α (Tnfa), interleukins (IL)-5 and -23 (Il6, Il23), and granulocyte colony stimulating factor (Gcsf). These results demonstrate that the CBD-mediated enhancement of LPS-induced pulmonary inflammation is mediated at the level of transcription of a variety of pro-inflammatory genes. The significance of these studies is that CBD is part of a therapeutic currently in use for spasticity and pain in multiple sclerosis patients, and therefore it is important to further understand mechanisms by which CBD alters immune function.

  17. Standardized Herbal Formula PM014 Inhibits Radiation-Induced Pulmonary Inflammation in Mice

    PubMed Central

    Kim, Jee-Youn; Shin, Dasom; Lee, Gihyun; Kim, Jin-Mo; Kim, Dongwook; An, Yong-Min; Yoo, Byung Rok; Chang, Hanna; Kim, Miran; Cho, Jaeho; Bae, Hyunsu

    2017-01-01

    Radiation therapy is widely used for thoracic cancers. However, it occasionally causes radiation-induced lung injuries, including pneumonitis and fibrosis. Chung-Sang-Bo-Ha-Tang (CSBHT) has been traditionally used to treat chronic pulmonary disease in Korea. PM014, a modified herbal formula derived from CSBHT, contains medicinal herbs of seven species. In our previous studies, PM014 exhibited anti-inflammatory effects in a chronic obstructive pulmonary disease model. In this study, we have evaluated the effects of PM014 on radiation-induced lung inflammation. Mice in the treatment group were orally administered PM014 six times for 2 weeks. Effects of PM014 on radiation pneumonitis were evaluated based on histological findings and differential cell count in bronchoalveolar lavage fluid. PM014 treatment significantly inhibited immune cell recruitment and collagen deposition in lung tissue. Normal lung volume, evaluated by radiological analysis, in PM014-treated mice was higher compared to that in irradiated control mice. PM014-treated mice exhibited significant changes in inspiratory capacity, compliance and tissue damping and elastance. Additionally, PM014 treatment resulted in the downregulation of inflammatory cytokines, chemokines, and fibrosis-related genes and a reduction in the transforming growth factor-β1-positive cell population in lung tissue. Thus, PM014 is a potent therapeutic agent for radiation-induced lung fibrosis and inflammation. PMID:28322297

  18. Butylated hydroxytoluene (BHT) induction of pulmonary inflammation: a role in tumor promotion.

    PubMed

    Bauer, A K; Dwyer-Nield, L D; Keil, K; Koski, K; Malkinson, A M

    2001-01-01

    Chronic pulmonary inflammatory diseases predispose towards lung cancer by unknown mechanisms. Butylated hydroxytoluene (BHT) administration to mice causes lung injury and a subsequent inflammatory response, and when administered chronically to certain inbred strains following carcinogen treatment, increases lung tumor multiplicity. We hypothesize that inflammation promotes lung tumor growth in this model system and have begun to examine this hypothesis by assessing inflammatory parameters in inbred strains that vary in their susceptibility to promotion. Positive correlations were found between susceptibilities to tumor promotion and BHT induction of alveolar macrophage and lymphocyte infiltration into alveolar airspaces, and increased vascular permeability (P < .03, P < .04, and P < .005, respectively). The amounts of pulmonary cyclooxygenase (COX)-1 and COX-2 did not strongly correlate with promotion. Because persistent elevation of macrophage content is the hallmark of a chronic inflammatory response, the alveolar macrophage population was depleted by adding chlorine to the drinking water prior to carcinogenesis. This treatment reduced lung tumor multiplicity following 2-stage carcinogenesis (P < .05). These correlations between inflammatory and tumorigenic responses to BHT, along with decreased tumorigenesis after macrophage depletion, are consistent with a role of inflammation in promotion. Inflammatory mediators may provide targets for early diagnosis and chemoprevention.

  19. Interleukin-1beta causes pulmonary inflammation, emphysema, and airway remodeling in the adult murine lung.

    PubMed

    Lappalainen, Urpo; Whitsett, Jeffrey A; Wert, Susan E; Tichelaar, Jay W; Bry, Kristina

    2005-04-01

    The production of the inflammatory cytokine interleukin (IL)-1 is increased in lungs of patients with chronic obstructive pulmonary disease (COPD) or asthma. To characterize the in vivo actions of IL-1 in the lung, transgenic mice were generated in which human IL-1beta was expressed in the lung epithelium with a doxycycline-inducible system controlled by the rat Clara cell secretory protein (CCSP) promoter. Induction of IL-1beta expression in the lungs of adult mice caused pulmonary inflammation characterized by neutrophil and macrophage infiltrates. IL-1beta caused distal airspace enlargement, consistent with emphysema. IL-1beta caused disruption of elastin fibers in alveolar septa and fibrosis in airway walls and in the pleura. IL-1beta increased the thickness of conducting airways, enhanced mucin production, and caused lymphocytic aggregates in the airways. Decreased immunostaining for the winged helix transcription factor FOXA2 was associated with goblet cell hyperplasia in IL-1beta-expressing mice. The production of the neutrophil attractant CXC chemokines KC (CXCL1) and MIP-2 (CXCL2), and of matrix metalloproteases MMP-9 and MMP-12, was increased by IL-1beta. Chronic production of IL-1beta in respiratory epithelial cells of adult mice causes lung inflammation, enlargement of distal airspaces, mucus metaplasia, and airway fibrosis in the adult mouse.

  20. TLR4 signalling in pulmonary stromal cells is critical for inflammation and immunity in the airways.

    PubMed

    Perros, Frederic; Lambrecht, Bart N; Hammad, Hamida

    2011-09-24

    Inflammation of the airways, which is often associated with life-threatening infection by Gram-negative bacteria or presence of endotoxin in the bioaerosol, is still a major cause of severe airway diseases. Moreover, inhaled endotoxin may play an important role in the development and progression of airway inflammation in asthma. Pathologic changes induced by endotoxin inhalation include bronchospasm, airflow obstruction, recruitment of inflammatory cells, injury of the alveolar epithelium, and disruption of pulmonary capillary integrity leading to protein rich fluid leak in the alveolar space. Mammalian Toll-like receptors (TLRs) are important signalling receptors in innate host defense. Among these receptors, TLR4 plays a critical role in the response to endotoxin. Lungs are a complex compartmentalized organ with separate barriers, namely the alveolar-capillary barrier, the microvascular endothelium, and the alveolar epithelium. An emerging theme in the field of lung immunology is that structural cells (SCs) of the airways such as epithelial cells (ECs), endothelial cells, fibroblasts and other stromal cells produce activating cytokines that determine the quantity and quality of the lung immune response. This review focuses on the role of TLR4 in the innate and adaptive immune functions of the pulmonary SCs.

  1. TLR4 signalling in pulmonary stromal cells is critical for inflammation and immunity in the airways

    PubMed Central

    2011-01-01

    Inflammation of the airways, which is often associated with life-threatening infection by Gram-negative bacteria or presence of endotoxin in the bioaerosol, is still a major cause of severe airway diseases. Moreover, inhaled endotoxin may play an important role in the development and progression of airway inflammation in asthma. Pathologic changes induced by endotoxin inhalation include bronchospasm, airflow obstruction, recruitment of inflammatory cells, injury of the alveolar epithelium, and disruption of pulmonary capillary integrity leading to protein rich fluid leak in the alveolar space. Mammalian Toll-like receptors (TLRs) are important signalling receptors in innate host defense. Among these receptors, TLR4 plays a critical role in the response to endotoxin. Lungs are a complex compartmentalized organ with separate barriers, namely the alveolar-capillary barrier, the microvascular endothelium, and the alveolar epithelium. An emerging theme in the field of lung immunology is that structural cells (SCs) of the airways such as epithelial cells (ECs), endothelial cells, fibroblasts and other stromal cells produce activating cytokines that determine the quantity and quality of the lung immune response. This review focuses on the role of TLR4 in the innate and adaptive immune functions of the pulmonary SCs. PMID:21943186

  2. Interleukin-6 neutralization alleviates pulmonary inflammation in mice exposed to cigarette smoke and poly(I:C).

    PubMed

    Hubeau, Cedric; Kubera, John E; Masek-Hammerman, Katherine; Williams, Cara M M

    2013-11-01

    Increased systemic and pulmonary levels of IL-6 (interleukin-6) are associated with the severity of exacerbations and decline of lung function in patients with COPD (chronic obstructive pulmonary disease). Whether IL-6 is directly involved or plays a bystander role in the pathophysiology of COPD remains unclear. Here we hypothesized that neutralizing circulating levels of IL-6 would modulate episodes of acute pulmonary inflammation following CS (cigarette smoke) exposure and virus-like challenges. For this purpose, we used a model where C57BL/6 mice were exposed to CS twice daily via a nose-only system, and concomitant periodic intranasal challenge with poly(I:C), a synthetic ligand for TLR3 (Toll-like receptor 3) that mimics the encounter with double stranded RNA that is carried by influenza-like viruses. This protocol recapitulates several aspects of acute pulmonary inflammation associated with COPD, including prominent airway neutrophilia, insensitivity to steroid treatment and increased levels of several inflammatory cytokines in BAL (bronchoalveolar lavage) samples. Although IL-6-deficient mice exposed to CS/poly(I:C) developed pulmonary inflammation similar to WT (wild-type) controls, WT mice exposed to CS/poly(I:C) and treated intraperitoneally with IL-6-neutralizing antibodies showed significantly lower blood counts of lymphocytes and monocytes, lower BAL levels of IL-6 and CXCL1 (CXC chemokine ligand 1)/KC (keratinocyte chemoattractant), as well as reduced numbers of BAL neutrophils, lymphocytes and macrophages. Our results thus indicate that the systemic neutralization of IL-6 significantly reduces CS/poly(I:C)-induced pulmonary inflammation, which may be a relevant approach to the treatment of episodes of acute pulmonary inflammation associated with COPD.

  3. Measurement of Pulmonary Flow Reserve and Pulmonary Index of Microcirculatory Resistance for Detection of Pulmonary Microvascular Obstruction

    PubMed Central

    Ilsar, Rahn; Chawantanpipat, Chirapan; Chan, Kim H.; Dobbins, Timothy A.; Waugh, Richard; Hennessy, Annemarie; Celermajer, David S.; Ng, Martin K. C.

    2010-01-01

    increased PIMR (5.7±0.6, 6.3±1.0, 6.8±0.6 & 7.6±0.6 mmHg.sec; p = 0.0048). Conclusions Thermodilution-derived mean transit time can be accurately and reproducibly measured in the pulmonary circulation using TPSG. Mean transit time-derived PFR and PIMR can be assessed using a TPSG and adenosine or papaverine as hyperemic agents. These novel indices detect progressive pulmonary microvascular obstruction and thus have with a potential role for pulmonary microcirculatory assessment in humans. PMID:20231900

  4. Clarithromycin ameliorates pulmonary inflammation induced by short term cigarette smoke exposure in mice.

    PubMed

    Nakamura, Masuo; Wada, Hiroo; Honda, Kojiro; Nakamoto, Keitaro; Inui, Toshiya; Sada, Mitsuru; Watanabe, Masato; Takata, Saori; Yokoyama, Takuma; Saraya, Takeshi; Kurai, Daisuke; Ishii, Haruyuki; Goto, Hajime; Kamma, Hiroshi; Takizawa, Hajime

    2015-12-01

    Cigarette smoking is considered to be one of major causes of acute worsening of asthma as well as chronic obstructive pulmonary disease (COPD). Macrolide antibiotics have been reported to reduce the risk of exacerbations of COPD, and possibly neutrophilic asthma. However, the effect of clarithromycin (CAM) on pulmonary inflammation caused by short term exposure to cigarette smoke still remains to be investigated. C57BL/6J female mice were daily exposed to tobacco smoke using a tobacco smoke exposure system, or clean air for 8 days, while simultaneously treated with either oral CAM or vehicles. Twenty four hours after the last exposure, mice were anaesthetized and sacrificed, and bronchoalveolar lavage (BAL) fluids were collected. Cellular responses in BAL fluids were evaluated. Levels of cytokine mRNA in the lung tissues were measured by quantitative RT-PCR. Paraffin-embedded lung tissues were evaluated to quantitate degree of neutrophil infiltration. The numbers of total cells, macrophages and neutrophils in the BAL fluid of smoke-exposed mice were significantly increased as compared to clean air group. These changes were significantly ameliorated in CAM-treated mice. The lung morphological analysis confirmed decrease of neutrophils by CAM treatment. Studies by quantitative PCR demonstrated CAM treatment significantly reduced lung expression levels of IL-17A, keratinocyte-derived chemokine (KC), granulocyte-macrophage colony stimulating factor (GM-CSF) and MMP-9 induced by cigarette smoke. We demonstrate that CAM administration resolves enhanced pulmonary inflammation induced by short term cigarette smoke exposure in mice. Copyright © 2015 Elsevier Ltd. All rights reserved.

  5. Arterial Carboxyhemoglobin Measurement Is Useful for Evaluating Pulmonary Inflammation in Subjects with Interstitial Lung Disease.

    PubMed

    Hara, Yu; Shinkai, Masaharu; Kanoh, Soichiro; Fujikura, Yuji; K Rubin, Bruce; Kawana, Akihiko; Kaneko, Takeshi

    2017-01-01

    Objective The arterial concentration of carboxyhemoglobin (CO-Hb) in subjects with inflammatory pulmonary disease is higher than that in healthy individuals. We retrospectively analyzed the relationship between the CO-Hb concentration and established markers of disease severity in subjects with interstitial lung disease (ILD). Methods The CO-Hb concentration was measured in subjects with newly diagnosed or untreated ILD and the relationships between the CO-Hb concentration and the serum biomarker levels, lung function, high-resolution CT (HRCT) findings, and the uptake in gallium-67 ((67)Ga) scintigraphy were evaluated. Results Eighty-one non-smoking subjects were studied (mean age, 67 years). Among these subjects, (A) 17 had stable idiopathic pulmonary fibrosis (IPF), (B) 9 had an acute exacerbation of IPF, (C) 44 had stable non-IPF, and (D) 11 had an exacerbation of non-IPF. The CO-Hb concentrations of these subjects were (A) 1.5±0.5%, (B) 2.1±0.5%, (C) 1.2±0.4%, and (D) 1.7±0.5%. The CO-Hb concentration was positively correlated with the serum levels of surfactant protein (SP)-A (r=0.38), SP-D (r=0.39), and the inflammation index (calculated from HRCT; r=0.57) and was negatively correlated with the partial pressure of oxygen in the arterial blood (r=-0.56) and the predicted diffusion capacity of carbon monoxide (r=-0.61). The CO-Hb concentrations in subjects with a negative heart sign on (67)Ga scintigraphy were higher than those in subjects without a negative heart sign (1.4±0.5% vs. 1.1±0.3%, p=0.018). Conclusion The CO-Hb levels of subjects with ILD were increased, particularly during an exacerbation, and were correlated with the parameters that reflect pulmonary inflammation.

  6. Effects of Sodium Houttuyfonate on Pulmonary Inflammation in COPD Model Rats.

    PubMed

    Wu, Zhonghua; Tan, Bo; Zhang, Haiying; Guo, Yinuo; Tu, Yanjie; Qiu, Furong; Yang, Aidong

    2017-08-15

    The anti-inflammatory effect of sodium houttuyfonate (SH), an herbal-originated drug that used in China clinically, was investigated on chronic obstructive pulmonary disease (COPD) inflammatory model rats induced by combination usage of cigarette smoke (CS) and lipopolysaccharide (LPS). The morphology of the lung tissue, the expression levels of cytokines in the bronchoalveolar lavage fluid (BALF), the protein levels of TLR4, NF-κB p65, and SIGIRR, and the mRNA levels of TLR4, MyD88, NF-κB p65, and SIGIRR in lung tissues were investigated, respectively. After treated by SH (24.3 mg/kg), the abnormal morphology changes of lung tissues in COPD rats, such as neutrophil infiltration and airway obstruction, were considerably alleviated, as well as both proinflammatory cytokines, TNF-α and IL-1β, significantly decreased in BALF. The mRNA level of TLR4, MyD88, and NF-κB p65 and protein expression of TLR4 and NF-κB p65 in lung tissues decreased significantly after SH treatment, while both SIGIRR mRNA and protein levels increased significantly. These results suggest that SH markedly attenuated the pulmonary inflammation induced by CS and LPS and protected the lung tissue in COPD model rat. The anti-inflammatory effects were related to suppress the TLR4/NF-κB pathway dependent on MyD88. TIR8/SIGIRR might contribute to the protective effects of SH on pulmonary inflammation.

  7. 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

  8. 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. Copyright © 2014 the American Physiological Society.

  9. Chronic allergic pulmonary inflammation is aggravated in angiotensin-(1-7) Mas receptor knockout mice.

    PubMed

    Magalhães, Giselle S; Rodrigues-Machado, Maria Glória; Motta-Santos, Daisy; Alenina, Natalia; Bader, Michael; Santos, Robson A; Barcelos, Lucíola S; Campagnole-Santos, Maria José

    2016-12-01

    The angiotensin-(1-7) [ANG-(1-7)]/Mas receptor pathway is currently recognized as a counterbalancing mechanism of the renin-angiotensin system in different pathophysiological conditions. We have previously described that treatment with ANG-(1-7) attenuates lung inflammation and remodeling in an experimental model of asthma. In the present study, we investigated whether lack of the Mas receptor could alter the inflammatory response in a model of chronic allergic lung inflammation induced by ovalbumin (OVA). Mas receptor wild-type (MasWT) and knockout (MasKO) mice were subjected to four doses of OVA (20 μg/mice ip) with a 14-day interval. At the 21st day, nebulization with OVA (1%) was started, three times per week until the 46th day. Control groups received saline (0.9% ip) and were nebulized with saline (0.9%). MasWT-OVA developed a modest inflammatory response and minor pulmonary remodeling to OVA challenge. Strikingly, MasKO-OVA presented a significant increase in inflammatory cell infiltrate, increase in extracellular matrix deposition, increase in thickening of the alveolar parenchyma, increase in thickening of the smooth muscle layer of the pulmonary arterioles, increase in proinflammatory cytokine and chemokine levels in the lungs, characteristic of chronic asthma. Additionally, MasKO-OVA presented an increase in ERK1/2 phosphorylation compared with MasWT-OVA. Furthermore, MasKO-OVA showed a worse performance in a test of maximum physical exercise compared with MasWT-OVA. Our study shows that effects triggered by the Mas receptor are important to attenuate the inflammatory and remodeling processes in a model of allergic lung inflammation in mice. Our data indicate that impairment of the ANG-(1-7)/Mas receptor pathway may lead to worsening of the pathophysiological changes of asthma. Copyright © 2016 the American Physiological Society.

  10. Dictionary learning-based CT detection of pulmonary nodules

    NASA Astrophysics Data System (ADS)

    Wu, Panpan; Xia, Kewen; Zhang, Yanbo; Qian, Xiaohua; Wang, Ge; Yu, Hengyong

    2016-10-01

    Segmentation of lung features is one of the most important steps for computer-aided detection (CAD) of pulmonary nodules with computed tomography (CT). However, irregular shapes, complicated anatomical background and poor pulmonary nodule contrast make CAD a very challenging problem. Here, we propose a novel scheme for feature extraction and classification of pulmonary nodules through dictionary learning from training CT images, which does not require accurately segmented pulmonary nodules. Specifically, two classification-oriented dictionaries and one background dictionary are learnt to solve a two-category problem. In terms of the classification-oriented dictionaries, we calculate sparse coefficient matrices to extract intrinsic features for pulmonary nodule classification. The support vector machine (SVM) classifier is then designed to optimize the performance. Our proposed methodology is evaluated with the lung image database consortium and image database resource initiative (LIDC-IDRI) database, and the results demonstrate that the proposed strategy is promising.

  11. Milano Summer Particulate Matter (PM10) Triggers Lung Inflammation and Extra Pulmonary Adverse Events in Mice

    PubMed Central

    Battaglia, Cristina; Tinaglia, Valentina; Mantecca, Paride; Camatini, Marina; Palestini, Paola

    2013-01-01

    Recent studies have suggested a link between particulate matter (PM) exposure and increased mortality and morbidity associated with pulmonary and cardiovascular diseases; accumulating evidences point to a new role for air pollution in CNS diseases. The purpose of our study is to investigate PM10sum effects on lungs and extra pulmonary tissues. Milano PM10sum has been intratracheally instilled into BALB/c mice. Broncho Alveolar Lavage fluid, lung parenchyma, heart and brain were screened for markers of inflammation (cell counts, cytokines, ET-1, HO-1, MPO, iNOS), cytotoxicity (LDH, ALP, Hsp70, Caspase8-p18, Caspase3-p17) for a putative pro-carcinogenic marker (Cyp1B1) and for TLR4 pathway activation. Brain was also investigated for CD68, TNF-α, GFAP. In blood, cell counts were performed while plasma was screened for endothelial activation (sP-selectin, ET-1) and for inflammation markers (TNF-α, MIP-2, IL-1β, MPO). Genes up-regulation (HMOX1, Cyp1B1, IL-1β, MIP-2, MPO) and miR-21 have been investigated in lungs and blood. Inflammation in the respiratory tract of PM10sum-treated mice has been confirmed in BALf and lung parenchyma by increased PMNs percentage, increased ET-1, MPO and cytokines levels. A systemic spreading of lung inflammation in PM10sum-treated mice has been related to the increased blood total cell count and neutrophils percentage, as well as to increased blood MPO. The blood-endothelium interface activation has been confirmed by significant increases of plasma ET-1 and sP-selectin. Furthermore PM10sum induced heart endothelial activation and PAHs metabolism, proved by increased ET-1 and Cyp1B1 levels. Moreover, PM10sum causes an increase in brain HO-1 and ET-1. These results state the translocation of inflammation mediators, ultrafine particles, LPS, metals associated to PM10sum, from lungs to bloodstream, thus triggering a systemic reaction, mainly involving heart and brain. Our results provided additional insight into the toxicity of PM10sum

  12. Pulmonary Inflammation Triggered by Ricin Toxin Requires Macrophages and IL-1 Signaling1

    PubMed Central

    Lindauer, Meghan L.; Wong, John; Iwakura, Yoichiro; Magun, Bruce E.

    2015-01-01

    Ricin is a potent ribotoxin considered to be a potentially dangerous bioterrorist agent due to its wide availability and the possibility of aerosol delivery to human populations. Studies in rodents and nonhuman primates have demonstrated that ricin delivered to the pulmonary system leads to acute lung injury and symptoms resembling acute respiratory distress syndrome. Increasing evidence suggests that the inflammatory effects triggered by ricin are responsible for its lethality. We demonstrated previously that ricin administered to the lungs of mice causes death of pulmonary macrophages and the release of proinflammatory cytokines, suggesting macrophages may be a primary target of ricin. Here we examined the requirement for macrophages in the development of ricinmediated pulmonary inflammation by employing transgenic (MAFIA) mice that express an inducible gene driven by the c-fms promoter for Fas-mediated apoptosis of macrophages upon injection of a synthetic dimerizer, AP20187. Administration of aerosolized ricin to macrophage-depleted mice led to reduced inflammatory responses, including recruitment of neutrophils, expression of proinflammatory transcripts, and microvascular permeability. When compared with control mice treated with ricin, macrophage-depleted mice treated with ricin displayed a reduction in pulmonary IL-1/3. Employing mice deficient in IL-1, we found that ricin-induced inflammatory responses were suppressed, including neutrophilia. Neutrophilia could be restored by co-administering ricin and exogenous IL-1β to IL-1α/β−/− mice. Furthermore, IL1Ra/anakinra cotreatment inhibited ricin-mediated inflammatory responses, including recruitment of neutrophils, expression of proinflammatory genes, and histopathology. These data suggest a central role for macrophages and IL-1 signaling in the inflammatory process triggered by ricin. PMID:19561099

  13. Pulmonary inflammation triggered by ricin toxin requires macrophages and IL-1 signaling.

    PubMed

    Lindauer, Meghan L; Wong, John; Iwakura, Yoichiro; Magun, Bruce E

    2009-07-15

    Ricin is a potent ribotoxin considered to be a potentially dangerous bioterrorist agent due to its wide availability and the possibility of aerosol delivery to human populations. Studies in rodents and nonhuman primates have demonstrated that ricin delivered to the pulmonary system leads to acute lung injury and symptoms resembling acute respiratory distress syndrome. Increasing evidence suggests that the inflammatory effects triggered by ricin are responsible for its lethality. We demonstrated previously that ricin administered to the lungs of mice causes death of pulmonary macrophages and the release of proinflammatory cytokines, suggesting macrophages may be a primary target of ricin. Here we examined the requirement for macrophages in the development of ricin-mediated pulmonary inflammation by employing transgenic (MAFIA) mice that express an inducible gene driven by the c-fms promoter for Fas-mediated apoptosis of macrophages upon injection of a synthetic dimerizer, AP20187. Administration of aerosolized ricin to macrophage-depleted mice led to reduced inflammatory responses, including recruitment of neutrophils, expression of proinflammatory transcripts, and microvascular permeability. When compared with control mice treated with ricin, macrophage-depleted mice treated with ricin displayed a reduction in pulmonary IL-1beta. Employing mice deficient in IL-1, we found that ricin-induced inflammatory responses were suppressed, including neutrophilia. Neutrophilia could be restored by co-administering ricin and exogenous IL-1beta to IL-1alpha/beta(-/-) mice. Furthermore, IL1Ra/anakinra cotreatment inhibited ricin-mediated inflammatory responses, including recruitment of neutrophils, expression of proinflammatory genes, and histopathology. These data suggest a central role for macrophages and IL-1 signaling in the inflammatory process triggered by ricin.

  14. Effect of Treatment of Cystic Fibrosis Pulmonary Exacerbations on Systemic Inflammation

    PubMed Central

    Thompson, Valeria; Chmiel, James F.; Montgomery, Gregory S.; Nasr, Samya Z.; Perkett, Elizabeth; Saavedra, Milene T.; Slovis, Bonnie; Anthony, Margaret M.; Emmett, Peggy; Heltshe, Sonya L.

    2015-01-01

    Rationale: In cystic fibrosis (CF), pulmonary exacerbations present an opportunity to define the effect of antibiotic therapy on systemic measures of inflammation. Objectives: Investigate whether plasma inflammatory proteins demonstrate and predict a clinical response to antibiotic therapy and determine which proteins are associated with measures of clinical improvement. Methods: In this multicenter study, a panel of 15 plasma proteins was measured at the onset and end of treatment for pulmonary exacerbation and at a clinically stable visit in patients with CF who were 10 years of age or older. Measurements and Main Results: Significant reductions in 10 plasma proteins were observed in 103 patients who had paired blood collections during antibiotic treatment for pulmonary exacerbations. Plasma C-reactive protein, serum amyloid A, calprotectin, and neutrophil elastase antiprotease complexes correlated most strongly with clinical measures at exacerbation onset. Reductions in C-reactive protein, serum amyloid A, IL-1ra, and haptoglobin were most associated with improvements in lung function with antibiotic therapy. Having higher IL-6, IL-8, and α1-antitrypsin (α1AT) levels at exacerbation onset were associated with an increased risk of being a nonresponder (i.e., failing to recover to baseline FEV1). Baseline IL-8, neutrophil elastase antiprotease complexes, and α1AT along with changes in several plasma proteins with antibiotic treatment, in combination with FEV1 at exacerbation onset, were predictive of being a treatment responder. Conclusions: Circulating inflammatory proteins demonstrate and predict a response to treatment of CF pulmonary exacerbations. A systemic biomarker panel could speed up drug discovery, leading to a quicker, more efficient drug development process for the CF community. PMID:25714657

  15. Prevention of Bleomycin-Induced Pulmonary Inflammation and Fibrosis in Mice by Paeonol

    PubMed Central

    Liu, Meng-Han; Lin, An-Hsuan; Ko, Hsin-Kuo; Perng, Diahn-Warng; Lee, Tzong-Shyuan; Kou, Yu Ru

    2017-01-01

    Pulmonary fibrosis is a severe and progressive disease that is characterized by an abnormal deposition of extracellular matrix, such as collagens. The pathogenesis of this disease may be initiated by oxidative damage of lung epithelial cells by fibrogenic stimuli, leading to lung inflammation, which in turn promotes various lung fibrotic responses. The profibrogenic effect of transforming growth factor-β1 (TGF-β1) on lung fibroblasts is crucial for the pathogenesis of this disease. Paeonol, the main phenolic compound present in the Chinese herb Paeonia suffruticosa, has antioxidant and anti-inflammatory properties. However, whether paeonol has therapeutic effects against pulmonary fibrosis remains unclear. Using a murine model, we showed that 21 days after the insult, intratracheal bleomycin caused pulmonary inflammation and fibrosis, as evidenced by lung histopathological manifestations and increase in various indices. The inflammatory indices included an increase in total cell count, differential cell count, and total protein concentration in bronchoalveolar lavage fluid. The fibrotic indices included an increase in lung levels of TGF-β1, total collagen, type 1α1 collagen (COL1A1), and α-smooth muscle actin (α-SMA; a marker of myofibroblasts). Bleomycin also was found to cause an increase in oxidative stress as reflected by increased levels of malondialdehyde and 4-hydroxynonenal in the lungs. Importantly, all these pathophysiological events were suppressed by daily treatment with paeonol. Using human lung fibroblasts, we further demonstrated that exposure of human lung fibroblasts to TGF-β1 increased productions of α-SMA and COL1A1, both of which were inhibited by inhibitors of Jun N-terminal kinase (JNK), p38, and Smad3. JNK and p38 are two subfamily members of mitogen-activated protein kinases (MAPKs), whereas Smad3 is a transcription factor. TGF-β1 exposure also increased the phosphorylation of JNK, p38, and Smad3 prior to the induction of α-SMA and

  16. Thioredoxin-1 Protects against Neutrophilic Inflammation and Emphysema Progression in a Mouse Model of Chronic Obstructive Pulmonary Disease Exacerbation

    PubMed Central

    Tanabe, Naoya; Hoshino, Yuma; Marumo, Satoshi; Kiyokawa, Hirofumi; Sato, Susumu; Kinose, Daisuke; Uno, Kazuko; Muro, Shigeo; Hirai, Toyohiro; Yodoi, Junji; Mishima, Michiaki

    2013-01-01

    Background Exacerbations of chronic obstructive pulmonary disease (COPD) are characterized by acute enhancement of airway neutrophilic inflammation under oxidative stress and can be involved in emphysema progression. However, pharmacotherapy against the neutrophilic inflammation and emphysema progression associated with exacerbation has not been established. Thioredoxin-1 has anti-oxidative and anti-inflammatory properties and it can ameliorate neutrophilic inflammation through anti-chemotactic effects and prevent cigarette smoke (CS)-induced emphysema. We aimed to determine whether thioredoxin-1 can suppress neutrophilic inflammation and emphysema progression in a mouse model of COPD exacerbation and if so, to reveal the underlying mechanisms. Results Mice were exposed to CS and then challenged with polyinosine-polycytidylic acid [poly(I:C)], an agonist for virus-induced innate immunity. Airway neutrophilic inflammation, oxidative stress and lung apoptosis were enhanced in smoke-sensitive C57Bl/6, but not in smoke-resistant NZW mice. Exposure to CS and poly(I:C) challenge accelerated emphysema progression in C57Bl/6 mice. Thioredoxin-1 suppressed neutrophilic inflammation and emphysema progression. Poly(I:C) caused early neutrophilic inflammation through keratinocyte-derived chemokine and granulocyte-macrophage colony-stimulating factor (GM-CSF) release in the lung exposed to CS. Late neutrophilic inflammation was caused by persistent GM-CSF release, which thioredoxin-1 ameliorated. Thioredoxin-1 enhanced pulmonary mRNA expression of MAP kinase phosphatase 1 (MKP-1), and the suppressive effects of thioredoxin-1 on prolonged GM-CSF release and late neutrophilic inflammation disappeared by inhibiting MKP-1. Conclusion Using a mouse model of COPD exacerbation, we demonstrated that thioredoxin-1 ameliorated neutrophilic inflammation by suppressing GM-CSF release, which prevented emphysema progression. Our findings deepen understanding of the mechanisms underlying the

  17. Molecular Ultrasound Imaging for the Detection of Neural Inflammation

    NASA Astrophysics Data System (ADS)

    Volz, Kevin R.

    Molecular imaging is a form of nanotechnology that enables the noninvasive examination of biological processes in vivo. Radiopharmaceutical agents are used to selectively target biochemical markers, which permits their detection and evaluation. Early visualization of molecular variations indicative of pathophysiological processes can aid in patient diagnoses and management decisions. Molecular imaging is performed by introducing molecular probes into the body. Molecular probes are often contrast agents that have been nanoengineered to selectively target and tether to molecules, enabling their radiologic identification. Ultrasound contrast agents have been demonstrated as an effective method of detecting perfusion at the tissue level. Through a nanoengineering process, ultrasound contrast agents can be targeted to specific molecules, thereby extending ultrasound's capabilities from the tissue to molecular level. Molecular ultrasound, or targeted contrast enhanced ultrasound (TCEUS), has recently emerged as a popular molecular imaging technique due to its ability to provide real-time anatomical and functional information in the absence of ionizing radiation. However, molecular ultrasound represents a novel form of molecular imaging, and consequently remains largely preclinical. A review of the TCEUS literature revealed multiple preclinical studies demonstrating its success in detecting inflammation in a variety of tissues. Although, a gap was identified in the existing evidence, as TCEUS effectiveness for detection of neural inflammation in the spinal cord was unable to be uncovered. This gap in knowledge, coupled with the profound impacts that this TCEUS application could have clinically, provided rationale for its exploration, and use as contributory evidence for the molecular ultrasound body of literature. An animal model that underwent a contusive spinal cord injury was used to establish preclinical evidence of TCEUS to detect neural inflammation. Imaging was

  18. Engineering Bacterial Thiosulfate and Tetrathionate Sensors for Detecting Gut Inflammation

    DTIC Science & Technology

    2017-04-03

    Article Engineering bacterial thiosulfate and tetrathionate sensors for detecting gut inflammation Kristina N-M Daeffler1 , Jeffrey D Galley2, Ravi U...mice harboring native gut microbiota. Our thiosulfate sensor may have applications in bacterial diagnostics or therapeutics. Finally, our approach can...be replicated for a wide range of bacterial sensors and should thus enable a new class of minimally invasive studies of gut microbiota pathways

  19. Monoclonal antibody therapy for the treatment of asthma and chronic obstructive pulmonary disease with eosinophilic inflammation.

    PubMed

    Nixon, John; Newbold, Paul; Mustelin, Tomas; Anderson, Gary P; Kolbeck, Roland

    2017-01-01

    Eosinophils have been linked with asthma for more than a century, but their role has been unclear. This review discusses the roles of eosinophils in asthma and chronic obstructive pulmonary disease (COPD) and describes therapeutic antibodies that affect eosinophilia. The aims of pharmacologic treatments for pulmonary conditions are to reduce symptoms, slow decline or improve lung function, and reduce the frequency and severity of exacerbations. Inhaled corticosteroids (ICS) are important in managing symptoms and exacerbations in asthma and COPD. However, control with these agents is often suboptimal, especially for patients with severe disease. Recently, new biologics that target eosinophilic inflammation, used as adjunctive therapy to corticosteroids, have proven beneficial and support a pivotal role for eosinophils in the pathology of asthma. Nucala® (mepolizumab; anti-interleukin [IL]-5) and Cinquair® (reslizumab; anti-IL-5), the second and third biologics approved, respectively, for the treatment of asthma, exemplifies these new treatment options. Emerging evidence suggests that eosinophils may contribute to exacerbations and possibly to lung function decline for a subset of patients with COPD. Here we describe the pharmacology of therapeutic antibodies inhibiting IL-5 or targeting the IL-5 receptor, as well as other cytokines contributing to eosinophilic inflammation. We discuss their roles as adjuncts to conventional therapeutic approaches, especially ICS therapy, when disease is suboptimally controlled. These agents have achieved a place in the therapeutic armamentarium for asthma and COPD and will deepen our understanding of the pathogenic role of eosinophils. Copyright © 2016 AstraZeneca. Published by Elsevier Inc. All rights reserved.

  20. Implication of Inflammation and Epigenetic Readers in Coronary Artery Remodeling in Patients With Pulmonary Arterial Hypertension.

    PubMed

    Meloche, Jolyane; Lampron, Marie-Claude; Nadeau, Valérie; Maltais, Mélanie; Potus, François; Lambert, Caroline; Tremblay, Eve; Vitry, Géraldine; Breuils-Bonnet, Sandra; Boucherat, Olivier; Charbonneau, Eric; Provencher, Steeve; Paulin, Roxane; Bonnet, Sébastien

    2017-08-01

    Pulmonary arterial hypertension (PAH) is a vascular disease not restricted to the lungs. Many signaling pathways described in PAH are also of importance in other vascular remodeling diseases, such as coronary artery disease (CAD). Intriguingly, CAD is 4× more prevalent in PAH compared with the global population, suggesting a link between these 2 diseases. Both PAH and CAD are associated with sustained inflammation and smooth muscle cell proliferation/apoptosis imbalance and we demonstrated in PAH that this phenotype is, in part, because of the miR-223/DNA damage/Poly[ADP-ribose] polymerase 1/miR-204 axis activation and subsequent bromodomain protein 4 (BRD4) overexpression. Interestingly, BRD4 is also a trigger for calcification and remodeling processes, both of which are important in CAD. Thus, we hypothesize that BRD4 activation in PAH influences the development of CAD. PAH was associated with significant remodeling of the coronary arteries in both human and experimental models of the disease. As observed in PAH distal pulmonary arteries, coronary arteries of patients with PAH also exhibited increased DNA damage, inflammation, and BRD4 overexpression. In vitro, using human coronary artery smooth muscle cells from PAH, CAD and non-PAH-non-CAD patients, we showed that both PAH and CAD smooth muscle cells exhibited increased proliferation and suppressed apoptosis in a BRD4-dependent manner. In vivo, improvement of PAH by BRD4 inhibitor was associated with a reduction in coronary remodeling and interleukin-6 expression. Overall, this study demonstrates that increased BRD4 expression in coronary arteries of patient with PAH contributes to vascular remodeling and comorbidity development. © 2017 American Heart Association, Inc.

  1. Systemic Inflammation in Chronic Obstructive Pulmonary Disease: May Adipose Tissue Play a Role? Review of the Literature and Future Perspectives

    PubMed Central

    Tkacova, Ruzena

    2010-01-01

    Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality worldwide. Low-grade systemic inflammation is considered a hallmark of COPD that potentially links COPD to increased rate of systemic manifestations of the disease. Obesity with/without the metabolic syndrome and cachexia represent two poles of metabolic abnormalities that may relate to systemic inflammation. On one hand systemic inflammatory syndrome likely reflects inflammation in the lungs, i.e. results from lung-to plasma spillover of inflammatory mediators. On the other hand, obesity-related hypoxia results in local inflammatory response within adipose tissue per se, and may contribute to elevations in circulatory mediators by spillover from the adipose tissue to the systemic compartment. The extent to which systemic hypoxia contributes to the adipose tissue inflammation remains unknown. We assume that in patients with COPD and concurrent obesity at least three factors play a role in the systemic inflammatory syndrome: the severity of pulmonary impairment, the degree of obesity-related adipose tissue hypoxia, and the severity of systemic hypoxia due to reduced pulmonary functions. The present review summarizes the epidemiological and clinical evidence linking COPD to obesity, the role of adipose tissue as an endocrine organ, and the role of hypoxia in adipose tissue inflammation. PMID:20414465

  2. The Prevalence of Oral Inflammation Among Denture Wearing Patients with Chronic Obstructive Pulmonary Disease.

    PubMed

    Przybyłowska, D; Rubinsztajn, R; Chazan, R; Swoboda-Kopeć, E; Kostrzewa-Janicka, J; Mierzwińska-Nastalska, E

    2015-01-01

    Oral inflammation is an important contributor to the etiology of chronic obstructive pulmonary disease, which can impact patient's health status. Previous studies indicate that people with poor oral health are at higher risk for nosocomial pneumonia. Denture wearing is one promoting factor in the development of mucosal infections. Colonization of the denture plaque by Gram-negative bacteria, Candida spp., or other respiratory pathogens, occurring locally, may be aspirated to the lungs. The studies showed that chronic obstructive pulmonary disease (COPD) patients treated with combinations of medicines with corticosteroids more frequently suffer from Candida-associated denture stomatitis. Treatment of oral candidiasis in patients with COPD constitutes a therapeutic problem. Therefore, it is essential to pay attention to the condition of oral mucosal membrane and denture hygiene habits. The guidelines for care and maintenance of dentures for COPD patients are presented in this paper. The majority of patients required improvement of their prosthetic and oral hygiene. Standard oral hygiene procedures in relation to dentures, conducted for prophylaxis of stomatitis complicated by mucosal infection among immunocompromised patients, are essential to maintain healthy oral tissues. The elimination of traumatic denture action in dental office, compliance with oral and denture hygiene, proper use and storage of prosthetic appliances in a dry environment outside the oral cavity can reduce susceptibility to infection. Proper attention to hygiene, including brushing and rinsing the mouth, may also help prevent denture stomatitis in these patients.

  3. IL-23 Is Essential for the Development of Elastase-Induced Pulmonary Inflammation and Emphysema.

    PubMed

    Fujii, Utako; Miyahara, Nobuaki; Taniguchi, Akihiko; Waseda, Koichi; Morichika, Daisuke; Kurimoto, Etsuko; Koga, Hikari; Kataoka, Mikio; Gelfand, Erwin W; Cua, Daniel J; Yoshimura, Akihiko; Tanimoto, Mitsune; Kanehiro, Arihiko

    2016-11-01

    We recently reported that IL-17A plays a critical role in the development of porcine pancreatic elastase (PPE)-induced emphysema. The proliferation of T-helper type 17 (Th17) cells was induced by IL-23. To determine the contribution of IL-23 to the development of pulmonary emphysema, a mouse model of PPE-induced emphysema was used in which responses of IL-23p19-deficient (IL-23(-/-)) and wild-type (WT) mice were compared. Intratracheal instillation of PPE induced emphysematous changes in the lungs and was associated with increased levels of IL-23 in lung homogenates. Compared with WT mice, IL-23(-/-) mice developed significantly lower static compliance values and markedly reduced emphysematous changes on histological analyses after PPE instillation. These changes were associated with lower levels of IL-17A and fewer Th17 cells in the lung. The neutrophilia seen in bronchoalveolar lavage fluid of WT mice was attenuated in IL-23(-/-) mice, and the reduction was associated with decreased levels of keratinocyte-derived cytokine and macrophage inflammatory protein-2 in bronchoalveolar lavage fluid. Treatment with anti-IL-23p40 monoclonal antibody significantly attenuated PPE-induced emphysematous changes in the lungs of WT mice. These data identify the important contributions of IL-23 to the development of elastase-induced pulmonary inflammation and emphysema, mediated through an IL-23/IL-17 pathway. Targeting IL-23 in emphysema is a potential therapeutic strategy for delaying disease progression.

  4. Recent insights into pulmonary repair following virus-induced inflammation of the respiratory tract

    PubMed Central

    Gorski, Stacey A.; Hufford, Matthew M.; Braciale, Thomas J.

    2012-01-01

    A hallmark of infection by respiratory viruses is productive infection of and the subsequent destruction of the airway epithelium. These viruses can also target other stromal cell types as well as in certain instances, CD45+ hematopoietic cells either resident in the lungs or part of the inflammatory response to infection. The mechanisms by which the virus produces injury to these cell types include direct infection with cytopathic effects as a consequence of replication. Host mediated damage is also a culprit in pulmonary injury as both innate and adaptive immune cells produce soluble and cell-associated pro-inflammatory mediators. Recently, it has become increasingly clear that in addition to control of excess inflammation and virus elimination, the resolution of infection requires an active repair process, which is necessary to regain normal respiratory function and restore the lungs to homeostasis. The repair response must re-establish the epithelial barrier and regenerate the microarchitecture of the lung. Emerging areas of research have highlighted the importance of innate immune cells, particularly the newly described innate lymphoid cells, as well as alternatively activated macrophages and pulmonary stem cells in the repair process. The mechanisms by which respiratory viruses may impede or alter the repair response will be important areas of research for identifying therapeutic targets aimed at limiting virus and host mediated injury and expediting recovery. PMID:22608464

  5. Age-dependent neutrophil and blood flow responsiveness in acute pulmonary inflammation in rabbits.

    PubMed

    Hyde, D M; Downey, G P; Tablin, F; Rosengren, S; Giclas, P C; Henson, P M; Worthen, G S

    1997-03-01

    Diminished ability of neonatal neutrophils to orient and move in a chemotactic gradient has been linked to compromised pulmonary host defense. We investigated whether deficiency of neonatal neutrophil function in vitro was evident in acute pulmonary inflammation. Analysis of neutrophils in vitro showed impaired chemotaxis in 4-wk-old compared with adult rabbits. In vivo-directed migration of labeled neutrophils into the alveolar space of adult rabbits in response to C5f instillation was significantly less for neutrophils donated from 4-wk-old rabbits compared with those from adults. In contrast, there were no differences in the alveolar accumulation of 4-wk-old and adult labeled neutrophils in 4-wk-old rabbits in response to C5f instillation, although the response showed a shorter time course than seen in adult rabbits. Adult rabbits diverted 46% of the blood away from the right cranial lung lobe, whereas 4-wk-old rabbits showed no change in blood flow after C5f instillation. Megakaryocytes (a source of blood flow mediators) were 3.2-fold greater in adult compared with 4-wk-old lung. These data suggest that the lack of blood flow diversion from inflamed neonatal lung increases neutrophil migration into alveoli, allowing for preservation of an inflammatory response despite neutrophil deficiencies in chemotaxis.

  6. Edge density based automatic detection of inflammation in colonoscopy videos.

    PubMed

    Ševo, I; Avramović, A; Balasingham, I; Elle, O J; Bergsland, J; Aabakken, L

    2016-05-01

    Colon cancer is one of the deadliest diseases where early detection can prolong life and can increase the survival rates. The early stage disease is typically associated with polyps and mucosa inflammation. The often used diagnostic tools rely on high quality videos obtained from colonoscopy or capsule endoscope. The state-of-the-art image processing techniques of video analysis for automatic detection of anomalies use statistical and neural network methods. In this paper, we investigated a simple alternative model-based approach using texture analysis. The method can easily be implemented in parallel processing mode for real-time applications. A characteristic texture of inflamed tissue is used to distinguish between inflammatory and healthy tissues, where an appropriate filter kernel was proposed and implemented to efficiently detect this specific texture. The basic method is further improved to eliminate the effect of blood vessels present in the lower part of the descending colon. Both approaches of the proposed method were described in detail and tested in two different computer experiments. Our results show that the inflammatory region can be detected in real-time with an accuracy of over 84%. Furthermore, the experimental study showed that it is possible to detect certain segments of video frames containing inflammations with the detection accuracy above 90%.

  7. Role of pulmonary artery reactivity and nitric oxide in injury and inflammation following lung contusion.

    PubMed

    Lakshminrusimha, Satyan; Suresh, Madathilparambil V; Knight, Paul R; Gugino, Sylvia F; Davidson, Bruce A; Helinski, Jadwiga D; Nielsen, Lori C; Russell, James A; Yu, Bi; Zeng, Lixia; Pennathur, Subramaniam; Raghavendran, Krishnan

    2013-03-01

    The mechanisms contributing to hypoxia in lung contusion (LC) remain unclear and not temporally associated with the peak onset of acute inflammation. We investigated the role of oxidative stress in alteration of pulmonary arterial (PA) reactivity following LC. In addition, the role of antioxidants in reversing this process was examined. PaO2 and PA reactivity were measured in rats subjected to bilateral LC. Rings were pretreated with a nitric oxide synthase (NOS) inhibitor, L-nitro arginine (10(-3) M), or PEG-superoxide dismutase (SOD) and PEG-catalase (CAT), or both (L-nitro arginine + SOD/CAT). Rings were constricted with norepinephrine and relaxed with an NOS agonist (A23187) or NO donor (SNAP [S-nitrosyl amino penicillamine]). Immunochemical and mass spectrometric quantification for nitrotyrosine was performed. Rats were hypoxemic at 4 h after contusion compared with controls, but recovered by 24 h (PaO(2)/FIO(2) ratio: baseline, 443 ± 28; 4 h, 288 ± 46; and 24 h, 417 ± 23). Pulmonary arterial constriction to NOS inhibition and relaxation to A23187 were impaired 4 h after LC. Pulmonary arterial relaxation to SNAP was decreased at 4 and 24 h after LC. These alterations in PA reactivity were reversed by SOD/CAT pretreatment. SOD1 and 2 mRNA were upregulated, and soluble guanylyl cyclase mRNA was downregulated 24 h after LC. Immunohistochemistry and mass spectrometry revealed that levels of 3-nitrotyrosine were increased markedly at 4 h following LC consistent with superoxide generation and formation of peroxynitrite. Collectively, these data suggest that consumption of NO due to excess superoxide resulting in peroxynitrite formation leads to diminished vascular reactivity following LC.

  8. Bilirubin treatment suppresses pulmonary inflammation in a rat model of smoke-induced emphysema.

    PubMed

    Wei, Jingjing; Zhao, Hui; Fan, Guoquan; Li, Jianqiang

    2015-09-18

    Cigarette smoking is a significant risk factor for emphysema, which is characterized by airway inflammation and oxidative damage. To assess the capacity of bilirubin to protect against smoke-induced emphysema. Smoking status and bilirubin levels were recorded in 58 patients with chronic obstructive pulmonary diseases (COPD) and 71 non-COPD participants. The impact of smoking on serum bilirubin levels and exogenous bilirubin (20 mg/kg/day) on pulmonary injury was assessed in a rat model of smoking-induced emphysema. At sacrifice lung histology, airway leukocyte accumulation and cytokine and chemokine levels in serum, bronchoalveolar lavage fluid (BALF) and lung were analyzed. Oxidative lipid damage and anti-oxidative components was assessed by measuring malondialdehyde, superoxide dismutase (SOD) activity and glutathione. Total serum bilirubin levels were lower in smokers with or without COPD than non-smoking patients without COPD (P < 0.05). Indirect serum bilirubin levels were lower in COPD patients than patients without COPD (P < 0.05). In rats, cigarette smoke reduced serum total and indirect bilirubin levels. Administration of bilirubin reduced mean linear intercept and mean alveoli area, increased mean alveoli number, reduced macrophage, neutrophil and TNF-α content of BALF, and increased BALF and serum IL-10 level, but lowered local and systemic CCL2, CXCL2, CXCL8 and IL-17 levels. Bilirubin suppressed the smoke-induced systemic and regional oxidative lipid damage associated with increased SOD activity. Bilirubin attenuated smoking-induced pulmonary injury by suppressing inflammatory cell recruitment and pro-inflammatory cytokine secretion, increasing anti-inflammatory cytokine levels, and anti-oxidant SOD activity in a rat model of smoke-induced emphysema. Copyright © 2015. Published by Elsevier Inc.

  9. Rhinovirus induced IL-25 in asthma exacerbation drives type-2 immunity and allergic pulmonary inflammation

    PubMed Central

    Macintyre, Jonathan D. R.; Edwards, Michael R.; Walton, Ross P.; Zhu, Jie; Man Ching, Yee; Shamji, Betty; Edwards, Matt; Westwick, John; Cousins, David J.; Yi Hwang, You; McKenzie, Andrew

    2014-01-01

    Rhinoviruses are the most common cause of virally-induced asthma exacerbations which continue to account for the greatest burden in terms of morbidity, mortality and cost associated with this disease. IL-25 activates type-2-driven inflammation and is potentially important in virally-induced asthma exacerbations. Rhinovirus-infected cultured asthmatic bronchial epithelial cells exhibited a heightened intrinsic capacity for IL-25 expression which correlated with donor atopic status. In vivo human IL-25 expression was greater in asthmatics at baseline and during experimental rhinovirus infection. In mice rhinovirus infection induced IL-25 expression and augmented allergen-induced IL-25. Blockade of the IL-25 receptor reduced many RV-induced exacerbation-specific responses including type-2 cytokine expression, mucus production and recruitment of eosinophils, neutrophils, basophils, T and non-T type-2 cells. We have identified that asthmatic epithelial cells possess increased intrinsic capacity for expression of a pro-type-2 cytokine in response to a viral infection and identify IL-25 as a key mediator in RV-induced exacerbations of pulmonary inflammation. PMID:25273095

  10. Mechanisms of particle-induced pulmonary inflammation in a mouse model: exposure to wood dust.

    PubMed

    Määttä, Juha; Lehto, Maili; Leino, Marina; Tillander, Sari; Haapakoski, Rita; Majuri, Marja-Leena; Wolff, Henrik; Rautio, Sari; Welling, Irma; Husgafvel-Pursiainen, Kirsti; Savolainen, Kai; Alenius, Harri

    2006-09-01

    Repeated airway exposure to wood dust has long been known to cause adverse respiratory effects such as asthma and chronic bronchitis and impairment of lung function. However, the mechanisms underlying the inflammatory responses of the airways after wood dust exposure are poorly known. We used a mouse model to elucidate the mechanisms of particle-induced inflammatory responses to fine wood dust particles. BALB/c mice were exposed to intranasally administered fine (more than 99% of the particles had a particle size of < or = 5 microm, with virtually identical size distribution) birch or oak dusts twice a week for 3 weeks. PBS, LPS, and titanium dioxide were used as controls. Intranasal instillation of birch or oak dusts elicited influx of inflammatory cells to the lungs in mice. Enhancement of lymphocytes and neutrophils was seen after oak dust exposure, whereas eosinophil infiltration was higher after birch dust exposure. Infiltration of inflammatory cells was associated with an increase in the mRNA levels of several cytokines, chemokines, and chemokine receptors in lung tissue. Oak dust appeared to be a more potent inducer of these inflammatory mediators than birch dust. The results from our in vivo mouse model show that repeated airway exposure to wood dust can elicit lung inflammation, which is accompanied by induction of several proinflammatory cytokines and chemokines. Oak and birch dusts exhibited quantitative and qualitative differences in the elicitation of pulmonary inflammation, suggesting that the inflammatory responses induced by the wood species may rise via different cellular mechanisms.

  11. Cigarette Smoke-Induced Pulmonary Inflammation and Autophagy Are Attenuated in Ephx2-Deficient Mice.

    PubMed

    Li, Yunxiao; Yu, Ganggang; Yuan, Shaopeng; Tan, Chunting; Lian, Puqiao; Fu, Lixia; Hou, Qi; Xu, Bo; Wang, Haoyan

    2016-12-27

    Cigarette smoke (CS) increases the risk of chronic obstructive pulmonary disease (COPD) by causing inflammation, emphysema, and reduced lung function. Additionally, CS can induce autophagy which contributes to COPD. Arachidonic acid-derived epoxyeicosatrienoic acids (EETs) have promising anti-inflammatory properties that may protect the heart and liver by regulating autophagy. For this reason, the effect of decreased soluble epoxide hydrolase (sEH, Ephx2)-mediated EET hydrolysis on inflammation, emphysema, lung function, and autophagy was here studied in CS-induced COPD in vivo. Adult male wild-type (WT) C57BL/6J and Ephx2(-/-) mice were exposed to air or CS for 12 weeks, and lung inflammatory responses, air space enlargement (emphysema), lung function, and autophagy were assessed. Lungs of Ephx2(-/-) mice had a less pronounced inflammatory response and less autophagy with mild distal airspace enlargement accompanied by restored lung function and steady weight gain. These findings support the idea that Ephx2 may hold promise as a therapeutic target for COPD induced by CS, and it may be protective property by inhibiting autophagy.

  12. Is airway inflammation in chronic obstructive pulmonary disease (COPD) a risk factor for cardiovascular events?

    PubMed

    Calverley, Peter M A; Scott, Stephen

    2006-12-01

    Cardiovascular disease (CVD) is a very common cause of death in patients with chronic obstructive pulmonary disease (COPD). Smoking is a well-described risk factor for both COPD and CVD, but CVD in patients with COPD is likely to be due to other factors in addition to smoking. Inflammation may be an important common etiological link between COPD and CVD, being well described in both diseases. It is hypothesized that in COPD a "spill-over" of local airway inflammation into the systemic circulation could contribute to increased CVD in these patients. Inhaled corticosteroids (ICS) have well-documented anti-inflammatory effects and are commonly used for the treatment of COPD, but their effects on cardiovascular endpoints and all-cause mortality have only just started to be examined. A recent meta-analysis has suggested that ICS may reduce all-cause mortality in COPD by around 25%. A case-controlled study specifically examined the effects of ICS on myocardial infarction and suggested that ICS may decrease the incidence of MI by as much as 32%. A large multicenter prospective randomized trial (Towards a Revolution in COPD Health [TORCH]) is now ongoing and will examine the effect of fluticasone propionate in combination with salmeterol on all-cause mortality.

  13. Rhinovirus-induced IL-25 in asthma exacerbation drives type 2 immunity and allergic pulmonary inflammation.

    PubMed

    Beale, Janine; Jayaraman, Annabelle; Jackson, David J; Macintyre, Jonathan D R; Edwards, Michael R; Walton, Ross P; Zhu, Jie; Ching, Yee Man; Shamji, Betty; Edwards, Matt; Westwick, John; Cousins, David J; Hwang, You Yi; McKenzie, Andrew; Johnston, Sebastian L; Bartlett, Nathan W

    2014-10-01

    Rhinoviruses (RVs), which are the most common cause of virally induced asthma exacerbations, account for much of the burden of asthma in terms of morbidity, mortality, and associated cost. Interleukin-25 (IL-25) activates type 2-driven inflammation and is therefore potentially important in virally induced asthma exacerbations. To investigate this, we examined whether RV-induced IL-25 could contribute to asthma exacerbations. RV-infected cultured asthmatic bronchial epithelial cells exhibited a heightened intrinsic capacity for IL-25 expression, which correlated with donor atopic status. In vivo human IL-25 expression was greater in asthmatics at baseline and during experimental RV infection. In addition, in mice, RV infection induced IL-25 expression and augmented allergen-induced IL-25. Blockade of the IL-25 receptor reduced many RV-induced exacerbation-specific responses including type 2 cytokine expression, mucus production, and recruitment of eosinophils, neutrophils, basophils, and T and non-T type 2 cells. Therefore, asthmatic epithelial cells have an increased intrinsic capacity for expression of a pro-type 2 cytokine in response to a viral infection, and IL-25 is a key mediator of RV-induced exacerbations of pulmonary inflammation.

  14. Erythromycin prevents the pulmonary inflammation induced by exposure to cigarette smoke.

    PubMed

    Mikura, Shinichiro; Wada, Hiroo; Higaki, Manabu; Yasutake, Tetsuo; Ishii, Haruyuki; Kamiya, Shigeru; Goto, Hajime

    2011-07-01

    The effect of erythromycin on the inflammation caused by exposure to cigarette smoke was investigated in this study. Mice were exposed either to cigarette smoke or to environmental air (control), and some mice exposed to cigarette smoke were treated with oral erythromycin (100 mg/kg/day for 8 days). Pulmonary inflammation was assessed by determining the cellular content of bronchoalveolar lavage (BAL) fluid. The messenger RNA (mRNA) levels of various mediators, including keratinocyte-derived chemokine (KC), macrophage inflammatory protein (MIP)-2, surfactant protein (SP)-D, granulocyte macrophage colony-stimulating factor (GM-CSF), tumor necrosis factor (TNF)-α, interleukin (IL)-6 in lung tissue were determined using quantitative reverse transcription polymerase chain reaction (qRT-PCR) assays. The exposure to cigarette smoke increased significantly the numbers of neutrophils (P = 0.029), macrophages (P = 0.029), and lymphocytes (P = 0.029) recovered in BAL fluid. Moreover, mRNA levels of KC (P = 0.029), MIP-2 (P = 0.029), SP-D (P = 0.029), and GM-CSF (P = 0.057) in the lung tissue were higher in mice exposed to cigarette smoke than in mice exposed to environmental air. In the erythromycin-treated mice that were exposed also to cigarette smoke, both neutrophil and lymphocyte counts were significantly lower in the BAL fluid than those in the vehicle-treated mice (P = 0.029). Erythromycin-treated mice exposed to cigarette smoke showed a trend of lower mRNA levels of KC and TNF-α in the lung tissue than those in the vehicle-treated mice, although the statistical significance was not achieved (P = 0.057). Our data demonstrated that erythromycin prevented lung inflammation induced by cigarette smoke, in parallel to the reduced mRNA levels of KC and TNF-α.

  15. Framework for 3D histologic reconstruction and fusion with in vivo MRI: Preliminary results of characterizing pulmonary inflammation in a mouse model.

    PubMed

    Rusu, Mirabela; Golden, Thea; Wang, Haibo; Gow, Andrew; Madabhushi, Anant

    2015-08-01

    Pulmonary inflammation is associated with a variety of diseases. Assessing pulmonary inflammation on in vivo imaging may facilitate the early detection and treatment of lung diseases. Although routinely used in thoracic imaging, computed tomography has thus far not been compellingly shown to characterize inflammation in vivo. Alternatively, magnetic resonance imaging (MRI) is a nonionizing radiation technique to better visualize and characterize pulmonary tissue. Prior to routine adoption of MRI for early characterization of inflammation in humans, a rigorous and quantitative characterization of the utility of MRI to identify inflammation is required. Such characterization may be achieved by considering ex vivo histology as the ground truth, since it enables the definitive spatial assessment of inflammation. In this study, the authors introduce a novel framework to integrate 2D histology, ex vivo and in vivo imaging to enable the mapping of the extent of disease from ex vivo histology onto in vivo imaging, with the goal of facilitating computerized feature analysis and interrogation of disease appearance on in vivo imaging. The authors' framework was evaluated in a preclinical preliminary study aimed to identify computer extracted features on in vivo MRI associated with chronic pulmonary inflammation. The authors' image analytics framework first involves reconstructing the histologic volume in 3D from individual histology slices. Second, the authors map the disease ground truth onto in vivo MRI via coregistration with 3D histology using the ex vivo lung MRI as a conduit. Finally, computerized feature analysis of the disease extent is performed to identify candidate in vivo imaging signatures of disease presence and extent. The authors evaluated the framework by assessing the quality of the 3D histology reconstruction and the histology-MRI fusion, in the context of an initial use case involving characterization of chronic inflammation in a mouse model. The authors

  16. Framework for 3D histologic reconstruction and fusion with in vivo MRI: Preliminary results of characterizing pulmonary inflammation in a mouse model

    PubMed Central

    Rusu, Mirabela; Golden, Thea; Wang, Haibo; Gow, Andrew; Madabhushi, Anant

    2015-01-01

    Purpose: Pulmonary inflammation is associated with a variety of diseases. Assessing pulmonary inflammation on in vivo imaging may facilitate the early detection and treatment of lung diseases. Although routinely used in thoracic imaging, computed tomography has thus far not been compellingly shown to characterize inflammation in vivo. Alternatively, magnetic resonance imaging (MRI) is a nonionizing radiation technique to better visualize and characterize pulmonary tissue. Prior to routine adoption of MRI for early characterization of inflammation in humans, a rigorous and quantitative characterization of the utility of MRI to identify inflammation is required. Such characterization may be achieved by considering ex vivo histology as the ground truth, since it enables the definitive spatial assessment of inflammation. In this study, the authors introduce a novel framework to integrate 2D histology, ex vivo and in vivo imaging to enable the mapping of the extent of disease from ex vivo histology onto in vivo imaging, with the goal of facilitating computerized feature analysis and interrogation of disease appearance on in vivo imaging. The authors’ framework was evaluated in a preclinical preliminary study aimed to identify computer extracted features on in vivo MRI associated with chronic pulmonary inflammation. Methods: The authors’ image analytics framework first involves reconstructing the histologic volume in 3D from individual histology slices. Second, the authors map the disease ground truth onto in vivo MRI via coregistration with 3D histology using the ex vivo lung MRI as a conduit. Finally, computerized feature analysis of the disease extent is performed to identify candidate in vivo imaging signatures of disease presence and extent. Results: The authors evaluated the framework by assessing the quality of the 3D histology reconstruction and the histology—MRI fusion, in the context of an initial use case involving characterization of chronic

  17. Framework for 3D histologic reconstruction and fusion with in vivo MRI: Preliminary results of characterizing pulmonary inflammation in a mouse model

    SciTech Connect

    Rusu, Mirabela Wang, Haibo; Madabhushi, Anant; Golden, Thea; Gow, Andrew

    2015-08-15

    Purpose: Pulmonary inflammation is associated with a variety of diseases. Assessing pulmonary inflammation on in vivo imaging may facilitate the early detection and treatment of lung diseases. Although routinely used in thoracic imaging, computed tomography has thus far not been compellingly shown to characterize inflammation in vivo. Alternatively, magnetic resonance imaging (MRI) is a nonionizing radiation technique to better visualize and characterize pulmonary tissue. Prior to routine adoption of MRI for early characterization of inflammation in humans, a rigorous and quantitative characterization of the utility of MRI to identify inflammation is required. Such characterization may be achieved by considering ex vivo histology as the ground truth, since it enables the definitive spatial assessment of inflammation. In this study, the authors introduce a novel framework to integrate 2D histology, ex vivo and in vivo imaging to enable the mapping of the extent of disease from ex vivo histology onto in vivo imaging, with the goal of facilitating computerized feature analysis and interrogation of disease appearance on in vivo imaging. The authors’ framework was evaluated in a preclinical preliminary study aimed to identify computer extracted features on in vivo MRI associated with chronic pulmonary inflammation. Methods: The authors’ image analytics framework first involves reconstructing the histologic volume in 3D from individual histology slices. Second, the authors map the disease ground truth onto in vivo MRI via coregistration with 3D histology using the ex vivo lung MRI as a conduit. Finally, computerized feature analysis of the disease extent is performed to identify candidate in vivo imaging signatures of disease presence and extent. Results: The authors evaluated the framework by assessing the quality of the 3D histology reconstruction and the histology—MRI fusion, in the context of an initial use case involving characterization of chronic

  18. Rac2 is involved in bleomycin-induced lung inflammation leading to pulmonary fibrosis

    PubMed Central

    2014-01-01

    Background Pulmonary fibrotic diseases induce significant morbidity and mortality, for which there are limited therapeutic options available. Rac2, a ras-related guanosine triphosphatase expressed mainly in hematopoietic cells, is a crucial molecule regulating a diversity of mast cell, macrophage, and neutrophil functions. All these cell types have been implicated in the development of pulmonary fibrosis in a variety of animal models. For the studies described here we hypothesized that Rac2 deficiency protects mice from bleomycin-induced pulmonary fibrosis. Methods To determine the role of Rac2 in pulmonary fibrosis we used a bleomycin-induced mouse model. Anesthetized C57BL/6 wild type and rac2 -/- mice were instilled intratracheally with bleomycin sulphate (1.25 U/Kg) or saline as control. Bronchoalveolar lavage (BAL) samples were collected at days 3 and 7 of treatment and analyzed for matrix metalloproteinases (MMPs). On day 21 after bleomycin treatment, we measured airway resistance and elastance in tracheotomized animals. Lung sections were stained for histological analysis, while homogenates were analyzed for hydroxyproline and total collagen content. Results BLM-treated rac2 -/- mice had reduced MMP-9 levels in the BAL on day 3 and reduced neutrophilia and TNF and CCL3/MIP-1α levels in the BAL on day 7 compared to BLM-treated WT mice. We also showed that rac2 -/- mice had significantly lower mortality (30%) than WT mice (70%) at day 21 of bleomycin treatment. Lung function was diminished in bleomycin-treated WT mice, while it was unaffected in bleomycin-treated rac2 -/- mice. Histological analysis of inflammation and fibrosis as well as collagen and hydroxyproline content in the lungs did not show significant differences between BLM-treated rac2 -/- and WT and mice that survived to day 21. Conclusion Rac2 plays an important role in bleomycin-induced lung injury. It is an important signaling molecule leading to BLM-induced mortality and it also mediates the

  19. Detection of inflammation following renal ischemia by magnetic resonance imaging.

    PubMed

    Jo, Sang-Kyung; Hu, Xuzhen; Kobayashi, Hisataka; Lizak, Martin; Miyaji, Takehiko; Koretsky, Alan; Star, Robert A

    2003-07-01

    Determining the disease culprits in human acute renal failure (ARF) has been difficult because of the paucity of renal biopsies and the lack of noninvasive methods to determine the location or cause of renal injury. Recently, ultrasmall superparamagnetic iron oxide (USPIO) particles have been used to detect inflammation in animal models. Therefore, we tested if USPIO enhanced magnetic resonance imaging (MRI) could detect inflammation in ischemic ARF in rats. Rats were subjected to 40 or 60 minutes of bilateral ischemia or injected with mercuric chloride. MR images were obtained before and 24 hours after USPIO injection, and the signal intensity decrease in the outer medulla was measured. Cells containing iron particles were identified by iron staining and transmission electron microscopy (TEM). Leukocytes were identified by ED-1 and chloracetate esterase staining. Injection of USPIO particles caused a black band to appear in the outer medulla at 48, 72, and 120 hours after ischemia. This band was not detected in normal animals, 24 hours after ischemia, or 48 hours after mercuric chloride injection. The signal intensity change in the outer medulla correlated with serum creatinine and the number of iron particle containing cells. Most infiltrating cells were macrophages, and iron particles were present inside lysosomes of macrophages. USPIO injection did not alter renal function in normal or ischemic animals. USPIO-enhanced MRI could detect inflammation noninvasively from 48 hours after 40 or 60 minutes of renal ischemia in rats. This method might be useful to understand the pathogenesis of human ARF and to evaluate the effectiveness of anti-inflammatory agents.

  20. Molecular MRI approaches to the detection of CNS inflammation.

    PubMed

    Sibson, Nicola R; Anthony, Daniel C; van Kasteren, Sander; Dickens, Alex; Perez-Balderas, Francisco; McAteer, Martina A; Choudhury, Robin P; Davis, Benjamin G

    2011-01-01

    Inflammation is a key component of many neurological diseases, yet our understanding of the contribution of these processes to tissue damage remains poor. For many such diseases, magnetic resonance imaging (MRI) has become the method of choice for clinical diagnosis. However, many of the MRI parameters that enable disease detection, such as passive contrast enhancement across a compromised blood-brain barrier, are weighted towards late-stage disease. Moreover, whilst these methods may report on disease severity, they are not able to provide information on either disease activity or the underlying molecular processes. There is a need, therefore, to develop methods that enable earlier disease detection, potentially long before clinical symptoms become apparent, together with identification of specific molecular processes that may guide specific therapy. This chapter describes the methodology for the synthesis and validation of two novel, functional MRI-detectable probes, based on microparticles of iron oxide (MPIO), which target endothelial adhesion molecules. These contrast agents enable the detection of acute brain inflammation in vivo, at a time when pathology is undetectable by conventional MRI. Such molecular MRI methods are opening new vistas for the acute diagnosis of CNS disease, together with the possibility for individually tailored therapy and earlier, more sensitive assessment of the efficacy of novel therapies.

  1. Lack of Correlation Between Pulmonary and Systemic Inflammation Markers in Patients with Chronic Obstructive Pulmonary Disease: A Simultaneous, Two-Compartmental Analysis.

    PubMed

    Núñez, Belen; Sauleda, Jaume; Garcia-Aymerich, Judith; Noguera, Aina; Monsó, Eduard; Gómez, Federico; Barreiro, Esther; Marín, Alicia; Antó, Josep Maria; Agusti, Alvar

    2016-07-01

    The origin of systemic inflammation in chronic obstructive pulmonary disease (COPD) patients remains to be defined, but one of the most widely accepted hypothesis is the 'spill over' of inflammatory mediators from the lung to the circulation. To evaluate the relationship between pulmonary and systemic inflammation in COPD quantifying several inflammatory markers in sputum and serum determined simultaneously. Correlations between various inflammatory variables (TNF-α, IL6, IL8) in sputum and serum were evaluated in 133 patients from the PAC-COPD cohort study. A secondary objective was the evaluation of relationships between inflammatory variables and lung function. Inflammatory markers were clearly higher in sputum than in serum. No significant correlation was found (absolute value, r=0.03-0.24) between inflammatory markers in blood and in sputum. There were no significant associations identified between those markers and lung function variables, such as FEV1, DLCO and PaO2 neither. We found no correlation between pulmonary and systemic inflammation in patients with stable COPD, suggesting different pathogenic mechanisms. Copyright © 2016 SEPAR. Published by Elsevier Espana. All rights reserved.

  2. Idiopathic pulmonary fibrosis: Early detection and referral

    PubMed Central

    Oldham, Justin M.; Noth, Imre

    2016-01-01

    Summary Idiopathic pulmonary fibrosis (IPF), a devastating progressive interstitial lung disease (ILD) with no known cause or cure, is the most common and deadly of the idiopathic interstitial pneumonias. With a median survival of 3–5 years following diagnosis, IPF is characterized by a progressive decline in lung function and quality of life in most patients. Vigilance among clinicians in recognizing IPF early in the disease course remains critical to properly caring for these patients, as this provides the widest range of management options. When IPF is suspected, a multidisciplinary evaluation (MDE) by a clinician, radiologist and pathologist with ILD expertise should occur, as this improves diagnostic agreement in both community and academic settings. When community MDE is not possible, or diagnostic doubt exists, referral to an ILD center should be considered. ILD center referral may also provide access specialized care, including clinical trials and lung transplantation, and should be considered for any patient with an established diagnosis of IPF. PMID:24746629

  3. IL-6/Stat3-driven pulmonary inflammation, but not emphysema, is dependent on interleukin-17A in mice.

    PubMed

    Ruwanpura, Saleela M; McLeod, Louise; Brooks, Gavin D; Bozinovski, Steven; Vlahos, Ross; Longano, Anthony; Bardin, Philip G; Anderson, Gary P; Jenkins, Brendan J

    2014-04-01

    Pulmonary emphysema is linked to T cell-mediated autoimmune inflammation, although the pathogenic role of specific pro-inflammatory cytokines remains unclear. The Th17 type response, characterized by the production of the cytokine interleukin (IL)-17A, is modulated in part by the IL-6/signal transducer and activator of transcription (Stat)3 signalling axis and is associated with numerous autoimmune diseases. We therefore evaluated a causal role for IL-17A in the IL-6-driven gp130(F/F) mouse model for spontaneous pulmonary inflammation and emphysema. The expression of Th17-related factors was quantified in the lungs of gp130(F/F) mice and emphysematous patients, and the degree of pulmonary inflammation and emphysema was measured in gp130(F/F)  : Il17a-/- mice by immunohistochemistry, stereology and respiratory mechanics. In gp130(F/F) mice, lung gene expression of Il17a and other Th17-related factors was augmented compared with gp130+/+ (wild-type), gp130(F/F)  : Il6-/- and gp130(F/F)  : Stat3-/+ mice displaying normalized Stat3 activity and no lung inflammation. Importantly, genetic ablation of Il17a in gp130(F/F)  : Il17a-/- mice prevented lung inflammation; however, emphysema still developed. Additionally, messenger RNA expression of inflammatory genes Cxcl1, Cxcl2, Ccl2 and Tnfα; as well as Il6 and the Stat3-target gene, Socs3, were upregulated in the lungs of gp130(F/F) mice compared with gp130(F/F)  : Il17a-/- and gp130+/+ mice. Consistent with these findings, augmented IL17A expression was observed in emphysema patients presenting with inflammation compared with inflammation-free individuals. Collectively, our data suggest that the integration of IL-17A into the IL-6/Stat3 signalling axis mediates lung inflammation, but not emphysema, and that discrete targeting of IL-17A may alleviate pulmonary inflammatory-related diseases. © 2014 The Authors. Respirology © 2014 Asian Pacific Society of Respirology.

  4. Mineralocorticoid receptor antagonists attenuate pulmonary inflammation and bleomycin-evoked fibrosis in rodent models.

    PubMed

    Lieber, Gissela B; Fernandez, Xiomara; Mingo, Garfield G; Jia, Yanlin; Caniga, Michael; Gil, Malgorzata A; Keshwani, Shanil; Woodhouse, Janice D; Cicmil, Milenko; Moy, Lily Y; Kelly, Nancy; Jimenez, Johanna; Crawley, Yvette; Anthes, John C; Klappenbach, Joel; Ma, Yu-Lu; McLeod, Robbie L

    2013-10-15

    Accumulating evidence indicates protective actions of mineralocorticoid antagonists (MR antagonists) on cardiovascular pathology, which includes blunting vascular inflammation and myocardial fibrosis. We examined the anti-inflammatory and anti-fibrotic potential of MR antagonists in rodent respiratory models. In an ovalbumin allergic and challenged Brown Norway rat model, the total cell count in nasal lavage was 29,348 ± 5451, which was blocked by spironolactone (0.3-60 mg/kg, p.o.) and eplerenone (0.3-30 mg/kg, p.o.). We also found that MR antagonists attenuated pulmonary inflammation in the Brown Norway rat. A series of experiments were conducted to determine the actions of MR blockade in acute/chronic lung injury models. (1) Ex vivo lung slice rat experiments found that eplerenone (0.01 and 10 µM) and spironolactone (10 µM) diminished lung hydroxyproline concentrations by 55 ± 5, 122 ± 9, and 83 ± 8%. (2) In in vivo studies, MR antagonists attenuated the increases in bronchioalveolar lavage (BAL) neutrophils and macrophages caused by lung bleomycin exposure. In separate studies, bleomycin (4.0 U/kg, i.t.) increased lung levels of hydroxyproline by approximately 155%, which was blocked by spironolactone (10-60 mg/kg, p.o.). In a rat Lipopolysaccharide (LPS) model, spironolactone inhibited acute increases in BAL cytokines with moderate effects on neutrophils. Finally, we found that chronic LPS exposure significantly increased end expiratory lung and decreased lung elastance in the mouse. These functional effects of chronic LPS were improved by MR antagonists. Our results demonstrate that MR antagonists have significant pharmacological actions in the respiratory system.

  5. [Characteristics of stable chronic obstructive pulmonary disease related to systemic inflammation].

    PubMed

    Solanes, Ingrid; Bolíbar, Ignasi; Llauger, Maria Antònia; Medrano, Casimira; Peiró, Meritxell; Fraga, Mar; Pou, Maria Antònia; Giner, Jordi; Freixas, Montserrat; Plaza, Vicente

    2012-10-20

    Chronic obstructive pulmonary disease (COPD) is characterized by a systemic inflammation. The aim of this study was to evaluate the association between systemic inflammation, measured with C reactive protein (CRP), and clinical and functional outcomes of the disease. A randomized sample of 413 COPD patients from 31 primary health care centers of Barcelona was evaluated. Medical history, anthropometric measurements, toxic habits, treatments, Chronic Respiratory Questionnaire (CRQ) and dyspnea were registered. Spirometry, exhaled CO concentration and CRP in capillary blood were performed. Median (standard deviation) of the age was 72 (8.4) years and forced expiratory volume in one second (FEV(1)) postbronchodilatador 1.65 (0.65) l. The correlation was negative between CRP and FEV(1) postbronchodilatador(r=-0.25, P<0.001) and between CRP and CRQ scores (r=-0.098, P=0.048) and positive between CRP and CO (r=0.1, P=0.039). The ratio of patients with elevated CRP was higher in advanced GOLD stage (P<0.001), worst dyspnea (P=0.042), patients treated with inhaled corticosteroids (P=0.018) and if they had been hospitalized during the last year (P=0.026). The multivariant analysis showed, as independent factors of elevated CRP, FEV(1) postbronchodilator and CO concentration. In COPD patients, active smoking habit and the airway's obstruction degree are associated with a greater intensity of the inflammatory systemic response measured by the CRP. Copyright © 2011 Elsevier España, S.L. All rights reserved.

  6. Detection of pulmonary amylase activity in exhaled breath condensate.

    PubMed

    Zweifel, M; Rechsteiner, T; Hofer, M; Boehler, A

    2013-12-01

    Amylase activity in exhaled breath condensate (EBC) is usually interpreted as an indication of oropharyngeal contamination despite the fact that amylase can be found in pulmonary excretions. The aim of this study was to recruit and refine an amylase assay in order to detect amylase activity in any EBC sample and to develop a method to identify EBC samples containing amylase of pulmonary origin. EBC was collected from 40 volunteers with an EcoScreen condenser. Amylase assays and methods to discriminate between oropharyngeal and pulmonary proteins were tested and developed using matched EBC and saliva samples. Our refined 2-chloro-4-nitrophenyl-α-D-maltotriosid (CNP-G3) assay was 40-fold more sensitive than the most sensitive commercial assay and allowed detection of amylase activity in 30 µl of EBC. We developed a dot-blot assay which allowed detection of salivary protein in saliva diluted up to 150 000-fold. By plotting amylase activity against staining intensity we identified a few EBC samples with high amylase activity which were aligned with diluted saliva. We believe that EBC samples aligned with diluted saliva contain amylase activity introduced during EBC collection and that all other EBC samples contain amylase activity of pulmonary origin and are basically free of oropharyngeal protein contamination.

  7. Adaptive contrast-based computer aided detection for pulmonary embolism

    NASA Astrophysics Data System (ADS)

    Dinesh, M. S.; Devarakota, Pandu; Raghupathi, Laks; Lakare, Sarang; Salganicoff, Marcos; Krishnan, Arun

    2009-02-01

    This work involves the computer-aided diagnosis (CAD) of pulmonary embolism (PE) in contrast-enhanced computed tomography pulmonary angiography (CTPA). Contrast plays an important role in analyzing and identifying PE in CTPA. At times the contrast mixing in blood may be insufficient due to several factors such as scanning speed, body weight and injection duration. This results in a suboptimal study (mixing artifact) due to non-homogeneous enhancement of blood's opacity. Most current CAD systems are not optimized to detect PE in sub optimal studies. To this effect, we propose new techniques for CAD to work robustly in both optimal and suboptimal situations. First, the contrast level at the pulmonary trunk is automatically detected using a landmark detection tool. This information is then used to dynamically configure the candidate generation (CG) and classification stages of the algorithm. In CG, a fast method based on tobogganing is proposed which also detects wall-adhering emboli. In addition, our proposed method correctly encapsulates potential PE candidates that enable accurate feature calculation over the entire PE candidate. Finally a classifier gating scheme has been designed that automatically switches the appropriate classifier for suboptimal and optimal studies. The system performance has been validated on 86 real-world cases collected from different clinical sites. Results show around 5% improvement in the detection of segmental PE and 6% improvement in lobar and sub segmental PE with a 40% decrease in the average false positive rate when compared to a similar system without contrast detection.

  8. Upregulation of HERV-K is Linked to Immunity and Inflammation in Pulmonary Arterial Hypertension.

    PubMed

    Saito, Toshie; Miyagawa, Kazuya; Chen, Shih-Yu; Tamosiuniene, Rasa; Wang, Lingli; Sharp, Orr; Samayoa, Erik; Harada, Daisuke; Moonen, Jan-Renier A J; Cao, Aiqin; Chen, Pin-I; Hennigs, Jan K; Gu, Mingxia; Li, Caiyun G; Leib, Ryan D; Li, Dan; Adams, Christopher M; Del Rosario, Patricia A; Bill, Matthew A; Haddad, Francois; Montoya, Jose G; Robinson, William; Fantl, Wendy J; Nolan, Garry P; Zamanian, Roham T; Nicolls, Mark R; Chiu, Charles Y; Ariza, Maria E; Rabinovitch, Marlene

    2017-09-21

    Background -Immune dysregulation has been linked to occlusive vascular remodeling in pulmonary arterial hypertension (PAH) that is hereditary, idiopathic or associated with other conditions. Circulating autoantibodies, lung perivascular lymphoid tissue and elevated cytokines have been related to PAH pathogenesis but without clear understanding of how these abnormalities are initiated, perpetuated and connected in the progression of disease. We therefore set out to identify specific target antigens in PAH lung immune complexes as a starting point toward resolving these issues to better inform future application of immunomodulatory therapies. Methods -Lung immune complexes were isolated and PAH target antigens were identified by liquid chromatography tandem mass spectrometry (LCMS), confirmed by ELISA, and localized by confocal microscopy. One PAH antigen linked to immunity and inflammation was pursued and a link to PAH pathophysiology was investigated by next generation sequencing, functional studies in cultured monocytes and endothelial cells (EC) and hemodynamic and lung studies in a rat. Results -SAM domain and HD1 domain-containing protein (SAMHD1), an innate immune factor that suppresses HIV replication was identified and confirmed as highly expressed in immune complexes from 16 hereditary and idiopathic PAH vs. 12 control lungs. Elevated SAMHD1 was localized to endothelial cells (EC), perivascular dendritic cells and macrophages and SAMHD1 antibodies were prevalent in tertiary lymphoid tissue. An unbiased screen using metagenomic sequencing related SAMHD1 to increased expression of human endogenous retrovirus K (HERV-K) in PAH vs. control lungs (n=4 each). HERV-K envelope and deoxyuridine triphosphate nucleotidohydrolase (dUTPase) mRNAs were elevated in PAH vs. control lungs (n=10) and proteins were localized to macrophages. HERV-K dUTPase induced SAMHD1 and pro-inflammatory cytokines (e.g., IL6, IL1β and TNFα) in circulating monocytes and pulmonary arterial

  9. Application of the open-lung concept during positive-pressure ventilation reduces pulmonary inflammation in newborn piglets.

    PubMed

    van Kaam, Anton H; Dik, Willem A; Haitsma, Jack J; De Jaegere, Anne; Naber, Birgitta A; van Aalderen, Wim M; Kok, Joke H; Lachmann, Burkhard

    2003-01-01

    It has been shown that application of the open-lung concept (OLC) during high-frequency oscillatory ventilation (HFOV) attenuates pulmonary inflammation. We hypothesized that this attenuation could also be achieved by applying the OLC during positive-pressure ventilation (PPV). After repeated whole-lung lavage, newborn piglets were assigned to one of three ventilation groups: (1) PPV(OLC); (2) HFOV(OLC), or (3) conventional PPV (PPV(CON)). After a ventilation period of 5 h, analysis of bronchoalveolar lavage fluid showed a reduced influx of polymorphonuclear neutrophils, interleukin 8, and thrombin activity in both OLC groups as compared with the PPV(CON) group. There were no differences in tumor necrosis factor alpha levels. We conclude that application of the OLC during PPV reduces pulmonary inflammation as compared with conventional PPV and that the magnitude of this reduction is comparable to that of HFOV.

  10. Foxa2 Regulates Leukotrienes to Inhibit Th2-mediated Pulmonary Inflammation

    PubMed Central

    Tang, Xiaoju; Liu, Xiaojing J.; Tian, Cuijie; Su, Qiaoli; Lei, Yi; Wu, Qingbo; He, Yangyan; Whitsett, Jeffrey A.

    2013-01-01

    Foxa2 is a member of the Forkhead family of nuclear transcription factors that is highly expressed in respiratory epithelial cells of the developing and mature lung. Foxa2 is required for normal airway epithelial differentiation, and its deletion causes goblet-cell metaplasia and Th2-mediated pulmonary inflammation during postnatal development. Foxa2 expression is inhibited during aeroallergen sensitization and after stimulation with Th2 cytokines, when its loss is associated with goblet-cell metaplasia. Mechanisms by which Foxa2 controls airway epithelial differentiation and Th2 immunity are incompletely known. During the first 2 weeks after birth, the loss of Foxa2 increases the production of leukotrienes (LTs) and Th2 cytokines in the lungs of Foxa2 gene–targeted mice. Foxa2 expression inhibited 15-lipoxygenase (Alox15) and increased Alox5 transcription, each encoding key lipoxygenases associated with asthma. The inhibition of the cysteinyl LT (CysLT) signaling pathway by montelukast inhibited IL-4, IL-5, eotaxin-2, and regulated upon activation normal T cell expressed and presumably secreted expression in the developing lungs of Foxa2 gene–targeted mice. Montelukast inhibited the expression of genes regulating mucus metaplasia, including Spdef, Muc5ac, Foxa3, and Arg2. Foxa2 plays a cell-autonomous role in the respiratory epithelium, and is required for the suppression of Th2 immunity and mucus metaplasia in the developing lung in a process determined in part by its regulation of the CysLT pathway. PMID:23822876

  11. Aging leads to impaired epicutaneous sensitization that causes attenuated allergy and pulmonary inflammation in mice.

    PubMed

    Langier, Sheila; Benor, Shira; Kadar, Laliv; Shani, Nir; Etkin, Sara; Stark, Moshe; Bondar, Ekaterina; Aizic, Asaf; Kivity, Shmuel

    2017-05-03

    Aging is associated with altered decreased barrier function in the skin, which can lead to different types of immunoglobulin E (IgE)-mediated sensitization to environmental allergens. Yet, allergen-specific respiratory sensitization among the elderly is not well described. The aim of this study was to investigate the effect of aging on allergic pulmonary inflammation induced by epicutaneous sensitization of mechanically irritated skin in mice. For this purpose, 6-week-, 6-month-, and 18-month-old female BALB/c mice, underwent epicutaneous sensitization with ovalbumin (OVA) or PBS, followed by an inhaled OVA challenge. Blood OVA-specific IgE levels measured after epicutaneous sensitization, as well as, bronchial alveolar lavage fluids (BALF) leucocyte, eosinophil, and cytokine levels measured after OVA inhalation challenge were similar among the 6-week-old (young) and 6-month-old (adult) groups. However, significantly decreased levels of systemic OVA-IgE, and BALF leukocyte, eosinophil and T helper cell type 2 cytokine levels, were measured after OVA inhalation challenge in elderly (18-month-old) mice compared to the other groups of mice. In addition, interleukin-10 (IL-10), a regulatory suppressor cytokine, was more abundant in the BALF of the elderly group after epicutaneous sensitization and inhalation challenge. Our results suggest that elderly mice have a reduced allergic response to induced sensitization with OVA, possibly regulated by increased IL-10 levels. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  12. 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

  13. Role of PPARγ in COX-2 activation in mycobacterial pulmonary inflammation.

    PubMed

    Kogiso, Mari; Shinohara, Tsutomu; Dorey, C Kathleen; Shibata, Yoshimi

    2012-10-01

    Preliminary studies show that intranasal (i.n.) administration of BCG in mice induces M1 activation of alveolar macrophages (M∅) that increase TNF-α production and cyclooxygenase-2 (COX-2) expression but reduce constitutive peroxisome proliferator-activated receptor gamma (PPARγ) expression. However, COX-2 is catalytically inactive for prostaglandin E(2) release, unlike COX-2 that is active in M1 activation in vitro by BCG. In this study, we determined the role of PPARγ for BCG-induced M1 activation in vivo and in vitro. We found that treatment of mice with GW9662, a PPARγ antagonist, prior to i.n. BCG, partially restored PPARγ expression, and decreased TNF-α production and COX-2 expression. But COX-2 was still inactive. The decreased effects on TNF-α and COX-2 were also observed when alveolar M∅ were treated in vitro with GW9662/BCG, but COX-2 was still active. Our results indicate that PPARγ upregulates M1 activation of alveolar M∅, but inactive COX-2 formation is independent of PPARγ in mycobacterial pulmonary inflammation.

  14. Peroxisome proliferator-activated receptor gamma as modulator of inflammation in pulmonary sarcoidosis.

    PubMed

    Pejcić, Tatjana; Stanković, Ivana; Petković, Tatjana Radjenović; Borovac, Desa Nastasijević; Djordjević, Ivanka; Jeftović-Stoimenov, Tatjana

    2013-01-01

    Peroxisome proliferator-activated receptor (PPAR) includes the family of ligand-activated transcription factors which belong to the group of nuclear hormone receptors and are connected to retinoid, glucocorticoid and thyroid hormone receptors. There are three subtypes of PPARs: PPARalpha (also known as NR1C3), PPARgamma (known as NR1C1) and PPARdelta (known as PPARbeta or NR1C2). All of them take part in the metabolism, cell proliferation and immune response. PPARgamma and PPARalpha are identified as important immunomodulators and potentially represent an anti-inflammatory target for respiratory diseases. PPARgamma deficiency in the lungs has been observed in the inflammatory diseases such as asthma, pulmonary alveolar proteinosis, fibrosis and sarcoidosis, as well as in the animal models of the lung inflammation. A small number of papers concerned with PPARgamma in sarcoidosis pointto the lowered activity of this factor in the alveolar macrophages and a lowered gene expression for the PPARgamma, while the activity is preserved in healthy individuals. At the same time, an increased activity of the nuclear factor kappa B (NF-kappaB) in the bronchoalveolar lavage has been recorded in patients with sarcoidosis. The reason for the decrease in the production of PPARgamma in sarcoidosis remains unknown. Several possible mechanisms are mentioned: genetic defect with lowered production, down-regulation due to the increased values of IFN-gamma or an increased decomposition of PPARgamma. Further investigation will explain the mechanisms regarding the decreased production of PPARgamma in sarcoidosis.

  15. Acid sphingomyelinase inhibitors normalize pulmonary ceramide and inflammation in cystic fibrosis.

    PubMed

    Becker, Katrin Anne; Riethmüller, Joachim; Lüth, Anja; Döring, Gerd; Kleuser, Burkhard; Gulbins, Erich

    2010-06-01

    Employing genetic mouse models we have recently shown that ceramide accumulation is critically involved in the pathogenesis of cystic fibrosis (CF) lung disease. Genetic or systemic inhibition of the acid sphingomyelinase (Asm) is not feasible for treatment of patients or might cause adverse effects. Thus, a manipulation of ceramide specifically in lungs of CF mice must be developed. We tested whether inhalation of different acid sphingomyelinase inhibitors does reduce Asm activity and ceramide accumulation in lungs of CF mice. The efficacy and specificity of the drugs was determined. Ceramide was determined by mass spectrometry, DAG-kinase assays, and fluorescence microscopy. We determined pulmonary and systemic Asm activity, neutral sphingomyelinase (Nsm), ceramide, cytokines, and infection susceptibility. Mass spectroscopy, DAG-kinase assays, and semiquantitative immune fluorescence microscopy revealed that a standard diet did not influence ceramide in bronchial respiratory epithelial cells, while a diet with Peptamen severely affected the concentration of sphingolipids in CF lungs. Inhalation of the Asm inhibitors amitriptyline, trimipramine, desipramine, chlorprothixene, fluoxetine, amlodipine, or sertraline restored normal ceramide concentrations in murine bronchial epithelial cells, reduced inflammation in the lung of CF mice and prevented infection with Pseudomonas aeruginosa. All drugs showed very similar efficacy. Inhalation of the drugs was without systemic effects and did not inhibit Nsm. These findings employing several structurally different Asm inhibitors identify Asm as primary target in the lung to reduce ceramide concentrations. Inhaling an Asm inhibitor may be a beneficial treatment for CF, with minimal adverse systemic effects.

  16. Acrolein induced both pulmonary inflammation and the death of lung epithelial cells.

    PubMed

    Sun, Yang; Ito, Sachiko; Nishio, Naomi; Tanaka, Yuriko; Chen, Nana; Isobe, Ken-Ichi

    2014-09-02

    Acrolein, a compound found in cigarette smoke, is a major risk factor for respiratory diseases. Previous research determined that both acrolein and cigarette smoke produced reactive oxygen species (ROS). As many types of pulmonary injuries are associated with inflammation, this study sought to ascertain the extent to which exposure to acrolein advanced inflammatory state in the lungs. Our results showed that intranasal exposure of mice to acrolein increased CD11c(+)F4/80(high) macrophages in the lungs and increased ROS formation via induction of NF-κB signaling. Treatment with acrolein activated macrophages and led to their increased production of ROS and expression of several key pro-inflammatory cytokines. In in vitro studies, acrolein treatment of bone marrow-derived GM-CSF-dependent immature macrophages (GM-IMs), activated the cells and led to their increased production of ROS and expression of several key pro-inflammatory cytokines. Acrolein treatment of macrophages induced apoptosis of lung epithelial cells. Inclusion of an inhibitor of ROS formation markedly decreased acrolein-mediated macrophage activation and reduced the extent of epithelial cell death. These results indicate that acrolein can cause lung damage, in great part by mediating the increased release of pro-inflammatory cytokines/factors by macrophages.

  17. FIZZ1, a novel cysteine-rich secreted protein associated with pulmonary inflammation, defines a new gene family

    PubMed Central

    Holcomb, Ilona N.; Kabakoff, Rhona C.; Chan, Betty; Baker, Thad W.; Gurney, Austin; Henzel, William; Nelson, Chris; Lowman, Henry B.; Wright, Barbara D.; Skelton, Nicholas J.; Frantz, Gretchen D.; Tumas, Daniel B.; Peale,Jr, Franklin V.; Shelton, David L.; Hébert, Caroline C.

    2000-01-01

    Bronchoalveolar lavage fluid from mice with experimentally induced allergic pulmonary inflammation contains a novel 9.4 kDa cysteine-rich secreted protein, FIZZ1 (found in inflammatory zone). Murine (m) FIZZ1 is the founding member of a new gene family including two other murine genes expressed, respectively, in intestinal crypt epithelium and white adipose tissue, and two related human genes. In control mice, FIZZ1 mRNA and protein expression occur at low levels in a subset of bronchial epithelial cells and in non-neuronal cells adjacent to neurovascular bundles in the peribronchial stroma, and in the wall of the large and small bowel. During allergic pulmonary inflammation, mFIZZ1 expression markedly increases in hypertrophic, hyperplastic bronchial epithelium and appears in type II alveolar pneumocytes. In vitro, recombinant mFIZZ1 inhibits the nerve growth factor (NGF)-mediated survival of rat embryonic day 14 dorsal root ganglion (DRG) neurons and NGF-induced CGRP gene expression in adult rat DRG neurons. In vivo, FIZZ1 may modulate the function of neurons innervating the bronchial tree, thereby altering the local tissue response to allergic pulmonary inflammation. PMID:10921885

  18. Detection of subclinical synovial inflammation by microwave radiometry.

    PubMed

    Zampeli, Evangelia; Raftakis, Ioannis; Michelongona, Archontoula; Nikolaou, Chara; Elezoglou, Antonia; Toutouzas, Konstantinos; Siores, Elias; Sfikakis, Petros P

    2013-01-01

    Microwave Radiometry is a non-invasive method which determines within seconds the in vivo temperature of internal tissues at a depth of 3-7 cm with an accuracy of ±0.2°C. In this proof-of-concept study, we tested the hypothesis that, in absence of relevant clinical signs, increased local temperature detected by microwave radiometry reflects subclinical synovial inflammation, using ultrasound as reference method. Knees of healthy controls, subjects with recent knee trauma and symptom-free patients with rheumatoid arthritis (RA) or osteoarthritis were examined by placing the microwave radiometry sensor, a) at the upper one third of the anterior surface of the thigh (control-point), and b) over the suprapatellar recess. Ultrasound was performed immediately after and the possible presence of fluid and/or synovitis was correlated with microwave radiometry findings. In 30 healthy and 10 injured knees the temperature was always lower than thigh (32.3±1.1 and 31.8±1.4 versus 34.1±0.9 and 33.6±1.2°C with a difference (ΔΤ) of -1.8±0.2 and -1.9±0.4°C respectively). Of 40 RA and 20 osteoarthritis knees examined, ultrasound findings indicative of subclinical inflammation (fluid effusion and/or Doppler signal) were found in 24 and 12, respectively, in which the temperature was higher than healthy knees and ΔΤ was lower (-0.9±0.7 in RA and -1.0±0.5 in osteoarthritis versus -1.8±0.2°C, p<0.001). The 5 RA knees with power Doppler findings indicative of grade 2 inflammation had a ΔΤ 3 times lower compared to healthy (-0.6±0.6, p = 0.007), whereas the 9 RA and the 7 osteoarthritis knees with additionally fluid effusion, had even lower ΔΤ (-0.4±0.7, p<0.001). Using a safe, rapid and easy-to-perform method, such as microwave radiometry, thermal changes within the knee joint may reflect non-clinically apparent joint inflammation. Refinement of this method, including production of sensors for small joints, could result to the development of the ideal objective

  19. Detection of Subclinical Synovial Inflammation by Microwave Radiometry

    PubMed Central

    Zampeli, Evangelia; Raftakis, Ioannis; Michelongona, Archontoula; Nikolaou, Chara; Elezoglou, Antonia; Toutouzas, Konstantinos; Siores, Elias; Sfikakis, Petros P.

    2013-01-01

    Objective Microwave Radiometry is a non-invasive method which determines within seconds the in vivo temperature of internal tissues at a depth of 3–7 cm with an accuracy of ±0.2°C. In this proof-of-concept study, we tested the hypothesis that, in absence of relevant clinical signs, increased local temperature detected by microwave radiometry reflects subclinical synovial inflammation, using ultrasound as reference method. Methods Knees of healthy controls, subjects with recent knee trauma and symptom-free patients with rheumatoid arthritis (RA) or osteoarthritis were examined by placing the microwave radiometry sensor, a) at the upper one third of the anterior surface of the thigh (control-point), and b) over the suprapatellar recess. Ultrasound was performed immediately after and the possible presence of fluid and/or synovitis was correlated with microwave radiometry findings. Results In 30 healthy and 10 injured knees the temperature was always lower than thigh (32.3±1.1 and 31.8±1.4 versus 34.1±0.9 and 33.6±1.2°C with a difference (ΔΤ) of −1.8±0.2 and −1.9±0.4°C respectively). Of 40 RA and 20 osteoarthritis knees examined, ultrasound findings indicative of subclinical inflammation (fluid effusion and/or Doppler signal) were found in 24 and 12, respectively, in which the temperature was higher than healthy knees and ΔΤ was lower (−0.9±0.7 in RA and −1.0±0.5 in osteoarthritis versus −1.8±0.2°C, p<0.001). The 5 RA knees with power Doppler findings indicative of grade 2 inflammation had a ΔΤ 3 times lower compared to healthy (−0.6±0.6, p = 0.007), whereas the 9 RA and the 7 osteoarthritis knees with additionally fluid effusion, had even lower ΔΤ (−0.4±0.7, p<0.001). Conclusion Using a safe, rapid and easy-to-perform method, such as microwave radiometry, thermal changes within the knee joint may reflect non-clinically apparent joint inflammation. Refinement of this method, including production of sensors for small joints

  20. Acute and chronic effects of treatment with mesenchymal stromal cells on LPS-induced pulmonary inflammation, emphysema and atherosclerosis development

    PubMed Central

    Khedoe, P. Padmini S. J.; de Kleijn, Stan; van Oeveren-Rietdijk, Annemarie M.; Plomp, Jaap J.; de Boer, Hetty C.; van Pel, Melissa; Rensen, Patrick C. N.

    2017-01-01

    Background COPD is a pulmonary disorder often accompanied by cardiovascular disease (CVD), and current treatment of this comorbidity is suboptimal. Systemic inflammation in COPD triggered by smoke and microbial exposure is suggested to link COPD and CVD. Mesenchymal stromal cells (MSC) possess anti-inflammatory capacities and MSC treatment is considered an attractive treatment option for various chronic inflammatory diseases. Therefore, we investigated the immunomodulatory properties of MSC in an acute and chronic model of lipopolysaccharide (LPS)-induced inflammation, emphysema and atherosclerosis development in APOE*3-Leiden (E3L) mice. Methods Hyperlipidemic E3L mice were intranasally instilled with 10 μg LPS or vehicle twice in an acute 4-day study, or twice weekly during 20 weeks Western-type diet feeding in a chronic study. Mice received 0.5x106 MSC or vehicle intravenously twice after the first LPS instillation (acute study) or in week 14, 16, 18 and 20 (chronic study). Inflammatory parameters were measured in bronchoalveolar lavage (BAL) and lung tissue. Emphysema, pulmonary inflammation and atherosclerosis were assessed in the chronic study. Results In the acute study, intranasal LPS administration induced a marked systemic IL-6 response on day 3, which was inhibited after MSC treatment. Furthermore, MSC treatment reduced LPS-induced total cell count in BAL due to reduced neutrophil numbers. In the chronic study, LPS increased emphysema but did not aggravate atherosclerosis. Emphysema and atherosclerosis development were unaffected after MSC treatment. Conclusion These data show that MSC inhibit LPS-induced pulmonary and systemic inflammation in the acute study, whereas MSC treatment had no effect on inflammation, emphysema and atherosclerosis development in the chronic study. PMID:28910300

  1. A Plant Proteinase Inhibitor from Enterolobium contortisiliquum Attenuates Pulmonary Mechanics, Inflammation and Remodeling Induced by Elastase in Mice

    PubMed Central

    Theodoro-Júnior, Osmar Aparecido; Righetti, Renato Fraga; Almeida-Reis, Rafael; Martins-Oliveira, Bruno Tadeu; Oliva, Leandro Vilela; Prado, Carla Máximo; Saraiva-Romanholo, Beatriz Mangueira; Leick, Edna Aparecida; Pinheiro, Nathalia Montouro; Lobo, Yara Aparecida; Martins, Mílton de Arruda; Oliva, Maria Luiza Vilela; Tibério, Iolanda de Fátima Lopes Calvo

    2017-01-01

    Proteinase inhibitors have been associated with anti-inflammatory and antioxidant activities and may represent a potential therapeutic treatment for emphysema. Our aim was to evaluate the effects of a plant Kunitz proteinase inhibitor, Enterolobium contortisiliquum trypsin inhibitor (EcTI), on several aspects of experimental elastase-induced pulmonary inflammation in mice. C57/Bl6 mice were intratracheally administered elastase (ELA) or saline (SAL) and were treated intraperitoneally with EcTI (ELA-EcTI, SAL-EcTI) on days 1, 14 and 21. On day 28, pulmonary mechanics, exhaled nitric oxide (ENO) and number leucocytes in the bronchoalveolar lavage fluid (BALF) were evaluated. Subsequently, lung immunohistochemical staining was submitted to morphometry. EcTI treatment reduced responses of the mechanical respiratory system, number of cells in the BALF, and reduced tumor necrosis factor-α (TNF-α), matrix metalloproteinase-9 (MMP-9), matrix metalloproteinase-12 (MMP-12), tissue inhibitor of matrix metalloproteinase (TIMP-1), endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS)-positive cells and volume proportion of isoprostane, collagen and elastic fibers in the airways and alveolar walls compared with the ELA group. EcTI treatment reduced elastase induced pulmonary inflammation, remodeling, oxidative stress and mechanical alterations, suggesting that this inhibitor may be a potential therapeutic tool for chronic obstructive pulmonary disease (COPD) management. PMID:28216579

  2. A Plant Proteinase Inhibitor from Enterolobium contortisiliquum Attenuates Pulmonary Mechanics, Inflammation and Remodeling Induced by Elastase in Mice.

    PubMed

    Theodoro-Júnior, Osmar Aparecido; Righetti, Renato Fraga; Almeida-Reis, Rafael; Martins-Oliveira, Bruno Tadeu; Oliva, Leandro Vilela; Prado, Carla Máximo; Saraiva-Romanholo, Beatriz Mangueira; Leick, Edna Aparecida; Pinheiro, Nathalia Montouro; Lobo, Yara Aparecida; Martins, Mílton de Arruda; Oliva, Maria Luiza Vilela; Tibério, Iolanda de Fátima Lopes Calvo

    2017-02-14

    Proteinase inhibitors have been associated with anti-inflammatory and antioxidant activities and may represent a potential therapeutic treatment for emphysema. Our aim was to evaluate the effects of a plant Kunitz proteinase inhibitor, Enterolobium contortisiliquum trypsin inhibitor (EcTI), on several aspects of experimental elastase-induced pulmonary inflammation in mice. C57/Bl6 mice were intratracheally administered elastase (ELA) or saline (SAL) and were treated intraperitoneally with EcTI (ELA-EcTI, SAL-EcTI) on days 1, 14 and 21. On day 28, pulmonary mechanics, exhaled nitric oxide (ENO) and number leucocytes in the bronchoalveolar lavage fluid (BALF) were evaluated. Subsequently, lung immunohistochemical staining was submitted to morphometry. EcTI treatment reduced responses of the mechanical respiratory system, number of cells in the BALF, and reduced tumor necrosis factor-α (TNF-α), matrix metalloproteinase-9 (MMP-9), matrix metalloproteinase-12 (MMP-12), tissue inhibitor of matrix metalloproteinase (TIMP-1), endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS)-positive cells and volume proportion of isoprostane, collagen and elastic fibers in the airways and alveolar walls compared with the ELA group. EcTI treatment reduced elastase induced pulmonary inflammation, remodeling, oxidative stress and mechanical alterations, suggesting that this inhibitor may be a potential therapeutic tool for chronic obstructive pulmonary disease (COPD) management.

  3. Automated detection of pulmonary nodules in CT images with support vector machines

    NASA Astrophysics Data System (ADS)

    Liu, Lu; Liu, Wanyu; Sun, Xiaoming

    2008-10-01

    Many methods have been proposed to avoid radiologists fail to diagnose small pulmonary nodules. Recently, support vector machines (SVMs) had received an increasing attention for pattern recognition. In this paper, we present a computerized system aimed at pulmonary nodules detection; it identifies the lung field, extracts a set of candidate regions with a high sensitivity ratio and then classifies candidates by the use of SVMs. The Computer Aided Diagnosis (CAD) system presented in this paper supports the diagnosis of pulmonary nodules from Computed Tomography (CT) images as inflammation, tuberculoma, granuloma..sclerosing hemangioma, and malignant tumor. Five texture feature sets were extracted for each lesion, while a genetic algorithm based feature selection method was applied to identify the most robust features. The selected feature set was fed into an ensemble of SVMs classifiers. The achieved classification performance was 100%, 92.75% and 90.23% in the training, validation and testing set, respectively. It is concluded that computerized analysis of medical images in combination with artificial intelligence can be used in clinical practice and may contribute to more efficient diagnosis.

  4. Genetics and Early Detection in Idiopathic Pulmonary Fibrosis

    PubMed Central

    Putman, Rachel K.; Rosas, Ivan O.

    2014-01-01

    Genetic studies hold promise in helping to identify patients with early idiopathic pulmonary fibrosis (IPF). Recent studies using chest computed tomograms (CTs) in smokers and in the general population have demonstrated that imaging abnormalities suggestive of an early stage of pulmonary fibrosis are not uncommon and are associated with respiratory symptoms, physical examination abnormalities, and physiologic decrements expected, but less severe than those noted in patients with IPF. Similarly, recent genetic studies have demonstrated strong and replicable associations between a common promoter polymorphism in the mucin 5B gene (MUC5B) and both IPF and the presence of abnormal imaging findings in the general population. Despite these findings, it is important to note that the definition of early-stage IPF remains unclear, limited data exist to definitively connect abnormal imaging findings to IPF, and genetic studies assessing early-stage pulmonary fibrosis remain in their infancy. In this perspective we provide updated information on interstitial lung abnormalities and their connection to IPF. We summarize information on the genetics of pulmonary fibrosis by focusing on the recent genetic findings of MUC5B. Finally, we discuss the implications of these findings and suggest a roadmap for the use of genetics in the detection of early IPF. PMID:24547893

  5. Genetics and early detection in idiopathic pulmonary fibrosis.

    PubMed

    Putman, Rachel K; Rosas, Ivan O; Hunninghake, Gary M

    2014-04-01

    Genetic studies hold promise in helping to identify patients with early idiopathic pulmonary fibrosis (IPF). Recent studies using chest computed tomograms (CTs) in smokers and in the general population have demonstrated that imaging abnormalities suggestive of an early stage of pulmonary fibrosis are not uncommon and are associated with respiratory symptoms, physical examination abnormalities, and physiologic decrements expected, but less severe than those noted in patients with IPF. Similarly, recent genetic studies have demonstrated strong and replicable associations between a common promoter polymorphism in the mucin 5B gene (MUC5B) and both IPF and the presence of abnormal imaging findings in the general population. Despite these findings, it is important to note that the definition of early-stage IPF remains unclear, limited data exist to definitively connect abnormal imaging findings to IPF, and genetic studies assessing early-stage pulmonary fibrosis remain in their infancy. In this perspective we provide updated information on interstitial lung abnormalities and their connection to IPF. We summarize information on the genetics of pulmonary fibrosis by focusing on the recent genetic findings of MUC5B. Finally, we discuss the implications of these findings and suggest a roadmap for the use of genetics in the detection of early IPF.

  6. Diet-induced obesity causes innate airway hyperresponsiveness to methacholine and enhances ozone-induced pulmonary inflammation.

    PubMed

    Johnston, Richard A; Theman, Todd A; Lu, Frank L; Terry, Raya D; Williams, Erin S; Shore, Stephanie A

    2008-06-01

    We previously reported that genetically obese mice exhibit innate airway hyperresponsiveness (AHR) and enhanced ozone (O(3))-induced pulmonary inflammation. Such genetic deficiencies in mice are rare in humans, and they may not be representative of human obesity. Thus the purpose of this study was to determine the pulmonary phenotype of mice with diet-induced obesity (DIO), which more closely mimics the cause of human obesity. Therefore, wild-type C57BL/6 mice were reared from the time of weaning until at least 30 wk of age on diets in which either 10 or 60% of the calories are derived from fat in the form of lard. Body mass was approximately 40% greater in mice fed 60 vs. 10% fat diets. Baseline airway responsiveness to intravenous methacholine, measured by forced oscillation, was greater in mice fed 60 vs. 10% fat diets. We also examined lung permeability and inflammation after exposure to room air or O(3) (2 parts/million for 3 h), an asthma trigger. Four hours after the exposure ended, O(3)-induced increases in bronchoalveolar lavage fluid protein, interleukin-6, KC, macrophage inflammatory protein-2, interferon-gamma-inducible protein-10, and eotaxin were greater in mice fed 60 vs. 10% fat diets. Innate AHR and augmented responses to O(3) were not observed in mice raised from weaning until 20-22 wk of age on a 60% fat diet. These results indicate that mice with DIO exhibit innate AHR and enhanced O(3)-induced pulmonary inflammation, similar to genetically obese mice. However, mice with DIO must remain obese for an extended period of time before this pulmonary phenotype is observed.

  7. Prolonged B cell depletion with rituximab is effective in treating refractory pulmonary granulomatous inflammation in granulomatosis with polyangiitis (GPA).

    PubMed

    Henderson, Scott R; Copley, Susan J; Pusey, Charles D; Ind, Philip W; Salama, Alan D

    2014-12-01

    Pulmonary nodule formation is a frequent feature of granulomatosis with polyangiitis (GPA). Traditional induction therapy includes methotrexate or cyclophosphamide, however, pulmonary nodules generally respond slower than vasculitic components of disease. Efficacy of rituximab (RTX) solely for the treatment of pulmonary nodules has not been assessed. In this observational cohort study, we report patient outcomes with RTX in GPA patients with pulmonary nodules who failed to achieve remission following conventional immunosuppression. Patients (n = 5) with persistent pulmonary nodules were identified from our clinic database and retrospectively evaluated. Systemic manifestations, inflammatory markers, disease activity, concurrent immunosuppression, and absolute B cell numbers were recorded pre-RTX and at 6 monthly intervals following treatment. Chest radiographs at each time point were scored by an experienced radiologist, blinded to clinical details. Five patients with GPA and PR3-ANCA were evaluated (2 male, 3 female), mean age 34 (22-52) years. Pulmonary nodules (median 4, range 2-6), with or without cavitation were present in all patients. RTX induced initial B cell depletion (<5 cells/μL) in all patients but re-population was observed in 3 patients. Repeated RTX treatment in these 3 and persistent B cell depletion in the whole cohort was associated with further significant radiological improvement. Radiographic scoring at each time interval showed reduction in both number of nodules (P =  <0.0001) and largest nodule diameter (P =  <0.0001) in all patients for at least 18 months following B cell depletion. In summary, RTX therapy induces resolution of pulmonary granulomatous inflammation in GPA following prolonged B cell depletion.

  8. 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. Copyright © 2016 the American Physiological Society.

  9. Scintigraphic detection of pulmonary embolism in patients with obstructive pulmonary disease

    SciTech Connect

    Alderson, P.O.; Biello, D.R.; Sachariah, K.G.; Siegel, B.A.

    1981-03-01

    The 133Xe ventilation studies, 99mTc perfusion lung images, and pulmonary angiograms of 83 patients with obstructive pulmonary disease and suspected pulmonary emboli were reviewed. Each patient had ventilation abnormalities suggesting OPD and at least one region showing matched V-P abnormalities. All angiograms were obtained within 72 hours of the V-P study and were reviewed independently. The overall sensitivity of V-P imaging for PE in this population was 0.83 and its specificity was 0.92. False-negative interpretations occurred in three of the 16 patients who showed ventilation abnormalities in more than 50% of their lung fields. In the 67 patients with ventilation abnormalities in less than or equal to 50% of their lung fields the sensitivity and specificity for detecting PE were high, V-P imaging is a reliable method for detecting PE in patients with regions of V-P match, if the ventilation abnormalities are limited in extent.

  10. Eosinophilic and neutrophilic inflammation in asthma, chronic bronchitis, and chronic obstructive pulmonary disease.

    PubMed

    Lacoste, J Y; Bousquet, J; Chanez, P; Van Vyve, T; Simony-Lafontaine, J; Lequeu, N; Vic, P; Enander, I; Godard, P; Michel, F B

    1993-10-01

    Eosinophils but not neutrophils may play a role in the airway inflammation of asthma. In chronic bronchitis (CB) and chronic obstructive pulmonary disease (COPD), neutrophils are present in the airways. To differentiate among the pathology of asthma, CB, and COPD eosinophils and neutrophils were studied in peripheral blood, bronchial biopsy specimens, and bronchoalveolar lavage fluid (BALF). We studied nine nonsmoking healthy subjects, 20 nonsmoking patients with asthma, 10 nonatopic smoking patients with CB (forced expiratory volume in 1 second: 98.4% +/- 11.3%) and 17 patients with COPD (forced expiratory volume in 1 second: 51.2% +/- 14.3%). Eosinophils were characterized by their enumeration in biopsy specimens (EG2 monoclonal antibody), peripheral blood, and BALF and by measurement of eosinophil cationic protein in BALF. Neutrophils were characterized by their enumeration in biopsy specimens (anti-elastase monoclonal antibody) and BALF and by measurement of neutrophil-specific myeloperoxidase in BALF. In patients with asthma we found degranulated eosinophils in biopsy specimens and significantly increased eosinophil cationic protein levels in BALF. In patients with CB or COPD, eosinophil numbers in biopsy specimens were not significantly different from those of patients with asthma, but cells were not degranulated and eosinophil cationic protein levels in BALF were similar to those of normal subjects. In patients with CB or COPD neutrophils were not increased in the mucosa, but neutrophil numbers and myeloperoxidase levels in BALF were significantly increased. The percentages of neutrophils in BALF were greater in patients with COPD than in those with CB, suggesting a role in the chronic airflow limitation.

  11. Role of Pulmonary Artery Reactivity and Nitric Oxide in Injury and Inflammation following Lung Contusion

    PubMed Central

    Lakshminrusimha, Satyan; Suresh, Madathilparambil V; Knight, Paul R.; Gugino, Sylvia F.; Davidson, Bruce A.; Helinski, Jadwiga D.; Nielsen, Lori C.; Russell, James A.; Yu, Bi; Zeng, Lixia; Pennathur, Subramaniam; Raghavendran, Krishnan

    2013-01-01

    Rationale The mechanisms contributing to hypoxia in lung contusion remain unclear and not temporally associated with the peak onset of acute inflammation. Objective We investigated the role of oxidative stress in alteration of pulmonary arterial (PA) reactivity following LC. Additionally, the role of antioxidants in reversing this process was examined. Methods PaO2 and PA reactivity were measured in rats subjected to bilateral LC. Rings were pretreated with a NO synthase (NOS) inhibitor, L-nitro arginine (LNA 10−3 M) or PEG-superoxide dismutase (SOD) and PEG-catalase (CAT) or both (LNA+SOD/CAT). Rings were constricted with norepinephrine (NE) and relaxed with an NOS agonist (A23187) or NO donor (SNAP). Immunochemical and mass spectrometric quantification for nitrotyrosine were performed. Results Rats were hypoxemic at 4h post-contusion compared to controls, but recovered by 24h (PaO2/FiO2 ratio: baseline- 443±28, 4h-288±46 and 24h-417±23). PA constriction to NOS inhibition and relaxation to A23187 were impaired 4h after LC. PA relaxation to SNAP was decreased at 4h and 24h after LC. These alterations in PA reactivity were reversed by SOD/CAT pretreatment. SOD1 and 2 mRNA was up-regulated and soluble guanylyl cyclase (sGC) mRNA was down-regulated 24h after LC. IHC and mass spectrometry revealed that levels of 3-nitrotyrosine were increased markedly at 4h following LC consistent with superoxide generation and formation of peroxynitrite. Conclusion Collectively, this data suggests that consumption of NO due to excess superoxide resulting in peroxynitrite formation leads to diminished vascular reactivity following LC. PMID:23364426

  12. 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

  13. Variability in ozone-induced pulmonary injury and inflammation in healthy and cardiovascular-compromised rat models.

    PubMed

    Kodavanti, Urmila P; Ledbetter, Allen D; Thomas, Ronald F; Richards, Judy E; Ward, William O; Schladweiler, Mette C; Costa, Daniel L

    2015-01-01

    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 dependent on the type and severity of disease. Healthy male 12-14-week-old Wistar Kyoto (WKY), Wistar (WS) and Sprague Dawley (SD); and CVD-compromised spontaneously hypertensive (SH), Fawn-Hooded hypertensive (FHH), stroke-prone spontaneously hypertensive (SHSP), obese spontaneously hypertensive heart failure (SHHF) and obese JCR (JCR) rats were exposed to 0.0, 0.25, 0.5, or 1.0 ppm ozone for 4 h; pulmonary injury and inflammation were analyzed immediately following (0-h) or 20-h later. Baseline bronchoalveolar lavage fluid (BALF) protein was higher in CVD strains except for FHH when compared to healthy. Ozone-induced increases in protein and inflammation were concentration-dependent within each strain but the degree of response varied from strain to strain and with time. Among healthy rats, SD were least affected. Among CVD strains, lean rats were more susceptible to protein leakage from ozone than obese rats. Ozone caused least neutrophilic inflammation in SH and SHHF while SHSP and FHH were most affected. BALF neutrophils and protein were poorly correlated when considering the entire dataset (r = 0.55). The baseline and ozone-induced increases in cytokine mRNA varied markedly between strains and did not correlate with inflammation. These data illustrate that the degree of ozone-induced lung injury/inflammation response is likely influenced by both genetic and physiological factors that govern the nature of cardiovascular compromise in CVD models.

  14. Exposure to Deepwater Horizon Crude Oil Burnoff Particulate Matter Induces Pulmonary Inflammation and Alters Adaptive Immune Response.

    PubMed

    Jaligama, Sridhar; Chen, Zaili; Saravia, Jordy; Yadav, Nikki; Lomnicki, Slawomir M; Dugas, Tammy R; Cormier, Stephania A

    2015-07-21

    The ″in situ burning" of trapped crude oil on the surface of Gulf waters during the 2010 Deepwater Horizon (DWH) oil spill released numerous pollutants, including combustion-generated particulate matter (PM). Limited information is available on the respiratory impact of inhaled in situ burned oil sail particulate matter (OSPM). Here we utilized PM collected from in situ burn plumes of the DWH oil spill to study the acute effects of exposure to OSPM on pulmonary health. OSPM caused dose-and time-dependent cytotoxicity and generated reactive oxygen species and superoxide radicals in vitro. Additionally, mice exposed to OSPM exhibited significant decreases in body weight gain, systemic oxidative stress in the form of increased serum 8-isoprostane (8-IP) levels, and airway inflammation in the form of increased macrophages and eosinophils in bronchoalveolar lavage fluid. Further, in a mouse model of allergic asthma, OSPM caused increased T helper 2 cells (Th2), peribronchiolar inflammation, and increased airway mucus production. These findings demonstrate that acute exposure to OSPM results in pulmonary inflammation and alteration of innate/adaptive immune responses in mice and highlight potential respiratory effects associated with cleaning up an oil spill.

  15. Oxidative stress-induced mitochondrial dysfunction drives inflammation and airway smooth muscle remodeling in patients with chronic obstructive pulmonary disease.

    PubMed

    Wiegman, Coen H; Michaeloudes, Charalambos; Haji, Gulammehdi; Narang, Priyanka; Clarke, Colin J; Russell, Kirsty E; Bao, Wuping; Pavlidis, Stelios; Barnes, Peter J; Kanerva, Justin; Bittner, Anton; Rao, Navin; Murphy, Michael P; Kirkham, Paul A; Chung, Kian Fan; Adcock, Ian M

    2015-09-01

    Inflammation and oxidative stress play critical roles in patients with chronic obstructive pulmonary disease (COPD). Mitochondrial oxidative stress might be involved in driving the oxidative stress-induced pathology. We sought to determine the effects of oxidative stress on mitochondrial function in the pathophysiology of airway inflammation in ozone-exposed mice and human airway smooth muscle (ASM) cells. Mice were exposed to ozone, and lung inflammation, airway hyperresponsiveness (AHR), and mitochondrial function were determined. Human ASM cells were isolated from bronchial biopsy specimens from healthy subjects, smokers, and patients with COPD. Inflammation and mitochondrial function in mice and human ASM cells were measured with and without the presence of the mitochondria-targeted antioxidant MitoQ. Mice exposed to ozone, a source of oxidative stress, had lung inflammation and AHR associated with mitochondrial dysfunction and reflected by decreased mitochondrial membrane potential (ΔΨm), increased mitochondrial oxidative stress, and reduced mitochondrial complex I, III, and V expression. Reversal of mitochondrial dysfunction by the mitochondria-targeted antioxidant MitoQ reduced inflammation and AHR. ASM cells from patients with COPD have reduced ΔΨm, adenosine triphosphate content, complex expression, basal and maximum respiration levels, and respiratory reserve capacity compared with those from healthy control subjects, whereas mitochondrial reactive oxygen species (ROS) levels were increased. Healthy smokers were intermediate between healthy nonsmokers and patients with COPD. Hydrogen peroxide induced mitochondrial dysfunction in ASM cells from healthy subjects. MitoQ and Tiron inhibited TGF-β-induced ASM cell proliferation and CXCL8 release. Mitochondrial dysfunction in patients with COPD is associated with excessive mitochondrial ROS levels, which contribute to enhanced inflammation and cell hyperproliferation. Targeting mitochondrial ROS represents

  16. Oxidative stress–induced mitochondrial dysfunction drives inflammation and airway smooth muscle remodeling in patients with chronic obstructive pulmonary disease

    PubMed Central

    Wiegman, Coen H.; Michaeloudes, Charalambos; Haji, Gulammehdi; Narang, Priyanka; Clarke, Colin J.; Russell, Kirsty E.; Bao, Wuping; Pavlidis, Stelios; Barnes, Peter J.; Kanerva, Justin; Bittner, Anton; Rao, Navin; Murphy, Michael P.; Kirkham, Paul A.; Chung, Kian Fan; Adcock, Ian M.; Brightling, Christopher E.; Davies, Donna E.; Finch, Donna K.; Fisher, Andrew J.; Gaw, Alasdair; Knox, Alan J.; Mayer, Ruth J.; Polkey, Michael; Salmon, Michael; Singh, David

    2015-01-01

    Background Inflammation and oxidative stress play critical roles in patients with chronic obstructive pulmonary disease (COPD). Mitochondrial oxidative stress might be involved in driving the oxidative stress–induced pathology. Objective We sought to determine the effects of oxidative stress on mitochondrial function in the pathophysiology of airway inflammation in ozone-exposed mice and human airway smooth muscle (ASM) cells. Methods Mice were exposed to ozone, and lung inflammation, airway hyperresponsiveness (AHR), and mitochondrial function were determined. Human ASM cells were isolated from bronchial biopsy specimens from healthy subjects, smokers, and patients with COPD. Inflammation and mitochondrial function in mice and human ASM cells were measured with and without the presence of the mitochondria-targeted antioxidant MitoQ. Results Mice exposed to ozone, a source of oxidative stress, had lung inflammation and AHR associated with mitochondrial dysfunction and reflected by decreased mitochondrial membrane potential (ΔΨm), increased mitochondrial oxidative stress, and reduced mitochondrial complex I, III, and V expression. Reversal of mitochondrial dysfunction by the mitochondria-targeted antioxidant MitoQ reduced inflammation and AHR. ASM cells from patients with COPD have reduced ΔΨm, adenosine triphosphate content, complex expression, basal and maximum respiration levels, and respiratory reserve capacity compared with those from healthy control subjects, whereas mitochondrial reactive oxygen species (ROS) levels were increased. Healthy smokers were intermediate between healthy nonsmokers and patients with COPD. Hydrogen peroxide induced mitochondrial dysfunction in ASM cells from healthy subjects. MitoQ and Tiron inhibited TGF-β–induced ASM cell proliferation and CXCL8 release. Conclusions Mitochondrial dysfunction in patients with COPD is associated with excessive mitochondrial ROS levels, which contribute to enhanced inflammation and cell

  17. Automated Detection of Uninformative Frames in Pulmonary Optical Endomicroscopy.

    PubMed

    Perperidis, Antonios; Akram, Ahsan; Altmann, Yoann; McCool, Paul; Westerfeld, Jody; Wilson, David; Dhaliwal, Kevin; McLaughlin, Stephen

    2017-01-01

    Optical endomicroscopy (OEM) is a novel real-time imaging technology that provides endoscopic images at a microscopic level. The nature of OEM data, as acquired in clinical use, gives rise to the presence of uninformative frames (i.e., pure-noise and motion-artefacts). Uninformative frames can comprise a considerable proportion (up to > 25%) of a dataset, increasing the resources required for analyzing the data (both manually and automatically), as well as diluting the results of any automated quantification analysis. There is, therefore, a need to automatically detect and remove as many of these uninformative frames as possible while keeping frames with structural information intact. This paper employs Gray Level Cooccurrence Matrix texture measures and detection theory to identify and remove such frames. The detection of pure-noise and motion-artefacts frames is treated as two independent problems. Pulmonary OEM frame sequences of the distal lung are employed for the development and assessment of the approach. The proposed approach identifies and removes uninformative frames with a sensitivity of 93% and a specificity of 92.6%. The detection algorithm is accurate and robust in pulmonary OEM frame sequences. Conditional to appropriate model refinement, the algorithms can become applicable in other organs.

  18. Mesenchymal stem cell-conditioned media suppresses inflammation-associated overproliferation of pulmonary artery smooth muscle cells in a rat model of pulmonary hypertension

    PubMed Central

    LIU, JUNFENG; HAN, ZHIBO; HAN, ZHONGCHAO; HE, ZHIXU

    2016-01-01

    Inflammation-associated overproliferation of pulmonary artery smooth muscle cells (PASMCs) is considered to be involved in the pathogenesis of pulmonary hypertension (PH). The administration of mesenchymal stem cell-conditioned media (MSC-CM) has displayed benefits in the treatment of PH, however, the exact mechanism has yet to be elucidated. The present study aimed to determine whether MSC-CM is able to suppress overproliferation of PASMCs in PH via immunoregulation. By the administration of MSC-CM to monocrotaline (MCT)-induced PH rats, and the development of an in vitro co-culture system comprised of PASMCs and activated T cells, the therapeutic effects of MSC-CM on PH, and the changes in the expression of correlated factors, including TNF-α, calcineurin (CaN) and nuclear factor of activated T cells (NFAT), were assessed. Immunohistochemical staining results indicated that MSC-CM was able to significantly suppress the production of TNF-α in MCT-induced PH and co-culture systems; and reverse transcription-quantitative polymerase chain reaction results showed significant downregulation of the expression of CaN and NFATc2 in PASMCs (P<0.01). Furthermore, MSC-CM was able to significantly suppress CaN activity and NFATc2 activation (P<0.01), thus inhibiting the overproliferation of PASMCs. Finally, MSC-CM improved abnormalities in hemodynamics and pulmonary histology in MCT-induced PH. In conclusion, the findings of the current study suggest that administration of MSC-CM has the potential to suppress inflammation-associated overproliferation of PASMCs due to its immunosuppressive effects in PH and, thus, may serve as a beneficial therapeutic strategy. PMID:26893632

  19. EETs alleviate ox-LDL-induced inflammation by inhibiting LOX-1 receptor expression in rat pulmonary arterial endothelial cells.

    PubMed

    Jiang, Jun-xia; Zhang, Shui-juan; Liu, Ya-nan; Lin, Xi-xi; Sun, Yan-hong; Shen, Hui-juan; Yan, Xiao-feng; Xie, Qiang-min

    2014-03-15

    Oxidized low-density lipoprotein (Ox-LDL) is associated with atherosclerotic events through the modulation of arachidonic acid (AA) metabolism and activation of inflammatory signaling. Cytochrome P450 (CYP) epoxygenase-derived epoxyeicosatrienoic acids (EETs) mitigate inflammation through nuclear factor-κB (NF-κB). In this study, we explored the effects and mechanisms of exogenous EETs on the ox-LDL-induced inflammation of pulmonary artery endothelial cells (PAECs), which were cultured from rat pulmonary arteries. We determined that pre-treatment with 11,12-EET or 14,15-EET attenuated the ox-LDL-induced expression and release of intercellular adhesion molecule-1 (ICAM-1), E-selectin, and monocyte chemoattractant protein-1 (MCP-1) in a concentration-dependent manner. In addition, the ox-LDL-induced expression of CYP2J4 was upregulated by 11,12-EET and 14,15-EET (1μM). Furthermore, the endothelial receptor of lectin-like oxidized low-density lipoprotein (LOX-1) was downregulated in PAECs treated with EETs. The inflammatory responses evoked by ox-LDL (100μg/mL) were blocked by pharmacological inhibitors of Erk1/2 mitogen-activated protein kinase (MAPK) (U0126), p38 MAPK (SB203580), and NF-κB (PDTC). In addition, we confirmed that 11,12-EET suppresses phosphorylation of p38, degradation of IκBα, and activation of NF-κB (p65), whereas 14,15-EET can significantly suppress the phosphorylation of p38 and Erk1/2. Our results indicate that EETs exert beneficial effects on ox-LDL-induced inflammation primarily through the inhibition of LOX-1 receptor upregulation, MAPK phosphorylation, and NF-κB activation and through the upregulation of CYP2J4 expression. This study helps focus the current understanding of the contribution of EETs to the regulation of the inflammation of pulmonary vascular endothelial cells. Furthermore, the therapeutic potential of targeting the EET pathway in pulmonary vascular disease will be highlighted.

  20. Acute pulmonary inflammation induced by exposure of the airways to staphylococcal enterotoxin type B in rats

    SciTech Connect

    Desouza, Ivani A. . E-mail: ivanidesouza@fcm.unicamp.br; Franco-Penteado, Carla F.; Camargo, Enilton A.; Lima, Carmen S.P.; Teixeira, Simone A.; Muscara, Marcelo N.; De Nucci, Gilberto; Antunes, Edson

    2006-11-15

    Staphylocococcus aureus is a gram-positive bacterium that produces several enterotoxins, which are responsible for most part of pathological conditions associated to staphylococcal infections, including lung inflammation. This study aimed to investigate the underlying inflammatory mechanisms involved in leukocyte recruitment in rats exposed to staphylococcal enterotoxin B (SEB). Rats were anesthetized with pentobarbital sodium and intratracheally injected with either SEB or sterile phosphate-buffered saline (PBS, 0.4 ml). Airways exposition to SEB (7.5-250 ng/trachea) caused a dose- and time-dependent neutrophil accumulation in BAL fluid, the maximal effects of which were observed at 4 h post-SEB exposure (250 ng/trachea). Eosinophils were virtually absent in BAL fluid, whereas mononuclear cell counts increased only at 24 h post-SEB. Significant elevations of granulocytes in bone marrow (mature and immature forms) and peripheral blood have also been detected. In BAL fluid, marked elevations in the levels of lipid mediators (LTB{sub 4} and PGE{sub 2}) and cytokines (TNF-{alpha}, IL-6 and IL-10) were observed after SEB instillation. The SEB-induced neutrophil accumulation in BAL fluid was reduced by pretreatment with dexamethasone (0.5 mg/kg), the COX-2 inhibitor celecoxib (3 mg/kg), the selective iNOS inhibitor compound 1400 W (5 mg/kg) and the lipoxygenase inhibitor AA-861 (200 {mu}g/kg). In separate experiments carried out with rat isolated peripheral neutrophils, SEB failed to induce neutrophil adhesion to serum-coated plates and chemotaxis. In conclusion, rat airways exposition to SEB causes a neutrophil-dependent lung inflammation at 4 h as result of the release of proinflammatory (NO, PGE{sub 2}, LTB{sub 4}, TNF-{alpha}, IL-6) and anti-inflammatory mediators (IL-10)

  1. PULMONARY INJURY AND INFLAMMATION FROM REPEATED EXPOSURE TO SOLUBLE COMPONENTS AND SOLID PARTICULATE MATTER (PM)

    EPA Science Inventory

    Pulmonary injury from acute exposures to PM and the role of soluble versus insoluble PM have received considerable attention; however, their long-term impacts are less well understood. This study compared pulmonary injury and inflammatory responses from repeated exposure to solub...

  2. PULMONARY INJURY AND INFLAMMATION FROM REPEATED EXPOSURE TO SOLUBLE COMPONENTS AND SOLID PARTICULATE MATTER (PM)

    EPA Science Inventory

    Pulmonary injury from acute exposures to PM and the role of soluble versus insoluble PM have received considerable attention; however, their long-term impacts are less well understood. This study compared pulmonary injury and inflammatory responses from repeated exposure to solub...

  3. Automatic two-step detection of pulmonary nodules

    NASA Astrophysics Data System (ADS)

    Dolejší, Martin; Kybic, Jan

    2007-03-01

    We present a computer-aided diagnosis (CAD) system to detect small-size (from 2mm to around 10mm) pulmonary nodules from helical CT scans. A pulmonary nodule is a small, round (parenchymal nodule) or worm (juxta-pleural) shaped lesion in the lungs. Both have greater radio density than lungs parenchyma. Lung nodules may indicate a lung cancer and its detection in early stage improves survival rate of patients. CT is considered to be the most accurate imaging modality for detection of nodules. However, the large amount of data per examination makes the interpretation difficult. This leads to omission of nodules by human radiologist. CAD system presented is designed to help lower the number of omissions. Our system uses two different schemes to locate juxtapleural nodules and parenchymal nodules. For juxtapleural nodules, morphological closing and thresholding is used to find nodule candidates. To locate non-pleural nodule candidates, 3D blob detector uses multiscale filtration. Ellipsoid model is fitted on nodules. To define which of the nodule candidates are in fact nodules, an additional classification step is applied. Linear and multi-threshold classifiers are used. System was tested on 18 cases (4853 slices) with total sensitivity of 96%, with about 12 false positives/slice. The classification step reduces number of false positives to 9 per slice without significantly decreasing sensitivity (89,6%).

  4. Klotho Reduction in Alveolar Macrophages Contributes to Cigarette Smoke Extract-induced Inflammation in Chronic Obstructive Pulmonary Disease.

    PubMed

    Li, Lingling; Wang, Yujie; Gao, Wei; Yuan, Cheng; Zhang, Sini; Zhou, Hong; Huang, Mao; Yao, Xin

    2015-11-13

    Abnormal inflammation and accelerated decline in lung function occur in patients with chronic obstructive pulmonary disease (COPD). Klotho, an anti-aging protein, has an anti-inflammatory function. However, the role of Klotho has never been investigated in COPD. The aim of this study is to investigate the possible role of Klotho by alveolar macrophages in airway inflammation in COPD. Klotho levels were assessed in the lung samples and peripheral blood mononuclear cells of non-smokers, smokers, and patients with COPD. The regulation of Klotho expression by cigarette smoke extract (CSE) was studied in vitro, and small interfering RNA (siRNA) and recombinant Klotho were employed to investigate the role of Klotho on CSE-induced inflammation. Klotho expression was reduced in alveolar macrophages in the lungs and peripheral blood mononuclear cells of COPD patients. CSE decreased Klotho expression and release from MH-S cells. Knockdown of endogenous Klotho augmented the expression of the inflammatory mediators, such as MMP-9, IL-6, and TNF-α, by MH-S cells. Exogenous Klotho inhibited the expression of CSE-induced inflammatory mediators. Furthermore, we showed that Klotho interacts with IκBα of the NF-κB pathway. Dexamethasone treatment increased the expression and release level of Klotho in MH-S cells. Our findings suggest that Klotho plays a role in sustained inflammation of the lungs, which in turn may have therapeutic implications in COPD.

  5. Phytic acid, an iron chelator, attenuates pulmonary inflammation and fibrosis in rats after intratracheal instillation of asbestos.

    PubMed

    Kamp, D W; Israbian, V A; Yeldandi, A V; Panos, R J; Graceffa, P; Weitzman, S A

    1995-01-01

    Reactive oxygen species, especially iron-catalyzed hydroxyl radicals (.OH) are implicated in the pathogenesis of asbestos-induced pulmonary toxicity. We previously demonstrated that phytic acid, an iron chelator, reduces amosite asbestos-induced .OH generation, DNA strand break formation, and injury to cultured pulmonary epithelial cells (268[1995, Am. J. Physiol.(Lung Cell. Mol. Physiol.) 12:L471-480]). To determine whether phytic acid diminishes pulmonary inflammation and fibrosis in rats after a single intratracheal (it) instillation of amosite asbestos, Sprague-Dawley rats were given either saline (1 ml), amosite asbestos (5 mg; 1 ml saline), or amosite treated with phytic acid (500 microM) for 24 hr and then instilled. At various times after asbestos exposure, the rats were euthanized and the lungs were lavaged and examined histologically. A fibrosis score was determined from trichrome-stained specimens. As compared to controls, asbestos elicited a significant pulmonary inflammatory response, as evidence by an increase (approximately 2-fold) in bronchoalveolar lavage (BAL) cell counts at 1 wk and the percentage of BAL neutrophils (PMNs) and giant cells at 2 wk (0.1 vs 6.5% and 1.3 vs 6.1%, respectively; p < 0.05). Asbestos significantly increased the fibrosis score at 2 wk (0 +/- 0 vs 5 +/- 1; p < 0.05). The inflammatory and fibrotic changes were, as expected, observed in the respiratory bronchioles and terminal alveolar duct bifurcations. The increased percentage of BAl PMNs and giant cells persisted at 4 wk, as did the fibrotic changes. Compared to asbestos alone, phytic acid-treated asbestos elicited significantly less BAL PMNs (6.5 vs 1.0%; p < 0.05) and giant cells (6.1 vs 0.2%; p < 0.05) and caused significantly less fibrosis (5 vs 0.8; p < 0.05) 2 wk after exposure. We conclude that asbestos causes pulmonary inflammation and fibrosis in rats after it instillation and that phytic acid reduces these effects. These data support the role of iron

  6. Acute respiratory changes and pulmonary inflammation involving a pathway of TGF-β1 induction in a rat model of chlorine-induced lung injury.

    PubMed

    Wigenstam, Elisabeth; Elfsmark, Linda; Koch, Bo; Bucht, Anders; Jonasson, Sofia

    2016-10-15

    We investigated acute and delayed respiratory changes after inhalation exposure to chlorine (Cl2) with the aim to understand the pathogenesis of the long-term sequelae of Cl2-induced lung-injury. In a rat model of nose-only exposure we analyzed changes in airway hyperresponsiveness (AHR), inflammatory responses in airways, expression of pro-inflammatory markers and development of lung fibrosis during a time-course from 5h up to 90days after a single inhalation of Cl2. A single dose of dexamethasone (10mg/kg) was administered 1h following Cl2-exposure. A 15-min inhalation of 200ppm Cl2 was non-lethal in Sprague-Dawley rats. At 24h post exposure, Cl2-exposed rats displayed elevated numbers of leukocytes with an increase of neutrophils and eosinophils in bronchoalveolar lavage (BAL) and edema was shown both in lung tissue and the heart. At 24h, the inflammasome-associated cytokines IL-1β and IL-18 were detected in BAL. Concomitant with the acute inflammation a significant AHR was detected. At the later time-points, a delayed inflammatory response was observed together with signs of lung fibrosis as indicated by increased pulmonary macrophages, elevated TGF-β expression in BAL and collagen deposition around airways. Dexamethasone reduced the numbers of neutrophils in BAL at 24h but did not influence the AHR. Inhalation of Cl2 in rats leads to acute respiratory and cardiac changes as well as pulmonary inflammation involving induction of TGF-β1. The acute inflammatory response was followed by sustained macrophage response and lack of tissue repair. It was also found that pathways apart from the acute inflammatory response contribute to the Cl2-induced respiratory dysfunction. Copyright © 2016 Elsevier Inc. All rights reserved.

  7. Early detection of susceptibility to acute lung inflammation by molecular imaging in mice exposed to cigarette smoke.

    PubMed

    Pérez-Rial, Sandra; Del Puerto-Nevado, Laura; González-Mangado, Nicolás; Peces-Barba, Germán

    2011-10-01

    Matrix metalloproteinases (MMPs) are extracellular proteolytic enzymes involved in acute lung inflammation in response to cigarette smoke exposure (CSE). We present the in vivo detection of MMP activity using a specific MMP-activatable, near-infrared, polymer-based proteolytic probe in strains of mice with different susceptibility to developing smoking-induced emphysema (susceptible mice, C57BL/6j, and resistant mice, 129S2/SvHsd) to characterize the distinctive profile of CSE-induced acute inflammation. In vivo imaging of pulmonary inflammation expressing MMPs revealed a significantly different median ratio twofold higher in smoker than in nonsmoker susceptible mice (C57BL/6j) and no significant differences between the smoker and the nonsmoker group in resistant mice (129S2/SvHsd). Ex vivo imaging of the lungs of each group of mice confirmed the same in vivo experiment results obtained for both strains of mice. In the biochemical study of lung tissue, the proteolytic signal colocalized with the endogenously expressed MMP protein levels, with MMP-9 levels that are 2.2 times higher than in the nonsmoke-exposed group in C57BL/6j mice and no significant differences in the 129S2/SvHsd mice. The MMP-activatable probe provides a useful reagent for the in vivo and ex vivo detection of MMP-selective proteolytic activity. We are able to distinguish between susceptible and resistant strains of mice in terms of the profile of MMP activity in the early stages of pulmonary disease.

  8. Accurate registration of temporal CT images for pulmonary nodules detection

    NASA Astrophysics Data System (ADS)

    Yan, Jichao; Jiang, Luan; Li, Qiang

    2017-02-01

    Interpretation of temporal CT images could help the radiologists to detect some subtle interval changes in the sequential examinations. The purpose of this study was to develop a fully automated scheme for accurate registration of temporal CT images for pulmonary nodule detection. Our method consisted of three major registration steps. Firstly, affine transformation was applied in the segmented lung region to obtain global coarse registration images. Secondly, B-splines based free-form deformation (FFD) was used to refine the coarse registration images. Thirdly, Demons algorithm was performed to align the feature points extracted from the registered images in the second step and the reference images. Our database consisted of 91 temporal CT cases obtained from Beijing 301 Hospital and Shanghai Changzheng Hospital. The preliminary results showed that approximately 96.7% cases could obtain accurate registration based on subjective observation. The subtraction images of the reference images and the rigid and non-rigid registered images could effectively remove the normal structures (i.e. blood vessels) and retain the abnormalities (i.e. pulmonary nodules). This would be useful for the screening of lung cancer in our future study.

  9. Association of air pollution sources and aldehydes with biomarkers of blood coagulation, pulmonary inflammation, and systemic oxidative stress.

    PubMed

    Altemose, Brent; Robson, Mark G; Kipen, Howard M; Ohman Strickland, Pamela; Meng, Qingyu; Gong, Jicheng; Huang, Wei; Wang, Guangfa; Rich, David Q; Zhu, Tong; Zhang, Junfeng

    2017-05-01

    Using data collected before, during, and after the 2008 Summer Olympic Games in Beijing, this study examines associations between biomarkers of blood coagulation (vWF, sCD62P and sCD40L), pulmonary inflammation (EBC pH, EBC nitrite, and eNO), and systemic oxidative stress (urinary 8-OHdG) with sources of air pollution identified utilizing principal component analysis and with concentrations of three aldehydes of health concern. Associations between the biomarkers and the air pollution source types and aldehydes were examined using a linear mixed effects model, regressing through seven lag days and controlling for ambient temperature, relative humidity, gender, and day of week for the biomarker measurements. The biomarkers for pulmonary inflammation, particularly EBC pH and eNO, were most consistently associated with vehicle and industrial combustion, oil combustion, and vegetative burning. The biomarkers for blood coagulation, particularly vWF and sCD62p, were most consistently associated with oil combustion. Systemic oxidative stress biomarker (8-OHdG) was most consistently associated with vehicle and industrial combustion. The associations of the biomarkers were generally not significant or consistent with secondary formation of pollutants and with the aldehydes. The findings support policies to control anthropogenic pollution sources rather than natural soil or road dust from a cardio-respiratory health standpoint.

  10. Donor smoking is associated with pulmonary edema, inflammation and epithelial dysfunction in ex vivo human donor lungs

    PubMed Central

    Ware, Lorraine B.; Lee, Jae W.; Wickersham, Nancy; Nguyen, John; Matthay, Michael A.; Calfee, Carolyn S.

    2014-01-01

    Although recipients of donor lungs from smokers have worse clinical outcomes, the underlying mechanisms are unknown. We tested the association between donor smoking and the degree of pulmonary edema (as estimated by lung weight), the rate of alveolar fluid clearance (measured by airspace instillation of 5% albumin) and biomarkers of lung epithelial injury and inflammation (bronchoalveolar lavage surfactant protein-D and IL-8) in ex vivo lungs recovered from 298 organ donors. The extent of pulmonary edema was higher in current smokers (n=127) compared to non-smokers (median 408g, IQR 364-500 vs. 385g, IQR 340 - 460, p=0.009). Oxygenation at study enrollment was worse in current smokers versus non-smokers (median PaO2/FiO2 214 mmHg, IQR 126-323 vs. 266 mmHg, IQR 154-370, p=0.02). Current smokers with the highest exposure (≥20 pack-years) had significantly lower rates of alveolar fluid clearance, suggesting that the effects of cigarette smoke on alveolar epithelial fluid transport function may be dose related. BAL IL-8 was significantly higher in smokers while surfactant protein-D was lower. These findings indicate that chronic exposure to cigarette smoke has important effects on inflammation, gas exchange, lung epithelial function and lung fluid balance in the organ donor that could influence lung function in the lung transplant recipient. PMID:25146497

  11. The Effect of PPE-Induced Emphysema and Chronic LPS-Induced Pulmonary Inflammation on Atherosclerosis Development in APOE*3-LEIDEN Mice

    PubMed Central

    Wagenaar, Gerry T. M.; Plomp, Jaap J.; van Eck, Miranda; Havekes, Louis M.; Rensen, Patrick C. N.; Hiemstra, Pieter S.; Berbée, Jimmy F. P.

    2013-01-01

    Background Chronic obstructive pulmonary disease (COPD) is characterized by pulmonary inflammation, airways obstruction and emphysema, and is a risk factor for cardiovascular disease (CVD). However, the contribution of these individual COPD components to this increased risk is unknown. Therefore, the aim of this study was to determine the contribution of emphysema in the presence or absence of pulmonary inflammation to the increased risk of CVD, using a mouse model for atherosclerosis. Because smoke is a known risk factor for both COPD and CVD, emphysema was induced by intratracheal instillation of porcine pancreatic elastase (PPE). Methods Hyperlipidemic APOE*3-Leiden mice were intratracheally instilled with vehicle, 15 or 30 µg PPE and after 4 weeks, mice received a Western-type diet (WTD). To study the effect of emphysema combined with pulmonary inflammation on atherosclerosis, mice received 30 µg PPE and during WTD feeding, mice were intranasally instilled with vehicle or low-dose lipopolysaccharide (LPS; 1 µg/mouse, twice weekly). After 20 weeks WTD, mice were sacrificed and emphysema, pulmonary inflammation and atherosclerosis were analysed. Results Intratracheal PPE administration resulted in a dose-dependent increase in emphysema, whereas atherosclerotic lesion area was not affected by PPE treatment. Additional low-dose intranasal LPS administration induced a low-grade systemic IL-6 response, as compared to vehicle. Combining intratracheal PPE with intranasal LPS instillation significantly increased the number of pulmonary macrophages and neutrophils. Plasma lipids during the study were not different. LPS instillation caused a limited, but significant increase in the atherosclerotic lesion area. This increase was not further enhanced by PPE. Conclusion This study shows for the first time that PPE-induced emphysema both in the presence and absence of pulmonary inflammation does not affect atherosclerotic lesion development. PMID:24303000

  12. Lipopolysaccharide and Interleukin 1 Augment the Effects of Hypoxia and Inflammation in Human Pulmonary Arterial Tissue

    NASA Astrophysics Data System (ADS)

    Ziesche, Rolf; Petkov, Venzeslav; Williams, John; Zakeri, Schaker M.; Mosgoller, Wilhelm; Knofler, Martin; Block, Lutz H.

    1996-10-01

    The combined effects of hypoxia and interleukin 1, lipopolysaccharide, or tumor necrosis factor α on the expression of genes encoding endothelial constitutive and inducible nitric oxide synthases, endothelin 1, interleukin 6, and interleukin 8 were investigated in human primary pulmonary endothelial cells and whole pulmonary artery organoid cultures. Hypoxia decreased the expression of constitutive endothelial nitric oxide synthase (NOS-3) mRNA and NOS-3 protein as compared with normoxic conditions. The inhibition of expression of NOS-3 corresponded with a reduced production of NO. A combination of hypoxia with bacterial lipopolysaccharide, interleukin 1β , or tumor necrosis factor α augmented both effects. In contrast, the combination of hypoxia and the inflammatory mediators superinduced the expression of endothelin 1, interleukin 6, and interleukin 8. Here, we have shown that inflammatory mediators aggravate the effect of hypoxia on the down-regulation of NOS-3 and increase the expression of proinflammatory cytokines in human pulmonary endothelial cells and whole pulmonary artery organoid cultures.

  13. Heme oxygenase-1 attenuates acute pulmonary inflammation by decreasing the release of segmented neutrophils from the bone marrow.

    PubMed

    Konrad, Franziska M; Braun, Stefan; Ngamsri, Kristian-Christos; Vollmer, Irene; Reutershan, Jörg

    2014-11-01

    Recruiting polymorphonuclear neutrophil granulocytes (PMNs) from circulation and bone marrow to the site of inflammation is one of the pivotal mechanisms of the innate immune system. During inflammation, the enzyme heme oxygenase 1 (HO-1) has been shown to reduce PMN migration. Although these effects have been described in various models, underlying mechanisms remain elusive. Recent studies revealed an influence of HO-1 on different cells of the bone marrow. We investigated the particular role of the bone marrow in terms of HO-1-dependent pulmonary inflammation. In a murine model of LPS inhalation, stimulation of HO-1 by cobalt (III) protoporphyrin-IX-chloride (CoPP) resulted in reduced segmented PMN migration into the alveolar space. In the CoPP group, segmented PMNs were also decreased intravascularly, and concordantly, mature and immature PMN populations were higher in the bone marrow. Inhibition of the enzyme by tin protoporphyrin-IX increased segmented and banded PMN migration into the bronchoalveolar lavage fluid with enhanced PMN release from the bone marrow and aggravated parameters of tissue inflammation. Oxidative burst activity was significantly higher in immature compared with mature PMNs. The chemokine stromal-derived factor-1 (SDF-1), which mediates homing of leukocytes into the bone marrow and is decreased in inflammation, was increased by CoPP. When SDF-1 was blocked by the specific antagonist AMD3100, HO-1 activation was no longer effective in curbing PMN trafficking to the inflamed lungs. In conclusion, we show evidence that the anti-inflammatory effects of HO-1 are largely mediated by inhibiting the release of segmented PMNs from the bone marrow rather than direct effects within the lung.

  14. Schistosome-induced pulmonary B cells inhibit allergic airway inflammation and display a reduced Th2-driving function.

    PubMed

    van der Vlugt, L E; Obieglo, K; Ozir-Fazalalikhan, A; Sparwasser, T; Haeberlein, S; Smits, H H

    2017-04-04

    Chronic schistosome infections protect against allergic airway inflammation (AAI) via the induction of IL-10-producing splenic regulatory B (Breg) cells. Previous experiments have demonstrated that schistosome-induced pulmonary B cells can also reduce AAI, but act independently of IL-10. We have now further characterized the phenotype and inhibitory activity of these protective pulmonary B cells. We excluded a role for regulatory T (Treg) cell induction as putative AAI-protective mechanisms. Schistosome-induced B cells showed increased CD86 expression and reduced cytokine expression in response to Toll-like receptor (TLR) ligands compared with control B cells. To investigate the consequences for T cell activation we cultured ovalbumin (OVA)-pulsed, schistosome-induced B cells with OVA-specific transgenic T cells and observed less Th2 cytokine expression and T cell proliferation compared with control conditions. This suppressive effect was preserved even under optimal T cell stimulation by anti-CD3/28. Blocking of the inhibitory cytokines IL-10 or TGF-β only marginally restored Th2 cytokine induction. These data suggest that schistosome-induced pulmonary B cells are impaired in their capacity to produce cytokines to TLR ligands and to induce Th2 cytokine responses independent of their antigen-presenting function. These findings underline the presence of distinct B cell subsets with different stimulatory or inhibitory properties even if induced by the same type of helminth.

  15. Lilium lancifolium Thunb. extract attenuates pulmonary inflammation and air space enlargement in a cigarette smoke-exposed mouse model.

    PubMed

    Lee, Euijeong; Yun, Nayoung; Jang, Young Pyo; Kim, Jinju

    2013-08-26

    Lilium lancifolium Thunb. (Liliaceae) has long been used as a traditional medicine in Korea and China to treat bronchitis, pneumonia, and other pulmonary ailments. Cigarette smoke (CS) is a major risk factor for the development of pulmonary inflammatory response; it also triggers pulmonary alveoli enlargement. In the present study, we investigate the effects of Lilium lancifolium Thunb. root extract on pulmonary inflammatory responses in a CS-exposed mouse model. Water extract of Lilium lancifolium Thunb. root was fed to C57BL/6 mice prior CS exposure every day for 3 weeks. The numbers of macrophages and neutrophils in bronchoalveolar lavage fluid (BALF) were counted. The relative inflammatory factors, tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), interleukin-1 beta (IL-1β), monocyte chemotactic protein-1 (MCP-1), and matrix metalloproteinase-12 (MMP-12) were measured by real-time PCR, ELISA, or Western blot analysis. The average alveoli size was determined by lung histology. Lilium lancifolium Thunb. root extract was found to significantly inhibit the numbers of macrophages and neutrophils in BALF due to CS exposure. Lilium lancifolium Thunb. root extract also reduced the protein secretion levels of TNF-α, IL-6, IL-1β, and MCP-1 in BALF and the RNA expression levels of TNF-α, IL-6, IL-1β, MCP-1, and MMP-12 in lung tissue compared with mice only exposed to CS. Moreover, MMP-12 in serum was down regulated in Lilium lancifolium Thunb. root extract treated mice compared with CS-exposed mice. Finally, a morphometric analysis of the lungs of Lilium lancifolium Thunb. root extract treated mice demonstrated a significant reduction in airspace size compared to mice only exposed to CS. Our results show that Lilium lancifolium Thunb. root extract reduces lung inflammation and airspace enlargement in a CS-exposed mouse model. These data indicate that Lilium lancifolium Thunb. root extract is a therapeutic candidate for pulmonary inflammation and emphysema

  16. 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.

  17. Systemic inflammation and skeletal muscle dysfunction in chronic obstructive pulmonary disease: state of the art and novel insights in regulation of muscle plasticity.

    PubMed

    Remels, Alexander H; Gosker, Harry R; van der Velden, Jos; Langen, Ramon C; Schols, Annemie M

    2007-09-01

    Systemic inflammation is a recognized hallmark of chronic obstructive pulmonary disease pathogenesis. Although the origin and mechanisms responsible for the persistent chronic inflammatory process remain to be elucidated, it is recognized that it plays an important role in skeletal muscle pathology as observed in chronic obstructive pulmonary disease and several other chronic inflammatory disorders. This article describes state-of-the-art knowledge and novel insights in the role of inflammatory processes on several aspects of inflammation-related skeletal muscle pathology and offers new insights in therapeutic perspectives.

  18. Pulmonary instillation of low doses of titanium dioxide nanoparticles in mice leads to particle retention and gene expression changes in the absence of inflammation

    SciTech Connect

    Husain, Mainul; Saber, Anne T.; Guo, Charles; Jacobsen, Nicklas R.; Jensen, Keld A.; Yauk, Carole L.; Williams, Andrew; Vogel, Ulla; Wallin, Hakan; Halappanavar, Sabina

    2013-06-15

    We investigated gene expression, protein synthesis, and particle retention in mouse lungs following intratracheal instillation of varying doses of nano-sized titanium dioxide (nano-TiO{sub 2}). Female C57BL/6 mice were exposed to rutile nano-TiO{sub 2} via single intratracheal instillations of 18, 54, and 162 μg/mouse. Mice were sampled 1, 3, and 28 days post-exposure. The deposition of nano-TiO{sub 2} in the lungs was assessed using nanoscale hyperspectral microscopy. Biological responses in the pulmonary system were analyzed using DNA microarrays, pathway-specific real-time RT-PCR (qPCR), gene-specific qPCR arrays, and tissue protein ELISA. Hyperspectral mapping showed dose-dependent retention of nano-TiO{sub 2} in the lungs up to 28 days post-instillation. DNA microarray analysis revealed approximately 3000 genes that were altered across all treatment groups (± 1.3 fold; p < 0.1). Several inflammatory mediators changed in a dose- and time-dependent manner at both the mRNA and protein level. Although no influx of neutrophils was detected at the low dose, changes in the expression of several genes and proteins associated with inflammation were observed. Resolving inflammation at the medium dose, and lack of neutrophil influx in the lung fluid at the low dose, were associated with down-regulation of genes involved in ion homeostasis and muscle regulation. Our gene expression results imply that retention of nano-TiO{sub 2} in the absence of inflammation over time may potentially perturb calcium and ion homeostasis, and affect smooth muscle activities. - Highlights: • Pulmonary effects following exposure to low doses of nano-TiO{sub 2} were examined. • Particle retention in lungs was assessed using nanoscale hyperspectral microscopy. • Particles persisted up to 28 days in lungs in all dose groups. • Inflammation was the pathway affected in the high dose group at all time points. • Ion homeostasis and muscle activity pathways were affected in the low dose

  19. Effects of formoterol and ipratropium bromide on repeated cadmium inhalation-induced pulmonary inflammation and emphysema in rats.

    PubMed

    Zhang, WenHui; Fievez, Laurence; Zhang, Fan; Cheu, Esteban; Antoine, Nadine; Delguste, Catherine; Zhang, Yong; Rong, WeiFang; Bureau, Fabrice; Advenier, Charles; Gustin, Pascal

    2010-11-25

    The anti-inflammatory properties of inhaled formoterol and ipratropium bromide, alone or in combination, were investigated in a rat model of chronic pulmonary inflammation with airspace enlargement induced by cadmium inhalation. At the end of the protocol, cadmium-induced increase of airway resistance was prevented by formoterol (4 mg/30 ml) or ipratropium (0.20 mg/20 ml). Formoterol elicited a significant decrease in total cell and neutrophil counts in bronchoalveolar lavage fluid as well as on the activity of gelatinase B (MMP-9), an enzyme strongly expressed in alveolar macrophages and epithelial cells. Additionally, a significant attenuation of the lung lesions characterized by inflammatory cell infiltration within the alveoli and the interstitium and a decrease in mean linear intercept were observed. Although ipratropium alone had no effects on the cadmium-induced pulmonary inflammation and emphysema, its combination with an inefficient concentration of formoterol (1 mg/30 ml) showed a synergistic inhibitory effect on neutrophil and total cell counts as well as on the mean linear intercept associated with a synergistic inhibition on the MMP-9 activity. Gelatinase A (MMP-2) activity was not influenced by drug pretreatments. Neither macrophage metalloelastase (MMP-12) activity nor levels of cytokines IL-1β, TNF-α and GM-CSF in bronchoalveolar lavage fluid were modified in rats chronically exposed to cadmium. No desensitization of β(2)-adrenoceptors or cholinergic receptors on airway smooth muscles and inflammatory cells during the protocol was observed. In conclusion, formoterol alone or combined with ipratropium bromide partially protects the lungs against the chronic inflammation and airspace enlargement by reducing neutrophilic infiltration possibly via the inhibition of MMP-9 activity.

  20. CT-base pulmonary artery measurement in the detection of pulmonary hypertension: a meta-analysis and systematic review.

    PubMed

    Shen, Yongchun; Wan, Chun; Tian, Panwen; Wu, Yanqiu; Li, Xiaoou; Yang, Ting; An, Jing; Wang, Tao; Chen, Lei; Wen, Fuqiang

    2014-12-01

    To summarize the performance of CT-based main pulmonary artery diameter or pulmonary artery to aorta ratio (PA:A ratio) measurement in detection of pulmonary hypertension by a systematic review and meta-analysis. A comprehensive literature search was performed to identify studies determining diagnostic accuracy of main pulmonary artery diameter or PA:A ratio measurement for pulmonary hypertension. The Quality Assessment of Diagnostic Accuracy Studies tool was used to assess the quality of the included studies. A bivariate random-effects model was used to pool sensitivity, specificity, positive/negative likelihood ratio (PLR/NLR), and diagnostic odds ratio (DOR). Summary receiver operating characteristic (SROC) curves and area under the curve (AUC) were used to summarize overall diagnostic performance. This meta-analysis included 20 publications involving 2134 subjects. Summary estimates for main pulmonary artery diameter measurement in the diagnosis of pulmonary hypertension were as follows: sensitivity, 0.79 (95% CI 0.72-0.84); specificity, 0.83 (95% CI 0.75-0.89); PLR, 4.68 (95% CI 3.13-6.99); NLR, 0.26 (95% CI 0.20-0.33); DOR, 18.13 (95% CI 10.87-30.24); and AUC 0.87. The corresponding summary performance estimates for using the PA:A ratio were as follows: sensitivity, 0.74 (95% CI 0.66-0.80); specificity, 0.81 (95% CI 0.74-0.86); PLR, 3.83 (95% CI, 2.70-5.43); NLR, 0.33 (95% CI 0.24-0.44); DOR, 11.77 (95% CI 6.60-21.00); and AUC 0.84. Both main pulmonary artery diameter and PA:A ratio are helpful for diagnosing pulmonary hypertension. Nevertheless, the results of pulmonary artery measurement should be interpreted in parallel with the results of traditional tests such as echocardiography.

  1. Early pulmonary inflammation and lung damage in children with cystic fibrosis.

    PubMed

    Schultz, André; Stick, Stephen

    2015-05-01

    Individuals with cystic fibrosis (CF) suffer progressive airway inflammation, infection and lung damage. Airway inflammation and infection are present from early in life, often before children are symptomatic. CF gene mutations cause changes in the CF transmembrane regulator protein that result in an aberrant airway microenvironment including airway surface liquid (ASL) dehydration, reduced ASL acidity, altered airway mucin and a dysregulated inflammatory response. This review discusses how an altered microenvironment drives CF lung disease before overt airway infection, the response of the CF airway to early infection, and methods to prevent inflammation and early lung disease.

  2. A novel method for pulmonary embolism detection in CTA images.

    PubMed

    Özkan, Haydar; Osman, Onur; Şahin, Sinan; Boz, Ali Fuat

    2014-03-01

    In this paper, we propose a new computer-aided detection (CAD) - based method to detect pulmonary embolism (PE) in computed tomography angiography images (CTAI). Since lung vessel segmentation is the main objective to provide high sensitivity in PE detection, this method performs accurate lung vessel segmentation. To concatenate clogged vessels due to PEs, the starting region of PEs and some reference points (RPs) are determined. These RPs are detected according to the fixed anatomical structures. After lung vessel tree is segmented, the region, intensity, and size of PEs are used to distinguish them. We used the data sets that have heart disease or abnormal tissues because of lung disease except PE in this work. According to the results, 428 of 450 PEs, labeled by the radiologists from 33 patients, have been detected. The sensitivity of the developed system is 95.1% at 14.4 false positive per data set (FP/ds). With this performance, the proposed CAD system is found quite useful to use as a second reader by the radiologists.

  3. Nano-sized Contrast Agents to Non-Invasively Detect Renal Inflammation by Magnetic Resonance Imaging

    PubMed Central

    Thurman, Joshua M.; Serkova, Natalie J.

    2013-01-01

    Several molecular imaging methods have been developed that employ nano-sized contrast agents to detect markers of inflammation within tissues. Renal inflammation contributes to disease progression in a wide range of autoimmune and inflammatory diseases, and a biopsy is currently the only method of definitively diagnosing active renal inflammation. However, the development of new molecular imaging methods that employ contrast agents capable of detecting particular immune cells or protein biomarkers will allow clinicians to evaluate inflammation throughout the kidneys, and to assess a patient's response to immunomodulatory drugs. These imaging tools will improve our ability to validate new therapies and to optimize the treatment of individual patients with existing therapies. This review describes the clinical need for new methods of monitoring renal inflammation, and recent advances in the development of nano-sized contrast agents for detection of inflammatory markers of renal disease. PMID:24206601

  4. Innate Lymphoid Cells Mediate Pulmonary Eosinophilic Inflammation, Airway Mucous Cell Metaplasia, and Type 2 Immunity in Mice Exposed to Ozone.

    PubMed

    Kumagai, Kazuyoshi; Lewandowski, Ryan P; Jackson-Humbles, Daven N; Buglak, Nicholas; Li, Ning; White, Kaylin; Van Dyken, Steven J; Wagner, James G; Harkema, Jack R

    2017-01-01

    Exposure to elevated levels of ambient ozone in photochemical smog is associated with eosinophilic airway inflammation and nonatopic asthma in children. In the present study, we determined the role of innate lymphoid cells (ILCs) in the pathogenesis of ozone-induced nonatopic asthma by using lymphoid cell-sufficient C57BL/6 mice, ILC-sufficient Rag2(-/-) mice (devoid of T and B cells), and ILC-deficient Rag2(-/-)Il2rg(-/-) mice (depleted of all lymphoid cells including ILCs). Mice were exposed to 0 or 0.8 parts per million ozone for 1 day or 9 consecutive weekdays (4 hr/day). A single exposure to ozone caused neutrophilic inflammation, airway epithelial injury, and reparative DNA synthesis in all strains of mice, irrespective of the presence or absence of ILCs. In contrast, 9-day exposures induced eosinophilic inflammation and mucous cell metaplasia only in the lungs of ILC-sufficient mice. Repeated ozone exposures also elicited increased messenger RNA expression of transcripts associated with type 2 immunity and airway mucus production in ILC-sufficient mice. ILC-deficient mice repeatedly exposed to ozone had no pulmonary pathology or increased gene expression related to type 2 immunity. These results suggest a new paradigm for the biologic mechanisms underlying the development of a phenotype of childhood nonatopic asthma that has been linked to ambient ozone exposures.

  5. Role of tumor necrosis factor-α and its receptors in diesel exhaust particle-induced pulmonary inflammation.

    PubMed

    Kumar, Smitha; Joos, Guy; Boon, Louis; Tournoy, Kurt; Provoost, Sharen; Maes, Tania

    2017-09-14

    Inhalation of diesel exhaust particles (DEP) induces an inflammatory reaction in the lung. However, the underlying mechanisms remain to be elucidated. Tumor necrosis factor alpha (TNF-α) is a pro-inflammatory cytokine that operates by binding to tumor necrosis factor receptor 1 (TNFR1) and tumor necrosis factor receptor 2 (TNFR2). The role of TNF-α signaling and the importance of either TNFR1 or TNFR2 in the DEP-induced inflammatory response has not yet been elucidated. TNF-α knockout (KO), TNFR1 KO, TNFR2 KO, TNFR1/TNFR2 double KO (TNFR-DKO) and wild type (WT) mice were intratracheally exposed to saline or DEP. Pro-inflammatory cells and cytokines were assessed in the bronchoalveolar lavage fluid (BALF). Exposure to DEP induced a dose-dependent inflammation in the BALF in WT mice. In addition, levels of TNF-α and its soluble receptors were increased upon exposure to DEP. The DEP-induced inflammation in the BALF was decreased in TNF-α KO, TNFR-DKO and TNFR2 KO mice. In contrast, the inflammatory response in the BALF of DEP-exposed TNFR1 KO mice was largely comparable with WT controls. In conclusion, these data provide evidence for a regulatory role of TNF-α in DEP-induced pulmonary inflammation and identify TNFR2 as the most important receptor in mediating these inflammatory effects.

  6. Chronic obstructive pulmonary disease and asthma-associated Proteobacteria, but not commensal Prevotella spp., promote Toll-like receptor 2-independent lung inflammation and pathology.

    PubMed

    Larsen, Jeppe M; Musavian, Hanieh S; Butt, Tariq M; Ingvorsen, Camilla; Thysen, Anna H; Brix, Susanne

    2015-02-01

    Recent studies of healthy human airways have revealed colonization by a distinct commensal bacterial microbiota containing Gram-negative Prevotella spp. However, the immunological properties of these bacteria in the respiratory system remain unknown. Here we compare the innate respiratory immune response to three Gram-negative commensal Prevotella strains (Prevotella melaninogenica, Prevotella nanceiensis and Prevotella salivae) and three Gram-negative pathogenic Proteobacteria known to colonize lungs of patients with chronic obstructive pulmonary disease (COPD) and asthma (Haemophilus influenzae B, non-typeable Haemophilus influenzae and Moraxella catarrhalis). The commensal Prevotella spp. and pathogenic Proteobacteria were found to exhibit intrinsic differences in innate inflammatory capacities on murine lung cells in vitro. In vivo in mice, non-typeable H. influenzae induced severe Toll-like receptor 2 (TLR2)-independent COPD-like inflammation characterized by predominant airway neutrophilia, expression of a neutrophilic cytokine/chemokine profile in lung tissue, and lung immunopathology. In comparison, P. nanceiensis induced a diminished neutrophilic airway inflammation and no detectable lung pathology. Interestingly, the inflammatory airway response to the Gram-negative bacteria P. nanceiensis was completely TLR2-dependent. These findings demonstrate weak inflammatory properties of Gram-negative airway commensal Prevotella spp. that may make colonization by these bacteria tolerable by the respiratory immune system. © 2014 John Wiley & Sons Ltd.

  7. Chronic obstructive pulmonary disease and asthma-associated Proteobacteria, but not commensal Prevotella spp., promote Toll-like receptor 2-independent lung inflammation and pathology

    PubMed Central

    Larsen, Jeppe M; Musavian, Hanieh S; Butt, Tariq M; Ingvorsen, Camilla; Thysen, Anna H; Brix, Susanne

    2015-01-01

    Recent studies of healthy human airways have revealed colonization by a distinct commensal bacterial microbiota containing Gram-negative Prevotella spp. However, the immunological properties of these bacteria in the respiratory system remain unknown. Here we compare the innate respiratory immune response to three Gram-negative commensal Prevotella strains (Prevotella melaninogenica, Prevotella nanceiensis and Prevotella salivae) and three Gram-negative pathogenic Proteobacteria known to colonize lungs of patients with chronic obstructive pulmonary disease (COPD) and asthma (Haemophilus influenzae B, non-typeable Haemophilus influenzae and Moraxella catarrhalis). The commensal Prevotella spp. and pathogenic Proteobacteria were found to exhibit intrinsic differences in innate inflammatory capacities on murine lung cells in vitro. In vivo in mice, non-typeable H. influenzae induced severe Toll-like receptor 2 (TLR2)-independent COPD-like inflammation characterized by predominant airway neutrophilia, expression of a neutrophilic cytokine/chemokine profile in lung tissue, and lung immunopathology. In comparison, P. nanceiensis induced a diminished neutrophilic airway inflammation and no detectable lung pathology. Interestingly, the inflammatory airway response to the Gram-negative bacteria P. nanceiensis was completely TLR2-dependent. These findings demonstrate weak inflammatory properties of Gram-negative airway commensal Prevotella spp. that may make colonization by these bacteria tolerable by the respiratory immune system. PMID:25179236

  8. Mechanisms of carbon nanotube-induced toxicity: focus on pulmonary inflammation.

    PubMed

    Bhattacharya, Kunal; Andón, Fernando Torres; El-Sayed, Ramy; Fadeel, Bengt

    2013-12-01

    Carbon nanotubes have gained tremendous interest in a wide range of applications due to their unique physical, chemical, and electronic properties. Needless to say, close attention to the potential toxicity of carbon nanotubes is of paramount importance. Numerous studies have linked exposure of carbon nanotubes to the induction of inflammation, a complex protective response to harmful stimuli including pathogens, damaged or dying cells, and other irritants. However, inflammation is a double-edged sword as chronic inflammation can lead to destruction of tissues thus compromising the homeostasis of the organism. Here, we provide an overview of the process of inflammation, the key cells and the soluble mediators involved, and discuss research on carbon nanotubes and inflammation, including recent studies on the activation of the so-called inflammasome complex in macrophages resulting in secretion of pro-inflammatory cytokines. Moreover, recent work has shown that inflammatory cells i.e. neutrophils and eosinophils are capable of enzymatic degradation of carbon nanotubes, with mitigation of the pro-inflammatory and pro-fibrotic effects of nanotubes thus underscoring that inflammation is both good and bad.

  9. A Wavelet-Based Instrument for Detection of Crackles in Pulmonary Sounds

    DTIC Science & Technology

    2001-10-25

    A WAVELET-BASED INSTRUMENT FOR DETECTION OF CRACKLES IN PULMONARY SOUNDS Yasemin P. Kahya , Serkan Yerer , Omer Cerid Department of Electrical and...Electronics Engineering, Bogazici University, Istanbul, Turkey Abstract-- Crackles are discontinuous adventitious respiratory sounds , which are...considered as signs of various pulmonary disorders, therefore their detection is important in the analysis of lung sounds . In this work, an instrument for

  10. 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...

  11. Pulmonary vascular inflammation: effect of TLR signalling on angiopoietin/TIE regulation.

    PubMed

    Hilbert, Tobias; Dornbusch, Kathrin; Baumgarten, Georg; Hoeft, Andreas; Frede, Stilla; Klaschik, Sven

    2017-01-01

    Increased pulmonary vascular resistance is a critical complication in sepsis. Toll-like receptor (TLR) as well as angiopoietin (ANG) signalling both contribute to the emergence of pulmonary arterial hypertension. We hypothesized that TLR stimulation by bacterial ligands directly affects expression and secretion of ligands and receptors of the angiopoietin/TIE axis. Microvascular endothelial (HPMEC) and smooth muscle cells (SMC) of pulmonary origin were incubated with thrombin and with ligands for TLR2, -4, -5, and -9. Expression and secretion of ANG1, -2, TIE2 and IL-8 were determined using quantitative real-time PCR and ELISA. TLR stimulation had no impact either on the expression of ANG2 and TIE2 in HPMEC or on that of ANG1 in SMC. However, overall levels of both released ANG1 and -2 were halved upon stimulation with the TLR9 ligand CpG, and ANG2 release was significantly enhanced by TLR4 activation when initially provoked by sequentially performed stimulation. Furthermore, enhanced ANG2 activity increased endothelial permeability, as demonstrated in an in vitro transwell assay. We conclude that sole TLR stimulation by bacterial ligands plays no significant role for altered expression and secretion of ANG1, -2 and TIE2 in human pulmonary vascular cells. The interplay between various stimuli is required to induce imbalances between ANG1 and -2.

  12. 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...

  13. Impaired exercise capacity and skeletal muscle function in a mouse model of pulmonary inflammation

    PubMed Central

    Tang, Kechun; Murano, George; Wagner, Harrieth; Nogueira, Leonardo; Wagner, Peter D.; Tang, Alisa; Dalton, Nancy D.; Gu, Yusu; Peterson, Kirk L.

    2013-01-01

    Pulmonary TNFα has been linked to reduced exercise capacity in a subset of patients with moderate to severe chronic obstructive pulmonary disease (COPD). We hypothesized that prolonged, high expression of pulmonary TNFα impairs cardiac and skeletal muscle function, and both contribute to exercise limitation. Using a surfactant protein C promoter-TNFα construct, TNFα was overexpressed throughout life in mouse lungs (SP-C/TNFα+). TNFα levels in wild-type (WT) female serum and lung were two- and threefold higher than in WT male mice. In SP-C/TNFα+ mice, TNFα increased similarly in both sexes. Treadmill exercise was impaired only in male SP-C/TNFα+ mice. While increases in lung volume and airspace size induced by TNFα were comparable in both sexes, pulmonary hypertension along with lower body and muscle mass were evident only in male mice. Left ventricular (LV) function (cardiac output, stroke volume, LV maximal pressure, and LV maximal pressure dP/dt) was not altered by TNFα overexpression. Fatigue measured in isolated soleus and EDL was more rapid only in soleus of male SP-C/TNFα+ mice and accompanied by a loss of oxidative IIa fibers, citrate synthase activity, and PGC-1α mRNA and increase in atrogin-1 and MuRF1 expression also only in male mice. In situ gastrocnemius fatigue resistance, reflecting both oxygen availability and contractility, was decreased similarly in female and male SP-C/TNFα+ mice. These data indicate that male, but not female, mice overexpressing pulmonary TNFα are susceptible to exercise limitation, possibly due to muscle wasting and loss of the oxidative muscle phenotype, with protection in females possibly due to estrogen. PMID:23449936

  14. Pulmonary dendritic cells and alveolar macrophages are regulated by γδ T cells during the resolution of S. pneumoniae-induced inflammation

    PubMed Central

    Kirby, AC; Newton, DJ; Carding, SR; Kaye, PM

    2007-01-01

    γδ T cells commonly associate with mucosal and epithelial sites, fulfilling a variety of immunoregulatory functions. While lung γδ T cells have well-characterized pro-inflammatory activity, their potential role in the resolution of lung inflammation has yet to be explored in any detail. Indeed, given the importance of minimizing inflammation, the cellular mechanisms driving the resolution of lung inflammation are poorly understood. Using a murine model of acute Streptococcus pneumoniae-mediated lung inflammation, we now show that resolution of inflammation following bacterial clearance is associated with a > 30-fold increase in γδ T-cell number. Although inflammation eventually resolves in TCRδ−/− mice, elevated numbers of alveolar macrophages and pulmonary dendritic cells, and the appearance of well-formed granulomas in lungs of TCRδ−/− mice, together indicated a role for γδ T cells in regulating mononuclear phagocyte number. Ex vivo, both alveolar macrophages and pulmonary dendritic cells were susceptible to lung γδ T cell-mediated cytotoxicity, the first demonstration of such activity against a dendritic cell population. These findings support a model whereby expansion of γδ T cells helps restore mononuclear phagocyte numbers to homeostatic levels, protecting the lung from the consequences of inappropriate inflammation. Copyright © 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID:17370296

  15. Mesenchymal stromal cell therapy reduces lung inflammation and vascular remodeling and improves hemodynamics in experimental pulmonary arterial hypertension.

    PubMed

    de Mendonça, Lucas; Felix, Nathane S; Blanco, Natália G; Da Silva, Jaqueline S; Ferreira, Tatiana P; Abreu, Soraia C; Cruz, Fernanda F; Rocha, Nazareth; Silva, Patrícia M; Martins, Vanessa; Capelozzi, Vera L; Zapata-Sudo, Gizele; Rocco, Patricia R M; Silva, Pedro L

    2017-10-03

    Experimental research has reported beneficial effects of mesenchymal stromal cell (MSC) therapy in pulmonary arterial hypertension (PAH). However, these studies either were based on prophylactic protocols or assessed basic remodeling features without evaluating possible mechanisms. We analyzed the effects of MSC therapy on lung vascular remodeling and hemodynamics and its possible mechanisms of action in monocrotaline (MCT)-induced PAH. Twenty-eight Wistar rats were randomly divided into two groups. In the PAH group, animals received MCT 60 mg/kg intraperitoneally, while a control group received saline (SAL) instead. On day 14, both groups were further randomized to receive 10(5) adipose-derived MSCs or SAL intravenously (n = 7/group). On day 28, right ventricular systolic pressure (RVSP) and the gene expression of mediators associated with apoptosis, inflammation, fibrosis, Smad-1 levels, cell proliferation, and endothelial-mesenchymal transition were determined. In addition, lung histology (smooth muscle cell proliferation and plexiform-like injuries), CD68(+) and CD163(+) macrophages, and plasma levels of vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) were evaluated. In the PAH group, adipose-derived MSCs, compared to SAL, reduced mean RVSP (29 ± 1 vs 39 ± 2 mmHg, p < 0.001), lung tissue collagen fiber content, smooth muscle cell proliferation, CD68(+) macrophages, interleukin-6 expression, and the antiapoptotic mediators Bcl-2 and survivin. Conversely, expression of the proapoptotic mediator procaspase-3 and plasma VEGF increased, with no changes in PDGF. In the pulmonary artery, MSCs dampened the endothelial-mesenchymal transition. In MCT-induced PAH, MSC therapy reduced lung vascular remodeling, thus improving hemodynamics. These beneficial effects were associated with increased levels of proapoptotic markers, mesenchymal-to-endothelial transition, reduced cell proliferation markers, and inflammation

  16. Benzo(a)pyrene-induced pulmonary inflammation, edema, surfactant dysfunction, and injuries in rats: alleviation by farnesol.

    PubMed

    Qamar, Wajhul; Khan, Abdul Quaiyoom; Khan, Rehan; Lateef, Abdul; Tahir, Mir; Rehman, Muneeb U; Ali, Farrah; Sultana, Sarwat

    2012-02-01

    Benzo(a)pyrene (B(a)P) is a well-known environmental contaminant and carcinogen. Its sources include tobacco smoke, automobile exhaust, forest fire, and other combustion processes. Farnesol, an active principle of Vachellia farnesiana and other aromatic plants, possesses preventive properties against various toxicities. Present study was designed to estimate chemopreventive effects of farnesol against B(a)P-induced pulmonary injuries. To determine the protective effects of farnesol, it was administered orally at 2 doses (100 and 200 mg/kg body weight [b.w.]) once daily for 14 days. Rats were exposed intratracheally to B(a)P, 5 mg/kg b.w. on days 12 and 14, thereafter assessed for pulmonary toxicities 24 hours post last dose of B(a)P. B(a)P-induced edema, inflammation, oxidative stress, and consequent damages in lungs were assessed in terms of total protein, total cell count, nitric oxide (NO), lactate dehydrogenase (LDH), alkaline phosphatase, and in bronchoalveolar lavage fluid (BALF). B(a)P also reduced the levels of phospholipids (lung surfactants) in BALF. However, pretreatment with farnesol at both the doses significantly reduced the lung injuries and inflammatory responses. Farnesol also protected the levels of phospholipids to normal when compared with control. It also modified the activities of B(a)P metabolizing enzymes NADPH-cytochrome P450 reductase, microsomal epoxide hydrolase (mEH), and glutathione S-transferase (GST) in lung tissue of rats. Present findings suggest a prominent role of farnesol against B(a)P-induced lung inflammation, edema, surfactant dysfunction, and epithelial damages in Wistar rats. In conclusion, farnesol shows lung protection against B(a)P toxicities in Wistar rats.

  17. Anti-inflammatory effects of formoterol and ipratropium bromide against acute cadmium-induced pulmonary inflammation in rats.

    PubMed

    Zhang, Wenhui; Fievez, Laurence; Cheu, Esteban; Bureau, Fabrice; Rong, Weifang; Zhang, Fan; Zhang, Yong; Advenier, Charles; Gustin, Pascal

    2010-02-25

    In this study, the anti-inflammatory properties of formoterol and ipratropium bromide, alone or in combination, were investigated in a rat model of acute pulmonary inflammation induced by cadmium inhalation. Airway resistance and inflammatory responses, including matrix metalloproteinease-2 (MMP-2) and matrix metalloproteinease-9 (MMP-9) activities, were evaluated. Compared to values obtained in rats exposed to cadmium, pretreatment by bronchodilators administered alone significantly prevented the cadmium-induced increase of airway resistance. Formoterol elicited a significant decrease in total cell number, neutrophil and macrophage counts in bronchoalveolar lavage fluid, whereas ipratropium bromide reduced neutrophil numbers. The two compounds administered alone significantly attenuated the lung lesions associated with parenchyma inflammatory cell influx and congestion observed in the cadmium group. The increased MMP-9 activity was significantly attenuated. Although only formoterol induced a decrease protein concentration in bronchoalveolar lavage fluid, both compounds inhibited the pulmonary edema by reducing wet-to-dry weight ratio which returned to values similar to those recorded in the sham group. All the effects of formoterol on the cadmium-induced inflammatory responses were reversed by propranolol. Similar anti-inflammatory effects were obtained in rats pretreated with ilomastat which showed a significant reduction on inflammatory cell infiltration and MMP-9 activity in bronchoalveolar lavage fluid. Neither synergistic nor additive effects were obtained when the two bronchodilators were administered in combination. In conclusion, formoterol and ipratropium bromide partially protect the lungs against the inflammation by reducing neutrophilic infiltration. This protective effect is associated with reduced MMP-9 activity known to play an important pro-inflammatory role in acute inflammatory process.

  18. NF-κB Mediates Mesenchymal Transition, Remodeling, and Pulmonary Fibrosis in Response to Chronic Inflammation by Viral RNA Patterns.

    PubMed

    Tian, Bing; Patrikeev, Igor; Ochoa, Lorenzo; Vargas, Gracie; Belanger, KarryAnne K; Litvinov, Julia; Boldogh, Istvan; Ameredes, Bill T; Motamedi, Massoud; Brasier, Allan R

    2017-04-01

    Airway remodeling is resultant of a complex multicellular response associated with a progressive decline of pulmonary function in patients with chronic airway disease. Here, repeated infections with respiratory viruses are linked with airway remodeling through largely unknown mechanisms. Although acute activation of the Toll-like receptor (TLR) 3 pathway by extracellular polyinosinic:polycytidylic acid (poly[I:C]) induces innate signaling through the NF-κB transcription factor in normal human small airway epithelial cells, prolonged (repetitive or tonic) poly(I:C) stimulation produces chronic stress fiber formation, mesenchymal transition, and activation of a fibrotic program. Chronic poly(I:C) stimulation enhanced the expression of core mesenchymal regulators Snail family zinc finger 1, zinc finger E-box binding homeobox, mesenchymal intermediate filaments (vimentin), and extracellular matrix proteins (fibronectin-1), and collagen 1A. This mesenchymal transition was prevented by silencing expression of NF-κB/RelA or administration of a small-molecule inhibitor of the IκB kinase, BMS345541. Acute poly(I:C) exposure in vivo induced profound neutrophilic airway inflammation. When administered repetitively, poly(I:C) resulted in enhanced fibrosis observed by lung micro-computed tomography, second harmonic generation microscopy of optically cleared lung tissue, and by immunohistochemistry. Epithelial flattening, expansion of the epithelial mesenchymal trophic unit, and enhanced Snail family zinc finger 1 and fibronectin 1 expression in airway epithelium were also observed. Repetitive poly(I:C)-induced airway remodeling, fibrosis, and epithelial-mesenchymal transition was inhibited by BMS345541 administration. Based on this novel model of viral inflammation-induced remodeling, we conclude that NF-κB is a major controller of epithelial-mesenchymal transition and pulmonary fibrosis, a finding that has potentially important relevance to airway remodeling produced by

  19. Pulmonary inflammation induced by subacute ozone is augmented in adiponectin deficient mice: role of IL-17A

    PubMed Central

    Kasahara, David I.; Kim, Hye Y.; Williams, Alison S.; Verbout, Norah G.; Tran, Jennifer; Si, Huiqing; Wurmbrand, Allison P.; Jastrab, Jordan; Hug, Christopher; Umetsu, Dale T.; Shore, Stephanie A.

    2012-01-01

    Pulmonary responses to ozone, a common air pollutant, are augmented in obese individuals. Adiponectin, an adipose derived hormone that declines in obesity, has regulatory effects on the immune system. To determine the role of adiponectin in the pulmonary inflammation induced by extended (48–72 h) low dose (0.3 ppm) exposure to ozone, adiponectin deficient (Adipo−/−) and wildtype mice were exposed to ozone or to room air. In wildtype mice, ozone exposure increased total bronchoalveolar lavage (BAL) adiponectin. Ozone induced lung inflammation, including increases in BAL neutrophils, protein (an index of lung injury), IL-6, KC, LIX and G-CSF were augmented in Adipo−/− versus wildtype mice. Ozone also increased IL-17A mRNA expression to a greater extent in Adipo−/− versus wildtype mice. Moreover, compared to control antibody, anti-IL-17A antibody attenuated ozone-induced increases in BAL neutrophils and G-CSF in Adipo−/− but not in wildtype mice, suggesting that IL-17A, by promoting G-CSF release, contributed to augmented neutrophilia in Adipo−/− mice. Flow-cytometric analysis of lung cells revealed that the number of CD45+/F4/80+/IL-17A+ macrophages and γδ T cells expressing IL-17A increased after ozone exposure in wildtype mice, and further increased in Adipo−/− mice. The IL-17+ macrophages were CD11c− (interstitial macrophages), whereas CD11c+ macrophages (alveolar macrophages) did not express IL-17A. Taken together, the data are consistent with the hypothesis that adiponectin protects against neutrophil recruitment induced by extended, low dose ozone exposure by inhibiting the induction and/or recruitment of IL-17A in interstitial macrophages and/or γδ T cells. PMID:22474022

  20. Elevated circulating PAI-1 levels are related to lung function decline, systemic inflammation, and small airway obstruction in chronic obstructive pulmonary disease.

    PubMed

    Wang, Hao; Yang, Ting; Li, Diandian; Wu, Yanqiu; Zhang, Xue; Pang, Caishuang; Zhang, Junlong; Ying, Binwu; Wang, Tao; Wen, Fuqiang

    2016-01-01

    Plasminogen activator inhibitor-1 (PAI-1) and soluble urokinase-type plasminogen activator receptor (suPAR) participate in inflammation and tissue remolding in various diseases, but their roles in chronic obstructive pulmonary disease (COPD) are not yet clear. This study aimed to investigate if PAI-1 and suPAR were involved in systemic inflammation and small airway obstruction (SAO) in COPD. Demographic and clinical characteristics, spirometry examination, and blood samples were obtained from 84 COPD patients and 51 healthy volunteers. Serum concentrations of PAI-1, suPAR, tissue inhibitor of metalloproteinase-1 (TIMP-1), Matrix metalloproteinase-9 (MMP-9), and C-reactive protein (CRP) were detected with Magnetic Luminex Screening Assay. Differences between groups were statistically analyzed using one-way analysis of variance or chi-square test. Pearson's partial correlation test (adjusted for age, sex, body mass index, cigarette status, and passive smoke exposure) and multivariable linear analysis were used to explore the relationships between circulating PAI-1 and indicators of COPD. First, we found that serum PAI-1 levels but not suPAR levels were significantly increased in COPD patients compared with healthy volunteers (125.56±51.74 ng/mL versus 102.98±36.62 ng/mL, P=0.007). Then, the correlation analysis showed that circulating PAI-1 was inversely correlated with pulmonary function parameters including the ratio of forced expiratory volume in 1 second to forced vital capacity (FEV1/FVC), FEV1/Pre (justified r=-0.308, P<0.001; justified r=-0.295, P=0.001, respectively) and SAO indicators such as FEV3/FVC, MMEF25-75/Pre (justified r=-0.289, P=0.001; justified r=-0.273, P=0.002, respectively), but positively related to the inflammatory marker CRP (justified r=0.351, P<0.001), the small airway remolding biomarker TIMP-1, and MMP-9 (justified r=0.498, P<0.001; justified r=0.267, P=0.002, respectively). Besides, multivariable linear analysis showed that FEV1/FVC

  1. Elevated circulating PAI-1 levels are related to lung function decline, systemic inflammation, and small airway obstruction in chronic obstructive pulmonary disease

    PubMed Central

    Wang, Hao; Yang, Ting; Li, Diandian; Wu, Yanqiu; Zhang, Xue; Pang, Caishuang; Zhang, Junlong; Ying, Binwu; Wang, Tao; Wen, Fuqiang

    2016-01-01

    Background Plasminogen activator inhibitor-1 (PAI-1) and soluble urokinase-type plasminogen activator receptor (suPAR) participate in inflammation and tissue remolding in various diseases, but their roles in chronic obstructive pulmonary disease (COPD) are not yet clear. This study aimed to investigate if PAI-1 and suPAR were involved in systemic inflammation and small airway obstruction (SAO) in COPD. Methods Demographic and clinical characteristics, spirometry examination, and blood samples were obtained from 84 COPD patients and 51 healthy volunteers. Serum concentrations of PAI-1, suPAR, tissue inhibitor of metalloproteinase-1 (TIMP-1), Matrix metalloproteinase-9 (MMP-9), and C-reactive protein (CRP) were detected with Magnetic Luminex Screening Assay. Differences between groups were statistically analyzed using one-way analysis of variance or chi-square test. Pearson’s partial correlation test (adjusted for age, sex, body mass index, cigarette status, and passive smoke exposure) and multivariable linear analysis were used to explore the relationships between circulating PAI-1 and indicators of COPD. Results First, we found that serum PAI-1 levels but not suPAR levels were significantly increased in COPD patients compared with healthy volunteers (125.56±51.74 ng/mL versus 102.98±36.62 ng/mL, P=0.007). Then, the correlation analysis showed that circulating PAI-1 was inversely correlated with pulmonary function parameters including the ratio of forced expiratory volume in 1 second to forced vital capacity (FEV1/FVC), FEV1/Pre (justified r=−0.308, P<0.001; justified r=−0.295, P=0.001, respectively) and SAO indicators such as FEV3/FVC, MMEF25–75/Pre (justified r=−0.289, P=0.001; justified r=−0.273, P=0.002, respectively), but positively related to the inflammatory marker CRP (justified r=0.351, P<0.001), the small airway remolding biomarker TIMP-1, and MMP-9 (justified r=0.498, P<0.001; justified r=0.267, P=0.002, respectively). Besides, multivariable

  2. Dietary long-chain omega-3 fatty acids do not diminish eosinophilic pulmonary inflammation in mice

    USDA-ARS?s Scientific Manuscript database

    The effects of fish oil supplements on diminishing airway inflammation in asthma have been studied in mouse models and human intervention trials with varying results. However, the independent effects of the main omega-3 PUFAs found in fish oil, eicosapentaenoic acid (EPA) and docosahexaenoic acid (D...

  3. The effects of aging on pulmonary oxidative damage, protein nitration, and extracellular superoxide dismutase down-regulation during systemic inflammation.

    PubMed

    Starr, Marlene E; Ueda, Junji; Yamamoto, Shoji; Evers, B Mark; Saito, Hiroshi

    2011-01-15

    Systemic inflammatory response syndrome (SIRS), a serious clinical condition characterized by whole-body inflammation, is particularly threatening for elderly patients, who suffer much higher mortality rates than the young. A major pathological consequence of SIRS is acute lung injury caused by neutrophil-mediated oxidative damage. Previously, we reported an increase in protein tyrosine nitration (a marker of oxidative/nitrosative damage) and a decrease in the antioxidant enzyme extracellular superoxide dismutase (EC-SOD) in the lungs of young mice during endotoxemia-induced SIRS. Here we demonstrate that during endotoxemia, down-regulation of EC-SOD is significantly more profound and prolonged, whereas up-regulation of iNOS is augmented, in aged compared to young mice. Aged mice also showed 2.5-fold higher protein nitration levels, compared to young mice, with particularly strong nitration in the pulmonary vascular endothelium during SIRS. Additionally, by two-dimensional gel electrophoresis, Western blotting, and mass spectrometry, we identified proteins that show increased tyrosine nitration in age- and SIRS-dependent manners; these proteins (profilin-1, transgelin-2, LASP 1, tropomyosin, and myosin) include components of the actin cytoskeleton responsible for maintaining pulmonary vascular permeability. Reduced EC-SOD in combination with increased oxidative/nitrosative damage and altered cytoskeletal protein function due to tyrosine nitration may contribute to augmented lung injury in the aged with SIRS.

  4. Pulmonary dysfunction is possibly a marker of malnutrition and inflammation but not mortality in patients with end-stage renal disease.

    PubMed

    Yoon, Se-Hee; Choi, Nak-Won; Yun, Sung-Ro

    2009-01-01

    Various studies have indicated that malnutrition and chronic inflammation are strong predictors of morbidity and mortality in patients with chronic kidney disease (CKD). The purpose of this study was to investigate the relationship between pulmonary function, malnutrition and chronic inflammation in patients with CKD. One hundred and six consenting patients with CKD were enrolled in the study between 2005 and 2007. Pulmonary function was assessed by forced vital capacity (FVC), forced expiratory volume in the first second (FEV(1)) and peak expiratory flow (PEF), expressed as the normal percentage of predicted values (%FEV(1), %FVC and %PEF, respectively). Nutritional status was evaluated by skeletal muscle index (SMI), subjective global nutritional assessment (SGA), lean body mass, body mass index and serum albumin. Inflammation was assessed by the serum measurement of high-sensitive C reactive protein (hsCRP) levels. Malnutrition (defined as SMI > or =1) and inflammation (defined as hsCRP >2 mg/l) in ESRD patients had significant negative associations with percentage predicted values for pulmonary function tests except %PEF (SMI: %FEV(1), p = 0.009, %FVC, p = 0.001; hsCRP: %FEV(1), p = 0.025, %FVC, p = 0.022). Multivariate Cox analysis showed that the ejection fraction in echocardiography and SGA were associated with poor survival, but there was no association for %FEV(1). Impaired pulmonary function was associated with malnutrition and inflammation in these dialysis patients. We were not able to determine a significant relationship between pulmonary function and mortality. Copyright 2008 S. Karger AG, Basel.

  5. Depletion of Neutrophils Promotes the Resolution of Pulmonary Inflammation and Fibrosis in Mice Infected with Paracoccidioides brasiliensis

    PubMed Central

    Arango, Julián Camilo

    2016-01-01

    Chronic stages of paracoccidioidomycosis (PCM) are characterized by granulomatous lesions which promote the development of pulmonary fibrosis leading to the loss of respiratory function in 50% of patients; in addition, it has been observed that neutrophils predominate during these chronic stages of P. brasiliensis infection. The goal of this study was to evaluate the role of the neutrophil during the chronic stages of experimental pulmonary PCM and during the fibrosis development and tissue repair using a monoclonal specific to this phagocytic cell. Male BALB/c mice were inoculated intranasally with 1.5x106 P. brasiliensis yeast cells. A monoclonal antibody specific to neutrophils was administered at 4 weeks post-inoculation followed by doses every 48h during two weeks. Mice were sacrificed at 8 and 12 weeks post-inoculation to assess cellularity, fungal load, cytokine/chemokine levels, histopathological analysis, collagen and expression of genes related to fibrosis development. Depletion of neutrophils was associated with a significant decrease in the number of eosinophils, dendritic cells, B cells, CD4-T cells, MDSCs and Treg cells, fungal load and levels of most of the pro-inflammatory cytokines/chemokines evaluated, including IL-17, TNF-α and TGF-β1. Recovery of lung architecture was also associated with reduced levels of collagen, high expression of TGF-β3, matrix metalloproteinase (MMP)-12 and -14, and decreased expression of tissue inhibitor metalloproteinase (TIMP)-2, and MMP-8. Depletion of neutrophils might attenuate lung fibrosis and inflammation through down-regulating TGF-β1, TNF-α, IL-17, MMP-8 and TIMP-2. These results suggest that neutrophil could be considered as a therapeutic target in pulmonary fibrosis induced by P. brasiliensis. PMID:27690127

  6. 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.

  7. Improving performance of computer-aided detection of pulmonary embolisms by incorporating a new pulmonary vascular-tree segmentation algorithm

    NASA Astrophysics Data System (ADS)

    Wang, Xingwei; Song, XiaoFei; Chapman, Brian E.; Zheng, Bin

    2012-03-01

    We developed a new pulmonary vascular tree segmentation/extraction algorithm. The purpose of this study was to assess whether adding this new algorithm to our previously developed computer-aided detection (CAD) scheme of pulmonary embolism (PE) could improve the CAD performance (in particular reducing false positive detection rates). A dataset containing 12 CT examinations with 384 verified pulmonary embolism regions associated with 24 threedimensional (3-D) PE lesions was selected in this study. Our new CAD scheme includes the following image processing and feature classification steps. (1) A 3-D based region growing process followed by a rolling-ball algorithm was utilized to segment lung areas. (2) The complete pulmonary vascular trees were extracted by combining two approaches of using an intensity-based region growing to extract the larger vessels and a vessel enhancement filtering to extract the smaller vessel structures. (3) A toboggan algorithm was implemented to identify suspicious PE candidates in segmented lung or vessel area. (4) A three layer artificial neural network (ANN) with the topology 27-10-1 was developed to reduce false positive detections. (5) A k-nearest neighbor (KNN) classifier optimized by a genetic algorithm was used to compute detection scores for the PE candidates. (6) A grouping scoring method was designed to detect the final PE lesions in three dimensions. The study showed that integrating the pulmonary vascular tree extraction algorithm into the CAD scheme reduced false positive rates by 16.2%. For the case based 3D PE lesion detecting results, the integrated CAD scheme achieved 62.5% detection sensitivity with 17.1 false-positive lesions per examination.

  8. Equivalent Dipole Vector Analysis for Detecting Pulmonary Hypertension

    NASA Technical Reports Server (NTRS)

    Harlander, Matevz; Salobir, Barbara; Toplisek, Janez; Schlegel, Todd T.; Starc, Vito

    2010-01-01

    Various 12-lead ECG criteria have been established to detect right ventricular hypertrophy as a marker of pulmonary hypertension (PH). While some criteria offer good specificity they lack sensitivity because of a low prevalence of positive findings in the PH population. We hypothesized that three-dimensional equivalent dipole (ED) model could serve as a better detection tool of PH. We enrolled: 1) 17 patients (12 female, 5 male, mean age 57 years, range 19-79 years) with echocardiographically detected PH (systolic pulmonary arterial pressure greater than 35 mmHg) and no significant left ventricular disease; and 2) 19 healthy controls (7 female, 12 male, mean age 44, range 31-53 years) with no known heart disease. In each subject we recorded a 5-minute high-resolution 12-lead conventional ECG and constructed principal signals using singular value decomposition. Assuming a standard thorax dimension of an adult person with homogenous and isotropic distribution of thorax conductance, we determined moving equivalent dipoles (ED), characterized by the 3D location in the thorax, dipolar strength and the spatial orientation, in time intervals of 5 ms. We used the sum of all ED vectors in the second half of the QRS complex to derive the amplitude of the right-sided ED vector (RV), if the orientation of ED was to the right side of the thorax, and in the first half the QRS to derive the amplitude of the left-sided vector (LV), if the orientation was leftward. Finally, the parameter RV/LV ratio was determined over an average of 256 complexes. The groups differed in age and gender to some extent. There was a non-significant trend toward higher RV in patients with PH (438 units 284) than in controls (280 plus or minus 140) (p = 0.066) but the overlap was such that RV alone was not a good predictor of PH. On the other hand, the RV/LV ratio was a better predictor of PH, with 11/17 (64.7%) of PH patients but only in 1/19 (5.3%) control subjects having RV/LV ratio greater than or

  9. Equivalent Dipole Vector Analysis for Detecting Pulmonary Hypertension

    NASA Technical Reports Server (NTRS)

    Harlander, Matevz; Salobir, Barbara; Toplisek, Janez; Schlegel, Todd T.; Starc, Vito

    2010-01-01

    Various 12-lead ECG criteria have been established to detect right ventricular hypertrophy as a marker of pulmonary hypertension (PH). While some criteria offer good specificity they lack sensitivity because of a low prevalence of positive findings in the PH population. We hypothesized that three-dimensional equivalent dipole (ED) model could serve as a better detection tool of PH. We enrolled: 1) 17 patients (12 female, 5 male, mean age 57 years, range 19-79 years) with echocardiographically detected PH (systolic pulmonary arterial pressure greater than 35 mmHg) and no significant left ventricular disease; and 2) 19 healthy controls (7 female, 12 male, mean age 44, range 31-53 years) with no known heart disease. In each subject we recorded a 5-minute high-resolution 12-lead conventional ECG and constructed principal signals using singular value decomposition. Assuming a standard thorax dimension of an adult person with homogenous and isotropic distribution of thorax conductance, we determined moving equivalent dipoles (ED), characterized by the 3D location in the thorax, dipolar strength and the spatial orientation, in time intervals of 5 ms. We used the sum of all ED vectors in the second half of the QRS complex to derive the amplitude of the right-sided ED vector (RV), if the orientation of ED was to the right side of the thorax, and in the first half the QRS to derive the amplitude of the left-sided vector (LV), if the orientation was leftward. Finally, the parameter RV/LV ratio was determined over an average of 256 complexes. The groups differed in age and gender to some extent. There was a non-significant trend toward higher RV in patients with PH (438 units 284) than in controls (280 plus or minus 140) (p = 0.066) but the overlap was such that RV alone was not a good predictor of PH. On the other hand, the RV/LV ratio was a better predictor of PH, with 11/17 (64.7%) of PH patients but only in 1/19 (5.3%) control subjects having RV/LV ratio greater than or

  10. Pneumocystis colonization, airway inflammation, and pulmonary function decline in acquired immunodeficiency syndrome.

    PubMed

    Norris, Karen A; Morris, Alison; Patil, Sangita; Fernandes, Eustace

    2006-01-01

    As a result of improved diagnosis, treatment, and supportive care for HIV-infected patients, AIDS in developed countries has now become a chronic infection with prolonged survival time, but longterm complications are increasing contributors to morbidity and mortality. HIV-infected patients are at increased risk for the development of pulmonary complications, including chronic obstructive pulmonary disease (COPD); however, the mechanisms associated with this increased susceptibility have not been defined. Infectious agents may contribute to the development of COPD by upregulating inflammatory mediators in the lung that act in concert with cigarette smoke to promote lung pathology. Studies in human subjects and non-human primate models of AIDS suggest that the inflammatory response to asymptomatic carriage or colonization by the opportunistic pathogen, Pneumocystis sp. (Pc), is similar to that of COPD, which is characterized by influx of CD8+ T cells, neutrophils, and macrophages into the lungs. We have shown a high frequency of Pc colonization among asymptomatic HIV-infected subjects and in non-HIV infected subjects with COPD. To investigate the role of Pc in the progression of obstructive lung disease in HIV infections, we developed a non-human primate model of Pc colonizatoin and infection in simian immunodeficiency virus (SIV)-infected macaques. These animals develop a prolonged colonization state characterized by a persistent influx of CD8+ T cells and neutrophils, and local increases in IL-8, IFN-gamma, and TNF-alpha. SIV-infected Pc-colonized monkeys show progressive decline in pulmonary function compared to SIV-infected monkeys. We hypothesize that in the context of AIDS-immune dysfunction, Pc colonization induces inflammatory responses leading to changes in pulmonary function and architecture similar to that seen in emphysema. Information gained from these studies will lead to the development of interventions to prevent lung injury associated with Pc

  11. Lesion conspicuity and AFROC performance in pulmonary nodule detection

    NASA Astrophysics Data System (ADS)

    Manning, David; Ethell, Susan C.

    2002-04-01

    A test bank of verified chest radiographs was compiled for visual search experiments. The purpose was to investigate human performance in the detection of significant pulmonary nodules. Synthesized nodules supplemented native lesions. The distribution of all the lesions in the lung fields was consistent with the naturally occurring locations of these features. A measure of the physical characteristics of the lesions was derived in order to approximate the conspicuity of the synthetic to the natural nodules. The measure of conspicuity was given as (chi) =Tan(theta-1)S/N where (theta) is the maximum slope angle to the edge of the lesion profile, S is the mean pixel value of the lesion profile taken in four orientations, and N is the mean background pixel value taken in four orientations over one lesion dimension adjacent to the lesion. The variation in (chi) for each of the 81 lesions (46 natural and 35 synthetic) was plotted against SNR and edge angle. The influence of edge angle on the resulting (chi) values was more powerful than SNR for all the lesions in this experiment. Although there was an overall significant difference in (chi) values (p=0.015), observers were unable to distinguish synthetic from native lesions. Observer performance in nodule detection was measured by AFROC and supplemented with visual search recording. Correlation of AFROC scores and the (chi) values has shown no overall relationship (R2=0.0452) and this surprising result may be partly explained through inspection of the visual search recordings.

  12. 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

  13. An Immature Myeloid/Myeloid-Suppressor Cell Response Associated with Necrotizing Inflammation Mediates Lethal Pulmonary Tularemia

    PubMed Central

    Periasamy, Sivakumar; Avram, Dorina; McCabe, Amanda; MacNamara, Katherine C.; Sellati, Timothy J.; Harton, Jonathan A.

    2016-01-01

    Inhalation of Francisella tularensis (Ft) causes acute and fatal pneumonia. The lung cytokine milieu favors exponential Ft replication, but the mechanisms underlying acute pathogenesis and death remain unknown. Evaluation of the sequential and systemic host immune response in pulmonary tularemia reveals that in contrast to overwhelming bacterial burden or cytokine production, an overt innate cellular response to Ft drives tissue pathology and host mortality. Lethal infection with Ft elicits medullary and extra-medullary myelopoiesis supporting recruitment of large numbers of immature myeloid cells and MDSC to the lungs. These cells fail to mature and die, leading to subsequent necrotic lung damage, loss of pulmonary function, and host death that is partially dependent upon immature Ly6G+ cells. Acceleration of this process may account for the rapid lethality seen with Ft SchuS4. In contrast, during sub-lethal infection with Ft LVS the pulmonary cellular response is characterized by a predominance of mature neutrophils and monocytes required for protection, suggesting a required threshold for lethal bacterial infection. Further, eliciting a mature phagocyte response provides transient, but dramatic, innate protection against Ft SchuS4. This study reveals that the nature of the myeloid cell response may be the primary determinant of host mortality versus survival following Francisella infection. PMID:27015566

  14. Biodiesel versus diesel exposure: Enhanced pulmonary inflammation, oxidative stress, and differential morphological changes in the mouse lung

    SciTech Connect

    Yanamala, Naveena; Birch, M. Eileen; Kisin, Elena; Bugarski, Aleksandar D.

    2013-10-15

    The use of biodiesel (BD) or its blends with petroleum diesel (D) is considered to be a viable approach to reduce occupational and environmental exposures to particulate matter (PM). Due to its lower particulate mass emissions compared to D, use of BD is thought to alleviate adverse health effects. Considering BD fuel is mainly composed of unsaturated fatty acids, we hypothesize that BD exhaust particles could induce pronounced adverse outcomes, due to their ability to readily oxidize. The main objective of this study was to compare the effects of particles generated by engine fueled with neat BD and neat petroleum-based D. Biomarkers of tissue damage and inflammation were significantly elevated in lungs of mice exposed to BD particulates. Additionally, BD particulates caused a significant accumulation of oxidatively modified proteins and an increase in 4-hydroxynonenal. The up-regulation of inflammatory cytokines/chemokines/growth factors was higher in lungs upon BD particulate exposure. Histological evaluation of lung sections indicated presence of lymphocytic infiltrate and impaired clearance with prolonged retention of BD particulate in pigment laden macrophages. Taken together, these results clearly indicate that BD exhaust particles could exert more toxic effects compared to D. - Highlights: • Exposure of mice to BDPM caused higher pulmonary toxicity compared to DPM. • Oxidative stress and inflammation were higher in BD vs to D exposed mice. • Inflammatory lymphocyte infiltrates were seen only in lungs of mice exposed to BD. • Ineffective clearance, prolonged PM retention was present only after BD exposure.

  15. Reconstitution fluid type does not affect pulmonary inflammation or DNA damage following infusion of lyophilized plasma.

    PubMed

    McCully, Sean P; Lee, Tim H; McCully, Belinda H; Sands, Claire L; Rick, Elizabeth A; Dean, Rondi K; Anderson, Nathan W; Hampton, David A; Louis, Scott G; Differding, Jerome A; Schreiber, Martin A

    2015-02-01

    Dysfunctional inflammation following traumatic hemorrhage can lead to multiple-organ failure and death. In our polytrauma swine model, lyophilized plasma (LP) reconstituted with sterile water and ascorbic acid suppressed systemic inflammation and attenuated DNA damage. However, it remains unknown whether the inflammatory response is affected by the type of fluid used to reconstitute LP. We hypothesized that common resuscitation fluids such as normal saline (LP-NS), lactated Ringer's solution (LP-LR), Hextend (LP-HX), or sterile water (LP-SW) would yield similar inflammation profiles and DNA damage following LP reconstitution and transfusion. This was a randomized, prospective, blinded animal study. LP was reconstituted to 50% of original volume with NS, LR, HX, or SW buffered with 15-mM ascorbic acid. Forty swine were subjected to a validated model of polytrauma, hemorrhagic shock, and Grade V liver injury and resuscitated with LP. Serum interleukin 6 (IL-6), IL-10, plasma C-reactive protein, and 8-hydroxy-2-deoxyguanosine concentrations were assessed for systemic inflammation and DNA damage at baseline, 2 hours, and 4 hours following liver injury. Lung inflammation was evaluated by Real Time Polymerize Chain Reaction (RT-PCR). Reconstituted LP pH was similar between groups before resuscitation. IL-6 and IL-10 increased at 2 hours and 4 hours compared with baseline in all groups (p < 0.017). DNA damage increased at 2 hours and 4 hours compared with baseline and from 2 hours to 4 hours in the LP-NS, LP-LR, and LP-SW groups (all p < 0.017). Animals resuscitated with LP-HX not only demonstrated increased DNA damage at 4 hours versus baseline but also had the lowest C-reactive protein level at 2 hours and 4-hours (p < 0.017). Overall, differences between groups were similar for DNA damage and lung inflammation. Reconstitution fluid type does not affect inflammatory cytokine profiles or DNA damage following LP transfusion in this swine polytrauma model. Based on

  16. The Effects of Resveratrol on Inflammation and Oxidative Stress in a Rat Model of Chronic Obstructive Pulmonary Disease.

    PubMed

    Wang, Xiao-Li; Li, Ting; Li, Ji-Hong; Miao, Shu-Ying; Xiao, Xian-Zhong

    2017-09-12

    Oxidative stress and inflammation are hypothesized to contribute to the pathogenesis of chronic obstructive pulmonary disease (COPD). Resveratrol (trans-3,5,4'-trihydroxystilbene) is known for its antioxidant and anti-inflammatory properties. The study aimed to investigate the effects of resveratrol in a rat model with COPD on the regulation of oxidative stress and inflammation via the activation of Sirtuin1 (SIRTl) and proliferator-activated receptor-γ coactivator-1α (PGC-1α). Thirty Wistar rats were randomly divided into three groups: control group, COPD group and resveratrol intervention group. The COPD model was established by instilling with lipopolysaccharide (LPS) and challenging with cigarette smoke (CS). The levels of interleukin-6 (IL-6) and interleukin-8 (IL-8) in serum were measured. The levels of malondialdehyde (MDA) and the activity of superoxide dismutase (SOD) were measured. The expression levels of SIRT1 and PGC-1α in the lung tissues were examined by immunohistochemistry as well as real-time reverse transcriptase polymerase chain reaction (real-time RT-PCR) and western blotting analysis. After the treatment with resveratrol (50 mg/kg), compared with the COPD group, alleviation of inflammation and reconstruction in the small airways of the lungs were seen. Resveratrol might be correlated not only with the lower level of MDA and the higher activity of SOD, but also with the upregulation of SIRT1 and PGC-1α expression. Resveratrol treatment decreased serum levels of IL-6 and IL-8. Our findings indicate that resveratrol had a therapeutic effect in our rat COPD model, which is related to the inhibition of oxidative stress and inflammatory response. The mechanism may be related to the activation and upgrading of the SIRT1/PGC-1α signaling pathways. Thus resveratrol might be a therapeutic modality in COPD.

  17. Use of Metal Oxide Nanoparticle Band Gap to Develop a Predictive Paradigm for Oxidative Stress and Acute Pulmonary Inflammation

    PubMed Central

    Zhang, Haiyuan; Ji, Zhaoxia; Xia, Tian; Meng, Huan; Low-Kam, Cecile; Liu, Rong; Pokhrel, Suman; Lin, Sijie; Wang, Xiang; Liao, Yu-Pei; Wang, Meiying; Li, Linjiang; Rallo, Robert; Damoiseaux, Robert; Telesca, Donatello; Mädler, Lutz; Cohen, Yoram; Zink, Jeffrey I.; Nel, Andre E.

    2014-01-01

    We demonstrate for 24 metal oxide (MOx) nanoparticles that it is possible to use conduction band energy levels to delineate their toxicological potential at cellular and whole animal levels. Among the materials, the overlap of conduction band energy (Ec) levels with the cellular redox potential (−4.12 to −4.84 eV) was strongly correlated to the ability of Co3O4, Cr2O3, Ni2O3, Mn2O3 and CoO nanoparticles to induce oxygen radicals, oxidative stress and inflammation. This outcome is premised on permissible electron transfers from the biological redox couples that maintain the cellular redox equilibrium to the conduction band of the semiconductor particles. Both single parameter cytotoxic as well as multi-parameter oxidative stress assays in cells showed excellent correlation to the generation of acute neutrophilic inflammation and cytokine responses in the lungs of CB57 Bl/6 mice. Co3O4, Ni2O3, Mn2O3 and CoO nanoparticles could also oxidize cytochrome c as a representative redox couple involved in redox homeostasis. While CuO and ZnO generated oxidative stress and acute pulmonary inflammation that is not predicted by Ec levels, the adverse biological effects of these materials could be explained by their solubility, as demonstrated by ICP-MS analysis. Taken together, these results demonstrate, for the first time, that it is possible to predict the toxicity of a large series of MOx nanoparticles in the lung premised on semiconductor properties and an integrated in vitro/in vivo hazard ranking model premised on oxidative stress. This establishes a robust platform for modeling of MOx structure-activity relationships based on band gap energy levels and particle dissolution. This predictive toxicological paradigm is also of considerable importance for regulatory decision-making about this important class of engineered nanomaterials. PMID:22502734

  18. Systemic inflammation in peripheral arterial disease with or without coexistent chronic obstructive pulmonary disease: analysis of selected markers

    PubMed Central

    Sleszycka, Justyna; Safianowska, Aleksandra; Wiechno, Wieslaw; Domagala-Kulawik, Joanna

    2012-01-01

    Introduction Low-grade systemic inflammation plays an important role in the pathogenesis and natural history of chronic obstructive pulmonary disease (COPD) and peripheral arterial disease (PAD). The aim of the study was to analyze plasma concentrations of selected markers of inflammation in patients suffering from PAD with or without coexistent COPD. Material and methods Thirty patients (6 women) with advanced PAD (at least IIb stage according to Fontaine scale) hospitalized due to critical limb ischemia were examined. In all patients spirometry was performed to confirm or exclude COPD. Plasma concentration of IL-6, IL-8 and TNF-α was measured using ELISA method. Statistical analysis was performed according to COPD status and according to smoking status independently. Results In the whole group of patients with PAD, COPD was recognized in 14 cases (for the first time in 10 cases). All patients were smokers (46.7% current, 53.3% ex-smokers). We found a significant correlation between FEV1%N (percent of norm of first second expiratory volume) and the number of years of smoking (r = –0.39; p < 0.05). We found similar concentrations of IL-6 (2.54 pg/ml vs. 2.31 pg/ml), IL-8 (8.55 pg/ml vs. 8.14 pg/ml, TNF-α (0.72 pg/ml vs. 1.75 pg/ml) in the COPD(+) group in comparison to the COPD(–) group (differences were not significant). We observed significant positive correlations (p < 0.05) between concentrations of measured markers and significant negative correlations between pain free walking distance and these markers. Conclusions Our study confirmed coexistence of PAD with COPD. The character of inflammation is similar in these smoking-related diseases PMID:22852003

  19. Characteristics of Allergic Pulmonary Inflammation in CXCR3Knockout Mice Sensitized and Challenged with House Dust Mite Protein

    PubMed Central

    Chen, Xiaolan; Gao, Jinming; Guo, Zijian

    2016-01-01

    Chemokine C-X-C motif receptor 3 (CXCR3) is a chemokine receptor that is mainly expressed by activated T lymphocytes. T cells play important roles in allergic pulmonary inflammation, which is a hallmark of asthma and elicits the localized accumulation of activated T cells in the lung. In China, a marked increase in the incidence rate of chronic allergic pulmonary inflammation has made it a major public health threat. In the present study, we investigated the role of CXCR3 and its ligands in airway inflammation induced by house dust mite protein (HDMP) in a CXCR3 knockout (CXCR3KO) asthma mouse model. Pathological manifestations in the lung, cell counts and bronchoalveolar lavage fluid (BALF) classifications were studied using hematoxylin and eosin (H&E) staining. The levels of IL-4 and IFN-γ in the BALF and splenocyte supernatants were measured using ELISA. CD4+ and CD8+ T cells in the lung and spleen were analyzed by flow cytometry. RT-PCR was applied to measure the mRNA transcript levels of monokines induced by IFN-γ(CXCL9) and IFN-γ inducible protein 10(CXCL10). The total cell counts, eosinophil counts, and IL-4 levels in the BALF and cultured splenocyte supernatants were significantly increased, while the levels of IFN-γ were reduced in the HDMP groups(P<0.01). Changes in the total cell counts, eosinophil counts, and lymphocyte counts, as well as the total protein levels in the BALF, the levels of IL-4 in splenocyte supernatants, and the pathological manifestations in the lung, were all greater in CXCR3KO mice than in C57BL/6 wild-type mice. Furthermore, the expression levels of CXCL9 and CXCL10 mRNA transcripts in the lungs of CXCR3KO mice were lower than those in C57BL/6 wild-type mice (P<0.05). CXCR3 and its ligands (i.e., CXCL9 and CXCL10) may play anti-inflammatory roles in this animal model. Promoting the expression of CXCR3 and its ligands may represent a novel therapeutic approach for preventing and curing asthma. PMID:27727269

  20. Radiotracers Used for the Scintigraphic Detection of Infection and Inflammation

    PubMed Central

    Tsopelas, Chris

    2015-01-01

    Over the last forty years, a small group of commercial radiopharmaceuticals have found their way into routine medical use, for the diagnostic imaging of patients with infection or inflammation. These molecular radiotracers usually participate in the immune response to an antigen, by tagging leukocytes or other molecules/cells that are endogenous to the process. Currently there is an advancing effort by researchers in the preclinical domain to design and develop new agents for this application. This review discusses radiopharmaceuticals used in the nuclear medicine clinic today, as well as those potential radiotracers that exploit an organism's defence mechanisms to an infectious or inflammatory event. PMID:25741532

  1. The role of neural inflammation in asthma and chronic obstructive pulmonary disease.

    PubMed

    Joos, Guy F; De Swert, Katelijne O; Schelfhout, Vanessa; Pauwels, Romain A

    2003-05-01

    The tachykinins substance P and neurokinin A are found within airway nerves and immune cells. They have various effects on the airways that can contribute to the changes observed in asthma and chronic obstructive pulmonary disease. Both tachykinin NK(1) and NK(2) receptors have been involved in the bronchoconstriction and the proinflammatory changes induced by substance P and neurokinin A. Tachykinin NK(1) and NK(2) receptor antagonists have activity in various animal models of allergic asthma and chronic bronchitis. It is suggested that dual NK(1)/NK(2) and triple NK(1)/NK(2)/NK(3) tachykinin receptor antagonists have potential in the treatment of obstructive airway diseases.

  2. Acute pulmonary exacerbation and lung function decline in patients with cystic fibrosis: high-mobility group box 1 (HMGB1) between inflammation and infection.

    PubMed

    Chirico, V; Lacquaniti, A; Leonardi, S; Grasso, L; Rotolo, N; Romano, C; Di Dio, G; Lionetti, E; David, A; Arrigo, T; Salpietro, C; La Rosa, M

    2015-04-01

    Airway inflammation plays a central role in cystic fibrosis (CF) lung disease, and biomarkers of inflammation, such as high-mobility group box 1 (HMGB1) could be used to monitor disease activity. The main aim of this study was to confirm the role of HMGB1 in CF patients, correlating its serum and sputum levels with pulmonary function and inflammation. Serum and sputum HMGB1 were evaluated in a cohort of 31 CF patients and 30 non-smoking healthy subjects (HS group). Acute pulmonary exacerbation events and lung function decline have been also evaluated during a 3-year follow-up period. Serum HMGB1 levels were significantly higher than those measured in HS, such as sputum HMGB1. Kaplan-Meier survival curves revealed that patients with high HMGB1 values experienced a significantly faster evolution to decline of lung function. A multiple Cox regression analysis assessed that an increase of serum HMGB1 was associated with 5% increased risk of pulmonary disease progression, whereas elevated sputum HMGB1 was related to a 10% increased risk of lung function decline. In CF patients, HMGB1 closely reflects the entity of pulmonary impairment and represents a strong and independent risk marker for progression of lung function decline.

  3. Evaluation of computerized detection of pulmonary embolism in independent data sets of computed tomographic pulmonary angiographic (CTPA) scans

    NASA Astrophysics Data System (ADS)

    Zhou, Chuan; Chan, Heang-Ping; Sahiner, Berkman; Hadjiiski, Lubomir M.; Chughtai, Aamer; Patel, Smita; Wei, Jun; Cascade, Philip N.; Kazerooni, Ella A.

    2009-02-01

    Computed tomographic pulmonary angiography (CTPA) has been reported to be an effective means for clinical diagnosis of pulmonary embolism (PE). We are developing a computer-aided diagnosis (CAD) system for assisting radiologists in detection of pulmonary embolism in CTPA images. The pulmonary vessel tree is extracted based on the analysis of eigenvalues of Hessian matrices at multiple scales followed by 3D hierarchical EM segmentation. A multiprescreening method is designed to identify suspicious PEs along the extracted vessels. A linear discriminant analysis (LDA) classifier with feature selection is then used to reduce false positives (FPs). Two data sets of 59 and 69 CTPA PE cases were randomly selected from patient files at the University of Michigan (UM) and the PIOPED II study, respectively, and used as independent training and test sets. The PEs that were identified by three experienced thoracic radiologists were used as the gold standard. The detection performance of the CAD system was assessed by free response receiver operating characteristic analysis. The results indicated that our PE detection system can achieve a sensitivity of 80% at 18.9 FPs/case on the PIOPED cases when the LDA classifier was trained with the UM cases. The test sensitivity with the UM cases is 80% at 22.6 FPs/cases when the LDA classifier was trained with the PIOPED cases.

  4. IL-13 induces disease-promoting type 2 cytokines, alternatively activated macrophages and allergic inflammation during pulmonary infection of mice with Cryptococcus neoformans.

    PubMed

    Müller, Uwe; Stenzel, Werner; Köhler, Gabriele; Werner, Christoph; Polte, Tobias; Hansen, Gesine; Schütze, Nicole; Straubinger, Reinhard K; Blessing, Manfred; McKenzie, Andrew N J; Brombacher, Frank; Alber, Gottfried

    2007-10-15

    In the murine model of Cryptococcus neoformans infection Th1 (IL-12/IFN-gamma) and Th17 (IL-23/IL-17) responses are associated with protection, whereas an IL-4-dependent Th2 response exacerbates disease. To investigate the role of the Th2 cytokine IL-13 during pulmonary infection with C. neoformans, IL-13-overexpressing transgenic (IL-13Tg(+)), IL-13-deficient (IL-13(-/-)), and wild-type (WT) mice were infected intranasally. Susceptibility to C. neoformans infection was found when IL-13 was induced in WT mice or overproduced in IL-13Tg(+) mice. Infected IL-13Tg(+) mice had a reduced survival time and higher pulmonary fungal load as compared with WT mice. In contrast, infected IL-13(-/-) mice were resistant and 89% of these mice survived the entire period of the experiment. Ag-specific production of IL-13 by susceptible WT and IL-13Tg(+) mice was associated with a significant type 2 cytokine shift but only minor changes in IFN-gamma production. Consistent with enhanced type 2 cytokine production, high levels of serum IgE and low ratios of serum IgG2a/IgG1 were detected in susceptible WT and IL-13Tg(+) mice. Interestingly, expression of IL-13 by susceptible WT and IL-13Tg(+) mice was associated with reduced IL-17 production. IL-13 was found to induce formation of alternatively activated macrophages expressing arginase-1, macrophage mannose receptor (CD206), and YM1. In addition, IL-13 production led to lung eosinophilia, goblet cell metaplasia and elevated mucus production, and enhanced airway hyperreactivity. This indicates that IL-13 contributes to fatal allergic inflammation during C. neoformans infection.

  5. Histologic and biochemical alterations predict pulmonary mechanical dysfunction in aging mice with chronic lung inflammation.

    PubMed

    Massa, Christopher B; Groves, Angela M; Jaggernauth, Smita U; Laskin, Debra L; Gow, Andrew J

    2017-08-01

    Both aging and chronic inflammation produce complex structural and biochemical alterations to the lung known to impact work of breathing. Mice deficient in surfactant protein D (Sftpd) develop progressive age-related lung pathology characterized by tissue destruction/remodeling, accumulation of foamy macrophages and alteration in surfactant composition. This study proposes to relate changes in tissue structure seen in normal aging and in chronic inflammation to altered lung mechanics using a computational model. Alterations in lung function in aging and Sftpd -/- mice have been inferred from fitting simple mechanical models to respiratory impedance data (Zrs), however interpretation has been confounded by the simultaneous presence of multiple coexisting pathophysiologic processes. In contrast to the inverse modeling approach, this study uses simulation from experimental measurements to recapitulate how aging and inflammation alter Zrs. Histologic and mechanical measurements were made in C57BL6/J mice and congenic Sftpd-/- mice at 8, 27 and 80 weeks of age (n = 8/group). An anatomic computational model based on published airway morphometry was developed and Zrs was simulated between 0.5 and 20 Hz. End expiratory pressure dependent changes in airway caliber and recruitment were estimated from mechanical measurements. Tissue elements were simulated using the constant phase model of viscoelasticity. Baseline elastance distribution was estimated in 8-week-old wild type mice, and stochastically varied for each condition based on experimentally measured alteration in elastic fiber composition, alveolar geometry and surfactant composition. Weighing reduction in model error against increasing model complexity allowed for identification of essential features underlying mechanical pathology and their contribution to Zrs. Using a maximum likelihood approach, alteration in lung recruitment and diminished elastic fiber density were shown predictive of mechanical alteration at

  6. Pulmonary Inflammation Is Regulated by the Levels of the Vesicular Acetylcholine Transporter

    PubMed Central

    Perini, Adenir; Câmara, Niels O. S.; Costa, Soraia K. P.; Alonso-Vale, Maria Isabel C.; Caperuto, Luciana C.; Tibério, Iolanda F. L. C.; Prado, Marco Antônio M.; Martins, Mílton A.; Prado, Vânia F.; Prado, Carla M.

    2015-01-01

    Acetylcholine (ACh) plays a crucial role in physiological responses of both the central and the peripheral nervous system. Moreover, ACh was described as an anti-inflammatory mediator involved in the suppression of exacerbated innate response and cytokine release in various organs. However, the specific contributions of endogenous release ACh for inflammatory responses in the lung are not well understood. To address this question we have used mice with reduced levels of the vesicular acetylcholine transporter (VAChT), a protein required for ACh storage in secretory vesicles. VAChT deficiency induced airway inflammation with enhanced TNF-α and IL-4 content, but not IL-6, IL-13 and IL-10 quantified by ELISA. Mice with decreased levels of VAChT presented increased collagen and elastic fibers deposition in airway walls which was consistent with an increase in inflammatory cells positive to MMP-9 and TIMP-1 in the lung. In vivo lung function evaluation showed airway hyperresponsiveness to methacholine in mutant mice. The expression of nuclear factor-kappa B (p65-NF-kB) in lung of VAChT-deficient mice were higher than in wild-type mice, whereas a decreased expression of janus-kinase 2 (JAK2) was observed in the lung of mutant animals. Our findings show the first evidence that cholinergic deficiency impaired lung function and produce local inflammation. Our data supports the notion that cholinergic system modulates airway inflammation by modulation of JAK2 and NF-kB pathway. We proposed that intact cholinergic pathway is necessary to maintain the lung homeostasis. PMID:25816137

  7. Effectiveness of computer aided detection for solitary pulmonary nodules

    NASA Astrophysics Data System (ADS)

    Yan, Jiayong; Li, Wenjie; Du, Xiangying; Lu, Huihai; Xu, Jianrong; Xu, Mantao; Rong, Dongdong

    2009-02-01

    This study is to investigate the incremental effect of using a high performance computer-aided detection (CAD) system in detection of solitary pulmonary nodules in chest radiographs. The Kodak Chest CAD system was evaluated by a panel of six radiologists at different levels of experience. The observer study consisted of two independent phases: readings without CAD and readings with assistance of CAD. The study was conducted over a set of chest radiographs comprising 150 cancer cases and 150 cancer-free cases. The actual sensitivity of the CAD system is 72% with 3.7 false positives per case. Receiver operating characteristic (ROC) analysis was used to assess the overall observer performance. The AUZ (area under ROC curve) showed a significantly improvement (P=0.0001) from 0.844 to 0.884 after using CAD. The ROC analysis was also applied for observer performances on nodules in different sizes and visibilities. The average AUZs are improved from 0.798 to 0.835 (P=0.0003) for 5-10mm nodules, 0.853 to 0.907 (P=0.001) for 10-15mm nodules, 0.864 to 0.897 (P=0.051) for 15-20 mm nodules and 0.859 to 0.896 (P=0.0342) for 20-30mm nodules, respectively. For different visibilities, the average AUZs are improved from 0.886 to 0.915 (P=0.0337), 0.803 to 0.840 (P=0.063), 0.830 to 0.893 (P=0.0001), and 0.813 to 0.847 (P=0.152), for nodules clearly visible, hidden by ribs, partially overlap with ribs, and overlap with other structures, respectively. These results showed that observer performance could be greatly improved when the CAD system is employed as a second reader, especially for small nodules and nodules occluded by ribs.

  8. Molecular Imaging of Activated Platelets Allows the Detection of Pulmonary Embolism with Magnetic Resonance Imaging

    PubMed Central

    Heidt, Timo; Ehrismann, Simon; Hövener, Jan-Bernd; Neudorfer, Irene; Hilgendorf, Ingo; Reisert, Marco; Hagemeyer, Christoph E.; Zirlik, Andreas; Reinöhl, Jochen; Bode, Christoph; Peter, Karlheinz; von Elverfeldt, Dominik; von zur Muhlen, Constantin

    2016-01-01

    Early and reliable detection of pulmonary embolism (PE) is critical for improving patient morbidity and mortality. The desire for low-threshold screening for pulmonary embolism is contradicted by unfavorable radiation of currently used computed tomography or nuclear techniques, while standard magnetic resonance imaging still struggles to provide sufficient diagnostic sensitivity in the lung. In this study we evaluate a molecular-targeted contrast agent against activated platelets for non-invasive detection of murine pulmonary thromboembolism using magnetic resonance imaging. By intravenous injection of human thrombin, pulmonary thromboembolism were consistently induced as confirmed by immunohistochemistry of the lung. Magnetic resonance imaging after thrombin injection showed local tissue edema in weighted images which co-localized with the histological presence of pulmonary thromboembolism. Furthermore, injection of a functionalized contrast agent targeting activated platelets provided sensitive evidence of focal accumulation of activated platelets within the edematous area, which, ex vivo, correlated well with the size of the pulmonary embolism. In summary, we here show delivery and specific binding of a functionalized molecular contrast agent against activated platelets for targeting pulmonary thromboembolism. Going forward, molecular imaging may provide new opportunities to increase sensitivity of magnetic resonance imaging for detection of pulmonary embolism. PMID:27138487

  9. Pulmonary Inflammation Impacts on CYP1A1-Mediated Respiratory Tract DNA Damage Induced by the Carcinogenic Air Pollutant Benzo[a]pyrene

    PubMed Central

    Arlt, Volker M.; Krais, Annette M.; Godschalk, Roger W.; Riffo-Vasquez, Yanira; Mrizova, Iveta; Roufosse, Candice A.; Corbin, Charmaine; Shi, Quan; Frei, Eva; Stiborova, Marie; van Schooten, Frederik-Jan; Phillips, David H.; Spina, Domenico

    2015-01-01

    Pulmonary inflammation can contribute to the development of lung cancer in humans. We investigated whether pulmonary inflammation alters the genotoxicity of polycyclic aromatic hydrocarbons (PAHs) in the lungs of mice and what mechanisms are involved. To model nonallergic acute inflammation, mice were exposed intranasally to lipopolysaccharide (LPS; 20 µg/mouse) and then instilled intratracheally with benzo[a]pyrene (BaP; 0.5 mg/mouse). BaP-DNA adduct levels, measured by 32P-postlabeling analysis, were approximately 3-fold higher in the lungs of LPS/BaP-treated mice than in mice treated with BaP alone. Pulmonary Cyp1a1 enzyme activity was decreased in LPS/BaP-treated mice relative to BaP-treated mice suggesting that pulmonary inflammation impacted on BaP-induced Cyp1a1 activity in the lung. Our results showed that Cyp1a1 appears to be important for BaP detoxification in vivo and that the decrease of pulmonary Cyp1a1 activity in LPS/BaP-treated mice results in a decrease of pulmonary BaP detoxification, thereby enhancing BaP genotoxicity (ie, DNA adduct formation) in the lung. Because less BaP was detoxified by Cyp1a1 in the lungs of LPS/BaP-treated mice, more BaP circulated via the blood to extrapulmonary tissues relative to mice treated with BaP only. Indeed, we observed higher BaP-DNA adduct levels in livers of LPS/BaP-treated mice compared with BaP-treated mice. Our results indicate that pulmonary inflammation could be a critical determinant in the induction of genotoxicity in the lung by PAHs like BaP. Cyp1a1 appears to be involved in both BaP bioactivation and detoxification although the contribution of other enzymes to BaP-DNA adduct formation in lung and liver under inflammatory conditions remains to be explored. PMID:25911668

  10. 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

  11. Adhesion Pulmonary Nodules Detection Based on Dot-Filter and Extracting Centerline Algorithm

    PubMed Central

    Liu, Liwei; Wang, Xin; Li, Yang

    2015-01-01

    A suspected pulmonary nodule detection method was proposed based on dot-filter and extracting centerline algorithm. In this paper, we focus on the distinguishing adhesion pulmonary nodules attached to vessels in two-dimensional (2D) lung computed tomography (CT) images. Firstly, the dot-filter based on Hessian matrix was constructed to enhance the circular area of the pulmonary CT images, which enhanced the circular suspected pulmonary nodule and suppresses the line-like areas. Secondly, to detect the nondistinguishable attached pulmonary nodules by the dot-filter, an algorithm based on extracting centerline was developed to enhance the circle area formed by the end or head of the vessels including the intersection of the lines. 20 sets of CT images were used in the experiments. In addition, 20 true/false nodules extracted were used to test the function of classifier. The experimental results show that the method based on dot-filter and extracting centerline algorithm can detect the attached pulmonary nodules accurately, which is a basis for further studies on the pulmonary nodule detection and diagnose. PMID:26089968

  12. Detection of pulmonary embolism during pregnancy: comparing radiation doses of CTPA and pulmonary scintigraphy.

    PubMed

    Astani, Seyed A; Davis, Leah C; Harkness, Beth A; Supanich, Mark P; Dalal, Ishani

    2014-07-01

    In pregnant patients pulmonary embolism is a common occurrence with potentially devastating outcomes, necessitating timely imaging diagnosis. In every patient, especially in pregnant patients, radiation exposure is an important consideration while selecting the best imaging modality. We performed a retrospective analysis comparing radiation doses of computed tomography pulmonary angiography (CTPA), perfusion scintigraphy, and perfusion/ventilation scintigraphy for suspected pulmonary embolism in 53 pregnant patients at our hospital between 2006 and 2012. Effective dose and breast-absorbed and uterus-absorbed doses for CTPA as well as effective dose and breast and fetus-absorbed doses for pulmonary scintigraphy were estimated using International Commission on Radiological Protection 103 weighting factors. For CTPA and perfusion scintigraphy, average doses were estimated as effective doses of 21 and 1.04 mSv, breast-absorbed doses of 44 and 0.28 mGy, and uterus-absorbed dose of 0.46 mGy and fetal-absorbed dose of 0.25 mGy, respectively. With inclusion of the ventilation component of pulmonary scintigraphy, doses increased to an effective dose of 1.29 mSv, a breast-absorbed dose of 0.37 mGy, and a fetal-absorbed dose of 0.40 mGy. Perfusion nuclear medicine study has a statistically significantly lower effective and breast-absorbed dose (P<0.0001) when compared with CTPA. Similarly, the fetal-absorbed dose for pulmonary scintigraphy has a statistically lower dose (P=0.0010) when compared with CTPA, even if the ventilation component of pulmonary scintigraphy is performed, although these values are so small that they are unlikely to be clinically significant.

  13. Negative regulation of pulmonary Th17 responses by C3a anaphylatoxin during allergic inflammation in mice.

    PubMed

    Lim, Hoyong; Kim, Young Uk; Drouin, Scott M; Mueller-Ortiz, Stacey; Yun, Kyoungah; Morschl, Eva; Wetsel, Rick A; Chung, Yeonseok

    2012-01-01

    Activation of complement is one of the earliest immune responses to exogenous threats, resulting in various cleavage products including anaphylatoxin C3a. In addition to its contribution to host defense, C3a has been shown to mediate Th2 responses in animal models of asthma. However, the role of C3a on pulmonary Th17 responses during allergic inflammation remains unclear. Here, we show that mice deficient in C3a receptor (C3aR) exhibited (i) higher percentages of endogenous IL-17-producing CD4(+) T cells in the lungs, (ii) higher amounts of IL-17 in the bronchoalveolar lavage fluid, and (iii) more neutrophils in the lungs than wild-type mice when challenged with intranasal allergens. Moreover, adoptive transfer experiments showed that the frequencies of antigen-specific IL-17-producing CD4(+) T cells were significantly higher in the lungs and bronchial lymph nodes of C3aR-deficient recipients than those of wild-types recipients. Bone-marrow reconstitution study indicated that C3aR-deficiency on hematopoietic cells was required for the increased Th17 responses. Furthermore, C3aR-deficient mice exhibited increased percentages of Foxp3(+) regulatory T cells; however, depletion of these cells minimally affected the induction of antigen-specific Th17 cell population in the lungs. Neutralization of IL-17 significantly reduced the number of neutrophils in bronchoalveolar lavage fluid of C3aR-deficient mice. Our findings demonstrate that C3a signals negatively regulate antigen-specific Th17 responses during allergic lung inflammation and the size of Foxp3(+) regulatory T cell population in the periphery.

  14. An index of daily step count and systemic inflammation predicts clinical outcomes in chronic obstructive pulmonary disease.

    PubMed

    Moy, Marilyn L; Teylan, Merilee; Danilack, Valery A; Gagnon, David R; Garshick, Eric

    2014-02-01

    Identification of persons with chronic obstructive pulmonary disease (COPD) at risk for acute exacerbations (AEs) targets them for close monitoring. We examined the ability of a novel index combining physical activity and systemic inflammation to identify persons at risk for AEs. In an observational cohort study of 167 persons with COPD, we assessed daily step count, a direct measure of physical activity, with the StepWatch Activity Monitor and measured plasma C-reactive protein (CRP) and IL-6 levels. AEs and COPD-related hospitalizations were assessed prospectively over a median of 16 months. Predictors of AEs and COPD-related hospitalizations were assessed using negative binomial models. Median daily step count was 5,203 steps (interquartile range, 3,627-7,024). Subjects with daily step count ≤ 5,203 and CRP > 3 mg/l had an increased rate of AEs (rate ratio [RR], 2.06; 95% confidence interval [CI], 1.30-3.27) and COPD-related hospitalizations (RR, 3.51; 95% CI, 1.73-7.11) compared with subjects with daily step count > 5,203 and CRP ≤ 3 mg/l, adjusting for FEV1% predicted and prednisone use for AE in the previous year. Similarly, subjects with daily step count ≤ 5,203 and IL-6 > 2 pg/ml had an increased rate of AEs (RR, 2.04; 95% CI, 1.14-3.63) and COPD-related hospitalizations (RR, 4.27; 95% CI, 1.56-11.7) compared with subjects with daily step count > 5,203 and IL-6 ≤ 2 pg/ml. An index combining daily step count and systemic inflammation can predict AEs and COPD-related hospitalizations. A validation study in a separate cohort is needed to confirm the utility of the proposed index as a clinical tool to risk stratify persons with COPD.

  15. Pulmonary inflammation induced by repeated inhalations of beta(1,3)-D-glucan and endotoxin.

    PubMed Central

    Fogelmark, B.; Sjöstrand, M.; Rylander, R.

    1994-01-01

    In an animal model of hypersensitivity pneumonitis (HP) guinea-pigs were exposed for 5 weeks to an aerosol of bacterial endotoxin, beta(1,3)-D-glucan (curdlan) or a combination. Exposure to endotoxin or curdlan showed only small changes in inflammatory cells in airways or the lung wall, histologically or in terms of enzyme secretion from alveolar macrophages. When the two agents were given together, a histology resembling HP was seen with alveolar infiltrates and early granulomas. Inflammatory cells in airways were increased and enzyme production of macrophages was changed, suggesting an effect of curdlan on the inflammatory regulating capacity of airway macrophages. The results suggest that interference with macrophage function and inflammation are important components in the development of HP. PMID:8199009

  16. Dietary long-chain omega-3 fatty acids do not diminish eosinophilic pulmonary inflammation in mice.

    PubMed

    Schuster, Gertrud U; Bratt, Jennifer M; Jiang, Xiaowen; Pedersen, Theresa L; Grapov, Dmitry; Adkins, Yuriko; Kelley, Darshan S; Newman, John W; Kenyon, Nicholas J; Stephensen, Charles B

    2014-03-01

    Although the effects of fish oil supplements on airway inflammation in asthma have been studied with varying results, the independent effects of the fish oil components, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), administered separately, are untested. Here, we investigated airway inflammation and hyperresponsiveness using a mouse ovalbumin exposure model of asthma assessing the effects of consuming EPA (1.5% wt/wt), DHA (1.5% wt/wt), EPA plus DHA (0.75% each), or a control diet with no added omega-3 polyunsaturated fatty acids. Consuming these diets for 6 weeks resulted in erythrocyte membrane EPA contents (molar %) of 9.0 (± 0.6), 3.2 (± 0.2), 6.8 (± 0.5), and 0.01 (± 0.0)%; DHA contents were 6.8 (± 0.1), 15.6 (± 0.5), 12.3 (± 0.3), and 3.8 (± 0.2)%, respectively. The DHA group had the highest bronchoalveolar lavage (BAL) fluid eosinophil and IL-6 levels (P < 0.05). Similar trends were seen for macrophages, IL-4, and IL-13, whereas TNF-α was lower in omega-3 polyunsaturated fatty acid groups than the control (P < 0.05). The DHA group also had the highest airway resistance, which differed significantly from the EPA plus DHA group (P < 0.05), which had the lowest. Oxylipins were measured in plasma and BAL fluid, with DHA and EPA suppressing arachidonic acid-derived oxylipin production. DHA-derived oxylipins from the cytochrome P450 and 15-lipoxygenase pathways correlated significantly with BAL eosinophil levels. The proinflammatory effects of DHA suggest that the adverse effects of individual fatty acid formulations should be thoroughly considered before any use as therapeutic agents in asthma.

  17. Local pulmonary structure classification for computer-aided nodule detection

    NASA Astrophysics Data System (ADS)

    Bahlmann, Claus; Li, Xianlin; Okada, Kazunori

    2006-03-01

    We propose a new method of classifying the local structure types, such as nodules, vessels, and junctions, in thoracic CT scans. This classification is important in the context of computer aided detection (CAD) of lung nodules. The proposed method can be used as a post-process component of any lung CAD system. In such a scenario, the classification results provide an effective means of removing false positives caused by vessels and junctions thus improving overall performance. As main advantage, the proposed solution transforms the complex problem of classifying various 3D topological structures into much simpler 2D data clustering problem, to which more generic and flexible solutions are available in literature, and which is better suited for visualization. Given a nodule candidate, first, our solution robustly fits an anisotropic Gaussian to the data. The resulting Gaussian center and spread parameters are used to affine-normalize the data domain so as to warp the fitted anisotropic ellipsoid into a fixed-size isotropic sphere. We propose an automatic method to extract a 3D spherical manifold, containing the appropriate bounding surface of the target structure. Scale selection is performed by a data driven entropy minimization approach. The manifold is analyzed for high intensity clusters, corresponding to protruding structures. Techniques involve EMclustering with automatic mode number estimation, directional statistics, and hierarchical clustering with a modified Bhattacharyya distance. The estimated number of high intensity clusters explicitly determines the type of pulmonary structures: nodule (0), attached nodule (1), vessel (2), junction (>3). We show accurate classification results for selected examples in thoracic CT scans. This local procedure is more flexible and efficient than current state of the art and will help to improve the accuracy of general lung CAD systems.

  18. Improving CAD performance in pulmonary embolism detection: preliminary investigation

    NASA Astrophysics Data System (ADS)

    Park, Sang Cheol; Chapman, Brian; Deible, Christopher; Lee, Sean; Zheng, Bin

    2010-03-01

    In this preliminary study, a new computer-aided detection (CAD) scheme for pulmonary embolism (PE) detection was developed and tested. The scheme applies multiple steps including lung segmentation, candidate extraction using intensity mask and tobogganing method, feature extraction, false positive reduction using a multifeature based artificial neural network (ANN) and a k-nearest neighbor (KNN) classifier to detect and classify suspicious PE lesions. In particular, a new method to define the surrounding background regions of interest (ROI) depicting PE candidates was proposed and tested in an attempt to reduce the detection of false positive regions. In this study, the authors also investigated following methods to improve CAD performance, which include a grouping and scoring method, feature selection using genetic algorithm, and limitation on allowed suspicious lesions to be cued in one examination. To test the scheme performance, a set of 20 chest CT examinations were selected. Among them, 18 are positive cases depicted 44 verified PE lesions and the remaining 2 were negative cases. The dataset was also divided into a training subset (9 examinations) and a testing subset (11 examinations), respectively. The experimental results showed when applying to the testing dataset CAD scheme using tobogganing method alone achieved 2D region-based sensitivity of 72.1% (220/305) and 3D lesion-based sensitivity of 83.3% (20/24) with total 19,653 2D false-positive (FP) PE regions (1,786.6 per case or approximately 6.3 per CT slice). Applying the proposed new method to improve lung region segmentation and better define the surrounding background ROI, the scheme reduced the region-based sensitivity by 6.5% to 65.6% or lesion-based sensitivity by 4.1% to 79.2% while reducing the FP rate by 65.6% to 6,752 regions (or 613.8 per case). After applying the methods of grouping, the maximum scoring, a genetic algorithm (GA) to delete "redundant" features, and limiting the maximum

  19. Clinical significance of pulmonary nodules detected on abdominal CT in pediatric patients.

    PubMed

    Breen, Micheál; Zurakowski, David; Lee, Edward Y

    2015-11-01

    The clinical significance of a pulmonary nodule that is detected incidentally on CT studies in children is unknown. In addition, there is limited information regarding the management of incidentally detected pulmonary nodules discovered on abdominal CT studies in children. The purpose of this study was to investigate the clinical significance of incidental pulmonary nodules detected on abdominal CT studies in children. This was a retrospective study performed following institutional review board approval. Abdominal CT reports in patients younger than 18 years of age from July 2004 to June 2011 were reviewed for the terms "nodule," "nodular" or "mass" in reference to the lung bases. The study population included those pediatric patients in whom pulmonary nodules were initially detected on abdominal CT studies. The largest pulmonary nodules detected on CT studies were evaluated for their features (size, shape, margin, attenuation, location, and presence of calcification and cavitation). Follow-up CT studies and clinical records were reviewed for demographic information, history of underlying malignancies and the clinical outcome of the incidental pulmonary nodules. Comparison of malignant versus benign pulmonary nodules was performed with respect to the size of the nodule, imaging features on CT, and patient history of malignancy using the Student's t-test and Fisher exact test. Youden J-index in receiver operating characteristic (ROC) analysis was used to determine the optimal cut-off size for suggesting a high risk of malignancy of incidentally detected pulmonary nodules. Pulmonary nodules meeting inclusion criteria were detected in 62 (1.2%) of 5,234 patients. The mean age of patients with nodules was 11.2 years (range: 5 months-18 years). Thirty-one patients (50%) had follow-up CT studies and two of these patients (6%) were subsequently found to have malignant pulmonary nodules. Both of these patients had a history of malignancy. Of the remaining 31 patients

  20. Group V secretory phospholipase A2 reveals its role in house dust mite-induced allergic pulmonary inflammation by regulation of dendritic cell function

    PubMed Central

    Giannattasio, Giorgio; Fujioka, Daisuke; Xing, Wei; Katz, Howard R.; Boyce, Joshua A.; Balestrieri, Barbara

    2010-01-01

    We have previously shown that group V secretory phospholipase A2 (sPLA2) regulates phagocytosis of zymosan and Candida albicans by a mechanism that depends on fusion of phagosomes with late endosomes in macrophages. Here we report that group V sPLA2 (Pla2g5)-null mice exposed to an extract of house dust mite Dermatophagoides farinae (Df) had markedly reduced pulmonary inflammation and goblet cell metaplasia compared to wild-type (WT) mice. Pla2g5-null mice had also impaired Th2-type adaptive immune responses to Df compared to WT mice. Pla2g5-null bone marrow-derived dendritic cells (BMDCs) activated by Df had delayed intracellular processing of allergen and impaired allergen-dependent maturation, a pattern recapitulated by the native lung DCs of Df-challenged mice. Adoptively transferred Df-loaded Pla2g5-null BMDCs were less able than Df-loaded WT BMDCs to induce pulmonary inflammation and Th2 polarization in WT mice. However, Pla2g5-null recipients transferred with WT or Pla2g5-null Df-loaded BMDCs exhibited significantly reduced local inflammatory responses to Df, even though the transfer of WT BMDCs still induced an intact Th2 cytokine response in regional lymph nodes. Thus, the expression of group V sPLA2 in APC regulates Ag processing and maturation of dendritic cells, and contributes to pulmonary inflammation and immune response against Df. Furthermore, an additional yet to be identified resident cell type is essential for the development of pulmonary inflammation, likely a cell in which group V sPLA2 is upregulated by Df and whose function is also regulated by group V sPLA2. PMID:20817863

  1. Pulmonary oxidative stress, inflammation and cancer: respirable particulate matter, fibrous dusts and ozone as major causes of lung carcinogenesis through reactive oxygen species mechanisms.

    PubMed

    Valavanidis, Athanasios; Vlachogianni, Thomais; Fiotakis, Konstantinos; Loridas, Spyridon

    2013-08-27

    Reactive oxygen or nitrogen species (ROS, RNS) and oxidative stress in the respiratory system increase the production of mediators of pulmonary inflammation and initiate or promote mechanisms of carcinogenesis. The lungs are exposed daily to oxidants generated either endogenously or exogenously (air pollutants, cigarette smoke, etc.). Cells in aerobic organisms are protected against oxidative damage by enzymatic and non-enzymatic antioxidant systems. Recent epidemiologic investigations have shown associations between increased incidence of respiratory diseases and lung cancer from exposure to low levels of various forms of respirable fibers and particulate matter (PM), at occupational or urban air polluting environments. Lung cancer increases substantially for tobacco smokers due to the synergistic effects in the generation of ROS, leading to oxidative stress and inflammation with high DNA damage potential. Physical and chemical characteristics of particles (size, transition metal content, speciation, stable free radicals, etc.) play an important role in oxidative stress. In turn, oxidative stress initiates the synthesis of mediators of pulmonary inflammation in lung epithelial cells and initiation of carcinogenic mechanisms. Inhalable quartz, metal powders, mineral asbestos fibers, ozone, soot from gasoline and diesel engines, tobacco smoke and PM from ambient air pollution (PM₁₀ and PM₂.₅) are involved in various oxidative stress mechanisms. Pulmonary cancer initiation and promotion has been linked to a series of biochemical pathways of oxidative stress, DNA oxidative damage, macrophage stimulation, telomere shortening, modulation of gene expression and activation of transcription factors with important role in carcinogenesis. In this review we are presenting the role of ROS and oxidative stress in the production of mediators of pulmonary inflammation and mechanisms of carcinogenesis.

  2. Hydrogen-rich saline inhibits tobacco smoke-induced chronic obstructive pulmonary disease by alleviating airway inflammation and mucus hypersecretion in rats.

    PubMed

    Liu, Zibing; Geng, Wenye; Jiang, Chuanwei; Zhao, Shujun; Liu, Yong; Zhang, Ying; Qin, Shucun; Li, Chenxu; Zhang, Xinfang; Si, Yanhong

    2017-09-01

    Chronic obstructive pulmonary disease induced by tobacco smoke has been regarded as a great health problem worldwide. The purpose of this study is to evaluate the protective effect of hydrogen-rich saline, a novel antioxidant, on chronic obstructive pulmonary disease and explore the underlying mechanism. Sprague-Dawley rats were made chronic obstructive pulmonary disease models via tobacco smoke exposure for 12 weeks and the rats were treated with 10 ml/kg hydrogen-rich saline intraperitoneally during the last 4 weeks. Lung function testing indicated hydrogen-rich saline decreased lung airway resistance and increased lung compliance and the ratio of forced expiratory volume in 0.1 s/forced vital capacity in chronic obstructive pulmonary disease rats. Histological analysis revealed that hydrogen-rich saline alleviated morphological impairments of lung in tobacco smoke-induced chronic obstructive pulmonary disease rats. ELISA assay showed hydrogen-rich saline lowered the levels of pro-inflammatory cytokines (IL-8 and IL-6) and anti-inflammatory cytokine IL-10 in bronchoalveolar lavage fluid and serum of chronic obstructive pulmonary disease rats. The content of malondialdehyde in lung tissue and serum was also determined and the data indicated hydrogen-rich saline suppressed oxidative stress reaction. The protein expressions of mucin MUC5C and aquaporin 5 involved in mucus hypersecretion were analyzed by Western blot and ELISA and the data revealed that hydrogen-rich saline down-regulated MUC5AC level in bronchoalveolar lavage fluid and lung tissue and up-regulated aquaporin 5 level in lung tissue of chronic obstructive pulmonary disease rats. In conclusion, these results suggest that administration of hydrogen-rich saline exhibits significant protective effect on chronic obstructive pulmonary disease through alleviating inflammation, reducing oxidative stress and lessening mucus hypersecretion in tobacco smoke-induced chronic obstructive pulmonary disease rats

  3. Etanercept Exacerbates Inflammation and Pathology in a Rabbit Model of Active Pulmonary Tuberculosis

    PubMed Central

    Tsenova, Liana; O'Brien, Paul; Holloway, Jennifer; Peixoto, Blas; Soteropoulos, Patricia; Fallows, Dorothy; Subbian, Selvakumar

    2014-01-01

    Treatment of chronic inflammatory diseases with tumor necrosis factor alpha (TNF-α) antagonists has been associated with increased risk of tuberculosis (TB). We examined the usefulness of the rabbit model of active pulmonary TB for studying the impact of the human immune modulatory reagent etanercept on the host immune response. Control of Mycobacterium tuberculosis (Mtb) infection, disease pathology, and the global transcriptional response in Mtb-infected lungs of rabbits were studied. Etanercept treatment exacerbated disease pathology and reduced bacillary control in the lungs, compared with infected untreated animals. Reduced collagen and fibrin deposition in the granulomas was associated with significant downregulation of the collagen metabolism and fibrosis network genes and upregulation of genes in the inflammatory response and cell recruitment networks in the lungs of etanercept treated, compared with untreated rabbits. Our results suggest that targeting the TNF-α signaling pathway disrupts the tissue remodeling process, which is required for the formation and maintenance of well-differentiated granulomas and for control of Mtb growth in the lungs. These results validate the use of the rabbit model for investigating the impact of selected human immune modulatory drugs, such as a TNF-α antagonist, on the host immune response and pathogenesis in TB. PMID:24831609

  4. Acute tropical pulmonary eosinophilia. Characterization of the lower respiratory tract inflammation and its response to therapy.

    PubMed Central

    Pinkston, P; Vijayan, V K; Nutman, T B; Rom, W N; O'Donnell, K M; Cornelius, M J; Kumaraswami, V; Ferrans, V J; Takemura, T; Yenokida, G

    1987-01-01

    Although acute tropical pulmonary eosinophilia (TPE) is well recognized as a manifestation of filarial infection, the processes that mediate the abnormalities of the lung in TPE are unknown. To evaluate the hypothesis that the derangements of the lower respiratory tract in this disorder are mediated by inflammatory cells in the local milieu, we utilized bronchoalveolar lavage to evaluate affected individuals before and after therapy. Inflammatory cells recovered from the lower respiratory tract of individuals with acute, untreated TPE (n = 8) revealed a striking eosinophilic alveolitis, with marked elevations in both the proportion of eosinophils (TPE 54 +/- 5%; normal 2 +/- 5%; P less than 0.001) and the concentration of eosinophils in the recovered epithelial lining fluid (ELF) (TPE 63 +/- 20 X 10(3)/microliter; normal 0.3 +/- 0.1 X 10(3)/microliter; P less than 0.01). Importantly, when individuals (n = 5) with acute TPE were treated with diethylcarbamazine (DEC), there was a marked decrease of the lung eosinophils and concomitant increase in lung function. These observations are consistent with the concept that at least some of the abnormalities found in the lung in acute TPE are mediated by an eosinophil-dominated inflammatory process in the lower respiratory tract. Images PMID:3298321

  5. Anergy-like immunosuppression in mice bearing pulmonary foreign-body granulomatous inflammation.

    PubMed Central

    Allred, D. C.; Kobayashi, K.; Yoshida, T.

    1985-01-01

    Pulmonary granulomas were induced in BALB/c mice by the intratracheal injection of insoluble polymerized dextran and latex microparticles. Very large granulomas developed around dextran beads, which reached peak intensity within 2-3 days and rapidly declined in size thereafter. Latex beads generated small stable lesions. The involvement of cell-mediated immunity could not be demonstrated in the inflammatory responses induced by either type of bead. Antigen-induced delayed type hypersensitivity (DTH) and mitogen-induced DTH-like footpad reactions were markedly suppressed in immunized mice bearing early dextran granulomas. Mitogen-induced DTH-like footpad reactions were suppressed in unimmunized animals bearing early dextran foreign-body granulomas. Antigen- and mitogen-induced footpad swelling recovered to normal levels as dextran granulomas diminished in size. No suppression of these footpad reactions was observed in mice bearing small latex foreign-body granulomas. The intraperitoneal injection of aqueous extracts prepared from the lungs of unimmunized donor animals bearing early dextran foreign-body granulomas could partially transfer suppression of mitogen DTH-like footpad responses to normal mice. These results suggest that cells within large, nonimmunologic lung granulomas produce a soluble factor which participates in the expression of anergy-like immunosuppression. Images Figure 2 PMID:3907366

  6. Computer-aided detection of pulmonary embolism in computed tomographic pulmonary angiography (CTPA): performance evaluation with independent data sets.

    PubMed

    Zhou, Chuan; Chan, Heang-Ping; Sahiner, Berkman; Hadjiiski, Lubomir M; Chughtai, Aamer; Patel, Smita; Wei, Jun; Cascade, Philip N; Kazerooni, Ella A

    2009-08-01

    The authors are developing a computer-aided detection system for pulmonary emboli (PE) in computed tomographic pulmonary angiography (CTPA) scans. The pulmonary vessel tree is extracted using a 3D expectation-maximization segmentation method based on the analysis of eigen-values of Hessian matrices at multiple scales. A parallel multiprescreening method is applied to the segmented vessels to identify volume of interests (VOIs) that contained suspicious PE. A linear discriminant analysis (LDA) classifier with feature selection is designed to reduce false positives (FPs). Features that characterize the contrast, gray level, and size of PE are extracted as input predictor variables to the LDA classifier. With the IRB approval, 59 CTPA PE cases were collected retrospectively from the patient files (UM cases). With access permission, 69 CTPA PE cases were randomly selected from the data set of the prospective investigation of pulmonary embolism diagnosis (PIOPED) II clinical trial. Extensive lung parenchymal or pleural diseases were present in 22/59 UM and 26/69 PIOPED cases. Experienced thoracic radiologists manually marked 595 and 800 PE as the reference standards in the UM and PIOPED data sets, respectively. PE occlusion of arteries ranged from 5% to 100%, with PE located from the main pulmonary artery to the subsegmental artery levels. Of the 595 PE identified in the UM cases, 245 and 350 PE were located in the subsegmental arteries and the more proximal arteries, respectively. The detection performance was assessed by free response ROC (FROC) analysis. The FROC analysis indicated that the PE detection system could achieve an overall sensitivity of 80% at 18.9 FPs/case for the PIOPED cases when the LDA classifier was trained with the UM cases. The test sensitivity with the UM cases was 80% at 22.6 FPs/cases when the LDA classifier was trained with the PIOPED cases. The detection performance depended on the arterial level where the PE was located and on the

  7. Computer-aided detection of pulmonary embolism in computed tomographic pulmonary angiography (CTPA): Performance evaluation with independent data sets

    PubMed Central

    Zhou, Chuan; Chan, Heang-Ping; Sahiner, Berkman; Hadjiiski, Lubomir M.; Chughtai, Aamer; Patel, Smita; Wei, Jun; Cascade, Philip N.; Kazerooni, Ella A.

    2009-01-01

    The authors are developing a computer-aided detection system for pulmonary emboli (PE) in computed tomographic pulmonary angiography (CTPA) scans. The pulmonary vessel tree is extracted using a 3D expectation-maximization segmentation method based on the analysis of eigenvalues of Hessian matrices at multiple scales. A parallel multiprescreening method is applied to the segmented vessels to identify volume of interests (VOIs) that contained suspicious PE. A linear discriminant analysis (LDA) classifier with feature selection is designed to reduce false positives (FPs). Features that characterize the contrast, gray level, and size of PE are extracted as input predictor variables to the LDA classifier. With the IRB approval, 59 CTPA PE cases were collected retrospectively from the patient files (UM cases). With access permission, 69 CTPA PE cases were randomly selected from the data set of the prospective investigation of pulmonary embolism diagnosis (PIOPED) II clinical trial. Extensive lung parenchymal or pleural diseases were present in 22∕59 UM and 26∕69 PIOPED cases. Experienced thoracic radiologists manually marked 595 and 800 PE as the reference standards in the UM and PIOPED data sets, respectively. PE occlusion of arteries ranged from 5% to 100%, with PE located from the main pulmonary artery to the subsegmental artery levels. Of the 595 PE identified in the UM cases, 245 and 350 PE were located in the subsegmental arteries and the more proximal arteries, respectively. The detection performance was assessed by free response ROC (FROC) analysis. The FROC analysis indicated that the PE detection system could achieve an overall sensitivity of 80% at 18.9 FPs∕case for the PIOPED cases when the LDA classifier was trained with the UM cases. The test sensitivity with the UM cases was 80% at 22.6 FPs∕cases when the LDA classifier was trained with the PIOPED cases. The detection performance depended on the arterial level where the PE was located and on the

  8. Current concepts on oxidative/carbonyl stress, inflammation and epigenetics in pathogenesis of chronic obstructive pulmonary disease

    PubMed Central

    Yao, Hongwei; Rahman, Irfan

    2011-01-01

    Chronic obstructive pulmonary disease (COPD) is a global health problem, and current therapy for COPD is poorly effective and the mainstays of pharmacotherapy are bronchodilators. A better understanding of the pathobiology of COPD is critical for the development of novel therapies. In the present review, we have discussed the roles of oxidative/aldehyde stress, inflammation/immunity, and chromatin remodeling in the pathogenesis of COPD. Imbalance of oxidant/antioxidant balance caused by cigarette smoke and other pollutants/biomass fuels plays an important role in the pathogenesis of COPD by regulating redox-sensitive transcription factors (e.g. NF-κB), autophagy and unfolded protein response leading to chronic lung inflammatory response. Cigarette smoke also activates canonical/alternative NF-κB pathways and their upstream kinases leading to sustained inflammatory response in lungs. Recently, epigenetic regulation has been shown to be critical for the development of COPD because the expression/activity of enzymes that regulate these epigenetic modifications have been reported to be abnormal in airways of COPD patients. Hence, the significant advances made in understanding the pathophysiology of COPD as described herein will identify novel therapeutic targets for intervening COPD. PMID:21296096

  9. Current concepts on oxidative/carbonyl stress, inflammation and epigenetics in pathogenesis of chronic obstructive pulmonary disease

    SciTech Connect

    Yao Hongwei; Rahman, Irfan

    2011-07-15

    Chronic obstructive pulmonary disease (COPD) is a global health problem. The current therapies for COPD are poorly effective and the mainstays of pharmacotherapy are bronchodilators. A better understanding of the pathobiology of COPD is critical for the development of novel therapies. In the present review, we have discussed the roles of oxidative/aldehyde stress, inflammation/immunity, and chromatin remodeling in the pathogenesis of COPD. An imbalance of oxidants/antioxidants caused by cigarette smoke and other pollutants/biomass fuels plays an important role in the pathogenesis of COPD by regulating redox-sensitive transcription factors (e.g., NF-{kappa}B), autophagy and unfolded protein response leading to chronic lung inflammatory response. Cigarette smoke also activates canonical/alternative NF-{kappa}B pathways and their upstream kinases leading to sustained inflammatory response in lungs. Recently, epigenetic regulation has been shown to be critical for the development of COPD because the expression/activity of enzymes that regulate these epigenetic modifications have been reported to be abnormal in airways of COPD patients. Hence, the significant advances made in understanding the pathophysiology of COPD as described herein will identify novel therapeutic targets for intervention in COPD.

  10. Resveratrol preserves cardiac function, but does not prevent endothelial dysfunction or pulmonary inflammation after environmental tobacco smoke exposure.

    PubMed

    Al-Dissi, Ahmad N; Weber, Lynn P

    2011-07-01

    The mechanisms by which environmental tobacco smoke (ETS) causes adverse cardiovascular effects remain unclear. Resveratrol is a natural polyphenol from red wine which may be beneficial to the cardiovascular system. Therefore, the ability of daily oral resveratrol (5mg/kg) to prevent adverse effects of a 14-day ETS exposure (1 h/day) on endothelial function (flow-mediated dilation), left ventricular function (echocardiography) and blood pressure (oscillometry) was assessed in juvenile male pigs (n=4 pigs/group). After a 14-day exposure to ETS, flow-mediated dilation was impaired while plasma nitrotyrosine was increased compared to sham-exposed pigs indicating impaired endothelial function. In ETS-exposed pigs, plasma C-reactive protein levels, lung cytochrome P4501A1 activity, bronchoalveolar lavage fluid total white blood cell count and leukocyte elastase activity were all significantly increased compared to sham-exposed pigs. Resveratrol treatment failed to prevent most ETS-mediated effects examined, but did increase left ventricular end-diastolic volume and ejection fraction in the presence of ETS exposure. In summary, ETS exposure impaired endothelial function and increased oxidative stress which was associated with pulmonary and systemic inflammation, but resveratrol failed to protect against these changes. More importantly, resveratrol exerted a positive effect on left ventricular function which may help explain the French paradox. Copyright © 2011 Elsevier Ltd. All rights reserved.

  11. RU486 blocks the anti-inflammatory effects of exercise in a murine model of allergen-induced pulmonary inflammation.

    PubMed

    Pastva, Amy; Estell, Kim; Schoeb, Trenton R; Schwiebert, Lisa M

    2005-09-01

    In an ovalbumin (OVA)-driven murine model of allergic pulmonary inflammation, we have shown previously that moderate-intensity aerobic exercise training attenuates inflammatory responses, disease progression, and NF-kappaB activation within the sensitized lung. Glucocorticoids (GCs), potent anti-inflammatory agents, have been shown to alter transcriptional events that are important in asthmatic pathogenesis, such as NF-kappaB activation. Notably, exercise training can alter the production and signaling capacity of endogenous GCs. Because GCs exert their anti-inflammatory effects through binding to intracellular glucocorticoid receptors (GRs), we examined the role of the GR in facilitating the anti-inflammatory effects of exercise. Results show that, in exercised OVA-sensitized mice, treatment with the GR antagonist RU486 blocked the exercise-induced reductions in cellular infiltration of the airways (p < .05), KC and soluble VCAM-1 protein levels in the bronchoalveloar lavage fluid (p < .05), and NF-kappaB translocation and DNA binding within the lung to levels similar to those observed in sedentary OVA-sensitized mice. Importantly, RU486 treatment also blocked exercise-induced increases in GR nuclear translocation to the levels seen in sensitized control mice. Together, these results suggest that GR nuclear translocation and NF-kappaB activation play roles in mediating the anti-inflammatory effects of exercise in allergen-mediated lung pathology.

  12. β-Glucans Are Masked but Contribute to Pulmonary Inflammation During Pneumocystis Pneumonia

    PubMed Central

    Kutty, Geetha; Davis, A. Sally; Ferreyra, Gabriela A.; Qiu, Ju; Huang, Da Wei; Sassi, Monica; Bishop, Lisa; Handley, Grace; Sherman, Brad; Lempicki, Richard; Kovacs, Joseph A.

    2016-01-01

    β-glucans, which can activate innate immune responses, are a major component in the cell wall of the cyst form of Pneumocystis. In the current study, we examined whether β-1,3-glucans are masked by surface proteins in Pneumocystis and what role β-glucans play in Pneumocystis-associated inflammation. For 3 species, including Pneumocystis jirovecii, which causes Pneumocystis pneumonia in humans, Pneumocystis carinii, and Pneumocystis murina, β-1,3-glucans were masked in most organisms, as demonstrated by increased exposure following trypsin treatment. Using quantitative polymerase chain reaction and microarray techniques, we demonstrated in a mouse model of Pneumocystis pneumonia that treatment with caspofungin, an inhibitor of β-1,3-glucan synthesis, for 21 days decreased expression of a broad panel of inflammatory markers, including interferon γ, tumor necrosis factor α, interleukin 1β, interleukin 6, and multiple chemokines/chemokine ligands. Thus, β-glucans in Pneumocystis cysts are largely masked, which likely decreases innate immune activation; this mechanism presumably was developed for interactions with immunocompetent hosts, in whom organism loads are substantially lower. In immunosuppressed hosts with a high organism burden, organism death and release of glucans appears to be an important contributor to deleterious host inflammatory responses. PMID:27324243

  13. Update on the Mechanisms of Pulmonary Inflammation and Oxidative Imbalance Induced by Exercise.

    PubMed

    Araneda, O F; Carbonell, T; Tuesta, M

    2016-01-01

    The mechanisms involved in the generation of oxidative damage and lung inflammation induced by physical exercise are described. Changes in lung function induced by exercise involve cooling of the airways, fluid evaporation of the epithelial surface, increased contact with polluting substances, and activation of the local and systemic inflammatory response. The present work includes evidence obtained from the different types of exercise in terms of duration and intensity, the effect of both acute performance and chronic performance, and the influence of special conditions such as cold weather, high altitude, and polluted environments. Levels of prooxidants, antioxidants, oxidative damage to biomolecules, and cellularity, as well as levels of soluble mediators of the inflammatory response and its effects on tissues, are described in samples of lung origin. These samples include tissue homogenates, induced sputum, bronchoalveolar lavage fluid, biopsies, and exhaled breath condensate obtained in experimental protocols conducted on animal and human models. Finally, the need to simultaneously explore the oxidative/inflammatory parameters to establish the interrelation between them is highlighted.

  14. Update on the Mechanisms of Pulmonary Inflammation and Oxidative Imbalance Induced by Exercise

    PubMed Central

    Araneda, O. F.; Carbonell, T.; Tuesta, M.

    2016-01-01

    The mechanisms involved in the generation of oxidative damage and lung inflammation induced by physical exercise are described. Changes in lung function induced by exercise involve cooling of the airways, fluid evaporation of the epithelial surface, increased contact with polluting substances, and activation of the local and systemic inflammatory response. The present work includes evidence obtained from the different types of exercise in terms of duration and intensity, the effect of both acute performance and chronic performance, and the influence of special conditions such as cold weather, high altitude, and polluted environments. Levels of prooxidants, antioxidants, oxidative damage to biomolecules, and cellularity, as well as levels of soluble mediators of the inflammatory response and its effects on tissues, are described in samples of lung origin. These samples include tissue homogenates, induced sputum, bronchoalveolar lavage fluid, biopsies, and exhaled breath condensate obtained in experimental protocols conducted on animal and human models. Finally, the need to simultaneously explore the oxidative/inflammatory parameters to establish the interrelation between them is highlighted. PMID:26881028

  15. β-Glucans Are Masked but Contribute to Pulmonary Inflammation During Pneumocystis Pneumonia.

    PubMed

    Kutty, Geetha; Davis, A Sally; Ferreyra, Gabriela A; Qiu, Ju; Huang, Da Wei; Sassi, Monica; Bishop, Lisa; Handley, Grace; Sherman, Brad; Lempicki, Richard; Kovacs, Joseph A

    2016-09-01

    β-glucans, which can activate innate immune responses, are a major component in the cell wall of the cyst form of Pneumocystis In the current study, we examined whether β-1,3-glucans are masked by surface proteins in Pneumocystis and what role β-glucans play in Pneumocystis-associated inflammation. For 3 species, including Pneumocystis jirovecii, which causes Pneumocystis pneumonia in humans, Pneumocystis carinii, and Pneumocystis murina, β-1,3-glucans were masked in most organisms, as demonstrated by increased exposure following trypsin treatment. Using quantitative polymerase chain reaction and microarray techniques, we demonstrated in a mouse model of Pneumocystis pneumonia that treatment with caspofungin, an inhibitor of β-1,3-glucan synthesis, for 21 days decreased expression of a broad panel of inflammatory markers, including interferon γ, tumor necrosis factor α, interleukin 1β, interleukin 6, and multiple chemokines/chemokine ligands. Thus, β-glucans in Pneumocystis cysts are largely masked, which likely decreases innate immune activation; this mechanism presumably was developed for interactions with immunocompetent hosts, in whom organism loads are substantially lower. In immunosuppressed hosts with a high organism burden, organism death and release of glucans appears to be an important contributor to deleterious host inflammatory responses.

  16. Hemorrhagic shock primes for lung vascular endothelial cell pyroptosis: role in pulmonary inflammation following LPS

    PubMed Central

    Yang, Jie; Zhao, Yanfeng; Zhang, Peng; Li, Yuehua; Yang, Yong; Yang, Yang; Zhu, Junjie; Song, Xiao; Jiang, Gening; Fan, Jie

    2016-01-01

    Hemorrhagic shock (HS) often renders patients more susceptible to lung injury by priming for an exaggerated response to a second infectious stimulus. Acute lung injury (ALI) is a major component of multiple organ dysfunction syndrome following HS and regularly serves as a major cause of patient mortality. The lung vascular endothelium is an active organ that has a central role in the development of ALI through synthesizing and releasing of a number of inflammatory mediators. Cell pyroptosis is a caspase-1-dependent regulated cell death, which features rapid plasma membrane rupture and release of proinflammatory intracellular contents. In this study, we demonstrated an important role of HS in priming for LPS-induced lung endothelial cell (EC) pyroptosis. We showed that LPS through TLR4 activates Nlrp3 (NACHT, LRR, and PYD domains containing protein 3) inflammasome in mouse lung vascular EC, and subsequently induces caspase-1 activation. However, HS induced release of high-mobility group box 1 (HMGB1), which acting through the receptor for advanced glycation end products initiates EC endocytosis of HMGB1, and subsequently triggers a cascade of molecular events, including cathepsin B release from ruptured lysosomes followed by pyroptosome formation and caspase-1 activation. These HS-induced events enhance LPS-induced EC pyroptosis. We further showed that lung vascular EC pyroptosis significantly exaggerates lung inflammation and injury. The present study explores a novel mechanism underlying HS-primed ALI and thus presents a potential therapeutic target for post-HS ALI. PMID:27607578

  17. Measured pulmonary and systemic markers of inflammation and oxidative stress following wildland firefighter simulations

    PubMed Central

    Ferguson, Matthew D.; Semmens, Erin O.; Dumke, Charles; Quindry, John C.; Ward, Tony J.

    2016-01-01

    Objective A controlled human exposure study was conducted to investigate the impact of inhalational exposures to wood smoke PM2.5 on measured concentrations of airway and systemic inflammatory biomarkers. Methods Mimicking wildland firefighter activities, 10 participants were exposed to three doses of wood smoke PM2.5 (filtered-air, 250 µg/m3, and 500 µg/m3) while exercising on a treadmill. Exhaled breath condensate (EBC) and blood plasma samples were obtained pre-, immediately post-, and 1-hour post-exposure. 8-isoprostane, pH, and myeloperoxidase were measured in EBC while H2O2, surfactant protein D, and pentraxin-3 (PTX3) were measured in both EBC and plasma. Results Only pH, 8-isoprostane, and PTX3 displayed significant changes when comparing pre- and post- exposures. Conclusions Markers of inflammation and oxidative stress, including PTX3, pH, and 8-isoprostane in EBC and/or plasma, are sensitive to wood smoke inhalation, with further investigations warranted. PMID:27058482

  18. Measured Pulmonary and Systemic Markers of Inflammation and Oxidative Stress Following Wildland Firefighter Simulations.

    PubMed

    Ferguson, Matthew D; Semmens, Erin O; Dumke, Charles; Quindry, John C; Ward, Tony J

    2016-04-01

    A controlled human exposure study was conducted to investigate the impact of inhalational exposures to wood smoke PM2.5 on measured concentrations of airway and systemic inflammatory biomarkers. Mimicking wildland firefighter activities, 10 participants were exposed to three doses of wood smoke PM2.5 (filtered-air, 250 μg/m, and 500 μg/m) while exercising on a treadmill. Exhaled breath condensate (EBC) and blood plasma samples were obtained pre-, immediately post-, and 1-hour postexposure. 8-isoprostane, pH, and myeloperoxidase were measured in EBC, while H2O2, surfactant protein D, and pentraxin-3 (PTX3) were measured in both EBC and plasma. Only pH, 8-isoprostane, and PTX3 displayed significant changes when comparing pre- and postexposures. Markers of inflammation and oxidative stress, including PTX3, pH, and 8-isoprostane in EBC and/or plasma, are sensitive to wood smoke inhalation, with further investigations warranted.

  19. Pentraxin 3 as a novel biomarker of inflammation in chronic obstructive pulmonary disease.

    PubMed

    Kurt, Ozlem Kar; Tosun, Mehmet; Kurt, Emine Bahar; Talay, Fahrettin

    2015-02-01

    Chronic obstructive pulmonary disease (COPD) is a complex chronic inflammatory disease of the lungs in which inflammatory markers are involved with significant extrapulmonary effects that may contribute to its severity and complications. Moreover, some of the inflammatory markers such as C-reactive protein (CRP) are associated with COPD. Pentraxin 3 (PTX3) is the member of long pentraxins. The aim of the present study was to investigate the level of PTX3 in patients with COPD. Fifty-four COPD patients and 31 controls were enrolled in this study. Demographical data such as age, sex, cigarette smoking status, comorbidities, drugs, habits, and modified Medical Research Council (MMRC) dyspnea scores were recorded. All patients were asked for COPD Assessment Test™ (CAT). The mean age was 65.7 ± 9.8 years, 92 % male. Plasma levels of PTX3 were found to be markedly higher in COPD patients [1.65 (0.32-12.72) ng/ml] than in controls [1.05 (0.43-3.26) ng/ml; p = 0.005]. On the other hand, PTX3 values did not differ between COPD stages [A, 1.73 (0.69-11.03); B, 1.49 (0.84-12.52); C, 0.79 (0.52-1.06); and D, 2.09 (0.32-12.72); p = 0.27]. The plasma PTX3 levels were positively correlated with MMRC scores. We conclude that circulating PTX3 levels are elevated in COPD patients. Plasma levels of PTX3 were correlated with dyspnea (MMRC scores). But PTX3 levels were not correlated with the severity of COPD.

  20. Subchronic exposures to fungal bioaerosols promotes allergic pulmonary inflammation in naïve mice

    PubMed Central

    Nayak, Ajay P.; Green, Brett J.; Lemons, Angela R.; Marshall, Nikki B.; Goldsmith, W. Travis; Kashon, Michael L.; Anderson, Stacey E.; Germolec, Dori R.; Beezhold, Donald H.

    2016-01-01

    Background Epidemiological surveys indicate that occupants of mold contaminated environments are at increased risk of respiratory symptoms. The immunological mechanisms associated with these responses require further characterization. Objective The aim of this study was to characterize the immunotoxicological outcomes following repeated inhalation of dry Aspergillus fumigatus spores aerosolized at concentrations potentially encountered in contaminated indoor environments. Methods A. fumigatus spores were delivered to the lungs of naïve BALB/cJ mice housed in a multi-animal nose-only chamber twice a week for a period of 13 weeks. Mice were evaluated at 24 and 48 hours post-exposure for histopathological changes in lung architecture, recruitment of specific immune cells to the airways, and serum antibody responses. Result Germinating A. fumigatus spores were observed in lungs along with persistent fungal debris in the perivascular regions of the lungs. Repeated exposures promoted pleocellular infiltration with concomitant epithelial mucus hypersecretion, goblet cell metaplasia, subepithelial fibrosis and enhanced airway hyperreactivity. Cellular infiltration in airways was predominated by CD4+ T cells expressing the pro-allergic cytokine IL-13. Furthermore, our studies show that antifungal T cell responses (IFN-γ+ or IL-17A+) co-expressed IL-13, revealing a novel mechanism for the dysregulated immune response to inhaled fungi. Total IgE production was augmented in animals repeatedly exposed to A. fumigatus. Conclusions & Clinical Relevance Repeated inhalation of fungal aerosols resulted in significant pulmonary pathology mediated by dynamic shifts in specific immune populations and their cytokines. These studies provide novel insights into the immunological mechanisms and targets that govern the health outcomes that result from repeated inhalation of fungal bioaerosols in contaminated environments. PMID:26892490

  1. Older age is associated with more MRI-detected inflammation in hand and foot joints.

    PubMed

    Nieuwenhuis, Wouter P; Mangnus, Lukas; van Steenbergen, Hanna W; Newsum, Elize C; Huizinga, Tom W J; Reijnierse, Monique; van der Helm-van Mil, Annette H M

    2016-12-01

    Although MRI is recommended for diagnostic use in detecting joint inflammation, its value in clinical practice has not been settled. Older symptom-free persons show more MRI-detected inflammation in their hands and feet. Within arthritis patients, a similar effect could be present (a general age effect). The association of age with MRI inflammation could also be enhanced by disease (disease-dependent age effect). Because both effects could have diagnostic consequences, we evaluated the association between age-at-onset and MRI-detected inflammation in early arthritis and RA. Unilateral contrast-enhanced MRI of the MCP joint, wrist and MTP joints was performed in 589 newly presenting early arthritis patients, of whom 229 had RA. Bone marrow oedema, synovitis and tenosynovitis were summed, yielding the MRI inflammation score. MRI findings were associated with age and compared with those of 193 (previously reported) symptom-free controls. Early arthritis and RA-patients had, respectively, 2.6 (95% CI: 2.3, 3.0, P < 0.001) and 3.7 times (95% CI: 3.2, 4.3, P < 0.001) higher MRI inflammation scores than controls (adjusted for age). At higher age of onset, early arthritis and RA patients had higher MRI inflammation scores (1.03/year, P < 0.001). A similar effect was observed in controls (1.03/year, P < 0.001). The interaction term age*group (arthritis/RA vs controls) was non-significant (P = 0.80 and P = 0.23), suggesting that the age effect was not disease dependent. At the joint level, older RA patients had more extended MRI inflammation, but the preferential locations were similar. Older age is associated with more MRI-detected inflammation, and the effect was similar in arthritis and controls. This age effect should be considered when interpreting hand and foot MRI for diagnostic purposes. © The Author 2016. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  2. [Effects of erdosteine on inflammation and fibrosis in rats with pulmonary fibrosis induced by bleomycin].

    PubMed

    Erden, Ersin Sükrü; Kirkil, Gamze; Deveci, Figen; Ilhan, Nevin; Cobanoğlu, Bengü; Turgut, Teyfik; Muz, Mehmet Hamdi

    2008-01-01

    We aimed to investigate the levels of some chemokines, inflammatory cell counts in bronchoalveolar lavage (BAL) fluid, histopathological changes in lung tissue, to determine the effect of erdosteine on acute inflammatory changes and fibrosis in a rat fibrosis model induced by bleomycine (BLM). Forty-five Wistar male rats were taken into the study. On day 0, intratracheal saline to control group (group 1, n= 15), intratracheal BLM 7.5 U/kg to BLM (group 2, n= 15) and erdosteine group (group 3, n= 15) was administered. In group 3, oral erdosteine (10 mg/kg/day) was applied two days before BLM. On day 0, 14, and 29th five rats in each groups were sacrificed, BAL fluid was performed. Malonyldialdehyde (MDA), macrophage inflammatory protein (MIP)-1alpha, MIP-2 levels in BAL fluid, hydroxyproline levels in lung tissue were measured. Histopathological examination was performed. When BLM group compared to erdosteine group, the levels of MDA, MIP-1alpha, MIP-2, and neutrophil counts, the hydroxyproline (OH-P) level of lung tissue were decreased in erdosteine group on acute inflammatory phase (day 14) (p< 0.001, p= 0.017, p= 0.009, p< 0.001, p= 0.009, respectively), and late fibrosis phase (day 29) except BAL MIP-2 (p= 0.022, p= 0.025, p= 0.01, p< 0.001, respectively). Fibrosis level was significantly lower in erdosteine group than BLM group on day 29 (p= 0.01). We conclude that erdosteine may prevent the acute lung inflammation and fibrosis by suppressing the accumulation of neutrophils, inhibition of lipid peroxydation, chemokine production, and release.

  3. Acute Meteorite Dust Exposure and Pulmonary Inflammation - Implications for Human Space Exploration

    NASA Technical Reports Server (NTRS)

    Harrington, A. D.; McCubbin, F. M.; Kaur, J.; Smirnov, A.; Galdanes, K.; Schoonen, M. A. A.; Chen, L. C.; Tsirka, S. E.; Gordon, T.

    2017-01-01

    The previous manned missions to the Moon represent milestones of human ingenuity, perseverance, and intellectual curiosity. However, one of the major ongoing concerns is the array of hazards associated with lunar surface dust. Not only did the dust cause mechanical and structural integrity issues with the suits, the dust 'storm' generated upon reentrance into the crew cabin caused "lunar hay fever" and "almost blindness [1-3]" (Figure 1). It was further reported that the allergic response to the dust worsened with each exposure [4]. The lack of gravity exacerbated the exposure, requiring the astronauts to wear their helmet within the module in order to avoid breathing the irritating particles [1]. Due to the prevalence of these high exposures, the Human Research Roadmap developed by NASA identifies the Risk of Adverse Health and Performance Effects of Celestial Dust Exposure as an area of concern [5]. Extended human exploration will further increase the probability of inadvertent and repeated exposures to celestial dusts. Going forward, hazard assessments of celestial dusts will be determined through sample return efforts prior to astronaut deployment. Studies on the lunar highland regolith indicate that the dust is not only respirable but also reactive [2, 6-9], and previous studies concluded that it is moderately toxic; generating a greater response than titanium oxide but a lower response than quartz [6]. The presence of reactive oxygen species (ROS) on the surface of the dust has been implicated. However, there is actually little data related to physicochemical characteristics of particulates and pulmonary toxicity, especially as it relates to celestial dust exposure. As a direct response to this deficit, the present study evaluates the role of a particulate's innate geochemical features (e.g., bulk chemistry, internal composition, morphology, size, and reactivity) in generating adverse toxicological responses in vitro and in vivo. This highly interdisciplinary

  4. Detection of pulmonary aspiration in children with gastroesophageal reflux

    SciTech Connect

    Orellana, P.; Olea, E.; Pino, C.; Rossel, M.; Ceresa, S.; Gonzalez, P.; Otarola, S.; Astudillo, S.

    1985-05-01

    The presence of pulmonary aspiration (PA) should be suspected in two groups of patients; those with symptoms of gastroesophageal reflux (GER) and pulmonary disease and patient's with pulmonary symptoms without signs of GER in whom other etiologies of pulmonary disease have been excluded. To determine if PA could be diagnosed in children using radionuclides 114 patients aged 3-12 months drank 500 ..mu..Ci of Tc-99m sulfur colloid mixed with infant formula and an additional 1.5 mCi was administered in the evening. All medicine was suspended 24 hours before. Images of the chest in supine position (ant, post views) were acquired on computer in 32 x 32 (byte mode) during 5 min each view at 2 and 18 hours. No outside pressure was applied. None of the patients with digestive symptomatology alone had positive exam. Of 88 patients with bronchopulmonary symptomatology 35 had abnormal examination 35% with moderate symptom were (Abn) and 55% with severe disease were abnormal. The radionuclide method appears to be the ideal study in patients where PA is suspected. The positivity of the method depends on the group of patients selected. The sensitivity is highest in patients with marked symptomatology.

  5. Systemic inflammation in chronic obstructive pulmonary disease: a population-based study

    PubMed Central

    2010-01-01

    Background Elevated circulating levels of several inflammatory biomarkers have been described in selected patient populations with COPD, although less is known about their population-based distribution. The aims of this study were to compare the levels of several systemic biomarkers between stable COPD patients and healthy subjects from a population-based sample, and to assess their distribution according to clinical variables. Methods This is a cross-sectional study design of participants in the EPI-SCAN study (40-80 years of age). Subjects with any other condition associated with an inflammatory process were excluded. COPD was defined as a post-bronchodilator FEV1/FVC < 0.70. The reference group was made of non-COPD subjects without respiratory symptoms, associated diseases or prescription of medication. Subjects were evaluated with quality-of-life questionnaires, spirometry and 6-minute walk tests. Serum C-reactive protein (CRP), tumor necrosis factor (TNF)-α, interleukins (IL-6 and IL-8), alpha1-antitrypsin, fibrinogen, albumin and nitrites/nitrates (NOx) were measured. Results We compared 324 COPD patients and 110 reference subjects. After adjusting for gender, age, BMI and tobacco consumption, COPD patients showed higher levels of CRP (0.477 ± 0.023 vs. 0.376 ± 0.041 log mg/L, p = 0.049), TNF-α (13.12 ± 0.59 vs. 10.47 ± 1.06 pg/mL, p = 0.033), IL-8 (7.56 ± 0.63 vs. 3.57 ± 1.13 pg/ml; p = 0.033) and NOx (1.42 ± 0.01 vs. 1.36 ± 0.02 log nmol/l; p = 0.048) than controls. In COPD patients, serum concentrations of some biomarkers were related to severity and their exercise tolerance was related to serum concentrations of CRP, IL-6, IL-8, fibrinogen and albumin. Conclusions Our results provide population-based evidence that COPD is independently associated with low-grade systemic inflammation, with a different inflammatory pattern than that observed in healthy subjects. PMID:20500811

  6. Multilevel Contextual 3-D CNNs for False Positive Reduction in Pulmonary Nodule Detection.

    PubMed

    Dou, Qi; Chen, Hao; Yu, Lequan; Qin, Jing; Heng, Pheng-Ann

    2017-07-01

    False positive reduction is one of the most crucial components in an automated pulmonary nodule detection system, which plays an important role in lung cancer diagnosis and early treatment. The objective of this paper is to effectively address the challenges in this task and therefore to accurately discriminate the true nodules from a large number of candidates. We propose a novel method employing three-dimensional (3-D) convolutional neural networks (CNNs) for false positive reduction in automated pulmonary nodule detection from volumetric computed tomography (CT) scans. Compared with its 2-D counterparts, the 3-D CNNs can encode richer spatial information and extract more representative features via their hierarchical architecture trained with 3-D samples. More importantly, we further propose a simple yet effective strategy to encode multilevel contextual information to meet the challenges coming with the large variations and hard mimics of pulmonary nodules. The proposed framework has been extensively validated in the LUNA16 challenge held in conjunction with ISBI 2016, where we achieved the highest competition performance metric (CPM) score in the false positive reduction track. Experimental results demonstrated the importance and effectiveness of integrating multilevel contextual information into 3-D CNN framework for automated pulmonary nodule detection in volumetric CT data. While our method is tailored for pulmonary nodule detection, the proposed framework is general and can be easily extended to many other 3-D object detection tasks from volumetric medical images, where the targeting objects have large variations and are accompanied by a number of hard mimics.

  7. Detection of acute inflammation with /sup 111/In-labeled nonspecific polyclonal IgG

    SciTech Connect

    Fischman, A.J.; Rubin, R.H.; Khaw, B.A.; Callahan, R.J.; Wilkinson, R.; Keech, F.; Nedelman, M.; Dragotakes, S.; Kramer, P.B.; LaMuraglia, G.M.

    1988-10-01

    The detection of focal sites of inflammation is an integral part of the clinical evaluation of the febrile patient. When anatomically distinct abscesses are present, lesion detection can be accomplished by standard radiographic techniques, particularly in patients with normal anatomy. At the phlegmon stage, however, and in patients who have undergone surgery, these techniques are considerably less effective. While radionuclide methods, such as Gallium-67 (67Ga)-citrate and Indium-111 (111In)-labeled WBCs have been relatively successful for the detection of early inflammation, neither approach is ideal. In the course of studies addressing the use of specific organism-directed antibodies for imaging experimental infections in animals, we observed that nonspecific polyclonal immunoglobulin G (IgG) localized as well as specific antibodies. Preliminary experiments suggested that the Fc portion of IgG is necessary for effective inflammation localization. Since polyclonal IgG in gram quantities has been safely used for therapy in patients with immune deficiency states, we decided to test whether milligram quantities of radiolabeled IgG could image focal sites of inflammation in humans. Thus far, we have studied a series of 84 patients with suspected lesions in the abdomen, pelvis, vascular grafts, lungs, or bones/joints. In 48 of 52 patients with focal lesions detected by surgery, computed tomography (CT), magnetic resonance imaging (MRI), or ultrasound (US), the IgG scan correctly localized the site, while 31 patients without focal inflammation had no abnormal focal localization of the radiopharmaceutical. Four patients had false negative scans and one patient had a false positive scan. For this small series, the overall sensitivity and specificity were 92% and 95%, respectively. In this report, we review our experience with this exciting new agent.

  8. Asthma-COPD overlap. Clinical relevance of genomic signatures of type 2 inflammation in chronic obstructive pulmonary disease.

    PubMed

    Christenson, Stephanie A; Steiling, Katrina; van den Berge, Maarten; Hijazi, Kahkeshan; Hiemstra, Pieter S; Postma, Dirkje S; Lenburg, Marc E; Spira, Avrum; Woodruff, Prescott G

    2015-04-01

    Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease and likely includes a subgroup that is biologically comparable to asthma. Studying asthma-associated gene expression changes in COPD could add insight into COPD pathogenesis and reveal biomarkers that predict a favorable response to corticosteroids. To determine whether asthma-associated gene signatures are increased in COPD and associated with asthma-related features. We compared disease-associated airway epithelial gene expression alterations in an asthma cohort (n = 105) and two COPD cohorts (n = 237, 171). The T helper type 2 (Th2) signature (T2S) score, a gene expression metric induced in Th2-high asthma, was evaluated in these COPD cohorts. The T2S score was correlated with asthma-related features and response to corticosteroids in COPD in a randomized, placebo-controlled trial, the Groningen and Leiden Universities study of Corticosteroids in Obstructive Lung Disease (GLUCOLD; n = 89). The 200 genes most differentially expressed in asthma versus healthy control subjects were enriched among genes associated with more severe airflow obstruction in these COPD cohorts (P < 0.001), suggesting significant gene expression overlap. A higher T2S score was associated with decreased lung function (P < 0.001), but not asthma history, in both COPD cohorts. Higher T2S scores correlated with increased airway wall eosinophil counts (P = 0.003), blood eosinophil percentage (P = 0.03), bronchodilator reversibility (P = 0.01), and improvement in hyperinflation after corticosteroid treatment (P = 0.019) in GLUCOLD. These data identify airway gene expression alterations that can co-occur in asthma and COPD. The association of the T2S score with increased severity and "asthma-like" features (including a favorable corticosteroid response) in COPD suggests that Th2 inflammation is important in a COPD subset that cannot be identified by clinical history of asthma.

  9. Nasal priming with immunobiotic Lactobacillus rhamnosus modulates inflammation-coagulation interactions and reduces influenza virus-associated pulmonary damage.

    PubMed

    Zelaya, Hortensia; Tada, Asuka; Vizoso-Pinto, Maria Guadalupe; Salva, Susana; Kanmani, Paulraj; Agüero, Graciela; Alvarez, Susana; Kitazawa, Haruki; Villena, Julio

    2015-08-01

    To evaluate the effect of the nasal administration of live and heat-killed Lactobacillus rhamnosus CRL1505 (Lr1505) on immune-coagulative response during influenza virus (IFV) infection to improve survival and reduce lung injury. Six-week-old BALB/c mice were treated with live or heat-killed Lr1505 by the nasal route during two consecutive days. Treated and untreated control mice were then nasally challenged with IFV. Both viable and non-viable Lr1505 protected infected mice by reducing pulmonary injury and lung viral loads trough several mechanisms: (a) Inflammatory cytokines were efficiently regulated allowing higher clearance of virus and reduction of inflammatory lung tissue damage, associated to higher levels of the regulatory cytokine IL-10. (b) The antiviral immune response was enhanced with improved levels of type I interferons, CD4(+)IFN-γ(+) lymphocytes, and lung CD11c(+)CD11b(low)CD103(+) and CD11c(+)CD11b(high)CD103(-) dendritic cells. (c) The procoagulant state was reversed mainly by down-regulating tissue factor expression and restoring thrombomodulin levels in lung. The capacity of Lr1505 to improve the outcome of IFV infection would be related to its ability to beneficially modulate lung TLR3-triggered immune response. Our work is the first to demonstrate the ability of an immunobiotic strain to beneficially modulate inflammation-coagulation interactions during IFV infection. Interestingly, non-viable L. rhamnosus CRL1505 was as effective as the viable strain to beneficially modulate respiratory antiviral immune response.

  10. Alum Adjuvant Enhances Protection against Respiratory Syncytial Virus but Exacerbates Pulmonary Inflammation by Modulating Multiple Innate and Adaptive Immune Cells

    PubMed Central

    Kim, Ki-Hye; Lee, Young-Tae; Hwang, Hye Suk; Kwon, Young-Man; Jung, Yu-Jin; Lee, Youri; Lee, Jong Seok; Lee, Yu-Na; Park, Soojin; Kang, Sang-Moo

    2015-01-01

    Respiratory syncytial virus (RSV) is well-known for inducing vaccine-enhanced respiratory disease after vaccination of young children with formalin-inactivated RSV (FI-RSV) in alum formulation. Here, we investigated alum adjuvant effects on protection and disease after FI-RSV immunization with or without alum in comparison with live RSV reinfections. Despite viral clearance, live RSV reinfections caused weight loss and substantial pulmonary inflammation probably due to high levels of RSV specific IFN-γ+IL4-, IFN-γ-TNF-α+, IFN-γ+TNF-α- effector CD4 and CD8 T cells. Alum adjuvant significantly improved protection as evidenced by effective viral clearance compared to unadjuvanted FI-RSV. However, in contrast to unadjuvanted FI-RSV, alum-adjuvanted FI-RSV (FI-RSV-A) induced severe vaccine-enhanced RSV disease including weight loss, eosinophilia, and lung histopathology. Alum adjuvant in the FI-RSV-A was found to be mainly responsible for inducing high levels of RSV-specific IFN-γ-IL4+, IFN-γ-TNF-α+ CD4+ T cells, and proinflammatory cytokines IL-6 and IL-4 as well as B220+ plasmacytoid and CD4+ dendritic cells, and inhibiting the induction of IFN-γ+CD8 T cells. This study suggests that alum adjuvant in FI-RSV vaccines increases immunogenicity and viral clearance but also induces atypical T helper CD4+ T cells and multiple inflammatory dendritic cell subsets responsible for vaccine-enhanced severe RSV disease. PMID:26468884

  11. Disruption of Sirtuin 1-Mediated Control of Circadian Molecular Clock and Inflammation in Chronic Obstructive Pulmonary Disease.

    PubMed

    Yao, Hongwei; Sundar, Isaac K; Huang, Yadi; Gerloff, Janice; Sellix, Michael T; Sime, Patricia J; Rahman, Irfan

    2015-12-01

    Chronic obstructive pulmonary disease (COPD) is the fourth most common cause of death, and it is characterized by abnormal inflammation and lung function decline. Although the circadian molecular clock regulates inflammatory responses, there is no information available regarding the impact of COPD on lung molecular clock function and its regulation by sirtuin 1 (SIRT1). We hypothesize that the molecular clock in the lungs is disrupted, leading to increased inflammatory responses in smokers and patients with COPD and its regulation by SIRT1. Lung tissues, peripheral blood mononuclear cells (PBMCs), and sputum cells were obtained from nonsmokers, smokers, and patients with COPD for measurement of core molecular clock proteins (BMAL1, CLOCK, PER1, PER2, and CRY1), clock-associated nuclear receptors (REV-ERBα, REV-ERBβ, and RORα), and SIRT1 by immunohistochemistry, immunofluorescence, and immunoblot. PBMCs were treated with the SIRT1 activator SRT1720 followed by LPS treatment, and supernatant was collected at 6-hour intervals. Levels of IL-8, IL-6, and TNF-α released from PBMCs were determined by ELISA. Expression of BMAL1, PER2, CRY1, and REV-ERBα was reduced in PBMCs, sputum cells, and lung tissues from smokers and patients with COPD when compared with nonsmokers. SRT1720 treatment attenuated LPS-mediated reduction of BMAL1 and REV-ERBα in PBMCs from nonsmokers. Additionally, LPS differentially affected the timing and amplitude of cytokine (IL-8, IL-6, and TNF-α) release from PBMCs in nonsmokers, smokers, and patients with COPD. Moreover, SRT1720 was able to inhibit LPS-induced cytokine release from cultured PBMCs. In conclusion, disruption of the molecular clock due to SIRT1 reduction contributes to abnormal inflammatory response in smokers and patients with COPD.

  12. Disruption of Sirtuin 1–Mediated Control of Circadian Molecular Clock and Inflammation in Chronic Obstructive Pulmonary Disease

    PubMed Central

    Yao, Hongwei; Sundar, Isaac K.; Huang, Yadi; Gerloff, Janice; Sellix, Michael T.; Sime, Patricia J.

    2015-01-01

    Chronic obstructive pulmonary disease (COPD) is the fourth most common cause of death, and it is characterized by abnormal inflammation and lung function decline. Although the circadian molecular clock regulates inflammatory responses, there is no information available regarding the impact of COPD on lung molecular clock function and its regulation by sirtuin 1 (SIRT1). We hypothesize that the molecular clock in the lungs is disrupted, leading to increased inflammatory responses in smokers and patients with COPD and its regulation by SIRT1. Lung tissues, peripheral blood mononuclear cells (PBMCs), and sputum cells were obtained from nonsmokers, smokers, and patients with COPD for measurement of core molecular clock proteins (BMAL1, CLOCK, PER1, PER2, and CRY1), clock-associated nuclear receptors (REV-ERBα, REV-ERBβ, and RORα), and SIRT1 by immunohistochemistry, immunofluorescence, and immunoblot. PBMCs were treated with the SIRT1 activator SRT1720 followed by LPS treatment, and supernatant was collected at 6-hour intervals. Levels of IL-8, IL-6, and TNF-α released from PBMCs were determined by ELISA. Expression of BMAL1, PER2, CRY1, and REV-ERBα was reduced in PBMCs, sputum cells, and lung tissues from smokers and patients with COPD when compared with nonsmokers. SRT1720 treatment attenuated LPS-mediated reduction of BMAL1 and REV-ERBα in PBMCs from nonsmokers. Additionally, LPS differentially affected the timing and amplitude of cytokine (IL-8, IL-6, and TNF-α) release from PBMCs in nonsmokers, smokers, and patients with COPD. Moreover, SRT1720 was able to inhibit LPS-induced cytokine release from cultured PBMCs. In conclusion, disruption of the molecular clock due to SIRT1 reduction contributes to abnormal inflammatory response in smokers and patients with COPD. PMID:25905433

  13. Sequential Treatments with Tongsai and Bufei Yishen Granules Reduce Inflammation and Improve Pulmonary Function in Acute Exacerbation-Risk Window of Chronic Obstructive Pulmonary Disease in Rats

    PubMed Central

    Lu, Xiaofan; Li, Ya; Wang, Haifeng; Wu, Zhaohuan; Li, Hangjie; Wang, Yang

    2016-01-01

    Background. Sequential treatments of Chinese medicines for acute exacerbation of chronic obstructive pulmonary disease (AECOPD) risk window (RW) have benefits for preventing reoccurrences of AEs; however, the effects on pulmonary function, pulmonary, and systemic inflammatory biomarkers remain unclear. Methods. Cigarette-smoke/bacterial infections induced rats were randomized into Control, COPD, AECOPD, Tongsai Granule/normal saline (TSG/NS), moxifloxacin + salbutamol/NS (MXF+STL/NS), TSG/Bufei Yishen Granule (BYG), MXF+STL/STL, and TSG+MXF+STL/BYG+STL groups and given corresponding medicine(s) in AE- and/or RW phase. Body temperature, pulmonary function, blood cytology, serum amyloid A (SAA) and C-reactive protein (CRP), pulmonary histomorphology and myeloperoxidase (MPO), polymorphonuclear (PMN) elastase, interleukins IL-1β, IL-6, and IL-10, and tumor necrosis factor- (TNF-) α expressions were determined. Results. Body temperature, inflammatory cells and cytokines, SAA, CRP, and pulmonary impairment were higher in AECOPD rats than stable COPD, while pulmonary function declined and recovered to COPD level in 14–18 days. All biomarkers were improved in treated groups with shorter recovery times of 4–10 days, especially in TSG+MXF+STL/BYG+STL group. Conclusion. Sequential treatments with Tongsai and Bufei Yishen Granules, during AECOPD-RW periods, can reduce inflammatory response and improve pulmonary function and shorten the recovery courses of AEs, especially the integrated Chinese and Western medicines. PMID:27563333

  14. Transforming growth factor-β plays divergent roles in modulating vascular remodeling, inflammation, and pulmonary fibrosis in a murine model of scleroderma.

    PubMed

    Tsujino, Kazuyuki; Reed, Nilgun Isik; Atakilit, Amha; Ren, Xin; Sheppard, Dean

    2017-01-01

    The efficacy and feasibility of targeting transforming growth factor-β (TGFβ) in pulmonary fibrosis and lung vascular remodeling in systemic sclerosis (SSc) have not been well elucidated. In this study we analyzed how blocking TGFβ signaling affects pulmonary abnormalities in Fos-related antigen 2 (Fra-2) transgenic (Tg) mice, a murine model that manifests three important lung pathological features of SSc: fibrosis, inflammation, and vascular remodeling. To interrupt TGFβ signaling in the Fra-2 Tg mice, we used a pan-TGFβ-blocking antibody, 1D11, and Tg mice in which TGFβ receptor type 2 (Tgfbr2) is deleted from smooth muscle cells and myofibroblasts (α-SMA-Cre(ER);Tgfbr2(flox/flox)). Global inhibition of TGFβ by 1D11 did not ameliorate lung fibrosis histologically or biochemically, whereas it resulted in a significant increase in the number of immune cells infiltrating the lungs. In contrast, 1D11 treatment ameliorated the severity of pulmonary vascular remodeling in Fra-2 Tg mice. Similarly, genetic deletion of Tgfbr2 from smooth muscle cells resulted in improvement of pulmonary vascular remodeling in the Fra-2 Tg mice, as well as a decrease in the number of Ki67-positive vascular smooth muscle cells, suggesting that TGFβ signaling contributes to development of pulmonary vascular remodeling by promoting the proliferation of vascular smooth muscle cells. Deletion of Tgfbr2 from α-smooth muscle actin-expressing cells had no effect on fibrosis or inflammation in this model. These results suggest that efforts to target TGFβ in SSc will likely require more precision than simply global inhibition of TGFβ function. Copyright © 2017 the American Physiological Society.

  15. A Single Aspiration of Rod-like Carbon Nanotubes Induces Asbestos-like Pulmonary Inflammation Mediated in Part by the IL-1 Receptor.

    PubMed

    Rydman, Elina M; Ilves, Marit; Vanhala, Esa; Vippola, Minnamari; Lehto, Maili; Kinaret, Pia A S; Pylkkänen, Lea; Happo, Mikko; Hirvonen, Maija-Riitta; Greco, Dario; Savolainen, Kai; Wolff, Henrik; Alenius, Harri

    2015-09-01

    Carbon nanotubes (CNT) have been eagerly studied because of their multiple applications in product development and potential risks on health. We investigated the difference of two different CNT and asbestos in inducing proinflammatory reactions in C57BL/6 mice after single pharyngeal aspiration exposure. We used long tangled and long rod-like CNT, as well as crocidolite asbestos at a dose of 10 or 40 µg/mouse. The mice were sacrificed 4 and 16 h or 7, 14, and 28 days after the exposure. To find out the importance of a major inflammatory marker IL-1β in CNT-induced pulmonary inflammation, we used etanercept and anakinra as antagonists as well as Interleukin 1 (IL-1) receptor (IL-1R-/-) mice. The results showed that rod-like CNT, and asbestos in lesser extent, induced strong pulmonary neutrophilia accompanied by the proinflammatory cytokines and chemokines 16 h after the exposure. Seven days after the exposure, neutrophilia had essentially disappeared but strong pulmonary eosinophilia peaked in rod-like CNT and asbestos-exposed groups. After 28 days, pulmonary granulomas, goblet cell hyperplasia, and Charcot-Leyden-like crystals containing acidophilic macrophages were observed especially in rod-like CNT-exposed mice. IL-1R-/- mice and antagonists-treated mice exhibited a significant decrease in neutrophilia and messenger ribonucleic acid (mRNA) levels of proinflammatory cytokines at 16 h. However, rod-like CNT-induced Th2-type inflammation evidenced by the expression of IL-13 and mucus production was unaffected in IL-1R-/- mice at 28 days. This study provides knowledge about the pulmonary effects induced by a single exposure to the CNT and contributes to hazard assessment of carbon nanomaterials on airway exposure. © The Author 2015. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  16. Non-Invasive Detection of Lung Inflammation by Near-Infrared Fluorescence Imaging Using Bimodal Liposomes.

    PubMed

    Desu, Hari R; Wood, George C; Thoma, Laura A

    2016-01-01

    Acute lung injury (ALI) and its more severe form, acute respiratory distress syndrome results in respiratory obstruction and severe lung inflammation. Critical characteristics of ALI are alveolar edema, infiltration of leukocytes (neutrophils and monocytes), release of pro-inflammatory cytokines and chemokines into broncho-alveolar lavage fluid, and activation of integrin receptors. The purpose of the study was to demonstrate non-invasive detection of lung inflammation using integrin receptor targeted fluorescence liposomes. An inflammation similar to that observed in ALI was elicited in rodents by intra-tracheal instillation of interleukin-1beta (IL-1beta). Cyclic arginine glycine-(D)-aspartic acid-peptide (cRGD-peptide) grafted fluorescence liposomes were administered to ALI induced male Sprague-Dawley rats for targeting lung integrin receptors. Near-infrared fluorescence imaging (NIRFI) was applied for visualization and quantitation of lung inflammation. NIRFI signals were correlated with inflammatory cellular and biochemical markers of lungs. A positive correlation was observed between NIRF signals and lung inflammation markers. Compared to control group, an intense NIRF signal was observed in ALI induced rats in the window 6-24 h post-IL-1beta instillation. Interaction of integrin receptors with targeted liposomes was assumed to contribute to intense NIRF signal. RT-PCR studies showed an elevated lung expression of alphavbeta5 integrin receptors, 12 h post-IL-1beta instillation. In vitro studies demonstrated integrin receptor specificity of targeted liposomes. These targeted liposomes showed binding to alphavbeta5 integrin receptors expressed on alveolar cells. Non-invasive detection of lung inflammation was demonstrated using a combination of integrin receptor targeting and NIRFI.

  17. The effects of short-term fish oil supplementation on pulmonary function and airway inflammation following a high-fat meal.

    PubMed

    Ade, Carl J; Rosenkranz, S K; Harms, C A

    2014-04-01

    Many environmental and dietary influences can cause immune cells to produce biological mediators that increase airway inflammation. A high-fat meal (HFM) is one stimulus that increases airway inflammation in healthy individuals. Supplementation with omega-3 fatty acids can reduce inflammation systemically and may be beneficial to the airways. To determine if omega-3 fatty acid supplementation via fish oil would mitigate the airway inflammatory response induced by a single HFM. Seventeen non-asthmatic men (22 ± 2 years.) were supplemented with 3,000 mg × day(-1) fish oil or a placebo for 3 weeks. Fractional exhaled nitric oxide (FENO; a marker of airway inflammation), impulse oscillometry (a measure of respiratory impedance), pulmonary function, and triglycerides were measured prior to and 2 h following a HFM. Following a HFM, triglycerides increased in both fish oil and placebo groups compared to pre-HFM (~59 and ~49 %, respectively, p < 0.05). The percent increase in FENO was greater in the placebo group compared to the fish oil group (25.7 ± 16.7 vs. -1.99 ± 10.5 %, respectively, p < 0.05). A significant correlation was observed between blood triglycerides and FENO in the placebo group (r = 0.61; p < 0.05), but not the fish oil group (p = 0.21). A single HFM increases airway inflammation and omega-3 fatty acid supplementation via fish oil protects against HFM associated changes in airway health.

  18. Detection rate of lung cancer among chronic obstructive pulmonary disease patients regularly followed up by pulmonary physicians.

    PubMed

    Laisaar, Tanel; Lill, Hille; Kullamaa, Anneli; Jõgi, Rain

    2011-11-01

      Chronic obstructive pulmonary disease (COPD) has been found to be an independent risk factor for lung cancer. The aim of this study was to evaluate whether regular follow up of COPD patients increases the diagnosis of lung cancer at an early stage.   Case reports of 105 male moderate to severe COPD patients who participated in a clinical study were analyzed retrospectively. Throughout the 3-year study period patients regularly visited a pulmonary physician. Investigations to detect lung cancer were ordered only with the presence of symptoms. The lung cancer incidence in the study group was compared to that of general male population matched by age.   At the beginning of the study the mean age was 67 (range 55-81) years, mean smoking history 36.2 (range 11-102) years and mean forced expiratory volume in 1 s (FEV1 ) 43.3% (range 22.7-59.7). During the study six lung cancers and five other cancers were diagnosed per 287 person-years of observation. Only one lung cancer was operable, others were locally advanced or had distant metastases.   Despite the patients being followed up regularly by a pulmonary physician, most cancers were diagnosed at an advanced stage. The relative risk of getting lung cancer was 6.0 times higher (95% CI 2.7-13.3) among COPD patients than among the general population. The current study confirms that COPD patients have an increased risk of lung cancer. Moreover simple regular follow up of patients without special lung cancer screening investigations do not help to detect the cancer in its early stage. This study stresses the need to establish a more detailed follow-up program for COPD patients to detect early lung cancer in this high risk population. © Tianjin Lung Cancer Institute and Blackwell Publishing Asia Pty. Ltd.

  19. Epithelial transglutaminase 2 is needed for T cell interleukin-17 production and subsequent pulmonary inflammation and fibrosis in bleomycin-treated mice

    PubMed Central

    Oh, Keunhee; Park, Hyung-Bae; Byoun, Ok-Jin; Shin, Dong-Myung; Jeong, Eui Man; Kim, Young Whan; Kim, Yon Su; Melino, Gerry

    2011-01-01

    Pulmonary fibrosis is a potentially life-threatening disease that may be caused by overt or asymptomatic inflammatory responses. However, the precise mechanisms by which tissue injury is translated into inflammation and consequent fibrosis remain to be established. Here, we show that in a lung injury model, bleomycin induced the secretion of IL-6 by epithelial cells in a transglutaminase 2 (TG2)–dependent manner. This response represents a key step in the differentiation of IL-17–producing T cells and subsequent inflammatory amplification in the lung. The essential role of epithelial cells, but not inflammatory cells, TG2 was confirmed in bone marrow chimeras; chimeras made in TG2-deficient recipients showed reduced inflammation and fibrosis, compared with those in wild-type mice, regardless of the bone marrow cell phenotype. Epithelial TG2 thus appears to be a critical inducer of inflammation after noninfectious pulmonary injury. We further demonstrated that fibroblast-derived TG2, acting downstream of transforming growth factor-β, is also important in the effector phase of fibrogenesis. Therefore, TG2 represents an interesting potential target for therapeutic intervention. PMID:21746810

  20. Epithelial transglutaminase 2 is needed for T cell interleukin-17 production and subsequent pulmonary inflammation and fibrosis in bleomycin-treated mice.

    PubMed

    Oh, Keunhee; Park, Hyung-Bae; Byoun, Ok-Jin; Shin, Dong-Myung; Jeong, Eui Man; Kim, Young Whan; Kim, Yon Su; Melino, Gerry; Kim, In-Gyu; Lee, Dong-Sup

    2011-08-01

    Pulmonary fibrosis is a potentially life-threatening disease that may be caused by overt or asymptomatic inflammatory responses. However, the precise mechanisms by which tissue injury is translated into inflammation and consequent fibrosis remain to be established. Here, we show that in a lung injury model, bleomycin induced the secretion of IL-6 by epithelial cells in a transglutaminase 2 (TG2)-dependent manner. This response represents a key step in the differentiation of IL-17-producing T cells and subsequent inflammatory amplification in the lung. The essential role of epithelial cells, but not inflammatory cells, TG2 was confirmed in bone marrow chimeras; chimeras made in TG2-deficient recipients showed reduced inflammation and fibrosis, compared with those in wild-type mice, regardless of the bone marrow cell phenotype. Epithelial TG2 thus appears to be a critical inducer of inflammation after noninfectious pulmonary injury. We further demonstrated that fibroblast-derived TG2, acting downstream of transforming growth factor-β, is also important in the effector phase of fibrogenesis. Therefore, TG2 represents an interesting potential target for therapeutic intervention.

  1. [Effects of secretary leukocyte protease inhibitor-transfected bone marrow mesenchymal stem cells on airway inflammation and mucus secretion in chronic obstructive pulmonary disease].

    PubMed

    Jiang, De-peng; Li, Qi; P Kolosov, Victor; M Perelman, Juliy; Zhou, Xiang-dong

    2011-12-27

    To explore the effects of secretary leukocyte protease inhibitor (SLPI)-transfected bone marrow mesenchymal stem cells (BMSCs) transplantation on airway inflammation and mucus secretion in chronic obstructive pulmonary disease (COPD) rats. Sixty rats were equally and randomly divided into negative control, COPD model, BMSCs and SLPI-transfected BMSCs groups. The COPD rat model was established in all rats with the exception of the negative control rats by smoking and intratracheal instillation of lipopolysaccharide (LPS). BMSCs with or without transfection of plasmid containing SLPI gene were delivered through caudal vein of rats at 30 days post-induction. The expression of SLPI was examined with Western blot. The levels of interleukin (IL)-8 and tumor necrosis factor (TNF)-α were detected by enzyme-linked immunosorbent assay (ELISA). Goblet cell hyperplasia of lung pathological section was observed on. Compared with the negative control group, the expression of SLPI increased significantly after the administration of SLPI-transfected BMSCs (0.79 ± 0.06 vs 0.24 ± 0.02, P < 0.05). The levels of IL-8 and TNF-α in BMSCs and SLPI-transfected BMSCs group were lower than those in the COPD model group. Compared with the negative control group, the administration of SLPI-transfected BMSCs resulted in a further decrease in IL-8 and TNF-α in bronchoalveolar lavage fluid [(17.6 ± 1.7) vs (36.6 ± 4.0) ng/L, P < 0.05]. SLPI-transfected BMSCs transplantation also significantly attenuated goblet cell hyperplasia in rats (P < 0.05). There is a potential role for cell-based SLPI gene therapy in the treatment of COPD.

  2. Significance of Follow-up in Detection of Pulmonary Metastasis of Colorectal Cancer

    PubMed Central

    Shin, Jae Won; Lee, Sun Il

    2010-01-01

    Purpose This study was performed to evaluate the effectiveness of conventional chest radiography, carcinoembrionic antigen (CEA) level and abdominal computed tomography (CT) or chest CT for early detection of pulmonary metastasis after a curative resection of colorectal cancer. Methods We retrospectively reviewed 84 cases of pulmonary metastasis from a group of colorectal cancer patients who had a curative surgical resection from 2000 to 2006 at the Korea University Medical Center. Results Stage I tumors were detected in 4 patients, stage II tumors in 18, stage III tumors in 43 and stage IV tumors in 19. The detection rates for pulmonary metastasis were 28.5% by conventional chest radiography, 40.5% by increased CEA level and 28.5% by abdominal CT or chest CT. Among them, fourteen patients underwent a radical pneumonectomy. After detection of pulmonary metastasis, the survival outcome for the patients who underwent a resection of the lung was superior to the survival outcome of the patients who did not undergo a resection of the lung (43.7 months vs. 17.4 months, P = 0.001). For patients who underwent resections of the lung, pulmonary metastasis was detected by conventional chest radiography in 2 (14%) patients, by elevated CEA level in 6 (42%) patients, and by abdominal CT or chest CT in 6 (42%) patients. Conclusion Conventional chest radiography is no more useful in detecting early pulmonary metastasis after a curative colorectal surgery than a routine chest CT. Thus, we propose the use of routine chest CT for screening for lung metastasis. PMID:21152232

  3. Improved Diagnosis of Acute Pulmonary Histoplasmosis by Combining Antigen and Antibody Detection

    PubMed Central

    Richer, Sarah M.; Smedema, Melinda L.; Durkin, Michelle M.; Herman, Katie M.; Hage, Chadi A.; Fuller, Deanna; Wheat, L. Joseph

    2016-01-01

    Background. Acute pulmonary histoplasmosis can be severe, especially following heavy inoculum exposure. Rapid diagnosis is critical and often possible by detection of antigen, but this test may be falsely negative in 17% of such cases. Antibody detection by enzyme immunoassay (EIA) may increase sensitivity and permit the measurement of immunoglobulin M (IgM) and immunoglobulin G (IgG) classes of antibodies separately. Methods. Microplates coated with Histoplasma antigen were used for testing of serum from patients with acute pulmonary histoplasmosis and controls in the MVista Histoplasma antibody EIA. Results for IgG and IgM were reported independently. Results. IgG antibodies were detected in 87.5%, IgM antibodies in 67.5%, and IgG and/or IgM antibodies in 88.8% of patients with acute pulmonary histoplasmosis in this assay, while immunodiffusion, complement fixation, and antigen testing showed sensitivities of 55.0%, 73.1%, and 67.5%, respectively (n = 80). Combining antigen and antibody detection increased the sensitivity to 96.3%. Conclusions. The MVista Histoplasma antibody EIA offers increased sensitivity over current antibody tests while also allowing separate detection of IgG and IgM antibodies and complementing antigen detection. Combining antigen and EIA antibody testing provides an optimal method for diagnosis of acute pulmonary histoplasmosis. PMID:26797210

  4. Improved Diagnosis of Acute Pulmonary Histoplasmosis by Combining Antigen and Antibody Detection.

    PubMed

    Richer, Sarah M; Smedema, Melinda L; Durkin, Michelle M; Herman, Katie M; Hage, Chadi A; Fuller, Deanna; Wheat, L Joseph

    2016-04-01

    Acute pulmonary histoplasmosis can be severe, especially following heavy inoculum exposure. Rapid diagnosis is critical and often possible by detection of antigen, but this test may be falsely negative in 17% of such cases. Antibody detection by enzyme immunoassay (EIA) may increase sensitivity and permit the measurement of immunoglobulin M (IgM) and immunoglobulin G (IgG) classes of antibodies separately. Microplates coated with Histoplasma antigen were used for testing of serum from patients with acute pulmonary histoplasmosis and controls in the MVista Histoplasma antibody EIA. Results for IgG and IgM were reported independently. IgG antibodies were detected in 87.5%, IgM antibodies in 67.5%, and IgG and/or IgM antibodies in 88.8% of patients with acute pulmonary histoplasmosis in this assay, while immunodiffusion, complement fixation, and antigen testing showed sensitivities of 55.0%, 73.1%, and 67.5%, respectively (n = 80). Combining antigen and antibody detection increased the sensitivity to 96.3%. The MVista Histoplasma antibody EIA offers increased sensitivity over current antibody tests while also allowing separate detection of IgG and IgM antibodies and complementing antigen detection. Combining antigen and EIA antibody testing provides an optimal method for diagnosis of acute pulmonary histoplasmosis. © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America.

  5. Pulmonary nodule detection in PET/CT images: improved approach using combined nodule detection and hybrid FP reduction

    NASA Astrophysics Data System (ADS)

    Teramoto, Atsushi; Fujita, Hiroshi; Tomita, Yoya; Takahashi, Katsuaki; Yamamuro, Osamu; Tamaki, Tsuneo

    2012-03-01

    In this study, an automated scheme for detecting pulmonary nodules in PET/CT images has been proposed using combined detection and hybrid false-positive (FP) reduction techniques. The initial nodule candidates were detected separately from CT and PET images. FPs were then eliminated in the initial candidates by using support vector machine with characteristic values obtained from CT and PET images. In the experiment, we evaluated proposed method using 105 cases of PET/CT images that were obtained in the cancer-screening program. We evaluated true positive fraction (TPF) and FP / case. As a result, TPFs of CT and PET detections were 0.76 and 0.44, respectively. However, by integrating the both results, TPF was reached to 0.82 with 5.14 FPs/case. These results indicate that our method may be of practical use for the detection of pulmonary nodules using PET/CT images.

  6. SOPROCARE - 450 nm wavelength detection tool for microbial plaque and gingival inflammation: a clinical study

    NASA Astrophysics Data System (ADS)

    Rechmann, P.; Liou, Shasan W.; Rechmann, Beate M.; Featherstone, John D.

    2014-02-01

    Gingivitis due to microbial plaque and calculus can lead over time if left untreated to advanced periodontal disease with non-physiological pocket formation. Removal of microbial plaque in the gingivitis stage typically achieves gingival health. The SOPROCARE camera system emits blue light at 450 nm wavelength using three blue diodes. The 450 nm wavelength is located in the non-ionizing, visible spectral wavelength region and thus is not dangerous. It is assumed that using the SOPROCARE camera in perio-mode inflamed gingiva can easily be observed and inflammation can be scored due to fluorescence from porphyrins in blood. The assumption is also that illumination of microbial plaque with blue light induces fluorescence due to the bacteria and porphyrin content of the plaque and thus can help to make microbial plaque and calculus visible. Aim of the study with 55 subjects was to evaluate the ability of the SOPROCARE fluorescence camera system to detect, visualize and allow scoring of microbial plaque in comparison to the Turesky modification of the Quigley and Hein plaque index. A second goal was to detect and score gingival inflammation and correlated the findings to the Silness and Löe gingival inflammation index. The study showed that scoring of microbial plaque as well as gingival inflammation levels similar to the established Turesky modified Quigley Hein index and the Silness and Löe gingival inflammation index can easily be done using the SOPROCARE fluorescence system in periomode. Linear regression fits between the different clinical indices and SOPROCARE scores in fluorescence perio-mode revealed the system's capacity for effective discrimination between scores.

  7. Osthole Alleviates Bleomycin-Induced Pulmonary Fibrosis via Modulating Angiotensin-Converting Enzyme 2/Angiotensin-(1-7) Axis and Decreasing Inflammation Responses in Rats.

    PubMed

    Hao, Yuewen; Liu, Yan

    2016-01-01

    Studies have shown that angiotensin-converting enzyme 2 (ACE2) plays modulating roles in lung pathophysiology, including pulmonary fibrosis (PF) and acute lung injury. Pulmonary fibrosis is a common complication in these interstitial lung diseases, and PF always has a poor prognosis and short survival. To date, there are few promising methods for treating PF, and they are invariably accompanied by severe side effects. Recent studies have showed that the traditional Chinese herbal extract, osthole, had beneficial effects on lipopolysaccharide (LPS) induced acute lung injury (ALI) via an ACE2 pathway. Here we further investigated the protective effects of osthole on bleomycin induced pulmonary fibrosis and attempted to determine the underlying mechanism. PF mode rats were induced by bleomycin (BLM) and then subsequently administered osthole. Histopathological analyses were employed to identify PF changes. The results showed that BLM resulted in severe PF and diffuse lung inflammation, together with significant elevation of inflammatory factors and a marked increase in expression of angiotensin II (ANG II) and transforming growth factor-beta 1 (TGF-β1). ACE2 and angiotensin-(1-7) [ANG-(1-7)] were both greatly reduced after BLM administration. Meanwhile, osthole treatment attenuated BLM induced PF and inflammation, decreased the expression of these inflammatory mediators, ANG II, and TGF-β1, and reversed ACE2 and ANG-(1-7) production in rat lungs. We conclude that osthole may exert beneficial effects on BLM induced PF in rats, perhaps via modulating the ACE2/ANG-(1-7) axis and inhibiting lung inflammation pathways.

  8. Potentiated interaction between ineffective doses of budesonide and formoterol to control the inhaled cadmium-induced up-regulation of metalloproteinases and acute pulmonary inflammation in rats.

    PubMed

    Zhang, Wenhui; Zhi, Jianming; Cui, Yongyao; Zhang, Fan; Habyarimana, Adélite; Cambier, Carole; Gustin, Pascal

    2014-01-01

    The anti-inflammatory properties of glucocorticoids are well known but their protective effects exerted with a low potency against heavy metals-induced pulmonary inflammation remain unclear. In this study, a model of acute pulmonary inflammation induced by a single inhalation of cadmium in male Sprague-Dawley rats was used to investigate whether formoterol can improve the anti-inflammatory effects of budesonide. The cadmium-related inflammatory responses, including matrix metalloproteinase-9 (MMP-9) activity, were evaluated. Compared to the values obtained in rats exposed to cadmium, pretreatment of inhaled budesonide (0.5 mg/15 ml) elicited a significant decrease in total cell and neutrophil counts in bronchoalveolar lavage fluid (BALF) associated with a significant reduction of MMP-9 activity which was highly correlated with the number of inflammatory cells in BALF. Additionally, cadmium-induced lung injuries characterized by inflammatory cell infiltration within alveoli and the interstitium were attenuated by the pre-treatment of budesonide. Though the low concentration of budesonide (0.25 mg/15 ml) exerted a very limited inhibitory effects in the present rat model, its combination with an inefficient concentration of formoterol (0.5 mg/30 ml) showed an enhanced inhibitory effect on neutrophil and total cell counts as well as on the histological lung injuries associated with a potentiation of inhibition on the MMP-9 activity. In conclusion, high concentration of budesonide alone could partially protect the lungs against cadmium exposure induced-acute neutrophilic pulmonary inflammation via the inhibition of MMP-9 activity. The combination with formoterol could enhance the protective effects of both drugs, suggesting a new therapeutic strategy for the treatment of heavy metals-induced lung diseases.

  9. Benefits of texture analysis of dual energy CT for Computer-Aided pulmonary embolism detection.

    PubMed

    Foncubierta-Rodríguez, Antonio; Jiménez del Toro, Óscar Alfonso; Platon, Alexandra; Poletti, Pierre-Alexandre; Müller, Henning; Depeursinge, Adrien

    2013-01-01

    Pulmonary embolism is an avoidable cause of death if treated immediately but delays in diagnosis and treatment lead to an increased risk. Computer-assisted image analysis of both unenhanced and contrast-enhanced computed tomography (CT) have proven useful for diagnosis of pulmonary embolism. Dual energy CT provides additional information over the standard single energy scan by generating four-dimensional (4D) data, in our case with 11 energy levels in 3D. In this paper a 4D texture analysis method capable of detecting pulmonary embolism in dual energy CT is presented. The method uses wavelet-based visual words together with an automatic geodesic-based region of interest detection algorithm to characterize the texture properties of each lung lobe. Results show an increase in performance with respect to the single energy CT analysis, as well as an accuracy gain compared to preliminary work on a small dataset.

  10. Asthma–COPD Overlap. Clinical Relevance of Genomic Signatures of Type 2 Inflammation in Chronic Obstructive Pulmonary Disease

    PubMed Central

    Steiling, Katrina; van den Berge, Maarten; Hijazi, Kahkeshan; Hiemstra, Pieter S.; Postma, Dirkje S.; Lenburg, Marc E.; Spira, Avrum; Woodruff, Prescott G.

    2015-01-01

    Rationale: Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease and likely includes a subgroup that is biologically comparable to asthma. Studying asthma-associated gene expression changes in COPD could add insight into COPD pathogenesis and reveal biomarkers that predict a favorable response to corticosteroids. Objectives: To determine whether asthma-associated gene signatures are increased in COPD and associated with asthma-related features. Methods: We compared disease-associated airway epithelial gene expression alterations in an asthma cohort (n = 105) and two COPD cohorts (n = 237, 171). The T helper type 2 (Th2) signature (T2S) score, a gene expression metric induced in Th2-high asthma, was evaluated in these COPD cohorts. The T2S score was correlated with asthma-related features and response to corticosteroids in COPD in a randomized, placebo-controlled trial, the Groningen and Leiden Universities study of Corticosteroids in Obstructive Lung Disease (GLUCOLD; n = 89). Measurements and Main Results: The 200 genes most differentially expressed in asthma versus healthy control subjects were enriched among genes associated with more severe airflow obstruction in these COPD cohorts (P < 0.001), suggesting significant gene expression overlap. A higher T2S score was associated with decreased lung function (P < 0.001), but not asthma history, in both COPD cohorts. Higher T2S scores correlated with increased airway wall eosinophil counts (P = 0.003), blood eosinophil percentage (P = 0.03), bronchodilator reversibility (P = 0.01), and improvement in hyperinflation after corticosteroid treatment (P = 0.019) in GLUCOLD. Conclusions: These data identify airway gene expression alterations that can co-occur in asthma and COPD. The association of the T2S score with increased severity and “asthma-like” features (including a favorable corticosteroid response) in COPD suggests that Th2 inflammation is important in a

  11. sTREM-1 in bronchoalveolar lavage fluid in patients with pulmonary sarcoidosis, effect of smoking and inflammation.

    PubMed

    Suchankova, M; Bucova, M; E, Tibenska; Demian, J; Majer, I; Novosadova, H; Tedlova, E; Durmanova, V; Paulovicova, E

    2013-01-01

    Soluble TREM-1 (sTREM-1; Triggering receptor expressed on myelocytes) is a new inflammatory marker indicating the intensity of myeloid cells activation and the presence of infection caused by extracellular bacteria and mould.The aim of our work was to detect and compare the levels of sTREM-1 in bronchoalveolar lavage fluid (BALF) in patients with pulmonary sarcoidosis (PS) and other ILD of non-infectious origin. The sTREM-1 levels were assessed by ELISA in 46 patients suffering from ILD, out of them 22 with PS. The levels of BALF sTREM-1 in PS patients were higher than in control group of ILD patients of non-infectious origin, however, the difference was not statistically significant. Since all PS patients except one were non-smokers we compared non-smokers PS with non-smokers ILD patients and found four times higher levels of BALF sTREM-1 in PS patients (P = 0.001). We also recorded the effect of smoking, ILD smokers had higher sTREM-1 levels than non-smokers (P = 0.0019). Higher concentrations of sTREM-1 were detected in BALF of patients with lymphadenopathy and with elevated inflammatory markers in BALF. Our results show that BALF sTREM-1 could be a good inflammatory marker and could help in diagnosis and PS monitoring. Detection of sTREM-1 in BALF indirectly points to myeloid cells activation in the lungs and helps to complete the information about the number of myeloid cells commonly determined in BALF with additional information concerning the intensity of their activation. This is the first study that analyses BALF sTREM-1 levels in patients with PS (Tab. 8, Ref. 28). Text in PDF www.elis.sk.

  12. Role of Chitinase 3-Like-1 in Interleukin-18-Induced Pulmonary Type 1, Type 2, and Type 17 Inflammation; Alveolar Destruction; and Airway Fibrosis in the Murine Lung.

    PubMed

    Kang, Min-Jong; Yoon, Chang Min; Nam, Milang; Kim, Do-Hyun; Choi, Je-Min; Lee, Chun Geun; Elias, Jack A

    2015-12-01

    Chitinase 3-like 1 (Chi3l1), which is also called YKL-40 in humans and BRP-39 in mice, is the prototypic chitinase-like protein. Recent studies have highlighted its impressive ability to regulate the nature of tissue inflammation and the magnitude of tissue injury and fibroproliferative repair. This can be appreciated in studies that highlight its induction after cigarette smoke exposure, during which it inhibits alveolar destruction and the genesis of pulmonary emphysema. IL-18 is also known to be induced and activated by cigarette smoke, and, in murine models, the IL-18 pathway has been shown to be necessary and sufficient to generate chronic obstructive pulmonary disease-like inflammation, fibrosis, and tissue destruction. However, the relationship between Chi3l1 and IL-18 has not been defined. To address this issue we characterized the expression of Chi3l1/BRP-39 in control and lung-targeted IL-18 transgenic mice. We also characterized the effects of transgenic IL-18 in mice with wild-type and null Chi3l1 loci. The former studies demonstrated that IL-18 is a potent stimulator of Chi3l1/BRP-39 and that this stimulation is mediated via IFN-γ-, IL-13-, and IL-17A-dependent mechanisms. The latter studies demonstrated that, in the absence of Chi3l1/BRP-39, IL-18 induced type 2 and type 17 inflammation and fibrotic airway remodeling were significantly ameliorated, whereas type 1 inflammation, emphysematous alveolar destruction, and the expression of cytotoxic T lymphocyte perforin, granzyme, and retinoic acid early transcript 1 expression were enhanced. These studies demonstrate that IL-18 is a potent stimulator of Chi3l1 and that Chi3l1 is an important mediator of IL-18-induced inflammatory, fibrotic, alveolar remodeling, and cytotoxic responses.

  13. Detection of Mycobacterium tuberculosis complex by nested polymerase chain reaction in pulmonary and extrapulmonary specimens* ,**

    PubMed Central

    Furini, Adriana Antônia da Cruz; Pedro, Heloisa da Silveira Paro; Rodrigues, Jean Francisco; Montenegro, Lilian Maria Lapa; Machado, Ricardo Luiz Dantas; Franco, Célia; Schindler, Haiana Charifker; Batista, Ida Maria Foschiani Dias; Rossit, Andrea Regina Baptista

    2013-01-01

    OBJECTIVE: To compare the performance of nested polymerase chain reaction (NPCR) with that of cultures in the detection of the Mycobacterium tuberculosis complex in pulmonary and extrapulmonary specimens. METHODS: We analyzed 20 and 78 pulmonary and extrapulmonary specimens, respectively, of 67 hospitalized patients suspected of having tuberculosis. An automated microbial system was used for the identification of Mycobacterium spp. cultures, and M. tuberculosis IS6110 was used as the target sequence in the NPCR. The kappa statistic was used in order to assess the level of agreement among the results. RESULTS: Among the 67 patients, 6 and 5, respectively, were diagnosed with pulmonary and extrapulmonary tuberculosis, and the NPCR was positive in all of the cases. Among the 98 clinical specimens, smear microscopy, culture, and NPCR were positive in 6.00%, 8.16%, and 13.26%, respectively. Comparing the results of NPCR with those of cultures (the gold standard), we found that NPCR had a sensitivity and specificity of 100% and 83%, respectively, in pulmonary specimens, compared with 83% and 96%, respectively, in extrapulmonary specimens, with good concordance between the tests (kappa, 0.50 and 0.6867, respectively). CONCLUSIONS: Although NPCR proved to be a very useful tool for the detection of M. tuberculosis complex, clinical, epidemiological, and other laboratory data should also be considered in the diagnosis and treatment of pulmonary and extrapulmonary tuberculosis. PMID:24473765

  14. NKT cells mediate pulmonary inflammation and dysfunction in murine sickle cell disease through production of IFN-γ and CXCR3 chemokines

    PubMed Central

    Wallace, Kori L.; Marshall, Melissa A.; Ramos, Susan I.; Lannigan, Joanne A.; Field, Joshua J.; Strieter, Robert M.

    2009-01-01

    Ischemia-reperfusion injury (IRI) triggers an inflammatory cascade that is initiated by the activation of CD1d-restricted iNKT cells. In sickle cell disease (SCD), misshapen erythrocytes evoke repeated transient bouts of microvascular IRI. Compared with C57BL/6 controls, NY1DD mice have more numerous and activated (CD69+, interferon-γ+ [IFN-γ+]) lung, liver, and spleen iNKT cells that are hyperresponsive to hypoxia/reoxygenation. NY1DD mice have increased pulmonary levels of IFN-γ, IFN-γ–inducible chemokines (CXCL9, CXCL10), and elevated numbers of lymphocytes expressing the chemokine receptor CXCR3. Treating NY1DD mice with anti-CD1d antibody to inhibit iNKT cell activation reverses baseline pulmonary dysfunction manifested as elevated vascular permeability, decreased arterial oxygen saturation, and increased numbers of activated leukocytes. Anti-CD1d antibodies decrease pulmonary levels of IFN-γ and CXCR3 chemokines. Neutralization of CXCR3 receptors ameliorates pulmonary dysfunction. Crossing NY1DD to lymphocyte-deficient Rag1−/− mice decreases pulmonary dysfunction. This is counteracted by the adoptive transfer of 1 million NKT cells. Like mice, people with SCD have increased numbers of activated circulating iNKT cells expressing CXCR3. Together, these data indicate that iNKT cells play a pivotal role in sustaining inflammation in SCD mice by a pathway involving IFN-γ and production of chemotactic CXCR3 chemokines and that this mechanism may translate to human disease. PMID:19433855

  15. Associated inflammation or increased flow-mediated shear stress, but not pressure alone, disrupts endothelial caveolin-1 in infants with pulmonary hypertension

    PubMed Central

    Dereddy, Narendra; Huang, Jing; Erb, Markus; Guzel, Sibel; Wolk, John H; Sett, Suvro S; Gewitz, Michael H; Mathew, Rajamma

    2012-01-01

    Endothelial caveolin-1 loss is an important feature of pulmonary hypertension (PH); the rescue of caveolin-1 abrogates experimental PH. Recent studies in human PH suggest that the endothelial caveolin-1 loss is followed by an enhanced expression of caveolin-1 in smooth muscle cells (SMC) with subsequent neointima formation. In order to evaluate caveolin-1 expression in infants with PH, we examined the available clinical histories, hemodynamic data, and the expression of caveolin-1, PECAM-1, vWF, and smooth muscle α-actin in the lung biopsy/autopsy specimens obtained from infants with congenital heart disease (CHD, n = 8) and lung disease (n = 9). In CHD group, PH associated with increased pulmonary blood flow exhibited loss of endothelial caveolin-1 and PECAM-1 in pulmonary arteries; additional vWF loss was associated with enhanced expression of caveolin-1 in SMC. In the absence of PH, increased or decreased pulmonary blood flow did not disrupt endothelial caveolin-1, PECAM-1, or vWF; nor was there any enhanced expression of caveolin-1 in SMC. In Lung Disease + PH group, caveolin-1, PECAM-1, and vWF were well preserved in seven infants, and importantly, SMC in these arteries did not exhibit enhanced caveolin-1 expression. Two infants with associated inflammatory disease exhibited loss of endothelial caveolin-1 and PECAM-1; additional loss of vWF was accompanied by enhanced expression of caveolin-1 in SMC. Thus, associated flow-induced shear stress or inflammation, but not elevated pulmonary artery pressure alone, disrupts endothelial caveolin-1. Subsequent vWF loss, indicative of extensive endothelial damage is associated with enhanced expression of caveolin-1 in SMC, which may worsen the disease. PMID:23372934

  16. Inflammable gas mixture detection with a single catalytic sensor based on the electric field effect.

    PubMed

    Tong, Ziyuan; Tong, Min-Ming; Meng, Wen; Li, Meng

    2014-04-08

    This paper introduces a new way to analyze mixtures of inflammable gases with a single catalytic sensor. The analysis technology was based on a new finding that an electric field on the catalytic sensor can change the output sensitivity of the sensor. The analysis of mixed inflammable gases results from processing the output signals obtained by adjusting the electric field parameter of the catalytic sensor. For the signal process, we designed a group of equations based on the heat balance of catalytic sensor expressing the relationship between the output signals and the concentration of gases. With these equations and the outputs of different electric fields, the gas concentration in a mixture could be calculated. In experiments, a mixture of methane, butane and ethane was analyzed by this new method, and the results showed that the concentration of each gas in the mixture could be detected with a single catalytic sensor, and the maximum relative error was less than 5%.

  17. Inflammable Gas Mixture Detection with a Single Catalytic Sensor Based on the Electric Field Effect

    PubMed Central

    Tong, Ziyuan; Tong, Min-Ming; Meng, Wen; Li, Meng

    2014-01-01

    This paper introduces a new way to analyze mixtures of inflammable gases with a single catalytic sensor. The analysis technology was based on a new finding that an electric field on the catalytic sensor can change the output sensitivity of the sensor. The analysis of mixed inflammable gases results from processing the output signals obtained by adjusting the electric field parameter of the catalytic sensor. For the signal process, we designed a group of equations based on the heat balance of catalytic sensor expressing the relationship between the output signals and the concentration of gases. With these equations and the outputs of different electric fields, the gas concentration in a mixture could be calculated. In experiments, a mixture of methane, butane and ethane was analyzed by this new method, and the results showed that the concentration of each gas in the mixture could be detected with a single catalytic sensor, and the maximum relative error was less than 5%. PMID:24717635

  18. Detecting Renal Allograft Inflammation Using Quantitative Urine Metabolomics and CXCL10

    PubMed Central

    Ho, Julie; Sharma, Atul; Mandal, Rupasri; Wishart, David S.; Wiebe, Chris; Storsley, Leroy; Karpinski, Martin; Gibson, Ian W.; Nickerson, Peter W.; Rush, David N.

    2016-01-01

    Background The goal of this study was to characterize urinary metabolomics for the noninvasive detection of cellular inflammation and to determine if adding urinary chemokine ligand 10 (CXCL10) improves the overall diagnostic discrimination. Methods Urines (n = 137) were obtained before biopsy in 113 patients with no (n = 66), mild (borderline or subclinical; n = 58), or severe (clinical; n = 13) rejection from a prospective cohort of adult renal transplant patients (n = 113). Targeted, quantitative metabolomics was performed with direct flow injection tandem mass spectrometry using multiple reaction monitoring (ABI 4000 Q-Trap). Urine CXCL10 was measured by enzyme-linked immunosorbent assay. A projection on latent structures discriminant analysis was performed and validated using leave-one-out cross-validation, and an optimal 2-component model developed. Chemokine ligand 10 area under the curve (AUC) was determined and net reclassification index and integrated discrimination index analyses were performed. Results PLS2 demonstrated that urinary metabolites moderately discriminated the 3 groups (Cohen κ, 0.601; 95% confidence interval [95% CI], 0.46-0.74; P < 0.001). Using binary classifiers, urinary metabolites and CXCL10 demonstrated an AUC of 0.81 (95% CI, 0.74-0.88) and 0.76 (95% CI, 0.68-0.84), respectively, and a combined AUC of 0.84 (95% CI, 0.78-0.91) for detecting alloimmune inflammation that was improved by net reclassification index and integrated discrimination index analyses. Urinary CXCL10 was the best univariate discriminator, followed by acylcarnitines and hexose. Conclusions Urinary metabolomics can noninvasively discriminate noninflamed renal allografts from those with subclinical and clinical inflammation, and the addition of urine CXCL10 had a modest but significant effect on overall diagnostic performance. These data suggest that urinary metabolomics and CXCL10 may be useful for noninvasive monitoring of alloimmune inflammation in renal

  19. Detection of pulmonary fat embolism with dual-energy CT: an experimental study in rabbits.

    PubMed

    Tang, Chun Xiang; Zhou, Chang Sheng; Zhao, Yan E; Schoepf, U Joseph; Mangold, Stefanie; Ball, B Devon; Han, Zong Hong; Qi, Li; Zhang, Long Jiang; Lu, Guang Ming

    2017-04-01

    To evaluate the use of dual-energy CT imaging of the lung perfused blood volume (PBV) for the detection of pulmonary fat embolism (PFE). Dual-energy CT was performed in 24 rabbits before and 1 hour, 1 day, 4 days and 7 days after artificial induction of PFE via the right ear vein. CT pulmonary angiography (CTPA) and lung PBV images were evaluated by two radiologists, who recorded the presence, number, and location of PFE on a per-lobe basis. Sensitivity, specificity, and accuracy of CTPA and lung PBV for detecting PFE were calculated using histopathological evaluation as the reference standard. A total of 144 lung lobes in 24 rabbits were evaluated and 70 fat emboli were detected on histopathological analysis. The overall sensitivity, specificity and accuracy were 25.4 %, 98.6 %, and 62.5 % for CTPA, and 82.6 %, 76.0 %, and 79.2 % for lung PBV. Higher sensitivity (p < 0.001) and accuracy (p < 0.01), but lower specificity (p < 0.001), were found for lung PBV compared with CTPA. Dual-energy CT can detect PFE earlier than CTPA (all p < 0.01). Dual-energy CT provided higher sensitivity and accuracy in the detection of PFE as well as earlier detection compared with conventional CTPA in this animal model study. • Fat embolism occurs commonly in patients with traumatic bone injury. • Dual-energy CT improves diagnostic performance for pulmonary fat embolism detection. • Dual-energy CT can detect pulmonary fat embolism earlier than CTPA.

  20. Therapeutic efficacy of AM156, a novel prostanoid DP2 receptor antagonist, in murine models of allergic rhinitis and house dust mite-induced pulmonary inflammation.

    PubMed

    Stebbins, Karin J; Broadhead, Alex R; Correa, Lucia D; Scott, Jill M; Truong, Yen P; Stearns, Brian A; Hutchinson, John H; Prasit, Peppi; Evans, Jilly F; Lorrain, Daniel S

    2010-07-25

    Prostaglandin D(2) (PGD(2)) is derived from arachidonic acid and binds with high affinity to the G protein coupled receptors prostanoid DP(1) and DP(2). Interaction with DP(2) results in cell chemotaxis, eosinophil degranulation, eosinophil shape change, adhesion molecule upregulation and Th2 cytokine production. In allergic rhinitis and allergic asthma PGD(2) is released from mast cells in response to allergen challenge and may trigger symptoms such as sneezing, rhinorrhea, pruritus, mucus hypersecretion and pulmonary inflammation. In Japan, ramatroban, a dual prostanoid DP(2)/prostanoid TP receptor antagonist, is marketed for allergic rhinitis while selective DP(2) antagonists are currently under investigation as therapeutics for asthma and allergic rhinitis. In the studies described herein, we investigated the efficacy of AM156, a novel selective prostanoid DP(2) receptor antagonist, in murine models of allergic rhinitis and asthma. AM156 inhibited sneezing and nasal rubs in a model of allergic rhinitis. AM156 inhibited pulmonary inflammation and mucus hypersecretion induced by chronic inhalation of house dust mite. These results suggest that selective prostanoid DP(2) receptor antagonists such as AM156 may provide beneficial effects for the clinical treatment of diseases such as allergic rhinitis and asthma. (c) 2010 Elsevier B.V. All rights reserved.

  1. External detection of pulmonary accumulation of indium-113m labelled transferrin in the guinea pig.

    PubMed Central

    Hultkvist-Bengtsson, U; Mårtensson, L

    1990-01-01

    Accumulation of radioisotope labelled transferrin in the lungs of guinea pigs was determined with an external detection system. The method is based on the intravascular and extravascular distribution of indium-113m labelled transferrin compared with the intravascular distribution of technetium-99m labelled red blood cells. Guinea pigs were given iloprost, a prostacyclin analogue and potent pulmonary vasodilator, and noradrenaline, a pulmonary vasoconstrictor, in an attempt to increase and decrease respectively the blood volume in the lungs. Neither agent altered transferrin accumulation in the lung by comparison with a saline infusion. Iloprost infused before and after oleic acid infusion reduced macro-molecular leakage when compared with oleic acid alone. These data suggest that the double isotope method can distinguish between hydrostatic and injury induced pulmonary oedema. PMID:1699294

  2. Detection of pulmonary aspiration in infants and children with respiratory disease: concise communication

    SciTech Connect

    Boonyaprapa, S.; Alderson, P.O.; Garfinkel, D.J.; Chipps, B.E.; Wagner, H.N. Jr.

    1980-04-01

    Twenty children with respiratory disease ingested 500 ..mu..Ci of Tc-99m sulfur colloid orally, and scintigrams of the thorax were obtained to determine whether pulmonaryaspiration of gastric contents could be detected. The children ranged in age from 1 mo to 14 y; 13 were 8 months of age or younger. Children were studied at 5 min and 4 h after ingestion of Tc-99m sulfur colloid using a high-sensitivity computer oscilloscope to record 100K-count images. Additional images were obtained after the children had slept overnight. Five children (25%) showed definite pulmonary accumulation of activity; four of these also had a barium swallow and three showed either pulmonary aspiration of barium or moderately severe gastroesophageal reflux. Oral ingestion of Tc-99m sulfur colloid provides a noninvasive means for diagnosing pulmonary aspiration under physiologic conditions in infants and children.

  3. Modern Age Pathology of Pulmonary Arterial Hypertension

    PubMed Central

    Stacher, Elvira; Graham, Brian B.; Hunt, James M.; Gandjeva, Aneta; Groshong, Steve D.; McLaughlin, Vallerie V.; Jessup, Marsha; Grizzle, William E.; Aldred, Michaela A.; Cool, Carlyne D.

    2012-01-01

    Rationale: The impact of modern treatments of pulmonary arterial hypertension (PAH) on pulmonary vascular pathology remains unknown. Objectives: To assess the spectrum of pulmonary vascular remodeling in the modern era of PAH medication. Methods: Assessment of pulmonary vascular remodeling and inflammation in 62 PAH and 28 control explanted lungs systematically sampled. Measurements and Main Results: Intima and intima plus media fractional thicknesses of pulmonary arteries were increased in the PAH group versus the control lungs and correlated with pulmonary hemodynamic measurements. Despite a high variability of morphological measurements within a given PAH lung and among all PAH lungs, distinct pathological subphenotypes were detected in cohorts of PAH lungs. These included a subset of lungs lacking intima or, most prominently, media remodeling, which had similar numbers of profiles of plexiform lesions as those in lungs with more pronounced remodeling. Marked perivascular inflammation was present in a high number of PAH lungs and correlated with intima plus media remodeling. The number of profiles of plexiform lesions was significantly lower in lungs of male patients and those never treated with prostacyclin or its analogs. Conclusions: Our results indicate that multiple features of pulmonary vascular remodeling are present in patients treated with modern PAH therapies. Perivascular inflammation may have an important role in the processes of vascular remodeling, all of which may ultimately lead to increased pulmonary artery pressure. Moreover, our study provides a framework to interpret and design translational studies in PAH. PMID:22679007

  4. Modern age pathology of pulmonary arterial hypertension.

    PubMed

    Stacher, Elvira; Graham, Brian B; Hunt, James M; Gandjeva, Aneta; Groshong, Steve D; McLaughlin, Vallerie V; Jessup, Marsha; Grizzle, William E; Aldred, Michaela A; Cool, Carlyne D; Tuder, Rubin M

    2012-08-01

    The impact of modern treatments of pulmonary arterial hypertension (PAH) on pulmonary vascular pathology remains unknown. To assess the spectrum of pulmonary vascular remodeling in the modern era of PAH medication. Assessment of pulmonary vascular remodeling and inflammation in 62 PAH and 28 control explanted lungs systematically sampled. Intima and intima plus media fractional thicknesses of pulmonary arteries were increased in the PAH group versus the control lungs and correlated with pulmonary hemodynamic measurements. Despite a high variability of morphological measurements within a given PAH lung and among all PAH lungs, distinct pathological subphenotypes were detected in cohorts of PAH lungs. These included a subset of lungs lacking intima or, most prominently, media remodeling, which had similar numbers of profiles of plexiform lesions as those in lungs with more pronounced remodeling. Marked perivascular inflammation was present in a high number of PAH lungs and correlated with intima plus media remodeling. The number of profiles of plexiform lesions was significantly lower in lungs of male patients and those never treated with prostacyclin or its analogs. Our results indicate that multiple features of pulmonary vascular remodeling are present in patients treated with modern PAH therapies. Perivascular inflammation may have an important role in the processes of vascular remodeling, all of which may ultimately lead to increased pulmonary artery pressure. Moreover, our study provides a framework to interpret and design translational studies in PAH.

  5. Hemoglobin induced lung vascular oxidation, inflammation, and remodeling contributes to the progression of hypoxic pulmonary hypertension and is attenuated in rats with repeat dose haptoglobin administration

    PubMed Central

    Baek, Jin Hyen; Hassell, Kathryn; Nuss, Rachelle; Eigenberger, Paul; Lisk, Christina; Loomis, Zoe; Maltzahn, Joanne; Stenmark, Kurt R; Nozik-Grayck, Eva

    2015-01-01

    Objective Haptoglobin (Hp) is an approved treatment in Japan with indications for trauma, burns and massive transfusion related hemolysis. Additional case reports suggest uses in other acute hemolytic events that lead to acute kidney injury. However, Hp's protective effects on the pulmonary vasculature have not been evaluated within the context of mitigating the consequences of chronic hemoglobin (Hb) exposure in the progression of pulmonary hypertension (PH) secondary to hemolytic diseases. This study was performed to assess the utility of chronic Hp therapy in a preclinical model of Hb and hypoxia mediated PH. Approach and results Rats were simultaneously exposed to chronic Hb-infusion (35 mg per day) and hypobaric hypoxia for five weeks in the presence or absence of Hp treatment (90 mg/kg twice a week). Hp inhibited the Hb plus hypoxia-mediated non-heme iron accumulation in lung and heart tissue, pulmonary vascular inflammation and resistance, and right ventricular hypertrophy, which suggest a positive impact on impeding the progression of PH. In addition, Hp therapy was associated with a reduction in critical mediators of PH, including lung adventitial macrophage population and endothelial ICAM-1 expression. Conclusions By preventing Hb-mediated pathology, Hp infusions: (1) demonstrate a critical role for Hb in vascular remodeling associated with hypoxia; and (2) suggest a novel therapy for chronic hemolysis associated PH. PMID:25656991

  6. Hemoglobin-induced lung vascular oxidation, inflammation, and remodeling contribute to the progression of hypoxic pulmonary hypertension and is attenuated in rats with repeated-dose haptoglobin administration.

    PubMed

    Irwin, David C; Baek, Jin Hyen; Hassell, Kathryn; Nuss, Rachelle; Eigenberger, Paul; Lisk, Christina; Loomis, Zoe; Maltzahn, Joanne; Stenmark, Kurt R; Nozik-Grayck, Eva; Buehler, Paul W

    2015-05-01

    Haptoglobin (Hp) is an approved treatment in Japan for trauma, burns, and massive transfusion-related hemolysis. Additional case reports suggest uses in other acute hemolytic events that lead to acute kidney injury. However, Hp's protective effects on the pulmonary vasculature have not been evaluated within the context of mitigating the consequences of chronic hemoglobin (Hb) exposure in the progression of pulmonary hypertension (PH) secondary to hemolytic diseases. This study was performed to assess the utility of chronic Hp therapy in a preclinical model of Hb and hypoxia-mediated PH. Rats were simultaneously exposed to chronic Hb infusion (35 mg per day) and hypobaric hypoxia for 5 weeks in the presence or absence of Hp treatment (90 mg/kg twice a week). Hp inhibited the Hb plus hypoxia-mediated nonheme iron accumulation in lung and heart tissue, pulmonary vascular inflammation and resistance, and right-ventricular hypertrophy, which suggests a positive impact on impeding the progression of PH. In addition, Hp therapy was associated with a reduction in critical mediators of PH, including lung adventitial macrophage population and endothelial ICAM-1 expression. By preventing Hb-mediated pathology, Hp infusions: (1) demonstrate a critical role for Hb in vascular remodeling associated with hypoxia and (2) suggest a novel therapy for chronic hemolysis-associated PH.

  7. MAP3K19 Is Overexpressed in COPD and Is a Central Mediator of Cigarette Smoke-Induced Pulmonary Inflammation and Lower Airway Destruction

    PubMed Central

    Franz-Bacon, Karin; Ludka, John; DiTirro, Danielle N.; Ly, Tai Wei; Bacon, Kevin B.

    2016-01-01

    Chronic obstructive pulmonary disease (COPD) is characterized by persistent airflow limitation and lung inflammation resulting in a progressive decline in lung function whose principle cause is cigarette smoke. MAP3K19 is a novel kinase expressed predominantly by alveolar and interstitial macrophages and bronchial epithelial cells in the lung. We found that MAP3K19 mRNA was overexpressed in a limited sampling of lung tissue from COPD patients, and a closer examination found it to be overexpressed in bronchoalveolar macrophages from COPD patients, as well as the bronchial epithelium and inflammatory cells in the lamina propria. We further found MAP3K19 to be induced in various cell lines upon environmental stress, such as cigarette smoke, oxidative and osmotic stress. Exogenous expression of MAP3K19 in cells caused an upregulation of transcriptionally active NF-κB, and secretion of the chemokines CXCL-8, CCL-20 and CCL-7. Inhibition of MAP3K19 activity by siRNA or small molecular weight inhibitors caused a decrease in cigarette smoke-induced inflammation in various murine models, which included a decrease in pulmonary neutrophilia and KC levels. In a chronic cigarette smoke model, inhibition of MAP3K19 significantly attenuated emphysematous changes in airway parenchyma. Finally, in a viral exacerbation model, mice exposed to cigarette smoke and influenza A virus showed a decrease in pulmonary neutrophilia, pro-inflammatory cytokines and viral load upon inhibition of MAP3K19. Collectively, these results suggest that inhibition of MAP3K19 may represent a novel strategy to target COPD that promises to have a potential therapeutic benefit for patients. PMID:27935962

  8. MAP3K19 Is Overexpressed in COPD and Is a Central Mediator of Cigarette Smoke-Induced Pulmonary Inflammation and Lower Airway Destruction.

    PubMed

    Boehme, Stefen A; Franz-Bacon, Karin; Ludka, John; DiTirro, Danielle N; Ly, Tai Wei; Bacon, Kevin B

    2016-01-01

    Chronic obstructive pulmonary disease (COPD) is characterized by persistent airflow limitation and lung inflammation resulting in a progressive decline in lung function whose principle cause is cigarette smoke. MAP3K19 is a novel kinase expressed predominantly by alveolar and interstitial macrophages and bronchial epithelial cells in the lung. We found that MAP3K19 mRNA was overexpressed in a limited sampling of lung tissue from COPD patients, and a closer examination found it to be overexpressed in bronchoalveolar macrophages from COPD patients, as well as the bronchial epithelium and inflammatory cells in the lamina propria. We further found MAP3K19 to be induced in various cell lines upon environmental stress, such as cigarette smoke, oxidative and osmotic stress. Exogenous expression of MAP3K19 in cells caused an upregulation of transcriptionally active NF-κB, and secretion of the chemokines CXCL-8, CCL-20 and CCL-7. Inhibition of MAP3K19 activity by siRNA or small molecular weight inhibitors caused a decrease in cigarette smoke-induced inflammation in various murine models, which included a decrease in pulmonary neutrophilia and KC levels. In a chronic cigarette smoke model, inhibition of MAP3K19 significantly attenuated emphysematous changes in airway parenchyma. Finally, in a viral exacerbation model, mice exposed to cigarette smoke and influenza A virus showed a decrease in pulmonary neutrophilia, pro-inflammatory cytokines and viral load upon inhibition of MAP3K19. Collectively, these results suggest that inhibition of MAP3K19 may represent a novel strategy to target COPD that promises to have a potential therapeutic benefit for patients.

  9. CD28/B7 Deficiency Attenuates Systolic Overload-Induced Congestive Heart Failure, Myocardial and Pulmonary Inflammation, and Activated T Cell Accumulation in the Heart and Lungs.

    PubMed

    Wang, Huan; Kwak, Dongmin; Fassett, John; Hou, Lei; Xu, Xin; Burbach, Brandon J; Thenappan, Thenappan; Xu, Yawei; Ge, Jun-Bo; Shimizu, Yoji; Bache, Robert J; Chen, Yingjie

    2016-09-01

    The inflammatory response regulates congestive heart failure (CHF) development. T cell activation plays an important role in tissue inflammation. We postulate that CD28 or B7 deficiency inhibits T cell activation and attenuates CHF development by reducing systemic, cardiac, and pulmonary inflammation. We demonstrated that chronic pressure overload-induced end-stage CHF in mice is characterized by profound accumulation of activated effector T cells (CD3(+)CD44(high) cells) in the lungs and a mild but significant increase of these cells in the heart. In knockout mice lacking either CD28 or B7, there was a dramatic reduction in the accumulation of activated effector T cells in both hearts and lungs of mice under control conditions and after transverse aortic constriction. CD28 or B7 knockout significantly attenuated transverse aortic constriction-induced CHF development, as indicated by less increase of heart and lung weight and less reduction of left ventricle contractility. CD28 or B7 knockout also significantly reduced transverse aortic constriction-induced CD45(+) leukocyte, T cell, and macrophage infiltration in hearts and lungs, lowered proinflammatory cytokine expression (such as tumor necrosis factor-α and interleukin-1β) in lungs. Furthermore, CD28/B7 blockade by CTLA4-Ig treatment (250 μg/mouse every 3 days) attenuated transverse aortic constriction-induced T cell activation, left ventricle hypertrophy, and left ventricle dysfunction. Our data indicate that CD28/B7 deficiency inhibits activated effector T cell accumulation, reduces myocardial and pulmonary inflammation, and attenuates the development of CHF. Our findings suggest that strategies targeting T cell activation may be useful in treating CHF.

  10. Electrocardiographic detection of right ventricular pressure overload in patients with suspected pulmonary hypertension.

    PubMed

    Kamphuis, Vivian P; Haeck, Marlieke L A; Wagner, Galen S; Maan, Arie C; Maynard, Charles; Delgado, Victoria; Vliegen, Hubert W; Swenne, Cees A

    2014-01-01

    Early, preferably noninvasive, detection of pulmonary hypertension improves prognosis. Our study evaluated the diagnostic accuracy of the electrocardiographically derived Butler-Leggett (BL) score and ventricular gradient (VG) to estimate mean pulmonary artery pressure (PAP). In 63 patients with suspected pulmonary hypertension, BL score and VG were calculated. The VG was projected on a direction optimized for detection of right ventricular pressure overload (VG-RVPO). BL score and VG-RVPO were entered in multiple linear regression analysis and the diagnostic performance to detect PH (invasively measured mean PAP ≥ 25 mmHg) was assessed with receiver operating characteristic analysis. Both BL score and VG-RVPO correlated significantly with mean PAP (r=0.45 and r=0.61, respectively; P<0.001). Combining BL score and VG-RVPO increased the correlation to 0.67 (P<0.001). The diagnostic performance of this combination for the detection of PH was good with an area under the curve of 0.79 (P<0.001). Combination of the BL score and VG-RVPO allows for accurate detection of increased PAP. Copyright © 2014 Elsevier Inc. All rights reserved.

  11. The standardized herbal formula, PM014, ameliorated cigarette smoke-induced lung inflammation in a murine model of chronic obstructive pulmonary disease

    PubMed Central

    2013-01-01

    Background In this study, we evaluated the anti-inflammatory effect of PM014 on cigarette smoke induced lung disease in the murine animal model of chronic obstructive pulmonary disease (COPD). Methods Mice were exposed to cigarette smoke (CS) for 2 weeks to induce COPD-like lung inflammation. Two hours prior to cigarette smoke exposure, the treatment group was administered PM014 via an oral injection. To investigate the effects of PM014, we assessed PM014 functions in vivo, including immune cell infiltration, cytokine profiles in bronchoalveolar lavage (BAL) fluid and histopathological changes in the lung. The efficacy of PM014 was compared with that of the recently developed anti-COPD drug, roflumilast. Results PM014 substantially inhibited immune cell infiltration (neutrophils, macrophages, and lymphocytes) into the airway. In addition, IL-6, TNF-α and MCP-1 were decreased in the BAL fluid of PM014-treated mice compared to cigarette smoke stimulated mice. These changes were more prominent than roflumilast treated mice. The expression of PAS-positive cells in the bronchial layer was also significantly reduced in both PM014 and roflumilast treated mice. Conclusions These data suggest that PM014 exerts strong therapeutic effects against CS induced, COPD-like lung inflammation. Therefore, this herbal medicine may represent a novel therapeutic agent for lung inflammation in general, as well as a specific agent for COPD treatment. PMID:24010767

  12. Short-term exposure to high ambient air pollution increases airway inflammation and respiratory symptoms in chronic obstructive pulmonary disease patients in Beijing, China.

    PubMed

    Wu, Shaowei; Ni, Yang; Li, Hongyu; Pan, Lu; Yang, Di; Baccarelli, Andrea A; Deng, Furong; Chen, Yahong; Shima, Masayuki; Guo, Xinbiao

    2016-09-01

    Few studies have investigated the short-term respiratory effects of ambient air pollution in chronic obstructive pulmonary disease (COPD) patients in the context of high pollution levels in Asian cities. A panel of 23 stable COPD patients was repeatedly measured for biomarkers of airway inflammation including exhaled nitric oxide (FeNO) and exhaled hydrogen sulfide (FeH2S) (215 measurements) and recorded for daily respiratory symptoms (794person-days) in two study periods in Beijing, China in January-September 2014. Daily ambient air pollution data were obtained from nearby central air-monitoring stations. Mixed-effects models were used to estimate the associations between exposures and health measurements with adjustment for potential confounders including temperature and relative humidity. Increasing levels of air pollutants were associated with significant increases in both FeNO and FeH2S. Interquartile range (IQR) increases in PM2.5 (76.5μg/m(3), 5-day), PM10 (75.0μg/m(3), 5-day) and SO2 (45.7μg/m(3), 6-day) were associated with maximum increases in FeNO of 13.6% (95% CI: 4.8%, 23.2%), 9.2% (95% CI: 2.1%, 16.8%) and 34.2% (95% CI: 17.3%, 53.4%), respectively; and the same IQR increases in PM2.5 (6-day), PM10 (6-day) and SO2 (7-day) were associated with maximum increases in FeH2S of 11.4% (95% CI: 4.6%, 18.6%), 7.8% (95% CI: 2.3%, 13.7%) and 18.1% (95% CI: 5.5%, 32.2%), respectively. Increasing levels of air pollutants were also associated with increased odds ratios of sore throat, cough, sputum, wheeze and dyspnea. FeH2S may serve as a novel biomarker to detect adverse respiratory effects of air pollution. Our results provide potential important public health implications that ambient air pollution may pose risk to respiratory health in the context of high pollution levels in densely-populated cities in the developing world. Copyright © 2016 Elsevier Ltd. All rights reserved.

  13. Effects of Schisandra chinensis extracts on cough and pulmonary inflammation in a cough hypersensitivity guinea pig model induced by cigarette smoke exposure.

    PubMed

    Zhong, Shan; Nie, Yi-chu; Gan, Zhen-yong; Liu, Xiao-dong; Fang, Zhang-fu; Zhong, Bo-nian; Tian, Jin; Huang, Chu-qin; Lai, Ke-fang; Zhong, Nan-shan

    2015-05-13

    Schisandra chinensis (S. chinensis) is a traditional Chinese medicine commonly used in prescription medications for the treatment of chronic cough. However, the material basis of S. chinensis in relieving cough has not been completely elucidated yet. This study established a guinea pig model of cough hypersensitivity induced by 14 days of cigarette smoke (CS) exposure, to evaluate the antitussive, antioxidant, and anti-inflammatory effects of three S. chinensis extracts. And then the function of four lignans in reducing expression of TRPV1 and TRPA1 was examined using A549 cells induced by cigarette smoke extract (CSE). The results demonstrated that both ethanol extract (EE) and ethanol-water extract (EWE) of S. chinensis, but not water extract (WE), significantly reduced the cough frequency enhanced by 0.4M citric acid solution in these cough hypersensitivity guinea pigs. Meanwhile, pretreatment with EE and EWE both significantly attenuated the CS-induced increase in infiltration of pulmonary neutrophils and total inflammatory cells, as well as pulmonary MDA, TNF-α, and IL-8, while remarkably increased activities of pulmonary SOD and GSH. According to H&E and immunofluorescence staining assays, airway epithelium hyperplasia, smooth muscle thickening, inflammatory cells infiltration, as well as expression of TRPV1 and TRPA1, were significantly attenuated in animals pretreatment with 1g/kg EE. Moreover, four lignans of EE, including schizandrin, schisantherin A, deoxyschizandrin and γ-schisandrin, significantly inhibited CSE-induced expression of TRPV1, TRPA1 and NOS3, as well as NO release in A549 cells. In conclusion, S. chinensis reduces cough frequency and pulmonary inflammation in the CS-induced cough hypersensitivity guinea pigs. Lignans may be the active components. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  14. Bioimpedance measurements in dentistry to detect inflammation: numerical modelling and experimental results.

    PubMed

    Cosoli, G; Scalise, L; Tricarico, G; Russo, P; Cerri, G

    2017-06-01

    Bioimpedance measurements represent an advantageous method to evaluate the physio-pathological conditions of biological tissues and their use is spreading in different application fields, from the evaluation of body composition to the vital signs monitoring, passing through the individuation of cancer tissues and the detection of different substances (e.g. glucose measurements in people affected by diabetes). In fact, tissues electric properties vary with their conditions; for example, electrical conductivity increases when there is an inflammatory process, because of the presence of oedema, hyperaemia and infiltration. Inflammatory phenomena are frequent in dentistry, in diseases like periodontitis and peri-implantitis; however, at present the diagnosis is mainly done with the naked eye, by observing the gingiva redness and swelling. The aim of this work is to prove the feasibility of the inflammation detection by means of bioimpedance measurements. Both numerical simulations and preliminary experimental measurements provide significant outcomes in differentiating between healthy and inflamed tissues. Percentage differences in the impedance modulus equal to 4-20% (numerical simulations) and 35-56% (experimental measurements), respectively, depending on the considered conditions (e.g. electrodes characteristics and inflammation severity), were found. Such a measure could be integrated in electromedical devices designed, for example, for the therapy of peri-implantitis, in order to personalise the therapeutic dose in terms of intensity and duration and focusing it on the impaired area, minimising the effects on the surrounding tissues.

  15. The association of dietary intake and supplementation of specific polyunsaturated fatty acids with inflammation and functional capacity in chronic obstructive pulmonary disease: a systematic review.

    PubMed

    Atlantis, Evan; Cochrane, Belinda

    2016-06-01

    This systematic review sought to identify the association of dietary intake and supplementation of specific polyunsaturated fatty acids with inflammation and function in people with chronic obstructive pulmonary disease (COPD). We searched electronic databases including PubMed, CINAHL, MEDLINE, EMBASE, The Cochrane Library, ProQuest Dissertations and Theses, Scopus, Google Scholar, Trove, and WHO International Clinical Trials Registry Platform and reference lists of retrieved articles published prior to August 2014. We considered observational studies that evaluated dietary intake of omega-3 (eicosapentaenoic acid, docosahexaenoic acid or α-linolenic acid) and/or omega-6 fatty acids (γ-linoleic acid or arachidonic acid), and experimental studies that evaluated omega-3 fatty acid supplementation (containing predominantly one or more omega-3 fatty acids) on airway and systemic inflammatory markers and/or functional capacity outcomes in people with COPD-related diagnoses. Since statistical pooling was not possible, the findings were presented in narrative form including tables and figures to aid in data presentation when appropriate. One 8-week randomized controlled trial conducted in 80 COPD patients in the Netherlands showed polyunsaturated fatty acid supplementation significantly improved exercise capacity compared with the control condition [between-group difference in mean peak workload was 9.7 W (2.5-17.0; P = 0.009); and mean duration was 4.3 min (0.6-7.9; P = 0.023)]. One cross-sectional study conducted in 250 COPD patients in Spain found associations of specific dietary omega-3 fatty acids with inflammation were inconsistent. Limited evidence provides weak support for the use of omega-3 fatty acid supplementation for reducing chronic inflammation and some support for improving functional capacity in COPD patients. There is no consistent evidence showing that low dietary intake of specific omega-3 fatty acids worsens inflammation and/or function

  16. Comparison of three-view thoracic radiography and computed tomography for detection of pulmonary nodules in dogs with neoplasia.

    PubMed

    Armbrust, Laura J; Biller, David S; Bamford, Aubrey; Chun, Ruthanne; Garrett, Laura D; Sanderson, Michael W

    2012-05-01

    To compare the detection of pulmonary nodules by use of 3-view thoracic radiography and CT in dogs with confirmed neoplasia. Prospective case series. 33 dogs of various breeds. 3 interpreters independently evaluated 3-view thoracic radiography images. The location and size of pulmonary nodules were recorded. Computed tomographic scans of the thorax were obtained and evaluated by a single interpreter. The location, size, margin, internal architecture, and density of pulmonary nodules were recorded. Sensitivity, specificity, positive predictive value, and negative predictive value were calculated for thoracic radiography (with CT as the gold standard). 21 of 33 (64%) dogs had pulmonary nodules or masses detected on CT. Of the dogs that had positive CT findings, 17 of 21 (81%) had pulmonary nodules or masses detected on radiographs by at least 1 interpreter. Sensitivity of radiography ranged from 71% to 95%, and specificity ranged from 67% to 92%. Radiography had a positive predictive value of 83% to 94% and a negative predictive value of 65% to 89%. The 4 dogs that were negative for nodules on thoracic radiography but positive on CT were all large-breed to giant-breed dogs with osteosarcoma. CT was more sensitive than radiography for detection of pulmonary nodules. This was particularly evident in large-breed to giant-breed dogs. Thoracic CT is recommended in large-breed to giant-breed dogs with osteosarcoma if the detection of pulmonary nodules will change treatment.

  17. Pulmonary nodule detection using a cascaded SVM classifier

    NASA Astrophysics Data System (ADS)

    Bergtholdt, Martin; Wiemker, Rafael; Klinder, Tobias

    2016-03-01

    Automatic detection of lung nodules from chest CT has been researched intensively over the last decades resulting also in several commercial products. However, solutions are adopted only slowly into daily clinical routine as many current CAD systems still potentially miss true nodules while at the same time generating too many false positives (FP). While many earlier approaches had to rely on rather few cases for development, larger databases become now available and can be used for algorithmic development. In this paper, we address the problem of lung nodule detection via a cascaded SVM classifier. The idea is to sequentially perform two classification tasks in order to select from an extremely large pool of potential candidates the few most likely ones. As the initial pool is allowed to contain thousands of candidates, very loose criteria could be applied during this pre-selection. In this way, the chances that a true nodule is falsely rejected as a candidate are reduced significantly. The final algorithm is trained and tested on the full LIDC/IDRI database. Comparison is done against two previously published CAD systems. Overall, the algorithm achieved sensitivity of 0.859 at 2.5 FP/volume where the other two achieved sensitivity values of 0.321 and 0.625, respectively. On low dose data sets, only slight increase in the number of FP/volume was observed, while the sensitivity was not affected.

  18. Design, Tuning and Performance Evaluation of an Automated Pulmonary Nodule Detection System.

    DTIC Science & Technology

    1983-02-01

    Lampeter TR 120 February 1983 This report reproduces a thesis submitted in partial fulfillment of the r qiiiis I’m the degree of Master of Science in...faculty All the rewatch contained in this thesis and the preparation of tho document were completed at the University of Rochester. This work was funded in...Detection of the Pulmonary Nodule by the Human Viewer 9 1.4 Previous Work: Digital Processing and Analysis of Chest Radiographs 13 2- INTRODUCTION

  19. Accuracy of pulmonary auscultation to detect abnormal respiratory mechanics: a cross-sectional diagnostic study.

    PubMed

    Xavier, Glaciele Nascimento; Duarte, Antonio Carlos Magalhães; Melo-Silva, César Augusto; dos Santos, Carlos Eduardo Ventura Gaio; Amado, Veronica Moreira

    2014-12-01

    Pulmonary auscultation is a method used in clinical practice for the evaluation and detection of abnormalities relating to the respiratory system. This method has limitations, as it depends on the experience and hearing acuity of the examiner to determine adventitious sounds. In this context, it's important to analyze whether there is a correlation between auscultation of lung sounds and the behavior of the respiratory mechanical properties of the respiratory system in patients with immediate postoperative cardiac surgery.

  20. Detection of pulmonary metastases with the novel radiolabeled molecular probe, 99mTc-RRL

    PubMed Central

    Yao, Ning; Yan, Ping; Wang, Rong-Fu; Zhang, Chun-Li; Ma, Chao; Chen, Xue-Qi; Zhao, Qian; Hao, Pan

    2015-01-01

    Background: To improve the detection of pulmonary metastases, experimental blood-borne pulmonary metastasis mouse models were established using three intravenously administered cell lines. In a previous study we demonstrated that 99mTc-radiolabeled arginine-arginine-leucine (RRL) could be used to non-invasively image malignant tumors. Methods: 99mTc-RRL was prepared and injected intravenously in mice with pulmonary metastases that arose from the intravenous injection of HepG2, B16, and Hela cells. The bio-distribution and imaging of 99mTc-RRL were determined in different pulmonary metastases mouse models and in normal mice. Results: 99mTc-RRL exhibited higher uptake values in the lungs of pulmonary metastatic mice compared to normal mice (P<0.05; 3.92±0.48% ID/g 2 h post-injection and 3.89±0.36% ID/g 4 h post-injection in metastatic hepatic carcinoma [HepG2]-bearing lungs; 5.49±0.84% ID/g 2 h post-injection and 5.11±0.75% ID/g 4 h post-injection in metastatic melanoma [B16]-bearing lungs; 3.72±0.52% ID/g 2 h post-injection and 3.51±0.35% ID/g 4 h post-injection in metastatic cervical carcinoma [Hela]-bearing lungs; 2.38±0.20% ID/g 2 h post-injection and 2.11±0.24% ID/g 4 h post-injection in normal lungs). The pulmonary metastatic lesions were clearly visualized using 99mTc-RRL. Conclusions: 99mTc-RRL exhibited favorable metastatic tumor targeting and imaging properties, thus highlighting its potential as an effective imaging probe for detection of pulmonary metastases. 99mTc-RRL can be used as a reasonable supplement to 18F-FDG imaging in the non-invasive imaging of tumor angiogenesis. PMID:25932101

  1. DIFFERENTIAL PULMONARY INFLAMMATION AND IN VITRO CYTOTOXICITY BY SIZE-FRACTIONATED FLY ASH PARTICLES FROM PULVERIZED COAL COMBUSTION

    EPA Science Inventory

    The paper presents results of research on the adverse health effects associated with exposure to airborne particulate matter. Pulmonary inflammatory responses were examined in CDI mice after intratracheal instillation of 25 or 100 micrograms of ultrafine (<0.2 micrometers), fine ...

  2. 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...

  3. 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...

  4. DIFFERENTIAL PULMONARY INFLAMMATION AND IN VITRO CYTOTOXICITY BY SIZE-FRACTIONATED FLY ASH PARTICLES FROM PULVERIZED COAL COMBUSTION

    EPA Science Inventory

    The paper presents results of research on the adverse health effects associated with exposure to airborne particulate matter. Pulmonary inflammatory responses were examined in CDI mice after intratracheal instillation of 25 or 100 micrograms of ultrafine (<0.2 micrometers), fine ...

  5. A hybrid preprocessing method using geometry based diffusion and elective enhancement filtering for pulmonary nodule detection

    NASA Astrophysics Data System (ADS)

    Dhara, Ashis K.; Mukhopadhyay, Sudipta

    2012-03-01

    The computer aided diagnostic (CAD) system has been developed to assist radiologist for early detection and analysis of lung nodules. For pulmonary nodule detection, image preprocessing is required to remove the anatomical structure of lung parenchyma and to enhance the visibility of pulmonary nodules. In this paper a hybrid preprocessing technique using geometry based diffusion and selective enhancement filtering have been proposed. This technique provides a unified preprocessing framework for solid nodule as well as ground glass opacity (GGO) nodules. Geometry based diffusion is applied to smooth the images by preserving the boundary. In order to improve the sensitivity of pulmonary nodule detection, selective enhancement filter is used to highlight blob like structure. But selective enhancement filter sometimes enhances the structures like blood vessel and airways other than nodule and results in large number of false positive. In first step, geometry based diffusion (GBD) is applied for reduction of false positive and in second step, selective enhancement filtering is used for further reduction of false negative. Geometry based diffusion and selective enhancement filtering has been used as preprocessing step separately but their combined effect was not investigated earlier. This hybrid preprocessing approach is suitable for accurate calculation of voxel based features. The proposed method has been validated on one public database named Lung Image Database Consortium (LIDC) containing 50 nodules (30 solid and 20 GGO nodule) from 30 subjects and one private database containing 40 nodules (25 solid and 15 GGO nodule) from 30 subjects.

  6. Automatic detection of subsolid pulmonary nodules in thoracic computed tomography images.

    PubMed

    Jacobs, Colin; van Rikxoort, Eva M; Twellmann, Thorsten; Scholten, Ernst Th; de Jong, Pim A; Kuhnigk, Jan-Martin; Oudkerk, Matthijs; de Koning, Harry J; Prokop, Mathias; Schaefer-Prokop, Cornelia; van Ginneken, Bram

    2014-02-01

    Subsolid pulmonary nodules occur less often than solid pulmonary nodules, but show a much higher malignancy rate. Therefore, accurate detection of this type of pulmonary nodules is crucial. In this work, a computer-aided detection (CAD) system for subsolid nodules in computed tomography images is presented and evaluated on a large data set from a multi-center lung cancer screening trial. The paper describes the different components of the CAD system and presents experiments to optimize the performance of the proposed CAD system. A rich set of 128 features is defined for subsolid nodule candidates. In addition to previously used intensity, shape and texture features, a novel set of context features is introduced. Experiments show that these features significantly improve the classification performance. Optimization and training of the CAD system is performed on a large training set from one site of a lung cancer screening trial. Performance analysis on an independent test from another site of the trial shows that the proposed system reaches a sensitivity of 80% at an average of only 1.0 false positive detections per scan. A retrospective analysis of the output of the CAD system by an experienced thoracic radiologist shows that the CAD system is able to find subsolid nodules which were not contained in the screening database.

  7. Exhaled nitric oxide, systemic inflammation, and the spirometric response to inhaled fluticasone propionate in severe chronic obstructive pulmonary disease: a prospective study.

    PubMed

    Kunisaki, Ken M; Rice, Kathryn L; Janoff, Edward N; Rector, Thomas S; Niewoehner, Dennis E

    2008-04-01

    A subset of patients with chronic obstructive pulmonary disease (COPD) may respond more favorably to inhaled corticosteroids (ICS), but no simple method is currently utilized to predict the presence or absence of ICS responses in patients with COPD.We evaluated the ability of exhaled nitric oxide (FENO) and serum inflammatory markers (C-reactive protein [CRP], interleukin-6 [IL-6], and interleukin-8 [IL-8]) to independently predict spirometric responses to ICS in patients with COPD. Among 60 ex-smokers with severe COPD (mean FEV1 1.07 L, 36% of predicted), we conducted a single-arm, open-label study. Participants spent four weeks free of any ICS, followed by four weeks of ICS use (fluticasone propionate 500 mcg twice daily). FENO, CRP, IL-6, IL-8, and pre-bronchodilator spirometry were measured immediately before and after the four weeks of ICS use. Baseline FENO, CRP, IL-6, and IL-8 showed no correlations to FEV1 responses to ICS. ICS responders (increase in FEV1 > or = 200 mL after four weeks of ICS) did have significantly higher baseline FENO levels compared with non-responders (46.5 parts per billion [ppb] vs. 25 ppb, p = 0.028). The receiver operating characteristic curve for FENO to discriminate responders from non-responders had an area under curve of 0.72. Baseline serum inflammatory markers did not differ between responders and non-responders. In ex-smokers with severe COPD, a measure of local pulmonary inflammation, FENO, may be more closely associated with FEV1 responses to four weeks of ICS than are standard markers of systemic inflammation, serum CRP, IL-6, and IL-8.

  8. Cost-effectiveness of a new strategy to detect pulmonary tuberculosis in household contacts in Myanmar.

    PubMed

    Htet, K K K; Liabsuetrakul, T; Thein, S

    2017-02-01

    Guidelines regarding household contact tracing for pulmonary tuberculosis (TB) in different countries vary according to case detection methods. To compare costs spent on detecting one TB case among household contacts between different contact tracing strategies in Mandalay City, Myanmar. Cost estimation of case detection and diagnostic procedures using two different strategies were calculated. A modified conventional model included screening for TB signs and symptoms, sputum examination for those with positive signs and symptoms and chest X-ray (CXR) for those with negative sputum results. An interventional model included CXR, sputum examination if CXR was abnormal and Xpert® MTB/RIF assay for those with negative sputum results. Estimated costs in each model were stratified by age <15 and 15 years. The additional cost per TB case detected using the interventional model was US$35.41 compared to the modified conventional model. The probability that the interventional model was cost-effective using a threshold of US$100 per case detected was 81% (83% for those aged 15 years and 65% for those aged <15 years). The interventional model was more cost-effective in detecting one more pulmonary TB case among household contacts than the modified conventional model.

  9. Computer-aided Detection Fidelity of Pulmonary Nodules in Chest Radiograph

    PubMed Central

    Dellios, Nikolaos; Teichgraeber, Ulf; Chelaru, Robert; Malich, Ansgar; Papageorgiou, Ismini E

    2017-01-01

    Aim: The most ubiquitous chest diagnostic method is the chest radiograph. A common radiographic finding, quite often incidental, is the nodular pulmonary lesion. The detection of small lesions out of complex parenchymal structure is a daily clinical challenge. In this study, we investigate the efficacy of the computer-aided detection (CAD) software package SoftView™ 2.4A for bone suppression and OnGuard™ 5.2 (Riverain Technologies, Miamisburg, OH, USA) for automated detection of pulmonary nodules in chest radiographs. Subjects and Methods: We retrospectively evaluated a dataset of 100 posteroanterior chest radiographs with pulmonary nodular lesions ranging from 5 to 85 mm. All nodules were confirmed with a consecutive computed tomography scan and histologically classified as 75% malignant. The number of detected lesions by observation in unprocessed images was compared to the number and dignity of CAD-detected lesions in bone-suppressed images (BSIs). Results: SoftView™ BSI does not affect the objective lesion-to-background contrast. OnGuard™ has a stand-alone sensitivity of 62% and specificity of 58% for nodular lesion detection in chest radiographs. The false positive rate is 0.88/image and the false negative (FN) rate is 0.35/image. From the true positive lesions, 20% were proven benign and 80% were malignant. FN lesions were 47% benign and 53% malignant. Conclusion: We conclude that CAD does not qualify for a stand-alone standard of diagnosis. The use of CAD accompanied with a critical radiological assessment of the software suggested pattern appears more realistic. Accordingly, it is essential to focus on studies assessing the quality-time-cost profile of real-time (as opposed to retrospective) CAD implementation in clinical diagnostics. PMID:28299236

  10. An essential role for the Stat3 in regulating IgG immune complex-induced pulmonary inflammation

    USDA-ARS?s Scientific Manuscript database

    Growing evidence suggests that transcription factor signal transducer and activator of transcription (Stat) 3 may play an important regulatory role during inflammation. However, the function of Stat3 in acute lung injury (ALI) is largely unknown. In the current study, by using an adenoviral vector e...

  11. Comparison of histochemical methods for murine eosinophil detection in a RSV vaccine-enhanced inflammation model

    PubMed Central

    Meyerholz, David K.; Griffin, Michelle A.; Castilow, Elaine M.; Varga, Steven M.

    2009-01-01

    A comparative study of histochemical detection of eosinophils in fixed murine tissue is lacking. Five histochemical methods previously reported for eosinophil detection were quantitatively and qualitatively compared in an established murine RSV vaccine-enhanced inflammation model. Nonspecific neutrophil staining was evaluated in tissue sections of neutrophilic soft tissue lesions and bone marrow from respective animals. Eosinophils had granular red to orange-red cytoplasmic staining, depending on the method, whereas neutrophils had, when stained, a more homogenous cytoplasmic pattern. Nonspecific background staining of similar coloration was variably seen in arterial walls and erythrocytes. Astra Blue/Vital New Red, Congo Red, Luna, Modified Hematoxylin & Eosin, and Sirius Red techniques were all effective in detecting increased eosinophil recruitment compared to controls; however, differences in eosinophil quantification significantly varied between techniques. Astra Blue/Vital New Red had the best specificity for differentiating eosinophils and neutrophils, but had a reduced ability to enumerate eosinophils and was the most time intensive. The Luna stain had excessive non specific staining of tissues and a reduced enumeration of infiltrating eosinophils making it suboptimal. For multiple parameters such as eosinophil detection, specificity, and contrast with background tissues, the Sirius Red followed by Congo Red and Modified Hematoxylin & Eosin methods were useful, each with their own staining qualities. PMID:19181630

  12. Ventilation-perfusion scintigraphy is more sensitive than multidetector CTPA in detecting chronic thromboembolic pulmonary disease as a treatable cause of pulmonary hypertension.

    PubMed

    Tunariu, Nina; Gibbs, Simon J R; Win, Zarni; Gin-Sing, Wendy; Graham, Alison; Gishen, Philip; Al-Nahhas, Adil

    2007-05-01

    Pulmonary hypertension (PH) is a progressive disease with a poor prognosis. Identifying chronic thromboembolic pulmonary disease as a cause of PH has major clinical implications as these patients could be potentially offered a surgical cure. Ventilation-perfusion (V/Q) scintigraphy has a high sensitivity to detect embolic disease but its value has been challenged with the emergence of multidetector CT pulmonary angiography (CTPA). We compared the value of V/Q scintigraphy with CTPA in detecting chronic thromboembolic pulmonary disease. We retrospectively reviewed the results of V/Q scintigraphy and CTPA performed on patients who had been referred to the Pulmonary Hypertension Service at Hammersmith Hospital between 2000 and 2005. A total of 227 patients (85 males, 142 females; age range, 18-81 y; mean age, 42 y) had all tests done at Hammersmith Hospital and were included in the study. Interpretation of scans was according to the modified PIOPED (Prospective Investigation of Pulmonary Embolism Diagnosis) criteria. CTPA was considered as suggestive of chronic thromboembolic pulmonary disease if it showed visualization of the thrombus or webs, recanalization, perfusion abnormalities, stenosis, or strictures. Standard pulmonary angiography was performed via femoral approach. In 90% of the cases, CTPA and V/Q scintigraphy were performed within 10 d. Seventy-eight patients (group A) had a final diagnosis of chronic thromboembolic pulmonary hypertension (CTEPH) and 149 (group B) had non-CTEPH etiology. Among group A, V/Q scintigraphy was reported as high probability in 75 patients, intermediate probability in 1 patient, and low probability in 2 patients. CTPA was positive in 40 patients and negative in 38 patients. Among group B, V/Q scintigraphy was reported as low probability in 134, intermediate probability in 7, and high probability in 8 patients. CTPA was negative in 148 patients and false-positive in 1 patient. Statistical analysis showed V/Q scintigraphy to have a

  13. Virus-like particle vaccines containing F or F and G proteins confer protection against respiratory syncytial virus without pulmonary inflammation in cotton rats.

    PubMed

    Hwang, Hye Suk; Kim, Ki-Hye; Lee, Youri; Lee, Young-Tae; Ko, Eun-Ju; Park, SooJin; Lee, Jong Seok; Lee, Byung-Cheol; Kwon, Young-Man; Moore, Martin L; Kang, Sang-Moo

    2017-01-27

    Vaccine-enhanced disease has been a major obstacle in developing a safe vaccine against respiratory syncytial virus (RSV). This study demonstrates the immunogenicity, efficacy, and safety of virus-like particle (VLP) vaccines containing RSV F (F VLP), G (G VLP), or F and G proteins (FG VLP) in cotton rats. RSV specific antibodies were effectively induced by vaccination of cotton rats with F VLP or FG VLP vaccines. After challenge, lung RSV clearance was observed with RSV F, G, FG VLP, and formalin inactivated RSV (FI-RSV) vaccines. Upon RSV infection, cotton rats with RSV VLP vaccines were protected against airway hyper-responsiveness and weight loss, which are different from FI-RSV vaccination exhibiting vaccine-enhanced disease of airway obstruction, weight loss, and severe histopathology with eosinophilia and mucus production. FG VLP and F VLP vaccines did not cause pulmonary inflammation whereas G VLP induced moderate lung inflammation with eosinophilia and mucus production. In particular, F VLP and FG VLP vaccines were found to be effective in inducing antibody secreting cell responses in bone marrow and lymphoid organs as well as avoiding the induction of T helper type 2 cytokines. These results provide further evidence to develop a safe RSV vaccine based on VLP platforms.

  14. Inducible nitric oxide synthase inhibition attenuates lung tissue responsiveness and remodeling in a model of chronic pulmonary inflammation in guinea pigs.

    PubMed

    Starling, Claudia M; Prado, Carla M; Leick-Maldonado, Edna A; Lanças, Tatiana; Reis, Fabiana G; Aristóteles, Luciana R C B R; Dolhnikoff, Marisa; Martins, Mílton A; Tibério, Iolanda F L C

    2009-02-28

    We evaluated the influence of iNOS-derived NO on the mechanics, inflammatory, and remodeling process in peripheral lung parenchyma of guinea pigs with chronic pulmonary allergic inflammation. Animals treated or not with 1400 W were submitted to seven exposures of ovalbumin in increasing doses. Seventy-two hours after the 7th inhalation, lung strips were suspended in a Krebs organ bath, and tissue resistance and elastance measured at baseline and after ovalbumin challenge. The strips were submitted to histopathological measurements. The ovalbumin-exposed animals showed increased maximal responses of resistance and elastance (p<0.05), eosinophils counting (p<0.001), iNOS-positive cells (p<0.001), collagen and elastic fiber deposition (p<0.05), actin density (p<0.05) and 8-iso-PGF2alpha expression (p<0.001) in alveolar septa compared to saline-exposed ones. Ovalbumin-exposed animals treated with 1400 W had a significant reduction in lung functional and histopathological findings (p<0.05). We showed that iNOS-specific inhibition attenuates lung parenchyma constriction, inflammation, and remodeling, suggesting NO-participation in the modulation of the oxidative stress pathway.

  15. Neutral Lipids and Peroxisome Proliferator-Activated Receptor-γ Control Pulmonary Gene Expression and Inflammation-Triggered Pathogenesis in Lysosomal Acid Lipase Knockout Mice

    PubMed Central

    Lian, Xuemei; Yan, Cong; Qin, Yulin; Knox, Lana; Li, Tingyu; Du, Hong

    2005-01-01

    The functional roles of neutral lipids in the lung are poorly understood. However, blocking cholesteryl ester and triglyceride metabolism in lysosomal acid lipase gene knockout mice (lal−/−) results in severe pathogenic phenotypes in the lung, including massive neutrophil infiltration, foamy macrophage accumulation, unwanted cell growth, and emphysema. To elucidate the mechanism underlining these pathologies, we performed Affymetrix GeneChip microarray analysis of 1-, 3-, and 6-month-old mice and identified aberrant gene expression that progressed with age. Among changed genes, matrix metalloproteinase (MMP)-12, apoptosis inhibitor 6 (Api-6), erythroblast transformation-specific domain (Ets) transcription factor family member Spi-C, and oncogene MafB were increased 100-, 70-, 40-, and 10-fold, respectively, in lal−/− lungs versus the wild-type lungs. The pathogenic increases of these molecules occurred primarily in alveolar type II epithelial cells. Transcriptional activities of the MMP-12 and Api-6 promoters were stimulated by Spi-C or MafB in respiratory epithelial cells. Treatment with 9-hydroxyoctadecanoic acids and ciglitazone significantly rescued lal−/− pulmonary inflammation and aberrant gene expression. In addition, both compounds as well as peroxisome proliferator-activated receptor gamma inhibited MMP-12 and Api-6 promoter activities. These data suggest that inflammation-triggered cell growth and emphysema during lysosomal acid lipase deficiency are partially caused by peroxisome proliferator-activated receptor-γ inactivation. PMID:16127159

  16. Effect of uterine inflammation and ultrasonically-detected uterine pathology on fertility in the mare.

    PubMed

    Adams, G P; Kastelic, J P; Bergfelt, D R; Ginther, O J

    1987-01-01

    The incidence of intrauterine fluid collections during dioestrus (12/43, 28%) and uterine cysts throughout the oestrous cycle (11/73, 15%) found in this study indicates that these ultrasonically detectable abnormalities are prevalent in mares. The hypothesis that uterine cysts do not affect pregnancy was not supported. Intrauterine fluid collections at dioestrus represented the presence of an inflammatory process as indicated by a high biopsy score, reduced progesterone concentrations, and a shorter interovulatory interval. Mares with fluid collections at dioestrus had a lower pregnancy rate at Day 11 and a higher embryonic loss rate by Day 20 than did mares without such collections. The progesterone profile and length of interovulatory interval for mares with uterine inflammation supported the hypotheses that embryonic loss in this herd was due to uterine-induced luteolysis rather than primary luteal inadequacy.

  17. Computer-assisted detection (CAD) of pulmonary nodules on thoracic CT scans using image processing and classification techniques

    NASA Astrophysics Data System (ADS)

    Dehmeshki, Jamshid; Valdivieso-Casique, Manlio; Siddique, Musib; Dehkordi, Mandana E.; Costello, John; Roddie, Mary

    2004-05-01

    Computer assisted methods for the detection of pulmonary nodules have become more important as the resolution of CT scanners has increased and as more accurate and reproducible detections are needed. In this paper we describe the results of a CAD system for the detection of lung nodules and compare them against the interpretations of three independent radiologists.

  18. Noninvasive Detection and Differentiation of Axonal Injury/Loss, Demyelination, and Inflammation

    DTIC Science & Technology

    2015-10-01

    spectrum imaging, diffusion tensor imaging, EAE, inflammation, axonal injury, curizone, demyelination, optic neuritis, axonal loss 16. SECURITY...diffusion basis spectrum imaging (DBSI) to simultaneously quantify axonal injury, demyelination, and inflammation in CNS white matter, correlating with...Multiple sclerosis, diffusion basis spectrum imaging, diffusion tensor imaging, EAE, inflammation, axonal injury, demyelination, axonal loss, optic

  19. New noncontact sensor for detecting pulmonary tumors during video-assisted thoracic surgery.

    PubMed

    Akayama, Koichi; Miyata, Yoshihiro; Kawahara, Tomohiro; Okada, Morihito; Kaneko, Makoto; Okajima, Masazumi; Ohdan, Hideki

    2017-06-15

    Small pulmonary tumors are difficult to localize during video-assisted thoracic surgery (VATS) because of lack of direct tissue contact. However, in partial lung resection, tumor localization is quite important. The aim of this study was to evaluate the safety and feasibility of a new noncontact sensor for detecting pulmonary nodules during VATS using human and porcine models. The sensor, based on the principle of phase differences, comprises an air nozzle for producing air pulse jets and an optical fiber sensor to measure phase differences and visualize object stiffness. For in vivo assessment, we developed a porcine model by inserting plastic balls mimicking tumors into the pig lungs after thoracotomy and then scanned the lungs. The sensor sensitivity was evaluated by measuring the ratio of the depth of the ball from the lung surface to the ball diameter (D/S). For the ex vivo human model, partially resected lung tissue with tumors was obtained from six patients and then scanned. In the porcine model, 32 of 37 (86.5%), 70 of 94 (74.5%), and 60 of 100 (60.0%) tumors were detected in the categories D/S ≤ 1, 1 < D/S ≤ 2, and D/S > 2, respectively. Sensor safety was confirmed with an air jet at pressures between 0.05 and 0.15 MPa directed onto the lung surface; all the examined lungs including the pleura remained intact microscopically. In six patients, all nodules were successfully detected. Our noncontact sensor is a safe and feasible tool for detecting small pulmonary tumors during VATS. Copyright © 2016 Elsevier Inc. All rights reserved.

  20. Identification of the appropriate dose metric for pulmonary inflammation of silver nanoparticles in an inhalation toxicity study.

    PubMed

    Braakhuis, Hedwig M; Cassee, Flemming R; Fokkens, Paul H B; de la Fonteyne, Liset J J; Oomen, Agnes G; Krystek, Petra; de Jong, Wim H; van Loveren, Henk; Park, Margriet V D Z

    2016-01-01

    A number of studies have shown that induction of pulmonary toxicity by nanoparticles of the same chemical composition depends on particle size, which is likely in part due to differences in lung deposition. Particle size mostly determines whether nanoparticles reach the alveoli, and where they might induce toxicity. For the risk assessment of nanomaterials, there is need for a suitable dose metric that accounts for differences in effects between different sized nanoparticles of the same chemical composition. The aim of the present study is to determine the most suitable dose metric to describe the effects of silver nanoparticles after short-term inhalation. Rats were exposed to different concentrations (ranging from 41 to 1105 µg silver/m(3) air) of 18, 34, 60 and 160 nm silver particles for four consecutive days and sacrificed at 24 h and 7 days after exposure. We observed a concentration-dependent increase in pulmonary toxicity parameters like cell counts and pro-inflammatory cytokines in the bronchoalveolar lavage fluid. All results were analysed using the measured exposure concentrations in air, the measured internal dose in the lung and the estimated alveolar dose. In addition, we analysed the results based on mass, particle number and particle surface area. Our study indicates that using the particle surface area as a dose metric in the alveoli, the dose-response effects of the different silver particle sizes overlap for most pulmonary toxicity parameters. We conclude that the alveolar dose expressed as particle surface area is the most suitable dose metric to describe the toxicity of silver nanoparticles after inhalation.

  1. C1q Deficiency Promotes Pulmonary Vascular Inflammation and Enhances the Susceptibility of the Lung Endothelium to Injury.

    PubMed

    Shah, Dilip; Romero, Freddy; Zhu, Ying; Duong, Michelle; Sun, Jianxin; Walsh, Kenneth; Summer, Ross

    2015-12-04

    The collectin proteins are innate immune molecules found in high concentrations on the epithelial and endothelial surfaces of the lung. While these proteins are known to have important anti-inflammatory actions in the airways of the lung little is known of their functional importance in the pulmonary circulation. We recently demonstrated that the circulating collectin protein adiponectin has potent anti-inflammatory effects on the lung endothelium, leading us to reason that other structurally related proteins might have similar effects. To test this hypothesis, we investigated the anti-inflammatory actions of C1q in lung endothelial homeostasis and the pulmonary vascular response to LPS or HCl injury. We show that lung endothelium from C1q-deficient (C1q(-/-)) mice expresses higher baseline levels of the vascular adhesion markers ICAM-1, VCAM-1, and E-selectin when compared with wild-type mice. Further, we demonstrate that these changes are associated with enhanced susceptibility of the lung to injury as evident by increased expression of adhesion markers, enhanced production of pro-inflammatory cytokines, and augmented neutrophil recruitment. Additionally, we found that C1q(-/-) mice also exhibited enhanced endothelial barrier dysfunction after injury as manifested by decreased expression of junctional adherens proteins and enhanced vascular leakage. Mechanistically, C1q appears to mediate its effects by inhibiting phosphorylation of p38 mitogen-activated protein kinase (MAPK) and blocking nuclear translocation of the P65 subunit of nuclear factor (NF)-κB. In summary, our findings indicate a previously unrecognized role for C1q in pulmonary vascular homeostasis and provide added support for the hypothesis that circulating collectin proteins have protective effects on the lung endothelium.

  2. Effect of morphing between unenhanced and multiscale enhanced chest radiographs on pulmonary nodule detection

    NASA Astrophysics Data System (ADS)

    Pietrzyk, Mariusz W.; Zöhrer, Fabian; Harz, Markus T.; McEntee, Mark; Hahn, Horst K.; Haygood, Tamara; Evanoff, Michael G.; Brennan, Patrick C.

    2012-02-01

    Aim: This study aims to determine the effectiveness of a novel image-processing algorithm for multi-scale enhancement of chest radiographs to improve detection and localization of real pulmonary nodules. Background: Our wavelet-based enhancement method interactively adjusts the contrast of medical images extracting the spatial frequency components at different scales, followed by a weighting procedure. This study aims to explore the usefulness of this novel procedure for chest image reporting. Method: Sixteen radiologists viewed 50 PA chest radiographs in order to localize pulmonary nodules. The databank contains 25 normal and 25 abnormal images, with multi-nodule cases. Subjects were allowed to mark unlimited number of locations followed by ranking confidence of nodule presence according to a 5-level scale. Subjects viewed all cases at least in two out of three conditions: unprocessed, enhanced and with morphing between these two. MCMR ROC and JAFROC analyses were conducted. Results: No significant differences were found in ROC AUC values across modalities and specialities. Only localization performance with morphing tool is significantly higher (F(1,8)=13.303, p=0.007) for chest expert (JAFROC FOM=0.6355) from non-chest (JAFROC FOM=0.4675) radiologists. Conclusion: Radiologists specialized in chest image interpretation performed consistently well in localizing pulmonary nodules, whereas non-chest radiologists were suffer from distracting effect of morphing tool.

  3. Comparative evaluation of physicians' pulmonary nodule detection with reduced slice thickness at CT screening

    NASA Astrophysics Data System (ADS)

    Sinsuat, Marodina; Shimamura, Ichiro; Saita, Shinsuke; Kubo, Mitsuru; Kawata, Yoshiki; Niki, Noboru; Ohmatsu, Hironobu; Kakinuma, Ryutaro; Eguchi, Kenji; Kaneko, Masahiro; Tominaga, Keigo; Moriyama, Noriyuki

    2008-03-01

    With thin and thick section Multi-slice CT images at lung cancer screening, we have statistically and quantitatively shown and evaluated the diagnostic capabilities of these slice thicknesses on physicians' pulmonary nodule diagnosis. To comparatively evaluate the 2 mm and 10 mm slice thicknesses, MSCT images of 360 people were read by six physicians. The reading criteria consisted of nodule for further examination (NFE), nodule for no further examination (NNFE) and no abnormality (NA) case. For reading results evaluation; firstly, cross-tabulation was carried out to roughly analyze the diagnoses based on whole lung field and each lung lobes. Secondly, from semi-automated extraction result of the nodule, detailed quantitative analysis was carried out to determine the diagnostic capabilities of two slice thicknesses. Finally, using the reading results of 2 mm thick image as the gold standard, the diagnostic capabilities were analyzed through the features and locations of pulmonary nodules. The study revealed that both slice thicknesses can depict lung cancer. Thin section may not be effective to diagnose nodules of <=3 mm in size and nodules of <= 5mm in size for thick section. Though thick section is less tiring for reading physicians, it is not good at depicting nodules located at the border of lung upper lobe and which have a pixel size distance of <=5 from the chest wall. The information presented may serve as a useful reference to determine in which particular pulmonary nodule condition the two slice thicknesses can be effectively used for early detection of lung cancer.

  4. Effect of radiation dose level on the detectability of pulmonary nodules in chest tomosynthesis.

    PubMed

    Asplund, Sara A; Johnsson, Åse A; Vikgren, Jenny; Svalkvist, Angelica; Flinck, Agneta; Boijsen, Marianne; Fisichella, Valeria A; Månsson, Lars Gunnar; Båth, Magnus

    2014-07-01

    To investigate the detectability of pulmonary nodules in chest tomosynthesis at reduced radiation dose levels. Eighty-six patients were included in the study and were examined with tomosynthesis and computed tomography (CT). Artificial noise was added to simulate that the tomosynthesis images were acquired at dose levels corresponding to 12, 32, and 70% of the default setting effective dose (0.12 mSv). Three observers (with >20, >20 and three years of experience) read the tomosynthesis cases for presence of nodules in a free-response receiver operating characteristics (FROC) study. CT served as reference. Differences between dose levels were calculated using the jack-knife alternative FROC (JAFROC) figure of merit (FOM). The JAFROC FOM was 0.45, 0.54, 0.55, and 0.54 for the 12, 32, 70, and 100% dose levels, respectively. The differences in FOM between the 12% dose level and the 32, 70, and 100% dose levels were 0.087 (p = 0.006), 0.099 (p = 0.003), and 0.093 (p = 0.004), respectively. Between higher dose levels, no significant differences were found. A substantial reduction from the default setting dose in chest tomosynthesis may be possible. In the present study, no statistically significant difference in detectability of pulmonary nodules was found when reducing the radiation dose to 32%. • A substantial radiation dose reduction in chest tomosynthesis may be possible. • Pulmonary nodule detectability remained unchanged at 32% of the effective dose. • Tomosynthesis might be performed at the dose of a lateral chest radiograph.

  5. Quantitative multiplexed detection of common pulmonary fungal pathogens by labeled primer polymerase chain reaction.

    PubMed

    Gu, Zhengming; Buelow, Daelynn R; Petraitiene, Ruta; Petraitis, Vidmantas; Walsh, Thomas J; Hayden, Randall T

    2014-11-01

    Invasive fungal infections are an important cause of morbidity and mortality among immunocompromised patients. To design and evaluate a multiplexed assay aimed at quantitative detection and differentiation of the 5 molds that are most commonly responsible for pulmonary infections. Using labeled primer polymerase chain reaction chemistry, an assay was designed to target the 5.8S and 28S ribosomal RNA genes of Aspergillus spp, Fusarium spp, Scedosporium spp, and members of the order Mucorales ( Rhizopus oryzae , Rhizopus microsporus, Cunninghamella bertholletiae, Mucor circinelloides, Lichtheimia corymbifera, and Rhizomucor pusillus). This assay was split into 2 multiplexed reactions and was evaluated using both samples seeded with purified nucleic acid from 42 well-characterized clinical fungal isolates and 105 archived samples (47 blood [45%], 42 bronchoalveolar lavage fluid [40%], and 16 tissue [15%]) collected from rabbit models of invasive pulmonary fungal infections. Assay detection sensitivity was less than 25 copies of the target sequence per reaction for Aspergillus spp, 5 copies for Fusarium spp and Scedosporium spp, and 10 copies for the Mucorales. The assay showed quantitative linearity from 5 × 10(1) to 5 × 10(5) copies of target sequence per reaction. Sensitivities and specificities for bronchoalveolar lavage fluid, tissue, and blood samples were 0.86 and 0.99, 0.60 and 1.00, and 0.46 and 1.00, respectively. Labeled primer polymerase chain reaction permits rapid, quantitative detection and differentiation of common agents of invasive fungal infection. The assay described herein shows promise for clinical implementation that may have a significant effect on the rapid diagnosis and treatment of patients' severe infections caused by these pulmonary fungal pathogens.

  6. Use of non-invasive haemodynamic measurements to detect treatment response in precapillary pulmonary hypertension.

    PubMed

    Lee, Wai-Ting Nicola; Brown, Aileen; Peacock, Andrew John; Johnson, Martin Keith

    2011-09-01

    Haemodynamic measurements may be superior to the 6-min walk distance (6MWD) as outcome measures in pulmonary hypertension (PH) as they are directly linked to the mechanisms of disease and are not subject to a ceiling effect. The aim of this study was to determine if treatment response in precapillary PH could be detected by pulmonary blood flow (PBF) and stroke volume (SV) measured non-invasively by the inert gas rebreathing (IGR) method at rest and during submaximal constant-load cycle exercise. Twenty-four patients with precapillary PH receiving de novo or modified disease-targeted therapy were studied. Isotime metabolic variables, PBF and SV were measured at rest and during constant-load cycle exercise at 40% maximal work rate alongside conventional outcome variables, at baseline and after 3 months of new therapy. At follow-up there was a significant increase in PBF (supine rest: mean 0.7±SD 0.9 l/min, erect rest: 0.7±0.8 l/min, exercise: 0.8±1.0 l/min, p<0.005) and SV (supine rest: 7±10 ml, erect rest: 10±11 ml, exercise: median 6 (IQR 3-11) ml, p<0.005). There was a trend for 6MWD to increase by 17±42 or 29 (13-47) m (p=0.061), whereas WHO functional class, N-terminal pro-brain natriuretic peptide or Cambridge Pulmonary Hypertension Outcome Review score were unchanged. In patients with higher baseline 6MWD, IGR measurements were more sensitive than 6MWD in detecting treatment response. Non-invasive IGR haemodynamic measurements could be used to detect treatment response in patients with precapillary PH and may be more responsive to change than 6MWD in fitter patients.

  7. The association of dietary intake and supplementation of specific polyunsaturated fatty acids with inflammation and functional capacity in chronic obstructive pulmonary disease: a systematic review

    PubMed Central

    Atlantis, Evan; Cochrane, Belinda

    2016-01-01

    ABSTRACT Objective: This systematic review sought to identify the association of dietary intake and supplementation of specific polyunsaturated fatty acids with inflammation and function in people with chronic obstructive pulmonary disease (COPD). Data sources: We searched electronic databases including PubMed, CINAHL, MEDLINE, EMBASE, The Cochrane Library, ProQuest Dissertations and Theses, Scopus, Google Scholar, Trove, and WHO International Clinical Trials Registry Platform and reference lists of retrieved articles published prior to August 2014. Inclusion criteria: We considered observational studies that evaluated dietary intake of omega-3 (eicosapentaenoic acid, docosahexaenoic acid or α-linolenic acid) and/or omega-6 fatty acids (γ-linoleic acid or arachidonic acid), and experimental studies that evaluated omega-3 fatty acid supplementation (containing predominantly one or more omega-3 fatty acids) on airway and systemic inflammatory markers and/or functional capacity outcomes in people with COPD-related diagnoses. Data synthesis: Since statistical pooling was not possible, the findings were presented in narrative form including tables and figures to aid in data presentation when appropriate. Results: One 8-week randomized controlled trial conducted in 80 COPD patients in the Netherlands showed polyunsaturated fatty acid supplementation significantly improved exercise capacity compared with the control condition [between-group difference in mean peak workload was 9.7 W (2.5–17.0; P = 0.009); and mean duration was 4.3 min (0.6–7.9; P = 0.023)]. One cross-sectional study conducted in 250 COPD patients in Spain found associations of specific dietary omega-3 fatty acids with inflammation were inconsistent. Conclusions: Limited evidence provides weak support for the use of omega-3 fatty acid supplementation for reducing chronic inflammation and some support for improving functional capacity in COPD patients. There is no consistent evidence

  8. The EP1/EP3 receptor agonist 17-pt-PGE2 acts as an EP4 receptor agonist on endothelial barrier function and in a model of LPS-induced pulmonary inflammation.

    PubMed

    Theiler, Anna; Konya, Viktoria; Pasterk, Lisa; Maric, Jovana; Bärnthaler, Thomas; Lanz, Ilse; Platzer, Wolfgang; Schuligoi, Rufina; Heinemann, Akos

    2016-12-01

    Endothelial dysfunction is a hallmark of inflammatory conditions. We recently demonstrated that prostaglandin (PG)E2 enhances the resistance of pulmonary endothelium in vitro and counteracts lipopolysaccharide (LPS)-induced pulmonary inflammation in vivo via EP4 receptors. The aim of this study was to investigate the role of the EP1/EP3 receptor agonist 17-phenyl-trinor-(pt)-PGE2 on acute lung inflammation in a mouse model. In LPS-induced pulmonary inflammation in mice, 17-pt-PGE2 reduced neutrophil infiltration and inhibited vascular leakage. These effects were unaltered by an EP1 antagonist, but reversed by EP4 receptor antagonists. 17-pt-PGE2 increased the resistance of pulmonary microvascular endothelial cells and prevented thrombin-induced disruption of endothelial junctions. Again, these effects were not mediated via EP1 or EP3 but through activation of the EP4 receptor, as demonstrated by the lack of effect of more selective EP1 and EP3 receptor agonists, prevention of these effects by EP4 antagonists and EP4 receptor knock-down by siRNA. In contrast, the aggregation enhancing effect of 17-pt-PGE2 in human platelets was mediated via EP3 receptors. Our results demonstrate that 17-pt-PGE2 enhances the endothelial barrier in vitro on pulmonary microvascular endothelial cells, and accordingly ameliorates the recruitment of neutrophils, via EP4 receptors in vivo. This suggests a beneficial effect of 17-pt-PGE2 on pulmonary inflammatory diseases. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  9. Cross-Sectional Detection of Acute HIV Infection: Timing of Transmission, Inflammation and Antiretroviral Therapy

    PubMed Central

    Gay, Cynthia; Dibben, Oliver; Anderson, Jeffrey A.; Stacey, Andrea; Mayo, Ashley J.; Norris, Philip J.; Kuruc, JoAnn D.; Salazar-Gonzalez, Jesus F.; Li, Hui; Keele, Brandon F.; Hicks, Charles; Margolis, David; Ferrari, Guido; Haynes, Barton; Swanstrom, Ronald; Shaw, George M.; Hahn, Beatrice H.; Eron, Joseph J.; Borrow, Persephone; Cohen, Myron S.

    2011-01-01

    Background Acute HIV infection (AHI) is a critical phase of infection when irreparable damage to the immune system occurs and subjects are very infectious. We studied subjects with AHI prospectively to develop better treatment and public health interventions. Methods Cross-sectional screening was employed to detect HIV RNA positive, antibody negative subjects. Date of HIV acquisition was estimated from clinical history and correlated with sequence diversity assessed by single genome amplification (SGA). Twenty-two cytokines/chemokines were measured from enrollment through week 24. Results Thirty-seven AHI subjects were studied. In 7 participants with limited exposure windows, the median exposure to HIV occurred 14 days before symptom onset. Lack of viral sequence diversification confirmed the short duration of infection. Transmission dates estimated by SGA/sequencing using molecular clock models correlated with transmission dates estimated by symptom onset in individuals infected with single HIV variants (mean of 28 versus 33 days). Only 10 of 22 cytokines/chemokines were significantly elevated among AHI participants at enrollment compared to uninfected controls, and only 4 participants remained seronegative at enrollment. Discussion The results emphasize the difficulty in recruiting subjects early in AHI. Viral sequence diversity proved accurate in estimating time of infection. Regardless of aggressive screening, peak viremia and inflammation occurred before enrollment and potential intervention. Given the personal and public health importance, improved AHI detection is urgently needed. PMID:21573003

  10. [Computed tomography with computer-assisted detection of pulmonary nodules in dogs and cats].

    PubMed

    Niesterok, C; Piesnack, S; Köhler, C; Ludewig, E; Alef, M; Kiefer, I

    2015-01-01

    The aim of this study was to assess the potential benefit of computer-assisted detection (CAD) of pulmonary nodules in veterinary medicine. Therefore, the CAD rate was compared to the detection rates of two individual examiners in terms of its sensitivity and false-positive findings. We included 51 dogs and 16 cats with pulmonary nodules previously diagnosed by computed tomography. First, the number of nodules ≥ 3 mm was recorded for each patient by two independent examiners. Subsequently, each examiner used the CAD software for automated nodule detection. With the knowledge of the CAD results, a final consensus decision on the number of nodules was achieved. The software used was a commercially available CAD program. The sensitivity of examiner 1 was 89.2%, while that of examiner 2 reached 87.4%. CAD had a sensitivity of 69.4%. With CAD, the sensitivity of examiner 1 increased to 94.7% and that of examiner 2 to 90.8%. The CAD-system, which we used in our study, had a moderate sensitivity of 69.4%. Despite its severe limitations, with a high level of false-positive and false-negative results, CAD increased the examiners' sensitivity. Therefore, its supportive role in diagnostics appears to be evident.

  11. Predictive model for the detection of pulmonary hypertension in dogs with myxomatous mitral valve disease

    PubMed Central

    MIKAWA, Shoma; MIYAGAWA, Yuichi; TODA, Noriko; TOMINAGA, Yoshinori; TAKEMURA, Naoyuki

    2014-01-01

    Pulmonary hypertension (PH) often occurs due to a left heart disease, such as myxomatous mitral valve disease (MMVD), in dogs and is diagnosed using Doppler echocardiography and estimated pulmonary arterial pressure. Diagnosis of PH in dogs requires expertise in echocardiography: however, the examination for PH is difficult to perform in a clinical setting. Thus, simple and reliable methods are required for the diagnosis of PH in dogs. The purpose of this study was to develop models using multiple logistic regression analysis to detect PH due to left heart disease in dogs with MMVD without echocardiography. The medical records of dogs with MMVD were retrospectively reviewed, and 81 dogs were included in this study and classified into PH and non-PH groups. Bivariate analysis was performed to compare all parameters between the groups, and variables with P values of <0.25 in bivariate analysis were included in multiple logistic regression analysis to develop models for the detection of PH. In multiple logistic regression analysis, the model included a vertebral heart scale short axis of >5.2 v, and a length of sternal contact of >3.3 v was considered suitable for the detection of PH. The predictive accuracy of this model (85.9%) was judged statistically adequate, and therefore, this model may be useful to screen for PH due to left heart disease in dogs with MMVD without echocardiography. PMID:25319513

  12. False positive reduction for pulmonary nodule detection using two-dimensional principal component analysis

    NASA Astrophysics Data System (ADS)

    Choi, Wook-Jin; Choi, Tae-Sun

    2009-08-01

    Pulmonary nodule detection is a binary classification problem. The main objective is to classify nodule from the lung computed tomography (CT) images. The intra class variability is mainly due to the grey-level variance, texture differences and shape. The purpose of this study is to develop a novel nodule detection method which is based on Two-dimensional Principal Component Analysis (2DPCA). We extract the futures using 2DPCA from nodule candidate images. Nodule candidates are classified using threshold. The proposed method reduces False Positive (FP) rate. We tested the proposed algorithm by using Lung Imaging Database Consortium (LIDC) database of National Cancer Institute (NCI). The experimental results demonstrate the effectiveness and efficiency of the proposed method. The proposed method achieved 85.11% detection rate with 1.13 FPs per scan.

  13. Pulmonary Nodule Detection Model Based on SVM and CT Image Feature-Level Fusion with Rough Sets

    PubMed Central

    Lu, Huiling; Zhang, Junjie; Shi, Hongbin

    2016-01-01

    In order to improve the detection accuracy of pulmonary nodules in CT image, considering two problems of pulmonary nodules detection model, including unreasonable feature structure and nontightness of feature representation, a pulmonary nodules detection algorithm is proposed based on SVM and CT image feature-level fusion with rough sets. Firstly, CT images of pulmonary nodule are analyzed, and 42-dimensional feature components are extracted, including six new 3-dimensional features proposed by this paper and others 2-dimensional and 3-dimensional features. Secondly, these features are reduced for five times with rough set based on feature-level fusion. Thirdly, a grid optimization model is used to optimize the kernel function of support vector machine (SVM), which is used as a classifier to identify pulmonary nodules. Finally, lung CT images of 70 patients with pulmonary nodules are collected as the original samples, which are used to verify the effectiveness and stability of the proposed model by four groups' comparative experiments. The experimental results show that the effectiveness and stability of the proposed model based on rough set feature-level fusion are improved in some degrees. PMID:27722173

  14. Oxygen requirement as a screening tool for the detection of late pulmonary hypertension in extremely low birth weight infants.

    PubMed

    Aswani, Rohit; Hayman, Lisa; Nichols, Gina; Luciano, Angel A; Amankwah, Ernest K; Leshko, Jennifer L; Dadlani, Gul H

    2016-03-01

    Many extremely low birth weight infants develop pulmonary hypertension late in their clinical course, and over 60% go undetected by early screening echocardiography. At present, no standardised screening protocol exists for detecting late pulmonary hypertension in extremely low birth weight infants. We assessed the utility of oxygen supplementation as a predictor of late pulmonary hypertension. A retrospective single-centre review of extremely low birth weight infants with no evidence of CHD and those surviving for >30 days was performed. The association between oxygen ⩾30% at day of life 30 and diagnosis of late pulmonary hypertension was estimated with an odds ratio and 95% confidence interval using logistic regression. Doppler echocardiography was used to diagnose pulmonary hypertension in the infants. A total of 230 infants met the study criteria. The incidence of late pulmonary hypertension was 8.3% (19/230). Infants with late pulmonary hypertension were more likely to have a lower mean birth weight (667.1±144 versus 799.3±140 g, p=0.001) and more likely to be small for gestational age (47.4 versus 14.2%, p=0.004). Oxygen requirement ⩾30% at day of life 30 was associated with increased risk of late pulmonary hypertension (odds ratio=3.77, 95% confidence interval=1.42-10.00, p=0.008) in univariate analysis and after adjusting for birth weight (odds ratio=2.47, 95% confidence interval=0.89-6.84, p=0.08). The need of oxygen supplementation ⩾30% at day of life 30 may be a good screening tool for detecting late pulmonary hypertension in extremely low birth weight infants.

  15. Silica-induced pulmonary inflammation and fibrosis in mice is altered by acute exposure to nitrogen dioxide

    SciTech Connect

    Vetrano, K.M.; Morris, J.B.; Hubbard, A.K. )

    1992-11-01

    The biologic impact of consecutive exposures to two environmental pollutants was examined in mice exposed to silica crystals (SI) by intratracheal (IT) injection followed by an inhalation exposure to nitrogen dioxide (NO2). C57Bl/6 mice received an IT injection of 2 mg SI or sterile saline (SAL) followed by a 2-h inhalation exposure to NO2 at 20 ppm either within 2 h of or 24 h after SI instillation. During acute inflammation (d 3 postsilica), mice exposed to NO2 at either time showed a dramatic and significant reduction in the number of lavaged alveolar neutrophils (PMN) when compared to silica/air-exposed mice. Animals exposed to NO[sub 2] 24 h after silica also evidenced significant decreases in levels of lavage albumin and lactate dehydrogenase (LDH) 3 d after silica, as well as significant decreases in hydroxyproline content of the lung 30 and 60 d postsilica injection when compared to silica/air-exposed animals. NO[sub 2] administration 24 h after silica appeared to shift the appearance of PMN in the lung from d 3 to d 14, but did not otherwise alter chronic cellular inflammation. These data suggest that the marked neutrophil response and collagen deposition induced by SI can be modulated by NO[sub 2] exposure and that the time of oxidant gas exposure after silica administration is critical to this modulation.

  16. Marijuana smoke induces severe pulmonary hyperresponsiveness, inflammation, and emphysema in a predictive mouse model not via CB1 receptor activation.

    PubMed

    Helyes, Z; Kemény, Á; Csekő, K; Szőke, É; Elekes, K; Mester, M; Sándor, K; Perkecz, A; Kereskai, L; Márk, L; Bona, Á; Benkő, A; Pintér, E; Szolcsányi, J; Ledent, C; Sperlágh, B; Molnár, T F

    2017-08-01

    Sporadic clinical reports suggested that marijuana smoking induces spontaneous pneumothorax, but no animal models were available to validate these observations and to study the underlying mechanisms. Therefore, we performed a systematic study in CD1 mice as a predictive animal model and assessed the pathophysiological alterations in response to 4-mo-long whole body marijuana smoke with integrative methodologies in comparison with tobacco smoke. Bronchial responsiveness was measured with unrestrained whole body plethysmography, cell profile in the bronchoalveolar lavage fluid with flow cytometry, myeloperoxidase activity with spectrophotometry, inflammatory cytokines with ELISA, and histopathological alterations with light microscopy. Daily marijuana inhalation evoked severe bronchial hyperreactivity after a week. Characteristic perivascular/peribronchial edema, atelectasis, apical emphysema, and neutrophil and macrophage infiltration developed after 1 mo of marijuana smoking; lymphocyte accumulation after 2 mo; macrophage-like giant cells, irregular or destroyed bronchial mucosa, goblet cell hyperplasia after 3 mo; and severe atelectasis, emphysema, obstructed or damaged bronchioles, and endothelial proliferation at 4 mo. Myeloperoxidase activity, inflammatory cell, and cytokine profile correlated with these changes. Airway hyperresponsiveness and inflammation were not altered in mice lacking the CB1 cannabinoid receptor. In comparison, tobacco smoke induced hyperresponsiveness after 2 mo and significantly later caused inflammatory cell infiltration/activation with only mild emphysema. We provide the first systematic and comparative experimental evidence that marijuana causes severe airway hyperresponsiveness, inflammation, tissue destruction, and emphysema, which are not mediated by the CB1 receptor. Copyright © 2017 the American Physiological Society.

  17. Comparison of thoracic radiographs and single breath-hold helical CT for detection of pulmonary nodules in dogs with metastatic neoplasia.

    PubMed

    Nemanic, Sarah; London, Cheryl A; Wisner, Erik R

    2006-01-01

    Imaging studies in people indicate that x-ray computed tomography (CT) is a more sensitive technique than thoracic radiography for the detection of pulmonary metastasic neoplasia. Systematic studies comparing CT and thoracic radiographic techniques in veterinary patients have not been performed. The present retrospective study was designed to directly compare the efficacy of these 2 techniques in detecting pulmonary nodules in dogs. Eighteen dogs with histologically confirmed pulmonary metastatic neoplasia had contemporaneous thoracic radiographs and pulmonary CT scans compared. Quantitative analyses included estimation of pulmonary nodule size, number, and lobar distribution on thoracic radiographs and CT images. Only 9% of CT-detected pulmonary nodules were identified on thoracic radiographs (P < .003). The lower size threshold was approximately 1 mm to detect pulmonary nodules on CT images and 7-9 mm to reliably detect nodules on radiographs (P < .0001). Additionally, pulmonary nodules were detected in a significantly greater number of lung lobes using CT as compared with thoracic radiographs (P < .0001). These data indicate that CT is significantly more sensitive than thoracic radiography for detecting soft-tissue nodules in dogs. As such, thoracic CT should be considered in any patient with neoplasia that has potential for pulmonary metastasis to more reliably stage the disease, particularly when accurate characterization of the extent and distribution of pulmonary metastatic disease affects therapeutic planning.

  18. IL-10 is necessary for the expression of airway hyperresponsiveness but not pulmonary inflammation after allergic sensitization

    NASA Astrophysics Data System (ADS)

    Mäkelä, M. J.; Kanehiro, A.; Borish, L.; Dakhama, A.; Loader, J.; Joetham, A.; Xing, Z.; Jordana, M.; Larsen, G. L.; Gelfand, E. W.

    2000-05-01

    Cytokines play an important role in modulating inflammatory responses and, as a result, airway tone. IL-10 is a regulatory cytokine that has been suggested for treatment of asthma because of its immunosuppressive and anti-inflammatory properties. In contrast to these suggestions, we demonstrate in a model of allergic sensitization that mice deficient in IL-10 (IL-10/) develop a pulmonary inflammatory response but fail to exhibit airway hyperresponsiveness in both in vitro and in vivo assessments of lung function. Reconstitution of these deficient mice with the IL-10 gene fully restores development of airway hyperresponsiveness comparable to control mice. These results identify an important role of IL-10, downstream of the inflammatory cascade, in regulating the tone of the airways after allergic sensitization and challenge.

  19. The administration of a high refined carbohydrate diet promoted an increase in pulmonary inflammation and oxidative stress in mice exposed to cigarette smoke.

    PubMed

    Pena, Karina Braga; Ramos, Camila de Oliveira; Soares, Nícia Pedreira; da Silva, Pamela Félix; Bandeira, Ana Carla Balthar; Costa, Guilherme de Paula; Cangussú, Sílvia Dantas; Talvani, André; Bezerra, Frank Silva

    2016-01-01

    This study aimed to evaluate the effects of a high refined carbohydrate diet and pulmonary inflammatory response in C57BL/6 mice exposed to cigarette smoke (CS). Twenty-four male mice were divided into four groups: control group (CG), which received a standard diet; cigarette smoke group (CSG), which was exposed to CS; a high refined carbohydrate diet group (RG), which received a high refined carbohydrate diet; and a high refined carbohydrates diet and cigarette smoke group (RCSG), which received a high refined carbohydrate diet and was exposed to CS. The animals were monitored for food intake and body weight gain for 12 weeks. After this period, the CSG and RCSG were exposed to CS for five consecutive days. At the end of the experimental protocol, all animals were euthanized for subsequent analyses. There was an increase of inflammatory cells in the bronchoalveolar lavage fluid (BALF) of CSG compared to CG and RCSG compared to CG, CSG, and RG. In addition, in the BALF, there was an increase of tumor necrosis factor alpha in RCSG compared to CG, CSG, and RG; interferon gamma increase in RCSG compared to the CSG; and increase in interleukin-10 in RCSG compared to CG and RG. Lipid peroxidation increased in RCSG compared to CG, CSG, and RG. Furthermore, the oxidation of proteins increased in CSG compared to CG. The analysis of oxidative stress showed an increase in superoxide dismutase in RCSG compared to CG, CSG, and RG and an increase in the catalase activity in RCSG compared with CG. In addition, there was a decrease in the glutathione reduced/glutathione total ratio of CSG, RG, and RCSG compared to CG. Therefore, the administration of a high refined carbohydrate diet promoted an increase in pulmonary inflammation and oxidative stress in mice exposed to CS.

  20. Cardiomyopathy confers susceptibility to particulate matter-induced oxidative stress, vagal dominance, arrhythmia and pulmonary inflammation in heart failure-prone rats.

    PubMed

    Carll, Alex P; Haykal-Coates, Najwa; Winsett, Darrell W; Hazari, Mehdi S; Ledbetter, Allen D; Richards, Judy H; Cascio, Wayne E; Costa, Daniel L; Farraj, Aimen K

    2015-02-01

    Acute exposure to ambient fine particulate matter (PM2.5) is tied to cardiovascular morbidity and mortality, especially among those with prior cardiac injury. The mechanisms and pathophysiological events precipitating these outcomes remain poorly understood but may involve inflammation, oxidative stress, arrhythmia and autonomic nervous system imbalance. Cardiomyopathy results from cardiac injury, is the leading cause of heart failure, and can be induced in heart failure-prone rats through sub-chronic infusion of isoproterenol (ISO). To test whether cardiomyopathy confers susceptibility to inhaled PM2.5 and can elucidate potential mechanisms, we investigated the cardiophysiologic, ventilatory, inflammatory and oxidative effects of a single nose-only inhalation of a metal-rich PM2.5 (580 µg/m(3), 4 h) in ISO-pretreated (35 days × 1.0 mg/kg/day sc) rats. During the 5 days post-treatment, ISO-treated rats had decreased HR and BP and increased pre-ejection period (PEP, an inverse correlate of contractility) relative to saline-treated rats. Before inhalation exposure, ISO-pretreated rats had increased PR and ventricular repolarization time (QT) and heterogeneity (Tp-Te). Relative to clean air, PM2.5 further prolonged PR-interval and decreased systolic BP during inhalation exposure; increased tidal volume, expiratory time, heart rate variability (HRV) parameters of parasympathetic tone and atrioventricular block arrhythmias over the hours post-exposure; increased pulmonary neutrophils, macrophages and total antioxidant status one day post-exposure; and decreased pulmonary glutathione peroxidase 8 weeks after exposure, with all effects occurring exclusively in ISO-pretreated rats but not saline-pretreated rats. Ultimately, our findings indicate that cardiomyopathy confers susceptibility to the oxidative, inflammatory, ventilatory, autonomic and arrhythmogenic effects of acute PM2.5 inhalation.

  1. The administration of a high refined carbohydrate diet promoted an increase in pulmonary inflammation and oxidative stress in mice exposed to cigarette smoke

    PubMed Central

    Pena, Karina Braga; Ramos, Camila de Oliveira; Soares, Nícia Pedreira; da Silva, Pamela Félix; Bandeira, Ana Carla Balthar; Costa, Guilherme de Paula; Cangussú, Sílvia Dantas; Talvani, André; Bezerra, Frank Silva

    2016-01-01

    This study aimed to evaluate the effects of a high refined carbohydrate diet and pulmonary inflammatory response in C57BL/6 mice exposed to cigarette smoke (CS). Twenty-four male mice were divided into four groups: control group (CG), which received a standard diet; cigarette smoke group (CSG), which was exposed to CS; a high refined carbohydrate diet group (RG), which received a high refined carbohydrate diet; and a high refined carbohydrates diet and cigarette smoke group (RCSG), which received a high refined carbohydrate diet and was exposed to CS. The animals were monitored for food intake and body weight gain for 12 weeks. After this period, the CSG and RCSG were exposed to CS for five consecutive days. At the end of the experimental protocol, all animals were euthanized for subsequent analyses. There was an increase of inflammatory cells in the bronchoalveolar lavage fluid (BALF) of CSG compared to CG and RCSG compared to CG, CSG, and RG. In addition, in the BALF, there was an increase of tumor necrosis factor alpha in RCSG compared to CG, CSG, and RG; interferon gamma increase in RCSG compared to the CSG; and increase in interleukin-10 in RCSG compared to CG and RG. Lipid peroxidation increased in RCSG compared to CG, CSG, and RG. Furthermore, the oxidation of proteins increased in CSG compared to CG. The analysis of oxidative stress showed an increase in superoxide dismutase in RCSG compared to CG, CSG, and RG and an increase in the catalase activity in RCSG compared with CG. In addition, there was a decrease in the glutathione reduced/glutathione total ratio of CSG, RG, and RCSG compared to CG. Therefore, the administration of a high refined carbohydrate diet promoted an increase in pulmonary inflammation and oxidative stress in mice exposed to CS. PMID:28008246

  2. Risk assessment in relation to the detection of small pulmonary nodules.

    PubMed

    Field, John K; Marcus, Michael W; Oudkerk, Matthijs

    2017-02-01

    The National Lung Cancer Screening trial (NLST) demonstrated that individuals assigned to the LDCT screening arm had a 20% lower mortality than those who were assigned to the conventional chest radiography. The NLST was thoroughly analyzed by the US Preventive Task Force on CT Screening and they recommended that lung cancer screening should be implemented. A number of other countries have also recommended implementation, whilst others are awaiting the outcome of the NELSON Trial. However, recommendations for the management of CT screen detected nodules have only recently had any clarity. The management of CT detected nodules in the NLST was based on the identification and reporting of 4 mm diameter nodules found on the CT screens but there was no NLST radiology protocol in place for the management of nodules. The use of volumetric analysis is not routinely used in the USA and there is still a reliance on utilising the CT nodule diameter as the management parameter. The first pulmonary risk model was developed by the Canadians, utilising data sets from the Pan-Canadian Early detection of Lung cancer (PanCan) and validated in the chemoprevention trial dataset at the British Columbian Agency. This Canadian model, known as the Brock Model, is currently available and has been integrated into the British Thoracic Society guidelines on the management of pulmonary nodules. The American College of Radiology setup a Lung Cancer Screening Committee subgroup on Lung-RADS, to standardize lung cancer screening CT reporting and provide management recommendations. However, it has been recommended that the Lung-RADS system should be revised as the system as it has never been studied in a prospective fashion. The NELSON trial introduced a third screening test, the "indeterminate" screening test result, this was done with the aim to reduce the false-positives CT screening results and also utilized by the UKLS trial successfully. On comparing the radiological CT screen volumetric and

  3. Risk assessment in relation to the detection of small pulmonary nodules

    PubMed Central

    Marcus, Michael W.

    2017-01-01

    The National Lung Cancer Screening trial (NLST) demonstrated that individuals assigned to the LDCT screening arm had a 20% lower mortality than those who were assigned to the conventional chest radiography. The NLST was thoroughly analyzed by the US Preventive Task Force on CT Screening and they recommended that lung cancer screening should be implemented. A number of other countries have also recommended implementation, whilst others are awaiting the outcome of the NELSON Trial. However, recommendations for the management of CT screen detected nodules have only recently had any clarity. The management of CT detected nodules in the NLST was based on the identification and reporting of 4 mm diameter nodules found on the CT screens but there was no NLST radiology protocol in place for the management of nodules. The use of volumetric analysis is not routinely used in the USA and there is still a reliance on utilising the CT nodule diameter as the management parameter. The first pulmonary risk model was developed by the Canadians, utilising data sets from the Pan-Canadian Early detection of Lung cancer (PanCan) and validated in the chemoprevention trial dataset at the British Columbian Agency. This Canadian model, known as the Brock Model, is currently available and has been integrated into the British Thoracic Society guidelines on the management of pulmonary nodules. The American College of Radiology setup a Lung Cancer Screening Committee subgroup on Lung-RADS, to standardize lung cancer screening CT reporting and provide management recommendations. However, it has been recommended that the Lung-RADS system should be revised as the system as it has never been studied in a prospective fashion. The NELSON trial introduced a third screening test, the “indeterminate” screening test result, this was done with the aim to reduce the false-positives CT screening results and also utilized by the UKLS trial successfully. On comparing the radiological CT screen volumetric

  4. Elevated Expression of IL-23/IL-17 Pathway-Related Mediators Correlates with Exacerbation of Pulmonary Inflammation During Polymicrobial Sepsis1

    PubMed Central

    Cauvi, David M.; Williams, Michael R.; Bermudez, Jose A.; Armijo, Gabrielle; De Maio, Antonio

    2014-01-01

    Sepsis is a leading cause of death in the United States, claiming more than 215,000 lives every year. A primary condition observed in septic patients is the incidence of acute respiratory distress syndrome (ARDS), which is characterized by the infiltration of neutrophils into the lung. Prior studies have shown differences in pulmonary neutrophil accumulation in C57BL/6J (B6) and A/J mice after endotoxic and septic shock. However, the mechanism by which neutrophils accumulate in the lung after polymicrobial sepsis induced by cecal ligation and puncture (CLP) still remains to be fully elucidated. We show in this study that lung inflammation, characterized by neutrophil infiltration and expression of inflammatory cytokines, was aggravated in B6 as compared to A/J mice and correlated with high expression of p19, the IL-23-specific subunit. Furthermore, LPS stimulation of B6- and A/J-derived macrophages, one of the main producers of IL-23 and IL-12, revealed that B6 mice favored the production of IL-23 whereas A/J-derived macrophages expressed higher levels of IL-12. In addition, expression of IL-17, known to be upregulated by IL-23, was also more elevated in the lung of B6 mice when compared to A/J mice. In contrast, pulmonary expression of IFN-γ was much more pronounced in A/J than in B6 mice, which was most likely a result of a higher production of IL-12. The expression of the IL-17-dependent neutrophil recruitment factors CXCL2 and G-CSF was also higher in B6 mice. Altogether, these results suggest that increased activation of the IL-23/IL-17 pathway has detrimental effects on sepsis-induced lung inflammation, whereas activation of the IL-12/IFN-γ pathway may lead, in contrast, to less pronounced inflammatory events. These two pathways may become possible therapeutic targets for the treatment of sepsis-induced ARDS. PMID:24978886

  5. Transcriptomic analysis of pathways regulated by toll-like receptor 4 in a murine model of chronic pulmonary inflammation and carcinogenesis

    PubMed Central

    2009-01-01

    Background Therapeutic strategies exist for human pulmonary neoplasia, however due to the heterogeneity of the disease, most are not very effective. The innate immunity gene, toll-like receptor 4 (TLR4), protects against chronic pulmonary inflammation and tumorigenesis in mice, but the mechanism is unclear. This study was designed to identify TLR4-mediated gene expression pathways that may be used as prognostic indicators of susceptibility to lung tumorigenesis in mice and provide insight into the mechanism. Methods Whole lung mRNA was isolated from C.C3H-Tlr4Lps-d (BALBLps-d; Tlr4 mutant) and BALB/c (Tlr4 normal) mice following butylated hydroxytoluene (BHT)-treatment (four weekly ip. injections; 150-200 mg/kg/each; "promotion"). mRNA from micro-dissected tumors (adenomas) and adjacent uninvolved tissue from both strains were also compared 27 wks after a single carcinogen injection (3-methylcholanthrene (MCA), 10 μg/g; "control") or followed by BHT (6 weekly ip. injections; 125-200 mg/kg/each; "progression"). Bronchoalveolar lavage fluid was analyzed for inflammatory cell content and total protein determination, a marker of lung hyperpermeability; inflammation was also assessed using immunohistochemical staining for macrophages (F4/80) and lymphocytes (CD3) in mice bearing tumors (progression). Results During promotion, the majority of genes identified in the BALBLps-d compared to BALB/c mice (P < 0.05) were involved in epithelial growth factor receptor (EGFR) signaling (e.g. epiregulin (Ereg)), secreted phosphoprotein 1(Spp1)), which can lead to cell growth and eventual tumor development. Inflammation was significantly higher in BALBLps-d compared to BALB/c mice during progression, similar to the observed response during tumor promotion in these strains. Increases in genes involved in signaling through the EGFR pathway (e.g. Ereg, Spp1) were also observed during progression in addition to continued inflammation, chemotactic, and immune response gene expression

  6. Automatic detection of large pulmonary solid nodules in thoracic CT images

    SciTech Connect

    Setio, Arnaud A. A. Jacobs, Colin; Gelderblom, Jaap; Ginneken, Bram van

    2015-10-15

    Purpose: Current computer-aided detection (CAD) systems for pulmonary nodules in computed tomography (CT) scans have a good performance for relatively small nodules, but often fail to detect the much rarer larger nodules, which are more likely to be cancerous. We present a novel CAD system specifically designed to detect solid nodules larger than 10 mm. Methods: The proposed detection pipeline is initiated by a three-dimensional lung segmentation algorithm optimized to include large nodules attached to the pleural wall via morphological processing. An additional preprocessing is used to mask out structures outside the pleural space to ensure that pleural and parenchymal nodules have a similar appearance. Next, nodule candidates are obtained via a multistage process of thresholding and morphological operations, to detect both larger and smaller candidates. After segmenting each candidate, a set of 24 features based on intensity, shape, blobness, and spatial context are computed. A radial basis support vector machine (SVM) classifier was used to classify nodule candidates, and performance was evaluated using ten-fold cross-validation on the full publicly available lung image database consortium database. Results: The proposed CAD system reaches a sensitivity of 98.3% (234/238) and 94.1% (224/238) large nodules at an average of 4.0 and 1.0 false positives/scan, respectively. Conclusions: The authors conclude that the proposed dedicated CAD system for large pulmonary nodules can identify the vast majority of highly suspicious lesions in thoracic CT scans with a small number of false positives.

  7. γδ T Cells Are Required for M2 Macrophage Polarization and Resolution of Ozone-Induced Pulmonary Inflammation in Mice.

    PubMed

    Mathews, Joel A; Kasahara, David I; Ribeiro, Luiza; Wurmbrand, Allison P; Ninin, Fernanda M C; Shore, Stephanie A

    2015-01-01

    We examined the role of γδ T cells in the induction of alternatively activated M2 macrophages and the resolution of inflammation after ozone exposure. Wildtype (WT) mice and mice deficient in γδ T cells (TCRδ-/- mice) were exposed to air or to ozone (0.3 ppm for up to 72h) and euthanized immediately or 1, 3, or 5 days after cessation of exposure. In WT mice, M2 macrophages accumulated in the lungs over the course of ozone exposure. Pulmonary mRNA abundance of the M2 genes, Arg1, Retnla, and Clec10a, also increased after ozone. In contrast, no evidence of M2 polarization was observed in TCRδ-/- mice. WT but not TCRδ-/- mice expressed the M2c polarizing cytokine, IL-17A, after ozone exposure and WT mice treated with an IL-17A neutralizing antibody exhibited attenuated ozone-induced M2 gene expression. In WT mice, ozone-induced increases in bronchoalveolar lavage neutrophils and macrophages resolved quickly after cessation of ozone exposure returning to air exposed levels within 3 days. However, lack of M2 macrophages in TCRδ-/- mice was associated with delayed clearance of inflammatory cells after cessation of ozone and increased accumulation of apoptotic macrophages in the lungs. Delayed restoration of normal lung architecture was also observed in TCRδ-/- mice. In summary, our data indicate that γδ T cells are required for the resolution of ozone-induced inflammation, likely because γδ T cells, through their secretion of IL-17A, contribute to changes in macrophage polarization that promote clearance of apoptotic cells.

  8. Feasibility of Using Wideband Microwave System for Non-Invasive Detection and Monitoring of Pulmonary Oedema

    PubMed Central

    Rezaeieh, S. Ahdi; Zamani, A.; Bialkowski, K. S.; Mahmoud, A.; Abbosh, A. M.

    2015-01-01

    Pulmonary oedema is a common manifestation of various fatal diseases that can be caused by cardiac or non-cardiac syndromes. The accumulated fluid has a considerably higher dielectric constant compared to lungs’ tissues, and can thus be detected using microwave techniques. Therefore, a non-invasive microwave system for the early detection of pulmonary oedema is presented. It employs a platform in the form of foam-based bed that contains two linear arrays of wideband antennas covering the band 0.7–1 GHz. The platform is designed such that during the tests, the subject lays on the bed with the back of the torso facing the antenna arrays. The antennas are controlled using a switching network that is connected to a compact network analyzer. A novel frequency-based imaging algorithm is used to process the recorded signals and generate an image of the torso showing any accumulated fluids in the lungs. The system is verified on an artificial torso phantom, and animal organs. As a feasibility study, preclinical tests are conducted on healthy subjects to determinate the type of obtained images, the statistics and threshold levels of their intensity to differentiate between healthy and unhealthy subjects. PMID:26365299

  9. Feasibility of Using Wideband Microwave System for Non-Invasive Detection and Monitoring of Pulmonary Oedema

    NASA Astrophysics Data System (ADS)

    Rezaeieh, S. Ahdi; Zamani, A.; Bialkowski, K. S.; Mahmoud, A.; Abbosh, A. M.

    2015-09-01

    Pulmonary oedema is a common manifestation of various fatal diseases that can be caused by cardiac or non-cardiac syndromes. The accumulated fluid has a considerably higher dielectric constant compared to lungs’ tissues, and can thus be detected using microwave techniques. Therefore, a non-invasive microwave system for the early detection of pulmonary oedema is presented. It employs a platform in the form of foam-based bed that contains two linear arrays of wideband antennas covering the band 0.7-1 GHz. The platform is designed such that during the tests, the subject lays on the bed with the back of the torso facing the antenna arrays. The antennas are controlled using a switching network that is connected to a compact network analyzer. A novel frequency-based imaging algorithm is used to process the recorded signals and generate an image of the torso showing any accumulated fluids in the lungs. The system is verified on an artificial torso phantom, and animal organs. As a feasibility study, preclinical tests are conducted on healthy subjects to determinate the type of obtained images, the statistics and threshold levels of their intensity to differentiate between healthy and unhealthy subjects.

  10. Immunohistochemical detection of the expression of pro-inflammatory cytokines by ovine pulmonary macrophages.

    PubMed

    Carrasco, L; Núñez, A; Sánchez-Cordón, P J; Pedrera, M; Fernández de Marco, M; Salguero, F J; Gómez-Villamandos, J C

    2004-11-01

    The aim of this study was to determine the expression of three proinflammatory cytokines by pulmonary macrophages of sheep in paraffin wax-embedded tissue. Samples of lung from seven healthy sheep were fixed by immersion in either 10% neutral buffered formalin, acetic formalin, paraformaldehyde-lysine-periodate or Bouin's solution and processed for structural and immunohistochemical studies. The expression of interleukin (IL)-1alpha, IL-6 and tumour necrosis factor (TNF)-alpha by pulmonary intravascular macrophages (PIMs) and alveolar macrophages (AMs) was detected by the avidin-biotin-peroxidase (ABC) technique. Bouin's solution proved to be the most suitable fixative and Tween 20 the most effective pretreatment for increasing permeability. Constitutive expression of IL-1alpha, IL-6 and TNF-alpha by both macrophage populations was detected. The number of PIMs expressing IL-1alpha (the predominant cytokine in ovine lung) was higher than that of AMs, while the expression of IL-6 was greater in AMs. No differences between PIMS and AMs were found in respect of TNF-alpha expression. The evaluation of cytokine expression represents a valuable tool for studying the pathogenesis of disease in the ovine lung.

  11. A modified murine model of systemic sclerosis: bleomycin given by pump infusion induced skin and pulmonary inflammation and fibrosis.

    PubMed

    Liang, Minrui; Lv, Jiaoyan; Zou, Linlin; Yang, Wei; Xiong, Yingluo; Chen, Xiangjun; Guan, Ming; He, Rui; Zou, Hejian

    2015-03-01

    Daily subcutaneous (sc) injection of bleomycin (BLM) causes dermal fibrosis but rarely causes lung changes in mice. There are also significant disadvantages to this traditional model for systemic sclerosis, including a variable distribution of lesions and a requirement for repetitive procedures. The present study was undertaken to develop a convenient method of BLM administration that yields stable dermal inflammation and fibrosis with extensive and reproducible interstitial lung disease (ILD) in mice. Osmotic minipumps containing BLM (150 mg/kg) or saline were implanted sc in C57BL/6 mice and the drug was delivered as a continuous infusion over 1∼4 weeks. The time course of morphological features, collagen content, and pro-inflammatory cytokine expression in the skin and the lungs were analyzed. Pathological examination demonstrated dominant inflammatory infiltrates at week 1 and significant fibrosis at week 4. Decreased microvessel density and increased myofibroblast counts were observed in the skin of BLM-treated mice at week 4. In addition, there were obvious increases in dermal infiltration of CD45(+) leukocytes, including F4/80(+) macrophages, Gr-1(+) neutrophils, and CD3(+) T lymphocytes in BLM-treated mice. IL-1β, IL-4, and CXCL2 transcripts were continually upregulated by BLM in the skin and lung tissues. In addition, lungs from BLM-treated mice showed significant inflammatory infiltrates and confluent subpleural fibrosis at week 4. In conclusion, this modified murine model for drug-induced systemic inflammation and fibrosis uses a single procedure and provides reproducible skin and lung lesions, mimicking human systemic sclerosis (SSc) with ILD-like manifestation.

  12. Detection of Heart Sounds in Children with and without Pulmonary Arterial Hypertension―Daubechies Wavelets Approach

    PubMed Central

    Elgendi, Mohamed; Kumar, Shine; Guo, Long; Rutledge, Jennifer; Coe, James Y.; Zemp, Roger; Schuurmans, Dale; Adatia, Ian

    2015-01-01

    Background Automatic detection of the 1st (S1) and 2nd (S2) heart sounds is difficult, and existing algorithms are imprecise. We sought to develop a wavelet-based algorithm for the detection of S1 and S2 in children with and without pulmonary arterial hypertension (PAH). Method Heart sounds were recorded at the second left intercostal space and the cardiac apex with a digital stethoscope simultaneously with pulmonary arterial pressure (PAP). We developed a Daubechies wavelet algorithm for the automatic detection of S1 and S2 using the wavelet coefficient ‘D6’ based on power spectral analysis. We compared our algorithm with four other Daubechies wavelet-based algorithms published by Liang, Kumar, Wang, and Zhong. We annotated S1 and S2 from an audiovisual examination of the phonocardiographic tracing by two trained cardiologists and the observation that in all subjects systole was shorter than diastole. Results We studied 22 subjects (9 males and 13 females, median age 6 years, range 0.25–19). Eleven subjects had a mean PAP < 25 mmHg. Eleven subjects had PAH with a mean PAP ≥ 25 mmHg. All subjects had a pulmonary artery wedge pressure ≤ 15 mmHg. The sensitivity (SE) and positive predictivity (+P) of our algorithm were 70% and 68%, respectively. In comparison, the SE and +P of Liang were 59% and 42%, Kumar 19% and 12%, Wang 50% and 45%, and Zhong 43% and 53%, respectively. Our algorithm demonstrated robustness and outperformed the other methods up to a signal-to-noise ratio (SNR) of 10 dB. For all algorithms, detection errors arose from low-amplitude peaks, fast heart rates, low signal-to-noise ratio, and fixed thresholds. Conclusion Our algorithm for the detection of S1 and S2 improves the performance of existing Daubechies-based algorithms and justifies the use of the wavelet coefficient ‘D6’ through power spectral analysis. Also, the robustness despite ambient noise may improve real world clinical performance. PMID:26629704

  13. Sensitivity of scintigraphy for detection of pulmonary capillary albumin leak in canine oleic acid ARDS

    SciTech Connect

    Sugerman, H.J.; Strash, A.M.; Hirsch, J.I.; Glauser, F.L.; Shirazi, K.K.; Sharp, D.E.; Greenfield, L.J.

    1981-07-01

    Computerized gamma scintigraphy was shown in this study to be a sensitive technique for the detection and kinetic analysis of a pulmonary capillary protein leak. A rising lung:heart radioactivity of slope of injury was found at each dose of intravenous oleic acid in dogs from 0.01 to 0.20 ml/kg (p less than 0.01). This slope of injury was proportional to the dose of oleic acid (r . +0.97; p less than 0.004) and was more sensitive than changes in arterial oxygen tension, standard chest radiography, bloodless wet:dry lung weight, or alveolar epithelial membrane permeability. Only standard light microscopy and right lymphatic duct flow were able to document the leakage of protein detected by gamma scintigraphy at 0.01 ml/kg oleic acid.

  14. Hand-Assisted Thoracoscopic Surgery for Pulmonary Metastasectomy through Sternocostal Triangle Access: Superiority in Detection of Non-Imaged Pulmonary Nodules

    PubMed Central

    Hao, Long; Long, Jiang; YongBin, Lin; DongRong, Situ; Yan, Zheng; YiGong, Zhang; GuoWei, Ma

    2014-01-01

    Hand-Assisted Thoracoscopic Surgery for pulmonary metastasectomy through sternocostal triangle access allows manual palpation of both lungs, thus permitting effective treatment of lung metastases. In our research, 62 patients from November 2001 to January 2012 underwent our Hand-Assisted Thoracoscopic Surgery procedures for pulmonary metastasectomy. Clinical data, including the number of pulmonary metastases determined by Computed Tomography/Positron Emission Tomography-Computed Tomography, surgical findings and survival data of these patients were collected. We found that the median follow-up time was 23.7 months (range 2.4 to 85.6 months). 30 cases of them had post-operative recurrences and the median disease-free survival period was 27.4 months. For Computed Tomography scan, the overall sensitivity for proved metastases was 63% (115/182). 67 non-imaged malignant nodules were palpated and removed in 14 cases. For Positron Emission Tomography-Computed Tomography scan, the overall sensitivity was 66% (79/120). 41 non-imaged malignant nodules were palpated and removed in 12 cases. This study show that the Hand-Assisted Thoracoscopic Surgery provides an easier way for routine bilateral pleural exploration, and thus is critical and effective in detection of non-imaged malignant pulmonary metastases, which might contribute to long-term disease-free survival. PMID:24687025

  15. Preliminary clinical results: an analyzing tool for 2D optical imaging in detection of active inflammation in rheumatoid arthritis

    NASA Astrophysics Data System (ADS)

    Adi Aizudin Bin Radin Nasirudin, Radin; Meier, Reinhard; Ahari, Carmen; Sievert, Matti; Fiebich, Martin; Rummeny, Ernst J.; No"l, Peter B.

    2011-03-01

    Optical imaging (OI) is a relatively new method in detecting active inflammation of hand joints of patients suffering from rheumatoid arthritis (RA). With the high number of people affected by this disease especially in western countries, the availability of OI as an early diagnostic imaging method is clinically highly relevant. In this paper, we present a newly in-house developed OI analyzing tool and a clinical evaluation study. Our analyzing tool extends the capability of existing OI tools. We include many features in the tool, such as region-based image analysis, hyper perfusion curve analysis, and multi-modality image fusion to aid clinicians in localizing and determining the intensity of inflammation in joints. Additionally, image data management options, such as the full integration of PACS/RIS, are included. In our clinical study we demonstrate how OI facilitates the detection of active inflammation in rheumatoid arthritis. The preliminary clinical results indicate a sensitivity of 43.5%, a specificity of 80.3%, an accuracy of 65.7%, a positive predictive value of 76.6%, and a negative predictive value of 64.9% in relation to clinical results from MRI. The accuracy of inflammation detection serves as evidence to the potential of OI as a useful imaging modality for early detection of active inflammation in patients with rheumatoid arthritis. With our in-house developed tool we extend the usefulness of OI imaging in the clinical arena. Overall, we show that OI is a fast, inexpensive, non-invasive and nonionizing yet highly sensitive and accurate imaging modality.-

  16. Automatic detection and quantification of pulmonary arterio-venous malformations in hereditary hemorrhagic telangiectasia

    NASA Astrophysics Data System (ADS)

    Fetita, Catalin; Fortemps de Loneux, Thierry; Kouvahe, Amélé Florence; El Hajjam, Mostafa

    2017-03-01

    Hereditary hemorrhagic telangiectasia (HHT) is an autosomic dominant disorder, which is characterized by the development of multiple arterio-venous malformations in the skin, mucous membranes, and/or visceral organs. Pulmonary Arterio-Venous Malformation (PAVM) is an abnormal connection where feeding arteries shunt directly into draining veins with no intervening capillary bed. This condition may lead to paradoxical embolism and hemorrhagic complications. PAVMs patients should systematically be screened as the spontaneous complication rate is high, reaching almost 50%. Chest enhanced contrast CT scanner is the reference screening and follow-up examination. When performed by experienced operators as the prime treatment, percutaneous embolization of PAVMs is a safe, efficient and sustained therapy. The accuracy of PAVM detection and quantification of its progression over time is the key of embolotherapy success. In this paper, we propose an automatic method for PAVM detection and quantification relying on a modeling of vessel deformation, i.e. local caliber increase, based on mathematical morphology. The pulmonary field and vessels are first segmented using geodesic operators. The vessel caliber is estimated by means of a granulometric measure and the local caliber increase is detected by using a geodesic operator, the h-maxdomes. The detection sensitivity can be tuned up according to the choice of the h value which models the irregularity of the vessel caliber along its axis and the PAVM selection is performed according to a clinical criterion of >3 mm diameter of the feeding artery of the PAVM. The developed method was tested on a 20 patient dataset. A sensitivity study allowed choosing the irregularity parameter to maximize the true positive ratio reaching 85.4% in average. A specific false positive reduction procedure targeting the vessel trunks of the arterio-venous tree near mediastinum allows a precision increase from 13% to 67% with an average number of 1

  17. GM-CSF Enhances Macrophage Glycolytic Activity In Vitro and Improves Detection of Inflammation In Vivo

    PubMed Central

    Singh, Parmanand; González-Ramos, Silvia; Mojena, Marina; Rosales-Mendoza, César Eduardo; Emami, Hamed; Swanson, Jeffrey; Morss, Alex; Fayad, Zahi A.; Rudd, James H.F.; Gelfand, Jeffrey; Paz-García, Marta; Martín-Sanz, Paloma; Boscá, Lisardo

    2016-01-01

    18F-FDG accumulates in glycolytically active tissues and is known to concentrate in tissues that are rich in activated macrophages. In this study, we tested the hypotheses that human granulocyte-macrophage colony-stimulating factor (GM-CSF), a clinically used cytokine, increases macrophage glycolysis and deoxyglucose uptake in vitro and acutely enhances 18F-FDG uptake within inflamed tissues such as atherosclerotic plaques in vivo. Methods: In vitro experiments were conducted on human macrophages whereby inflammatory activation and uptake of radiolabeled 2-deoxyglucose was assessed before and after GM-CSF exposure. In vivo studies were performed on mice and New Zealand White rabbits to assess the effect of GM-CSF on 18F-FDG uptake in normal versus inflamed arteries, using PET. Results: Incubation of human macrophages with GM-CSF resulted in increased glycolysis and increased 2-deoxyglucose uptake (P < 0.05). This effect was attenuated by neutralizing antibodies against tumor necrosis factor–α or after silencing or inhibition of 6-phosphofructo-2-kinase. In vivo, in mice and in rabbits, intravenous GM-CSF administration resulted in a 70% and 73% increase (P < 0.01 for both), respectively, in arterial 18F-FDG uptake in atherosclerotic animals but not in nonatherosclerotic controls. Histopathologic analysis demonstrated a significant correlation between in vivo 18F-FDG uptake and macrophage staining (R = 0.75, P < 0.01). Conclusion: GM-CSF substantially augments glycolytic flux in vitro (via a mechanism dependent on ubiquitous type 6-phosphofructo-2-kinase and tumor necrosis factor–α) and increases 18F-FDG uptake within inflamed atheroma in vivo. These findings demonstrate that GM-CSF can be used to enhance detection of inflammation. Further studies should explore the role of GM-CSF stimulation to enhance the detection of inflammatory foci in other disease states. PMID:27081166

  18. GM-CSF Enhances Macrophage Glycolytic Activity In Vitro and Improves Detection of Inflammation In Vivo.

    PubMed

    Singh, Parmanand; González-Ramos, Silvia; Mojena, Marina; Rosales-Mendoza, César Eduardo; Emami, Hamed; Swanson, Jeffrey; Morss, Alex; Fayad, Zahi A; Rudd, James H F; Gelfand, Jeffrey; Paz-García, Marta; Martín-Sanz, Paloma; Boscá, Lisardo; Tawakol, Ahmed

    2016-09-01

    (18)F-FDG accumulates in glycolytically active tissues and is known to concentrate in tissues that are rich in activated macrophages. In this study, we tested the hypotheses that human granulocyte-macrophage colony-stimulating factor (GM-CSF), a clinically used cytokine, increases macrophage glycolysis and deoxyglucose uptake in vitro and acutely enhances (18)F-FDG uptake within inflamed tissues such as atherosclerotic plaques in vivo. In vitro experiments were conducted on human macrophages whereby inflammatory activation and uptake of radiolabeled 2-deoxyglucose was assessed before and after GM-CSF exposure. In vivo studies were performed on mice and New Zealand White rabbits to assess the effect of GM-CSF on (18)F-FDG uptake in normal versus inflamed arteries, using PET. Incubation of human macrophages with GM-CSF resulted in increased glycolysis and increased 2-deoxyglucose uptake (P < 0.05). This effect was attenuated by neutralizing antibodies against tumor necrosis factor-α or after silencing or inhibition of 6-phosphofructo-2-kinase. In vivo, in mice and in rabbits, intravenous GM-CSF administration resulted in a 70% and 73% increase (P < 0.01 for both), respectively, in arterial (18)F-FDG uptake in atherosclerotic animals but not in nonatherosclerotic controls. Histopathologic analysis demonstrated a significant correlation between in vivo (18)F-FDG uptake and macrophage staining (R = 0.75, P < 0.01). GM-CSF substantially augments glycolytic flux in vitro (via a mechanism dependent on ubiquitous type 6-phosphofructo-2-kinase and tumor necrosis factor-α) and increases (18)F-FDG uptake within inflamed atheroma in vivo. These findings demonstrate that GM-CSF can be used to enhance detection of inflammation. Further studies should explore the role of GM-CSF stimulation to enhance the detection of inflammatory foci in other disease states. © 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

  19. Effects of Astragalus and Codonopsis pilosula polysaccharides on alveolar macrophage phagocytosis and inflammation in chronic obstructive pulmonary disease mice exposed to PM2.5.

    PubMed

    Chu, Xu; Liu, Xiao-Ju; Qiu, Jing-Man; Zeng, Xiao-Li; Bao, Hai-Rong; Shu, Juan

    2016-12-01

    Astragalus and Codonopsis pilosula are used for their immunomodulatory and anti-inflammatory effects. Here, we investigated the effects of Astragalus polysaccharides (APS) and Codonopsis pilosula polysaccharides (CPP) on alveolar macrophage (AM) phagocytosis and inflammation in chronic obstructive pulmonary disease (COPD) associated with exposure to particulate matter with a mean aerodynamic diameter ≤2.5μm (PM2.5). A mouse model of COPD was established by cigarette smoke exposure. PM2.5 exposure was performed by inhalation of a PM2.5 solution aerosol. APS and CPP were administered intragastrically. COPD showed defective AM phagocytosis and increased levels of interleukin (IL)-6, IL-8, and tumor necrosis factor (TNF)-α in bronchoalveolar lavage fluid and serum. PM2.5 exposure aggravated the damage, and this effect was reversed by APS and CPP gavage. The results indicate that APS and CPP may promote defective AM phagocytosis and ameliorate the inflammatory response in COPD with or without PM2.5 exposure. Copyright © 2016 Elsevier B.V. All rights reserved.

  20. Transcriptome of Cultured Lung Fibroblasts in Idiopathic Pulmonary Fibrosis: Meta-Analysis of Publically Available Microarray Datasets Reveals Repression of Inflammation and Immunity Pathways

    PubMed Central

    Plantier, Laurent; Renaud, Hélène; Respaud, Renaud; Marchand-Adam, Sylvain; Crestani, Bruno

    2016-01-01

    Heritable profibrotic differentiation of lung fibroblasts is a key mechanism of idiopathic pulmonary fibrosis (IPF). Its mechanisms are yet to be fully understood. In this study, individual data from four independent microarray studies comparing the transcriptome of fibroblasts cultured in vitro from normal (total n = 20) and IPF (total n = 20) human lung were compiled for meta-analysis following normalization to z-scores. One hundred and thirteen transcripts were upregulated and 115 were downregulated in IPF fibroblasts using the Significance Analysis of Microrrays algorithm with a false discovery rate of 5%. Downregulated genes were highly enriched for Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional classes related to inflammation and immunity such as Defense response to virus, Influenza A, tumor necrosis factor (TNF) mediated signaling pathway, interferon-inducible absent in melanoma2 (AIM2) inflammasome as well as Apoptosis. Although upregulated genes were not enriched for any functional class, select factors known to play key roles in lung fibrogenesis were overexpressed in IPF fibroblasts, most notably connective tissue growth factor (CTGF) and serum response factor (SRF), supporting their role as drivers of IPF. The full data table is available as a supplement. PMID:27983601

  1. Effects of Mikania glomerata Spreng. and Mikania laevigata Schultz Bip. ex Baker (Asteraceae) extracts on pulmonary inflammation and oxidative stress caused by acute coal dust exposure

    SciTech Connect

    Freitas, T.P.; Silveira, P.C.; Rocha, L.G.; Rezin, G.T.; Rocha, J.; Citadini-Zanette, V.; Romao, P.T.; Dal-Pizzol, F.; Pinho, R.A.; Andrade, V.M.; Streck, E.L.

    2008-12-15

    Several studies have reported biological effects of Mikania glomerata and Mikania laevigata, used in Brazilian folk medicine for respiratory diseases. Pneumoconiosis is characterized by pulmonary inflammation caused by coal dust exposure. In this work, we evaluated the effect of pretreatment with M. glomerata and M. laevigata extracts (MGE and MLE, respectively) (100 mg/kg, s.c.) on inflammatory and oxidative stress parameters in lung of rats subjected to a single coal dust intratracheal instillation. Rats were pretreated for 2 weeks with saline solution, MGE, or MLE. On day 15, the animals were anesthetized, and gross mineral coal dust or saline solutions were administered directly in the lung by intratracheal instillation. Fifteen days after coal dust instillation, the animals were killed. Bronchoalveolar lavage (BAL) was obtained; total cell count and lactate dehydrogenase (LDH) activity were determined. In the lung, myeloperoxidase activity, thiobarbituric acid-reactive substances (TBARS) level, and protein carbonyl and sulfhydryl contents were evaluated. In BAL of treated animals, we verified an increased total cell count and LDH activity. MGE and MLE prevented the increase in cell count, but only MLE prevented the increase in LDH. Myeloperoxidase and TBARS levels were not affected, protein carbonylation was increased, and the protein thiol levels were decreased by acute coal dust intratracheal administration. The findings also suggest that both extracts present an important protective effect on the oxidation of thiol groups. Moreover, pretreatment with MGE and MLE also diminished lung inflammatory infiltration induced by coal dust, as assessed by histopathologic analyses.

  2. Transcriptome of Cultured Lung Fibroblasts in Idiopathic Pulmonary Fibrosis: Meta-Analysis of Publically Available Microarray Datasets Reveals Repression of Inflammation and Immunity Pathways.

    PubMed

    Plantier, Laurent; Renaud, Hélène; Respaud, Renaud; Marchand-Adam, Sylvain; Crestani, Bruno

    2016-12-13

    Heritable profibrotic differentiation of lung fibroblasts is a key mechanism of idiopathic pulmonary fibrosis (IPF). Its mechanisms are yet to be fully understood. In this study, individual data from four independent microarray studies comparing the transcriptome of fibroblasts cultured in vitro from normal (total n = 20) and IPF (total n = 20) human lung were compiled for meta-analysis following normalization to z-scores. One hundred and thirteen transcripts were upregulated and 115 were downregulated in IPF fibroblasts using the Significance Analysis of Microrrays algorithm with a false discovery rate of 5%. Downregulated genes were highly enriched for Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional classes related to inflammation and immunity such as Defense response to virus, Influenza A, tumor necrosis factor (TNF) mediated signaling pathway, interferon-inducible absent in melanoma2 (AIM2) inflammasome as well as Apoptosis. Although upregulated genes were not enriched for any functional class, select factors known to play key roles in lung fibrogenesis were overexpressed in IPF fibroblasts, most notably connective tissue growth factor (CTGF) and serum response factor (SRF), supporting their role as drivers of IPF. The full data table is available as a supplement.

  3. Pulmonary Hypertension in Sarcoidosis.

    PubMed

    Baughman, Robert P; Engel, Peter J; Nathan, Steven

    2015-12-01

    Pulmonary hypertension is a complication of sarcoidosis leading to dyspnea and associated with increased morbidity and mortality. Sarcoidosis-associated pulmonary hypertension (SAPH) can be due to several factors, including vascular involvement by the granulomatous inflammation, compression of the pulmonary arteries by adenopathy, fibrotic changes within the lung, and left ventricular diastolic dysfunction. Several case series have suggested that some patients with SAPH benefit from specific therapy for pulmonary hypertension. A randomized, placebo-controlled trial found 16 weeks' bosentan therapy to be associated with significant improvement in pulmonary artery pressure. Future studies may better define who would respond to treatment of pulmonary hypertension.

  4. The Evaluation of a Pulmonary Display to Detect Adverse Respiratory Events Using High Resolution Human Simulator

    PubMed Central

    Wachter, S. Blake; Johnson, Ken; Albert, Robert; Syroid, Noah; Drews, Frank; Westenskow, Dwayne

    2006-01-01

    Objective Authors developed a picture-graphics display for pulmonary function to present typical respiratory data used in perioperative and intensive care environments. The display utilizes color, shape and emergent alerting to highlight abnormal pulmonary physiology. The display serves as an adjunct to traditional operating room displays and monitors. Design To evaluate the prototype, nineteen clinician volunteers each managed four adverse respiratory events and one normal event using a high-resolution patient simulator which included the new displays (intervention subjects) and traditional displays (control subjects). Between-group comparisons included (i) time to diagnosis and treatment for each adverse respiratory event; (ii) the number of unnecessary treatments during the normal scenario; and (iii) self-reported workload estimates while managing study events. Measurements Two expert anesthesiologists reviewed video-taped transcriptions of the volunteers to determine time to treat and time to diagnosis. Time values were then compared between groups using a Mann-Whitney-U Test. Estimated workload for both groups was assessed using the NASA-TLX and compared between groups using an ANOVA. P-values < 0.05 were considered significant. Results Clinician volunteers detected and treated obstructed endotracheal tubes and intrinsic PEEP problems faster with graphical rather than conventional displays (p < 0.05). During the normal scenario simulation, 3 clinicians using the graphical display, and 5 clinicians using the conventional display gave unnecessary treatments. Clinician-volunteers reported significantly lower subjective workloads using the graphical display for the obstructed endotracheal tube scenario (p < 0.001) and the intrinsic PEEP scenario (p < 0.03). Conclusion Authors conclude that the graphical pulmonary display may serve as a useful adjunct to traditional displays in identifying adverse respiratory events. PMID:16929038

  5. The Translational Repressor T-cell Intracellular Antigen-1 (TIA-1) is a Key Modulator of Th2 and Th17 Responses Driving Pulmonary Inflammation Induced by Exposure to House Dust Mite

    PubMed Central

    Simarro, Maria; Giannattasio, Giorgio; Xing, Wei; Lundequist, Emma-Maria; Stewart, Samantha; Stevens, Richard L.; Orduña, Antonio; Boyce, Joshua A.; Anderson, Paul J.

    2012-01-01

    T-cell Intracellular Antigen-1 (TIA-1) is a translational repressor that dampens the production of proinflammatory cytokines and enzymes. In this study we investigated the role of TIA-1 in a mouse model of pulmonary inflammation induced by exposure to the allergenic extract (Df) of the house dust mite Dermatophagoides farinae. When intranasally challenged with a low dose of Df, mice lacking TIA-1 protein (Tia-1−/−) showed more severe airway and tissue eosinophilia, infiltration of lung bronchovascular bundles, and goblet cell metaplasia than wild-type littermates. Tia-1−/− mice also had higher levels of Df-specific IgE and IgG1 in serum and ex vivo restimulated Tia-1−/− lymph node cells and splenocytes transcribed and released more Th2/Th17 cytokines. To evaluate the site of action of TIA-1, we studied the response to Df in bone marrow chimeras. These experiments revealed that TIA-1 acts on both hematopoietic and non-hematopoietic cells to dampen pulmonary inflammation. Our results identify TIA-1 as a negative regulator of allergen-mediated pulmonary inflammation in vivo. Thus, TIA-1 might be an important player in the pathogenesis of bronchial asthma. PMID:22525013

  6. The translational repressor T-cell intracellular antigen-1 (TIA-1) is a key modulator of Th2 and Th17 responses driving pulmonary inflammation induced by exposure to house dust mite.

    PubMed

    Simarro, Maria; Giannattasio, Giorgio; Xing, Wei; Lundequist, Emma-Maria; Stewart, Samantha; Stevens, Richard L; Orduña, Antonio; Boyce, Joshua A; Anderson, Paul J

    2012-08-30

    T-cell intracellular antigen-1 (TIA-1) is a translational repressor that dampens the production of proinflammatory cytokines and enzymes. In this study we investigated the role of TIA-1 in a mouse model of pulmonary inflammation induced by exposure to the allergenic extract (Df) of the house dust mite Dermatophagoides farinae. When intranasally challenged with a low dose of Df, mice lacking TIA-1 protein (Tia-1(-/-)) showed more severe airway and tissue eosinophilia, infiltration of lung bronchovascular bundles, and goblet cell metaplasia than wild-type littermates. Tia-1(-/-) mice also had higher levels of Df-specific IgE and IgG(1) in serum and ex vivo restimulated Tia-1(-/-) lymph node cells and splenocytes transcribed and released more Th2/Th17 cytokines. To evaluate the site of action of TIA-1, we studied the response to Df in bone marrow chimeras. These experiments revealed that TIA-1 acts on both hematopoietic and non-hematopoietic cells to dampen pulmonary inflammation. Our results identify TIA-1 as a negative regulator of allergen-mediated pulmonary inflammation in vivo. Thus, TIA-1 might be an important player in the pathogenesis of bronchial asthma. Copyright © 2012 Elsevier B.V. All rights reserved.

  7. Pulmonary hypertension

    MedlinePlus

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

  8. Biodiesel versus diesel exposure: Enhanced pulmonary inflammation, oxidative stress, and differential morphological changes in the mouse lung

    PubMed Central

    Yanamala, Naveena; Hatfield, Meghan K.; Farcas, Mariana T.; Schwegler-Berry, Diane; Hummer, Jon A.; Shurin, Michael R.; Birch, M. Eileen; Gutkin, Dmitriy W.; Kisin, Elena; Kagan, Valerian E.; Bugarski, Aleksandar D.; Shvedova, Anna A.

    2015-01-01

    The use of biodiesel (BD) or its blends with petroleum diesel (D) is considered to be a viable approach to reduce occupational and environmental exposures to particulate matter (PM). Due to its lower particulate mass emissions compared to D, use of BD is thought to alleviate adverse health effects. Considering BD fuel is mainly composed of unsaturated fatty acids, we hypothesize that BD exhaust particles could induce pronounced adverse outcomes, due to their ability to readily oxidize. The main objective of this study was to compare the effects of particles generated by engine fueled with neat BD and neat petroleum-based D. Biomarkers of tissue damage and inflammation were significantly elevated in lungs of mice exposed to BD particulates. Additionally, BD particulates caused a significant accumulation of oxidatively modified proteins and an increase in 4-hydroxynonenal. The up-regulation of inflammatory cytokines/chemokines/growth factors was higher in lungs upon BD particulate exposure. Histological evaluation of lung sections indicated presence of lymphocytic infiltrate and impaired clearance with prolonged retention of BD particulate in pigment laden macrophages. Taken together, these results clearly indicate that BD exhaust particles could exert more toxic effects compared to D. PMID:23886933

  9. Computer-aided detection of lung cancer: combining pulmonary nodule detection systems with a tumor risk prediction model

    NASA Astrophysics Data System (ADS)

    Setio, Arnaud A. A.; Jacobs, Colin; Ciompi, Francesco; van Riel, Sarah J.; Winkler Wille, Mathilde M.; Dirksen, Asger; van Rikxoort, Eva M.; van Ginneken, Bram

    2015-03-01

    Computer-Aided Detection (CAD) has been shown to be a promising tool for automatic detection of pulmonary nodules from computed tomography (CT) images. However, the vast majority of detected nodules are benign and do not require any treatment. For effective implementation of lung cancer screening programs, accurate identification of malignant nodules is the key. We investigate strategies to improve the performance of a CAD system in detecting nodules with a high probability of being cancers. Two strategies were proposed: (1) combining CAD detections with a recently published lung cancer risk prediction model and (2) the combination of multiple CAD systems. First, CAD systems were used to detect the nodules. Each CAD system produces markers with a certain degree of suspicion. Next, the malignancy probability was automatically computed for each marker, given nodule characteristics measured by the CAD system. Last, CAD degree of suspicion and malignancy probability were combined using the product rule. We evaluated the method using 62 nodules which were proven to be malignant cancers, from 180 scans of the Danish Lung Cancer Screening Trial. The malignant nodules were considered as positive samples, while all other findings were considered negative. Using a product rule, the best proposed system achieved an improvement in sensitivity, compared to the best individual CAD system, from 41.9% to 72.6% at 2 false positives (FPs)/scan and from 56.5% to 88.7% at 8 FPs/scan. Our experiment shows that combining a nodule malignancy probability with multiple CAD systems can increase the performance of computerized detection of lung cancer.

  10. [Effect of basic therapy on clinical symptoms, quality of life and systemic inflammation in patients with chronic obstructive pulmonary disease].

    PubMed

    Baranova, I I; Leshchenko, I V

    2013-01-01

    The study included 38 men with moderately severe chronic obstructive pulmonary disease (COPD) (mean age 60.6 ± 10.2 yr) and 42 ones with severe COPD (mean age 61.2 ± 7.2 yr). They were treated with tiotropium bromide, formoterol and beclomethasone dipropionate for 24 weeks (stage 1), TB alone for 12 weeks (stage 2) and TB+formoterol (long-acting bronchodilators, LABD) for another 12 weeks. Each stage was followed by evaluation of COPD symptoms using the St-George's Hospital questionnaire, daily requirements for short-acting beta-2 agonists (SABA), heart rate (HR), forced expiratory volume in the 1st second (FEV-1) before and after SABA test, hemoglobin saturation with oxygen in arterial blood during pulse oxymetry before and after 6 min walking test, blood surfactant protein D level (SP-D). The control group was comprised of 34 healthy men (mean age 62.3 ± 5.8 yr). Patients with moderately severe COPD experienced worsening of clinical symptoms (p < 0.001), required more SABA (p < 0.001), had increased HR (p = 0.01) and SP-D levels (p = 0.01) whereas FEV-1 (p = 0.05) decreased during stage 2 as compared with stage 1. Positive dynamics of all these variables except COPD symptoms and HR was observed at stage 3. Alteration in the extent of basal therapy in patients with stage III COPD did not result in dynamics of clinical and laboratory characteristics. The data obtained suggest the necessity of combined therapy with LABD or triple basal therapy of moderately severe COPD and the possibility of therapy with one or two LABD having different sites of action in the patients with clinically stable stage II COPD.

  11. Detecting inflammation and fibrosis in bowel wall with photoacoustic imaging in a Crohn's disease animal model

    NASA Astrophysics Data System (ADS)

    Xu, Guan; Johnson, Laura A.; Hu, Jack; Dillman, Jonathan R.; Higgins, Peter D. R.; Wang, Xueding

    2015-03-01

    Crohn's disease (CD) is an autoimmune disease affecting 700,000 people in the United States. This condition may cause obstructing intestinal narrowings (strictures) due to inflammation, fibrosis (deposition of collagen), or a combination of both. Utilizing the unique strong optical absorption of hemoglobin at 532 nm and collagen at 1370 nm, this study investigated the feasibility of non-invasively characterizing intestinal strictures using photoacoustic imaging (PAI). Three normal controls, ten pure inflammation and 9 inflammation plus fibrosis rat bowel wall samples were imaged. Statistical analysis of the PA measurements has shown the capability of discriminating the purely inflammatory from mixed inflammatory and fibrotic strictures.

  12. Guideline-Based Early Detection of Chronic Obstructive Pulmonary Disease in Eight Danish Municipalities: The TOP-KOM Study

    PubMed Central

    Hemmingsen, Ulla Borup; Stycke, Margit; Dollerup, Jens

    2017-01-01

    Background. Early detection of chronic obstructive pulmonary disease (COPD) and prevention of disease progression are important. Only 40% of COPD cases are diagnosed in Denmark. Recommendations for early case finding have been established. This study investigates early detection of pulmonary obstruction in a Danish municipality setting. Methods. Eight municipalities participated. Citizens fulfilling national case finding recommendations, age ≥35 years, smokers/ex-smokers/relevant occupational exposure, and at least one respiratory symptom, were invited to spirometry. Citizens with indication of pulmonary obstruction, forced expiratory volume in one second (FEV1)/forced vital capacity (FVC) < 0.70, were referred to their general practitioner (GP). Results. 1,499 citizens were examined (53.6% male, mean age 57.2 years). 44.8% were current smokers with 57% planning for smoking cessation. The citizens recorded significant airway symptoms with dyspnea being the most important (71%). The mean FEV1/FVC score was 73.54 (SD 22.84). 456 citizens (30.4%) were found to have indication for pulmonary obstruction and were referred to GP for further diagnosis. Conclusion. Early detection in Danish municipalities proved effective finding nearly 1/3 being pulmonary obstructive. It seems to be of value to have municipalities to perform case finding together with smoking cessation as a primary intervention in COPD management. PMID:28321336

  13. Intraindividual comparison of gadolinium- and iodine-enhanced 64-slice multidetector CT pulmonary angiography for the detection of pulmonary embolism in a porcine model.

    PubMed

    Henes, Frank Oliver Gerhard; Groth, Michael; Begemann, Philipp G C; Adam, Gerhard; Regier, Marc

    2011-06-01

    This study is an evaluation of the diagnostic accuracy of gadolinium-enhanced computed tomography pulmonary angiography (CTPA) for the detection of pulmonary embolism (PE) in comparison with iodine-enhanced CTPA. PE was induced in five anesthetized pigs by administration of blood clots through an 11-F catheter inside the jugular vein. Animals underwent CTPA in breathhold with i.v. bolus injection of 50 ml gadopentetate dimeglumine (0.4 mmol/kg, 4 ml/s). Subsequently, CTPA was performed using the same imaging parameters but under administration of 70 ml nonionic iodinated contrast material (400 mg/ml, 4 ml/s). All images were reconstructed with 1 mm slice thickness. A consensus readout of the iodium-enhanced CTPAs by both radiologists served as reference standard. Gadolinium-enhanced CTPAs were evaluated independently by two experienced radiologists, and differences in detection rate between both contrast agents were assessed on a per embolus basis using the Wilcoxon signed-rank test. Interobserver agreement was determined by calculation of қ values. PE was diagnosed independently by both readers in all five pigs by the use of gadolinium-enhanced CTPA. Out of 60 pulmonary emboli detected in the iodine-enhanced scans, 47 (78.3%; reader 1) and 44 (62.8%; reader 2) emboli were detected by the use of gadolinium. All 13 (100%) emboli in lobar arteries (by both readers) and 26 (reader 1) and 25 (reader 2) out of 27 emboli (96.3% and 92.6%) in segmental arteries were detected by the use of the gadolinium-enhanced CTPA. In subsegmental arteries, only 8 (40%; reader 1) and 6 (30%; reader 2) out of 20 emboli were detected by the gadolinium-enhanced CTPA. By comparing both scans on a per vessel basis (Wilcoxon test), Gd-enhanced CTPA was significantly inferior in emboli detection on subsegmental level (P < 0.0001). The interobserver agreement was excellent on lobar and segmental level (қ = 1.0 and 0.93, respectively), whereas readers only reached moderate

  14. Automatic 3D pulmonary nodule detection in CT images: A survey.

    PubMed

    Valente, Igor Rafael S; Cortez, Paulo César; Neto, Edson Cavalcanti; Soares, José Marques; de Albuquerque, Victor Hugo C; Tavares, João Manuel R S

    2016-02-01

    This work presents a systematic review of techniques for the 3D automatic detection of pulmonary nodules in computerized-tomography (CT) images. Its main goals are to analyze the latest technology being used for the development of computational diagnostic tools to assist in the acquisition, storage and, mainly, processing and analysis of the biomedical data. Also, this work identifies the progress made, so far, evaluates the challenges to be overcome and provides an analysis of future prospects. As far as the authors know, this is the first time that a review is devoted exclusively to automated 3D techniques for the detection of pulmonary nodules from lung CT images, which makes this work of noteworthy value. The research covered the published works in the Web of Science, PubMed, Science Direct and IEEEXplore up to December 2014. Each work found that referred to automated 3D segmentation of the lungs was individually analyzed to identify its objective, methodology and results. Based on the analysis of the selected works, several studies were seen to be useful for the construction of medical diagnostic aid tools. However, there are certain aspects that still require attention such as increasing algorithm sensitivity, reducing the number of false positives, improving and optimizing the algorithm detection of different kinds of nodules with different sizes and shapes and, finally, the ability to integrate with the Electronic Medical Record Systems and Picture Archiving and Communication Systems. Based on this analysis, we can say that further research is needed to develop current techniques and that new algorithms are needed to overcome the identified drawbacks. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  15. Recommendations for Screening and Detection of Connective-Tissue Disease Associated Pulmonary Arterial Hypertension

    PubMed Central

    Khanna, Dinesh; Gladue, Heather; Channick, Richard; Chung, Lorinda; Distler, Oliver; Furst, Daniel E.; Hachulla, Eric; Humbert, Marc; Langleben, David; Mathai, Stephen C.; Saggar, Rajeev; Visovatti, Scott; Altorok, Nezam; Townsend, Whitney; FitzGerald, John; McLaughlin, Vallerie

    2013-01-01

    Objectives Pulmonary arterial hypertension (PAH) affects up to 15% of patients with connective tissue diseases (CTD). Previous recommendations developed as part of larger efforts in PAH did not provide detailed recommendations for patients with CTD-PAH. Therefore, we sought to develop recommendations for screening and early detection of CTD-PAH. Methods We performed a systematic review for the screening and diagnosis of PAH in CTD b