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Irina Petrache, MD

Pulmonary

Professor of Medicine (BIOM). Dr. Calvin H. English Professor

Academic Office

Joseph E. Walther Hall
Room C400
Indianapolis IN 46202 Map

Contact Information

Phone: (317) 278-0050
Fax: (317) 988-3976
Email:

Research Interests

Our laboratory investigates the pathogenesis of and repair strategies for the lung injury that occurs in emphysema (COPD). Primarily caused by cigarette smoking, COPD is now the 3rd cause of mortality in the US. For the past decades the predominant paradigm in the emphysema research was that of a protease /antiprotease imbalance. Our work contributed to solidify the notion that cell death of structural components of the lung alveolus, epithelial and endothelial cells is sufficient to cause emphysema. We demonstrated that modifications in the abundance of the signaling sphingolipid ceramide trigger a cascade of events that culminates in emphysema-like disease in animals. To rebalance the sphingolipid homeostasis, we recently demonstrated that augmentation of endothelial pro-survival signaling with sphingosine-1 phosphate agonists is effective in preventing lung structural cell apoptosis and airspace enlargement. In addition, our laboratory studies mechanisms by which the anti-protease alpha 1 antitrypsin (A1AT) protects the lung. We showed that lung endothelial cells take up A1AT, and that A1AT has an anti-apoptotic function in lung vascular cells, which improved our understanding of emphysema pathogenesis and may expand the applications for A1AT therapies. The main established, ongoing projects in the lab are to understand the role and application of sphingolipid signaling in COPD and to investigate the mechanisms by which A1AT has direct cellular protective mechanisms in COPD, with the goal of enhancing its therapeutic application and effectiveness. In addition, we have several ongoing collaborative projects in the lab: 1) with Matthias Clauss, PhD, we study the mechanistic link between apoptosis and inflammation in the lung via the cytokine EMAPII; 2) with Keith March, MD PhD, we investigate the application of adult adipose progenitor cells as regenerative anti-apoptotic therapy in experimental emphysema; 3) with Hal Broxmeyer we investigate the effect of cigarette smoking on hematopoiesis and crosstalk of bone marrow with the lung in COPD; 4) using our expertise in vascular lung biology, with Tim Lahm, MD, we investigate of hypoxic PH both in vivo, in rats and mice, and in vitro, in primary lung endothelial cells; 5) since mechanistic investigation of emphysema and PH requires sophisticated lung function assessment and modern imaging, we implemented a novel intravital two photon excitation microscopy model of the lung in intact rodents, via close collaboration with the IU Biologic Microscopy Core and Robert G. Presson, MD.

Clinical Interests

COPD, Emphysema, Alpha-1 Antitrypsin Deficiency, Sarcoidosis, Acute Lung Injury, Cystic Fibrosis, Pulmonary Hypertension

Education and Training

Clinical Fellowship in Pulmonary and Critical Care Medicine Johns Hopkins University School of Medicine, Baltimore, MD 2000
Research and Clinical Fellowship in Pulmonary and Critical Care Medicine Johns Hopkins University School of Medicine, Baltimore, MD 1999
Internship and Residency, Internal Medicine Saint Luke's Medical Center, Case Western Reserve University, Cleveland, Ohio 1996
Mathematics 1992
Medicine (M.D.) 1986

Board Certifications

Internal Medicine 1997
Pulmonary Medicine 2000
Critical Care Medicine 2002

Publications (45)¹

Neonatal Hyperoxic Lung Injury Favorably Alters Adult Right Ventricular Remodeling Response to Chronic Hypoxia Exposure.
Journal: American journal of physiology. Lung cellular and molecular physiology
Authors: Goss KN; Cucci AR; Fisher AJ; Albrecht M; Frump AL; Tursunova R; Gao Y; Brown MB; Petrache I; Tepper RS; Ahlfeld SK; Lahm T;
Publication Date: 2015 Feb 6

Abstract

The development of pulmonary hypertension (PH) requires multiple pulmonary vascular insults, yet the role of early oxygen therapy as an initial pulmonary vascular insult remains poorly defined. Here, we employ a two-hit model of PH, utilizing postnatal hyperoxia followed by adult hypoxia exposure, to evaluate the role of early hyperoxic lung injury in the development of later PH. Sprague-Dawley pups were exposed to 90% oxygen during postnatal days 0-4 or 0-10 or to room air. All pups were then allowed to mature in room air. At 10 wk of age, a subset of rats from each group was exposed to 2 wk of hypoxia (Patm = 362 mmHg). Physiological, structural, and biochemical endpoints were assessed at 12 wk. Prolonged (10 days) postnatal hyperoxia was independently associated with elevated right ventricular (RV) systolic pressure, which worsened after hypoxia exposure later in life. These findings were only partially explained by decreases in lung microvascular density. Surprisingly, postnatal hyperoxia resulted in robust RV hypertrophy and more preserved RV function and exercise capacity following adult hypoxia compared with nonhyperoxic rats. Biochemically, RVs from animals exposed to postnatal hyperoxia and adult hypoxia demonstrated increased capillarization and a switch to a fetal gene pattern, suggesting an RV more adept to handle adult hypoxia following postnatal hyperoxia exposure. We concluded that, despite negative impacts on pulmonary artery pressures, postnatal hyperoxia exposure may render a more adaptive RV phenotype to tolerate late pulmonary vascular insults.
View details for PubMedID 25659904
Conditioned media from adipose stromal cells limit lipopolysaccharide-induced lung injury, endothelial hyperpermeability and apoptosis.
Journal: Journal of translational medicine
Authors: Lu H; Poirier C; Cook T; Traktuev DO; Merfeld-Clauss S; Lease B; Petrache I; March KL; Bogatcheva NV;
Publication Date: 2015 Feb 21

Abstract

Acute Respiratory Distress Syndrome (ARDS) is a condition that contributes to morbidity and mortality of critically ill patients. We investigated whether factors secreted by adipose stromal cells (ASC) into conditioned media (ASC-CM) will effectively decrease lung injury in the model of lipopolysaccharide (LPS)-induced ARDS.
View details for PubMedID 25889857
Human Adipose-Derived Stem Cells Ameliorate Cigarette Smoke-Induced Murine Myelosuppression via Secretion of TSG-6.
Journal: Stem cells (Dayton, Ohio)
Authors: Xie J; Broxmeyer HE; Feng D; Schweitzer KS; Yi R; Cook TG; Chitteti BR; Barwinska D; Traktuev DO; Van Demark MJ; Justice MJ; Ou X; Srour EF; Prockop DJ; Petrache I; March KL;
Publication Date: 2015 Feb

Abstract

Bone marrow-derived hematopoietic stem and progenitor cells (HSC/HPC) are critical to homeostasis and tissue repair. The aims of this study were to delineate the myelotoxicity of cigarette smoking (CS) in a murine model, to explore human adipose-derived stem cells (hASC) as a novel approach to mitigate this toxicity, and to identify key mediating factors for ASC activities.
View details for PubMedID 25329668
Novel assessment of hemodynamic kinetics with acute exercise in a rat model of pulmonary arterial hypertension.
Journal: Experimental physiology
Authors: Brown MB; Chingombe TJ; Zinn AB; Reddy JG; Novack RA; Cooney SA; Fisher AJ; Presson RG; Lahm T; Petrache I;
Publication Date: 2015 Apr 13

Abstract

Exercise improves outcomes of multiple chronic conditions, but controversial results, including increased pulmonary artery (PA) pressure, prevented its routine implementation in pulmonary arterial hypertension (PAH), an incurable disease that drastically reduces exercise tolerance. Individualized, optimized exercise prescription for PAH requires a better understanding of disease-specific exercise responses. We investigated the acute impact of exercise on already-elevated PA pressure and right ventricular (RV) wall stress and inflammation in a rat model of PAH (PAH group, n = 12) induced by monocrotaline (MCT, 50 mg/kg; 2 weeks), compared to healthy controls (CON, n = 8). Single bouts of exercise consisted of a 45 min treadmill run at 75% of individually-determined aerobic capacity (VO2 max). Immediately following exercise, RV systolic pressure (RVSP) and systemic pressure measurements were performed via jugular and carotid cannulation, and were followed by tissue collection. MCT induced moderate PAH, evidenced by RV hypertrophy, decreased VO2 max, PA muscularization, and RV and skeletal muscle cytoplasmic glycolysis, detected by increased Glut-1 expression. Acute exercise normalized MCT-induced elevation in RVSP and augmented pulmonary endothelial nitric oxide synthase (eNOS) activation, without evidence of increased RV inflammation or apoptosis. Real-time recordings of pulmonary and systemic pressures during and following single bouts of exercise performed using novel implantable telemetry in the same animal for up to 11 weeks post-MCT (40 mg/kg) corroborated the finding of acute PA pressure decreases with exercise in PAH. The PA pressure-lowering effects of individualized exercise associated with RV-neutral effects and increases in vasorelaxor signaling encourages further development of optimized exercise regimens as adjunctive PAH therapy. This article is protected by copyright. All rights reserved.
View details for PubMedID 25867528
Cathepsin E promotes pulmonary emphysema via mitochondrial fission.
Journal: The American journal of pathology
Authors: Zhang X; Shan P; Homer R; Zhang Y; Petrache I; Mannam P; Lee PJ;
Publication Date: 2014 Oct

Abstract

Emphysema is characterized by loss of lung elasticity and irreversible air space enlargement, usually in the later decades of life. The molecular mechanisms of emphysema remain poorly defined. We identified a role for a novel cathepsin, cathepsin E, in promoting emphysema by inducing mitochondrial fission. Unlike previously reported cysteine cathepsins, which have been implicated in cigarette smoke-induced lung disease, cathepsin E is a nonlysosomal intracellular aspartic protease whose function has been described only in antigen processing. We examined lung tissue sections of persons with chronic obstructive pulmonary disease, a clinical entity that includes emphysematous change. Human chronic obstructive pulmonary disease lungs had markedly increased cathepsin E protein in the lung epithelium. We generated lung epithelial-targeted transgenic cathepsin E mice and found that they develop emphysema. Overexpression of cathepsin E resulted in increased E3 ubiquitin ligase parkin, mitochondrial fission protein dynamin-related protein 1, caspase activation/apoptosis, and ultimately loss of lung parenchyma resembling emphysema. Inhibiting dynamin-related protein 1, using a small molecule inhibitor in vitro or in vivo, inhibited cathepsin E-induced apoptosis and emphysema. To the best of our knowledge, our study is the first to identify links between cathepsin E, mitochondrial fission, and caspase activation/apoptosis in the pathogenesis of pulmonary emphysema. Our data expand the current understanding of molecular mechanisms of emphysema development and may provide new therapeutic targets.
View details for PubMedID 25239563
Progress in solving the sex hormone paradox in pulmonary hypertension.
Journal: American journal of physiology. Lung cellular and molecular physiology
Authors: Lahm T; Tuder RM; Petrache I;
Publication Date: 2014 May 9

Abstract

Pulmonary arterial hypertension (PAH) is a devastating and progressive disease with marked morbidity and mortality. Even though being female represents one of the most powerful risk factors for PAH, multiple questions about the underlying mechanisms remain, and two "estrogen paradoxes" in PAH exist. First, it is puzzling why estrogens have been found to be protective in various animal models of PAH, whereas PAH registries uniformly demonstrate a female susceptibility to the disease. Second, despite the pronounced tendency for the disease to develop in women, female PAH patients exhibit better survival than men. Recent mechanistic studies in classical and in novel animal models of PAH, as well as recent studies in PAH patients, have significantly advanced the field. In particular, it is now accepted that estrogen metabolism and receptor signaling, as well as estrogen interactions with key pathways in PAH development, appear to be potent disease modifiers. A better understanding of these interactions may lead to novel PAH therapies. It is the purpose of this review to 1) review sex hormone synthesis, metabolism, and receptor physiology; 2) assess the context in which sex hormones affect PAH pathogenesis; 3) provide a potential explanation for the observed estrogen paradoxes and gender differences in PAH; and 4) identify knowledge gaps and future research opportunities. Because the majority of published studies investigated 17ß-estradiol and/or its metabolites, this review will primarily focus on pulmonary vascular and right ventricular effects of estrogens. Data for other sex hormones will be discussed very briefly.
View details for PubMedID 24816487
Smoking exposure induces human lung endothelial cell adaptation to apoptotic stress.
Journal: American journal of respiratory cell and molecular biology
Authors: Petrusca DN; Van Demark M; Gu Y; Justice MJ; Rogozea A; Hubbard WC; Petrache I;
Publication Date: 2014 Mar

Abstract

Prolonged exposure to cigarette smoking is the main risk factor for emphysema, a component of chronic obstructive pulmonary diseases (COPDs) characterized by destruction of alveolar walls. Moreover, smoking is associated with pulmonary artery remodeling and pulmonary hypertension, even in the absence of COPD, through as yet unexplained mechanisms. In murine models, elevations of intra- and paracellular ceramides in response to smoking have been implicated in the induction of lung endothelial cell apoptosis, but the role of ceramides in human cell counterparts is yet unknown. We modeled paracrine increases (outside-in) of palmitoyl ceramide (Cer16) in primary human lung microvascular cells. In naive cells, isolated from nonsmokers, Cer16 significantly reduced cellular proliferation and induced caspase-independent apoptosis via mitochondrial membrane depolarization, apoptosis-inducing factor translocation, and poly(ADP-ribose) polymerase cleavage. In these cells, caspase-3 was inhibited by ceramide-induced Akt phosphorylation, and by the induction of autophagic microtubule-associated protein-1 light-chain 3 lipidation. In contrast, cells isolated from smokers exhibited increased baseline proliferative features associated with lack of p16(INK4a) expression and Akt hyperphosphorylation. These cells were resistant to Cer16-induced apoptosis, despite presence of both endoplasmic reticulum stress response and mitochondrial membrane depolarization. In cells from smokers, the prominent up-regulation of Akt pathways inhibited ceramide-triggered apoptosis, and was associated with elevated sphingosine and high-mobility group box 1, skewing the cell's response toward autophagy and survival. In conclusion, the cell responses to ceramide are modulated by an intricate cross-talk between Akt signaling and sphingolipid metabolites, and profoundly modified by previous cigarette smoke exposure, which selects for an apoptosis-resistant phenotype.
View details for PubMedID 24079644
Selective endothelin-A receptor blockade attenuates endotoxin-induced pulmonary hypertension and pulmonary vascular dysfunction.
Journal: Pulmonary circulation
Authors: Toney BM; Fisher AJ; Albrecht M; Lockett AD; Presson RG; Petrache I; Lahm T;
Publication Date: 2014 Jun

Abstract

Endothelin-1 is a potent mediator of sepsis-induced pulmonary hypertension (PH). The pulmonary vascular effects of selective blockade of endothelin receptor subtype A (ETAR) during endotoxemia remain unknown. We hypothesized that selective ETAR antagonism attenuates endotoxin-induced PH and improves pulmonary artery (PA) vasoreactivity. Adult male Sprague-Dawley rats (250-450 g) received lipopolysaccharide (LPS; Salmonella typhimurium; 20 mg/kg intraperitoneally) or vehicle 6 hours before hemodynamic assessment and tissue harvest. The selective ETAR antagonist sitaxsentan (10 or 20 mg/kg) or vehicle was injected intravenously 3 hours after receipt of LPS. Right ventricular systolic pressure, mean arterial pressure (MAP), cardiac output (CO), oxygenation (P/F ratio), and serum bicarbonate were measured. Bronchoalveolar lavage (BAL) cell differential and lung wet-to-dry ratios were obtained. Endothelium-dependent and endothelium-independent vasorelaxations were determined in isolated PA rings. PA interleukin (IL)-1ß, IL-6, tumor necrosis factor a (TNF-a), and inducible nitric oxide synthase (iNOS) messenger RNA (mRNA) were measured. LPS caused PH, decreased MAP, CO, and serum bicarbonate, and increased PA IL-1ß, IL-6, TNF-a, and iNOS mRNA. Sitaxsentan attenuated sepsis-induced PH and increased MAP. The P/F ratio, CO, serum bicarbonate, and BAL neutrophilia were not affected by sitaxsentan. In isolated PA rings, while not affecting phenylephrine-induced vasocontraction or endothelium-dependent relaxation, sitaxsentan dose-dependently attenuated LPS-induced alterations in endothelium-independent relaxation. PA cytokine mRNA levels were not significantly attenuated by ETAR blockade. We conclude that ETAR blockade attenuates endotoxin-induced alterations in systemic and PA pressures without negatively affecting oxygenation. This protective effect appears to be mediated not by attenuation of sepsis-induced cardiac dysfunction, acidosis, or alveolar inflammation but rather by improved endothelium-independent vasorelaxation.
View details for PubMedID 25006449
Loss of cystic fibrosis transmembrane conductance regulator impairs lung endothelial cell barrier function and increases susceptibility to microvascular damage from cigarette smoke.
Journal: Pulmonary circulation
Authors: Brown MB; Hunt WR; Noe JE; Rush NI; Schweitzer KS; Leece TC; Moldobaeva A; Wagner EM; Dudek SM; Poirier C; Presson RG Jr; Gulbins E; Petrache I;
Publication Date: 2014 Jun

Abstract

Abnormal lung microvascular endothelial vascular barrier function may contribute to pulmonary inflammation, such as that occurring during inhalation of cigarette smoke (CS). Cystic fibrosis transmembrane conductance regulator (CFTR), an anion channel expressed in both epithelial and endothelial cells, regulates the organization of tight junctions between epithelial cells and has also been implicated in the transport of sphingosine-1 phosphate (S1P), a vascular barrier-enhancing sphingolipid. Because CS has been shown to affect CFTR function, we hypothesized that CFTR function contributes to lung endothelial cell barrier and that CFTR dysfunction worsens CS-induced injury. CFTR inhibitors GlyH-101 or CFTRinh172 caused a dose-dependent increase in pulmonary or bronchial endothelial monolayer permeability, which peaked after 4 hours. CFTR inhibition was associated with both intercellular gaps and actin stress fiber formation compared with vehicle-treated cells. Increasing endothelial S1P, either by exogenous treatment or by inhibition of its degradation, significantly improved the barrier function in CFTR-inhibited monolayers. Both cultured lung endothelia and the lung microcirculation visualized in vivo with intravital two-photon imaging of transgenic mice deficient in CFTR showed that CFTR dysfunction increased susceptibility to CS-induced permeability. These results suggested that CFTR function might be required for lung endothelial barrier, including adherence junction stability. Loss of CFTR function, especially concomitant to CS exposure, might promote lung inflammation by increasing endothelial cell permeability, which could be ameliorated by S1P.
View details for PubMedID 25006445
Transient and persistent metabolomic changes in plasma following chronic cigarette smoke exposure in a mouse model.
Journal: PloS one
Authors: Cruickshank-Quinn CI; Mahaffey S; Justice MJ; Hughes G; Armstrong M; Bowler RP; Reisdorph R; Petrache I; Reisdorph N;
Publication Date: 2014 Jul 9

Abstract

Cigarette smoke exposure is linked to the development of a variety of chronic lung and systemic diseases in susceptible individuals. Metabolomics approaches may aid in defining disease phenotypes, may help predict responses to treatment, and could identify biomarkers of risk for developing disease. Using a mouse model of chronic cigarette smoke exposure sufficient to cause mild emphysema, we investigated whether cigarette smoke induces distinct metabolic profiles and determined their persistence following smoking cessation. Metabolites were extracted from plasma and fractionated based on chemical class using liquid-liquid and solid-phase extraction prior to performing liquid chromatography mass spectrometry-based metabolomics. Metabolites were evaluated for statistically significant differences among group means (p-value=0.05) and fold change =1.5). Cigarette smoke exposure was associated with significant differences in amino acid, purine, lipid, fatty acid, and steroid metabolite levels compared to air exposed animals. Whereas 60% of the metabolite changes were reversible, 40% of metabolites remained persistently altered even following 2 months of smoking cessation, including nicotine metabolites. Validation of metabolite species and translation of these findings to human plasma metabolite signatures induced by cigarette smoking may lead to the discovery of biomarkers or pathogenic pathways of smoking-induced disease.
View details for PubMedID 25007263
Vertebral erosion: an uncommon complication of tracheal tubes.
Journal: American journal of respiratory and critical care medicine
Authors: Petrache I; Patel D; Wolf KM; Winer-Muram H;
Publication Date: 2014 Jul 15
Impact of alginate-producing Pseudomonas aeruginosa on alveolar macrophage apoptotic cell clearance.
Journal: Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society
Authors: McCaslin CA; Petrusca DN; Poirier C; Serban KA; Anderson GG; Petrache I;
Publication Date: 2014 Jul 12

Abstract

Pseudomonas aeruginosa infection is a hallmark of lung disease in cystic fibrosis. Acute infection with P. aeruginosa profoundly inhibits alveolar macrophage clearance of apoptotic cells (efferocytosis) via direct effect of virulence factors. During chronic infection, P. aeruginosa evades host defense by decreased virulence, which includes the production or, in the case of mucoidy, overproduction of alginate. The impact of alginate on innate immunity, in particular on macrophage clearance of apoptotic cells is not known. We hypothesized that P. aeruginosa strains that exhibit reduced virulence impair macrophage clearance of apoptotic cells and we investigated if the polysaccharide alginate produced by mucoid P. aeruginosa is sufficient to inhibit alveolar macrophage efferocytosis. Rat alveolar or human peripheral blood monocyte (THP-1)-derived macrophage cell lines were exposed in vitro to exogenous alginate or to wild type or alginate-overproducing mucoid P. aeruginosa prior to challenge with apoptotic human Jurkat T-lymphocytes. The importance of LPS contamination and that of structural integrity of alginate polymers was tested using alginate of different purities and alginate lyase, respectively. Alginate inhibited alveolar macrophage efferocytosis in a dose- and time-dependent manner. This effect was augmented but not exclusively attributed to lipopolysaccharide (LPS) present in alginates. Alginate-producing P. aeruginosa inhibited macrophage efferocytosis by more than 50%. A mannuronic-specific alginate lyase did not restore efferocytosis inhibited by exogenous guluronic-rich marine alginate, but had a marked beneficial effect on efferocytosis of alveolar macrophages exposed to mucoid P. aeruginosa. Despite decreased virulence, mucoid P. aeruginosa may contribute to chronic airway inflammation through significant inhibition of alveolar clearance of apoptotic cells and debris. The mechanism by which mucoid bacteria inhibit efferocytosis may involve alginate production and synergy with LPS, suggesting that alginate lyase may be an attractive therapeutic approach to airway inflammation in cystic fibrosis and other chronic obstructive pulmonary diseases characterized by P. aeruginosa colonization.
View details for PubMedID 25027418
Effects of lipid interactions on model vesicle engulfment by alveolar macrophages.
Journal: Biophysical journal
Authors: Justice MJ; Petrusca DN; Rogozea AL; Williams JA; Schweitzer KS; Petrache I; Wassall SR; Petrache HI;
Publication Date: 2014 Feb 4

Abstract

The engulfment function of macrophages relies on complex molecular interactions involving both lipids and proteins. In particular, the clearance of apoptotic bodies (efferocytosis) is enabled by externalization on the cell target of phosphatidylserine lipids, which activate receptors on macrophages, suggesting that (local) specific lipid-protein interactions are required at least for the initiation of efferocytosis. However, in addition to apoptotic cells, macrophages can engulf foreign bodies that vary substantially in size from a few nanometers to microns, suggesting that nonspecific interactions over a wide range of length scales could be relevant. Here, we use model lipid membranes (made of phosphatidylcholine, phosphatidylserine, and ceramide) and rat alveolar macrophages to show how lipid bilayer properties probed by small-angle x-ray scattering and solid-state (2)H NMR correlate with engulfment rates measured by flow cytometry. We find that engulfment of protein-free model lipid vesicles is promoted by the presence of phosphatidylserine lipids but inhibited by ceramide, in accord with a previous study of apoptotic cells. We conclude that the roles of phosphatidylserine and ceramide in phagocytosis is based, at least in part, on lipid-mediated modification of membrane physical properties, including interactions at large length scales as well as local lipid ordering and possible domain formation.
View details for PubMedID 24507600
Space radiation-associated lung injury in a murine model.
Journal: American journal of physiology. Lung cellular and molecular physiology
Authors: Christofidou-Solomidou M; Pietrofesa RA; Arguiri E; Schweitzer KS; Berdyshev EV; McCarthy M; Corbitt A; Alwood JS; Yu Y; Globus RK; Solomides CC; Ullrich RL; Petrache I;
Publication Date: 2014 Dec 19

Abstract

Despite considerable progress in identifying health risks to crewmembers related to exposure to galactic/cosmic rays and solar particle events (SPE) during space travel, its long-term effects on the pulmonary system are unknown. We used a murine risk projection model to investigate the impact of exposure to space-relevant radiation (SR) on the lung. C3H mice were exposed to (137)Cs gamma rays, protons (acute, low-dose exposure mimicking the 1972 SPE), 600 MeV/u (56)Fe ions, or 350 MeV/u (28)Si ions at the NASA Space Radiation Laboratory at Brookhaven National Laboratory. Animals were irradiated at the age of 2.5 mo and evaluated 23.5 mo postirradiation, at 26 mo of age. Compared with age-matched nonirradiated mice, SR exposures led to significant air space enlargement and dose-dependent decreased systemic oxygenation levels. These were associated with late mild lung inflammation and prominent cellular injury, with significant oxidative stress and apoptosis (caspase-3 activation) in the lung parenchyma. SR, especially high-energy (56)Fe or (28)Si ions markedly decreased sphingosine-1-phosphate levels and Akt- and p38 MAPK phosphorylation, depleted anti-senescence sirtuin-1 and increased biochemical markers of autophagy. Exposure to SR caused dose-dependent, pronounced late lung pathological sequelae consistent with alveolar simplification and cellular signaling of increased injury and decreased repair. The associated systemic hypoxemia suggested that this previously uncharacterized space radiation-associated lung injury was functionally significant, indicating that further studies are needed to define the risk and to develop appropriate lung-protective countermeasures for manned deep space missions.
View details for PubMedID 25526737
Overexpression of type VI collagen in neoplastic lung tissues.
Journal: Oncology reports
Authors: Voiles L; Lewis DE; Han L; Lupov IP; Lin TL; Robertson MJ; Petrache I; Chang HC;
Publication Date: 2014 Aug 22

Abstract

Type VI collagen (COL6), an extracellular matrix protein, is important in maintaining the integrity of lung tissue. An increase in COL6 mRNA and protein deposition was found in the lungs of patients with pulmonary fibrosis, a chronic inflammatory condition with a strong association with lung cancer. In the present study, we demonstrated overexpression of COL6 in the lungs of non-small cell lung cancers. We hypothesized that excessive COL6 in the lung interstitium may exert stimulatory effects on the adjacent cells. In vitro stimulation of monocytes with COL6 resulted in the production of IL-23, which may promote tumor development in an environment of IL-23-mediated lung inflammation, where tissue modeling occurs concurrently with excessive COL6 production. In addition, COL6 was capable of stimulating signaling pathways that activate focal adhesion kinase and extracellular signal-regulated kinase 1/2 in lung epithelial cells, which may also facilitate the development of lung neoplasms. Taken together, our data suggest the potential role of COL6 in promoting lung neoplasia in diseased lungs where COL6 is overexpressed.
View details for PubMedID 25176343
Active trafficking of alpha 1 antitrypsin across the lung endothelium.
Journal: PloS one
Authors: Lockett AD; Brown MB; Santos-Falcon N; Rush NI; Oueini H; Oberle AJ; Bolanis E; Fragoso MA; Petrusca DN; Serban KA; Schweitzer KS; Presson RG Jr; Campos M; Petrache I;
Publication Date: 2014 Apr 17

Abstract

The homeostatic lung protective effects of alpha-1 antitrypsin (A1AT) may require the transport of circulating proteinase inhibitor across an intact lung endothelial barrier. We hypothesized that uninjured pulmonary endothelial cells transport A1AT to lung epithelial cells. Purified human A1AT was rapidly taken up by confluent primary rat pulmonary endothelial cell monolayers, was secreted extracellularly, both apically and basolaterally, and was taken up by adjacent rat lung epithelial cells co-cultured on polarized transwells. Similarly, polarized primary human lung epithelial cells took up basolaterally-, but not apically-supplied A1AT, followed by apical secretion. Evidence of A1AT transcytosis across lung microcirculation was confirmed in vivo by two-photon intravital microscopy in mice. Time-lapse confocal microscopy indicated that A1AT co-localized with Golgi in the endothelium whilst inhibition of the classical secretory pathway with tunicamycin significantly increased intracellular retention of A1AT. However, inhibition of Golgi secretion promoted non-classical A1AT secretion, associated with microparticle release. Polymerized A1AT or A1AT supplied to endothelial cells exposed to soluble cigarette smoke extract had decreased transcytosis. These results suggest previously unappreciated pathways of A1AT bidirectional uptake and secretion from lung endothelial cells towards the alveolar epithelium and airspaces. A1AT trafficking may determine its functional bioavailablity in the lung, which could be impaired in individuals exposed to smoking or in those with A1AT deficiency.
View details for PubMedID 24743137
MSPrep--summarization, normalization and diagnostics for processing of mass spectrometry-based metabolomic data.
Journal: Bioinformatics (Oxford, England)
Authors: Hughes G; Cruickshank-Quinn C; Reisdorph R; Lutz S; Petrache I; Reisdorph N; Bowler R; Kechris K;
Publication Date: 2013 Oct 29

Abstract

Although R packages exist for the pre-processing of metabolomic data, they currently do not incorporate additional analysis steps of summarization, filtering and normalization of aligned data. We developed the MSPrep R package to complement other packages by providing these additional steps, implementing a selection of popular normalization algorithms and generating diagnostics to help guide investigators in their analyses.
View details for PubMedID 24174567
Ceramide synthases expression and role of ceramide synthase-2 in the lung: insight from human lung cells and mouse models.
Journal: PloS one
Authors: Petrache I; Kamocki K; Poirier C; Pewzner-Jung Y; Laviad EL; Schweitzer KS; Van Demark M; Justice MJ; Hubbard WC; Futerman AH;
Publication Date: 2013 May 14

Abstract

Increases in ceramide levels have been implicated in the pathogenesis of both acute or chronic lung injury models. However, the role of individual ceramide species, or of the enzymes that are responsible for their synthesis, in lung health and disease has not been clarified. We now show that C24- and C16-ceramides are the most abundant lung ceramide species, paralleled by high expression of their synthetic enzymes, ceramide synthase 2 (CerS2) and CerS5, respectively. Furthermore, the ceramide species synthesis in the lung is homeostatically regulated, since mice lacking very long acyl chain C24-ceramides due to genetic deficiency of CerS2 displayed a ten-fold increase in C16-ceramides and C16-dihydroceramides along with elevation of acid sphingomyelinase and CerS5 activities. Despite relatively preserved total lung ceramide levels, inhibition of de novo sphingolipid synthesis at the level of CerS2 was associated with significant airflow obstruction, airway inflammation, and increased lung volumes. Our results suggest that ceramide species homeostasis is crucial for lung health and that CerS2 dysfunction may predispose to inflammatory airway and airspace diseases.
View details for PubMedID 23690971
a1-Antitrypsin modulates lung endothelial cell inflammatory responses to TNF-a.
Journal: American journal of respiratory cell and molecular biology
Authors: Lockett AD; Kimani S; Ddungu G; Wrenger S; Tuder RM; Janciauskiene SM; Petrache I;
Publication Date: 2013 Jul

Abstract

a1-Antitrypsin (A1AT) is an acute-phase reactant, but also a major protective factor against the development of chronic obstructive pulmonary disease, a complex disease with sustained chronic inflammation. The lung-protective effects of A1AT have been attributed to the inhibition of proteases involved in lung matrix fragmentation, macrophage activation, and endothelial-cell apoptosis. More recently, A1AT has been shown to directly interact with or modulate the actions of cytokines such as TNF-a or IL-1 in inflammatory cells, but its effect on the lung endothelium, an active participant in the amplification and resolution of inflammation, has received little attention. An important role of A1AT in modulating lung endothelial inflammatory responses is expected, given the high concentrations of circulating A1AT during inflammation and its active uptake by endothelial cells. We investigated the role of A1AT in primary lung microvascular endothelial cell activation by relevant cytokines such as TNF-a or IL-1ß. Despite an initial marked augmentation of TNF-a self-induced transcription, A1AT inhibited TNF-a receptor 1 up-regulation and significantly reduced TNF-a secretion, effects that were associated with inhibition of TNF-a-converting enzyme activity. Furthermore, A1AT inhibited calpain activity, whose activation by TNF-a contributed to decreased intracellular A1AT concentrations. These data indicate that A1AT initially facilitates acute responses of the endothelium to TNF-a, followed by selective inhibition of TNF-a-induced-self amplification, which may assist the vasculature in the resolution of chronic inflammation.
View details for PubMedID 23526215
Cigarette smoke exposure inhibits contact hypersensitivity via the generation of platelet-activating factor agonists.
Journal: Journal of immunology (Baltimore, Md. : 1950)
Authors: Sahu RP; Petrache I; Van Demark MJ; Rashid BM; Ocana JA; Tang Y; Yi Q; Turner MJ; Konger RL; Travers JB;
Publication Date: 2013 Jan 25

Abstract

Previous studies have established that pro-oxidative stressors suppress host immunity because of their ability to generate oxidized lipids with platelet-activating factor receptor (PAF-R) agonist activity. Although exposure to the pro-oxidative stressor cigarette smoke (CS) is known to exert immunomodulatory effects, little is known regarding the role of PAF in these events. The current studies sought to determine the role of PAF-R signaling in CS-mediated immunomodulatory effects. We demonstrate that CS exposure induces the generation of a transient PAF-R agonistic activity in the blood of mice. CS exposure inhibits contact hypersensitivity in a PAF-R-dependent manner as PAF-R-deficient mice were resistant to these effects. Blocking PAF-R agonist production either by systemic antioxidants or treatment with serum PAF-acetyl hydrolase enzyme blocked both the CS-mediated generation of PAF-R agonists and PAF-R-dependent inhibition of contact hypersensitivity (CHS) reactions, indicating a role for oxidized glycerophosphocholines with PAF-R agonistic activity in this process. In addition, cyclooxygenase-2 inhibition did not block PAF-R agonist production but prevented CS-induced inhibition of CHS. This suggests that cyclooxygenase-2 acts downstream of the PAF-R in mediating CS-induced systemic immunosuppression. Moreover, CS exposure induced a significant increase in the expression of the regulatory T cell reporter gene in Foxp3(EGFP) mice but not in Foxp3(EGFP) mice on a PAF-R-deficient background. Finally, regulatory T cell depletion via anti-CD25 Abs blocked CS-mediated inhibition of CHS, indicating the potential involvement of regulatory T cells in CS-mediated systemic immunosuppression. These studies provide the first evidence, to our knowledge, that the pro-oxidative stressor CS can modulate cutaneous immunity via the generation of PAF-R agonists produced through lipid oxidation.
View details for PubMedID 23355733
HIV envelope protein gp120-induced apoptosis in lung microvascular endothelial cells by concerted upregulation of EMAP II and its receptor, CXCR3.
Journal: American journal of physiology. Lung cellular and molecular physiology
Authors: Green LA; Yi R; Petrusca D; Wang T; Elghouche A; Gupta SK; Petrache I; Clauss M;
Publication Date: 2013 Dec 6

Abstract

Chronic lung diseases, such as pulmonary emphysema, are increasingly recognized complications of infection with the human immunodeficiency virus (HIV). Emphysema in HIV may occur independent of cigarette smoking, via mechanisms that are poorly understood but may involve lung endothelial cell apoptosis induced by the HIV envelope protein gp120. Recently, we have demonstrated that lung endothelial apoptosis is an important contributor to the development of experimental emphysema, via upregulation of the proinflammatory cytokine endothelial monocyte-activating polypeptide II (EMAP II) in the lung. Here we investigated the role of EMAP II and its receptor, CXCR3, in gp120-induced lung endothelial cell apoptosis. We could demonstrate that gp120 induces a rapid and robust increase in cell surface expression of EMAP II and its receptor CXCR3. This surface expression occurred via a mechanism involving gp120 signaling through its CXCR4 receptor and p38 MAPK activation. Both EMAP II and CXCR3 were essentially required for gp120-induced apoptosis and exposures to low gp120 concentrations enhanced the susceptibility of endothelial cells to undergo apoptosis when exposed to soluble cigarette smoke extract. These data indicate a novel mechanism by which HIV infection causes endothelial cell loss involved in lung emphysema formation, independent but potentially synergistic with smoking, and suggest therapeutic targets for emphysema prevention and/or treatment.
View details for PubMedID 24318111
The involvement of sphingolipids in chronic obstructive pulmonary diseases.
Journal: Handbook of experimental pharmacology
Authors: Petrache I; Petrusca DN;
Publication Date: 2013

Abstract

Chronic obstructive pulmonary disease (COPD) includes a spectrum of conditions that have in common varying degrees of airflow obstruction, such as chronic bronchitis and emphysema. There is an increasing evidence of involvement of sphingolipids as key molecular mediators or biomarkers of disease in emphysema, chronic bronchitis, and more recently in asthma, another disease characterized by (reversible) airflow obstruction. Given the recognized central role of oxidative stress and inflammatory stimuli along with involvement of immune responses, apoptosis, and tissue remodeling in the development of chronic obstructive lung diseases, it is not surprising that sphingolipids have been shown to play important role in their pathobiology. In particular the pro-apoptotic effects of ceramide were suspected as events in the lung destruction that occurs as a result of apoptotic loss of structural cells comprising the alveolar walls, such as microvascular endothelial cells and alveolar epithelial cells. In addition, the role of ceramide was investigated in models of larger airway epithelial cell stress responses to cigarette smoke, in the context of ensuing airway remodeling and inflammation. This chapter discusses current evidence of sphingolipid perturbations in experimental models of COPD and relevant links to human disease based on translational and epidemiological data.
View details for PubMedID 23563660
Effect of cigarette smoke exposure and structural modifications on the a-1 Antitrypsin interaction with caspases.
Journal: Molecular medicine (Cambridge, Mass.)
Authors: Lockett AD; Van Demark M; Gu Y; Schweitzer KS; Sigua N; Kamocki K; Fijalkowska I; Garrison J; Fisher AJ; Serban K; Wise RA; Flotte TR; Mueller C; Presson RG Jr; Petrache HI; Tuder RM; Petrache I;
Publication Date: 2012 May 9

Abstract

a-1 Antitrypsin (A1AT) is a serpin with a major protective effect against cigarette smoke-induced emphysema development, and patients with mutations of the A1AT gene display a markedly increased risk for developing emphysema. We reported that A1AT protects lung endothelial cells from apoptosis and inhibits caspase-3 activity. It is not clear if cigarette smoking or A1AT mutations alter the caspase-3 inhibitory activity of A1AT and if this serpin alters the function of other caspases. We tested the hypothesis that the caspase-3 inhibitory activity of A1AT is impaired by cigarette smoking and that the A1AT RCL, the key antiprotease domain of the serpin, is required for its interaction with the caspase. We examined the caspase-3 inhibitory activity of human A1AT purified from plasma of actively smoking and nonsmoking individuals, either affected or unaffected with chronic obstructive pulmonary disease. We also tested the caspase inhibitory activity of two mutant forms of A1AT, the recombinant human piZZ and the RCL-deleted (RCL-null) A1AT forms. A1AT purified from the blood of active smokers exhibited marked attenuation in its caspase-3 inhibitory activity, independent of disease status. In vitro exposure of the normal (MM) form of A1AT to cigarette smoke extract reduced its ability to interact with caspase-3, measured by isothermal titration calorimetry, as did the deletion of the RCL, but not the ZZ point mutation. In cell-free assays A1AT was capable of inhibiting all executioner caspases, -3, -7 and especially -6, but not the initiator or inflammatory caspases. The inhibitory effect of A1AT against caspase-6 was tested in vivo, where overexpression of both human MM and ZZ-A1AT via adeno-associated virus transduction significantly protected against apoptosis and against airspace damage induced by intratracheal instillation of caspase-6 in mice. These data indicate a specific inhibitory effect of A1AT on executioner caspases, which is profoundly attenuated by active exposure to cigarette smoking and is dependent on the protein RCL, but is not affected by the PiZZ mutation.
View details for PubMedID 22245800
LC3 as a potential therapeutic target in hypoxia-induced pulmonary hypertension.
Journal: Autophagy
Authors: Lahm T; Petrache I;
Publication Date: 2012 May 25

Abstract

Recent research suggests that microtubule-associated protein 1 light chain 3B (LC3B) confers protection against hypoxia-induced pulmonary hypertension (HPH) by inhibiting proliferation of pulmonary artery (PA) wall cells. We recently demonstrated that 17ß-estradiol (E2), a sex hormone with known protective properties in HPH, increases lung LC3-II expression in chronically hypoxic male Sprague-Dawley rats. Stimulatory E2 effects on LC3-II were recapitulated in isolated hypoxic (1% O 2 for 48 h), but not room air-exposed primary rat PA endothelial cells (PAECs), and were accompanied by hypoxia-specific inhibitory effects on other parameters involved in proproliferative signaling (MAPK3/ERK1-MAPK1/ERK2 activation, VEGF secretion), as well as inhibitory effects on PAEC proliferation. Taken together, these results suggest that E2 mediates hypoxia-specific antiproliferative effects in PAECs, and that stimulation of autophagy may be one of the underlying mechanisms of E2-mediated protection in HPH. Viewed in the context of previously published data, these results indicate that LC3 1) exerts protective effects in the pathogenesis of HPH, and 2) may represent a potential target for future therapeutic interventions in HPH.
View details for PubMedID 22627195
17ß-Estradiol attenuates hypoxic pulmonary hypertension via estrogen receptor-mediated effects.
Journal: American journal of respiratory and critical care medicine
Authors: Lahm T; Albrecht M; Fisher AJ; Selej M; Patel NG; Brown JA; Justice MJ; Brown MB; Van Demark M; Trulock KM; Dieudonne D; Reddy JG; Presson RG; Petrache I;
Publication Date: 2012 Mar 1

Abstract

17ß-Estradiol (E2) attenuates hypoxic pulmonary vasoconstriction and hypoxic pulmonary hypertension (HPH) through an unknown mechanism that may involve estrogen receptors (ER) or E2 conversion to catecholestradiols and methoxyestradiols with previously unrecognized effects on cardiopulmonary vascular remodeling.
View details for PubMedID 22383500
Cigarette smoke-induced CXCR3 receptor up-regulation mediates endothelial apoptosis.
Journal: American journal of respiratory cell and molecular biology
Authors: Green LA; Petrusca D; Rajashekhar G; Gianaris T; Schweitzer KS; Wang L; Justice MJ; Petrache I; Clauss M;
Publication Date: 2012 Aug 30

Abstract

Endothelial monocyte-activating polypeptide II (EMAP II) and interferon-inducible protein (IP)-10 are proinflammatory mediators, which in addition to their chemokine activities, selectively induce apoptosis in endothelial cells and are up-regulated in the lungs of cigarette smoke-exposed humans. Previously, we showed that EMAP II is an essential mediator of cigarette smoke-induced lung emphysema in mice linking endothelial cell apoptosis with inflammation. Here we addressed the role of the CXCR3 receptor in EMAP II-induced and IP-10-induced apoptosis in endothelial cells and its regulation by cigarette smoke. We found that both neutralizing antibodies and small inhibitory RNA to CXCR3 abrogated EMAP II-induced and IP-10-induced endothelial caspase-3 activation and DNA fragmentation. CXCR3 receptor surface expression in human lung microvascular endothelial cells and in lung tissue endothelium was up-regulated by exposure to cigarette smoke. In tissue culture conditions, EMAP II-induced and IP-10-induced apoptosis was enhanced by preincubation with cigarette smoke extract. Interestingly, serum starvation also induced CXCR3 up-regulation and enhanced EMAP II-induced endothelial apoptosis. Signal transduction via p38 mitogen-activated protein kinase activation was essential for CXCR3-induced cell death, but not for CXCR3 receptor up-regulation by cigarette smoke. In turn, protein nitration was required for CXCR3 receptor up-regulation by cigarette smoke and consequently for subsequent CXCR3-induced cell death. In conclusion, the concerted up-regulation of proinflammatory EMAP II, IP-10, and CXCR3 by cigarette smoke could sustain a cascade of cell death that may promote the alveolar tissue loss noted in human emphysema.
View details for PubMedID 22936405
Dihydroceramide-based response to hypoxia.
Journal: The Journal of biological chemistry
Authors: Devlin CM; Lahm T; Hubbard WC; Van Demark M; Wang KC; Wu X; Bielawska A; Obeid LM; Ivan M; Petrache I;
Publication Date: 2011 Sep 13

Abstract

To understand the mechanisms of ceramide-based responses to hypoxia, we performed a mass spectrometry-based survey of ceramide species elicited by a wide range of hypoxic conditions (0.2-5% oxygen). We describe a rapid, time-dependent, marked up-regulation of dihydroceramides (DHCs) in mammalian cells and in the lungs of hypoxic rats. The increase affected all DHC species and was proportional with the depth and duration of hypoxia, ranging from 2- (1 h) to 10-fold (24 h), with complete return to normal after 1 h of reoxygenation at the expense of increased ceramides. We demonstrate that a DHC-based response to hypoxia occurs in a hypoxia-inducible factor-independent fashion and is catalyzed by the DHC desaturase (DEGS) in the de novo ceramide pathway. Both the impact of hypoxia on DHC molecular species and its inhibitory effect on cell proliferation were reproduced by knockdown of DEGS1 or DEGS2 by siRNA during normoxia. Conversely, overexpression of DEGS1 or DEGS2 attenuated the DHC accumulation and increased cell proliferation during hypoxia. Based on the amplitude and kinetics of DHC accumulation, the enzymatic desaturation of DHCs fulfills the criteria of an oxygen sensor across physiological hypoxic conditions, regulating the balance between biologically active components of ceramide metabolism.
View details for PubMedID 21914808
Involvement of ceramide in cell death responses in the pulmonary circulation.
Journal: Proceedings of the American Thoracic Society
Authors: Petrache I; Petrusca DN; Bowler RP; Kamocki K;
Publication Date: 2011 Nov

Abstract

Ceramides are signaling sphingolipids involved in cellular homeostasis but also in pathological processes such as unwanted apoptosis, growth arrest, oxidative stress, or senescence. Several enzymatic pathways are responsible for the synthesis of ceramides, which can be activated in response to exogenous stimuli such as cytokines, radiation, or oxidative stress. Endothelial cells are particularly rich in acid sphingomyelinases, which can be rapidly activated to produce ceramides, both intracellular and at the plasma membrane. In addition, neutral sphingomyelinases, the de novo pathway and the ceramide recycling pathway, may generate excessive ceramides involved in endothelial cell responses. When up-regulated, ceramides trigger signaling pathways that culminate in endothelial cell death, which in murine lungs has been linked to the development of emphysema-like disease. Furthermore, ceramides may be released paracellularly where they are believed to exert paracrine activities. Such effects, along with ceramides released by inflammatory mediators, may contribute to lung inflammation and pulmonary edema, because ceramide-challenged pulmonary endothelial cells exhibit decreased barrier function, independent of apoptosis. Reestablishing the sphingolipid homeostasis, either by modulating ceramide synthesis or by opposing its biological effects through augmentation of the prosurvival sphingosine-1 phosphate, may alleviate acute or chronic pulmonary conditions characterized by vascular endothelial cell death or dysfunction.
View details for PubMedID 22052925
Two-photon imaging within the murine thorax without respiratory and cardiac motion artifact.
Journal: The American journal of pathology
Authors: Presson RG Jr; Brown MB; Fisher AJ; Sandoval RM; Dunn KW; Lorenz KS; Delp EJ; Salama P; Molitoris BA; Petrache I;
Publication Date: 2011 May 7

Abstract

Intravital microscopy has been recognized for its ability to make physiological measurements at cellular and subcellular levels while maintaining the complex natural microenvironment. Two-photon microscopy (TPM), using longer wavelengths than single-photon excitation, has extended intravital imaging deeper into tissues, with minimal phototoxicity. However, due to a relatively slow acquisition rate, TPM is especially sensitive to motion artifact, which presents a challenge when imaging tissues subject to respiratory and cardiac movement. Thoracoabdominal organs that cannot be exteriorized or immobilized during TPM have generally required the use of isolated, pump-perfused preparations. However, this approach entails significant alteration of normal physiology, such as a lack of neural inputs, increased vascular resistance, and leukocyte activation. We adapted techniques of intravital microscopy that permitted TPM of organs maintained within the thoracoabdominal cavity of living, breathing rats or mice. We obtained extended intravital TPM imaging of the intact lung, arguably the organ most susceptible to both respiratory and cardiac motion. Intravital TPM detected the development of lung microvascular endothelial activation manifested as increased leukocyte adhesion and plasma extravasation in response to oxidative stress inducers PMA or soluble cigarette smoke extract. The pulmonary microvasculature and alveoli in the intact animal were imaged with comparable detail and fidelity to those in pump-perfused animals, opening the possibility for TPM of other thoracoabdominal organs under physiological and pathophysiological conditions.
View details for PubMedID 21703395
Lung endothelial monocyte-activating protein 2 is a mediator of cigarette smoke-induced emphysema in mice.
Journal: The Journal of clinical investigation
Authors: Clauss M; Voswinckel R; Rajashekhar G; Sigua NL; Fehrenbach H; Rush NI; Schweitzer KS; Yildirim AÖ; Kamocki K; Fisher AJ; Gu Y; Safadi B; Nikam S; Hubbard WC; Tuder RM; Twigg HL 3rd; Presson RG; Sethi S; Petrache I;
Publication Date: 2011 May 16

Abstract

Pulmonary emphysema is a disease characterized by alveolar cellular loss and inflammation. Recently, excessive apoptosis of structural alveolar cells has emerged as a major mechanism in the development of emphysema. Here, we investigated the proapoptotic and monocyte chemoattractant cytokine endothelial monocyte-activating protein 2 (EMAPII). Lung-specific overexpression of EMAPII in mice caused simplification of alveolar structures, apoptosis, and macrophage accumulation, compared with that in control transgenic mice. Additionally, in a mouse model of cigarette smoke-induced (CS-induced) emphysema, EMAPII levels were significantly increased in murine lungs. This upregulation was necessary for emphysema development, as neutralizing antibodies to EMAPII resulted in reduced alveolar cell apoptosis, inflammation, and emphysema-associated structural changes in alveoli and small airways and improved lung function. The mechanism of EMAPII upregulation involved an apoptosis-dependent feed-forward loop, since caspase-3 instillation in the lung markedly increased EMAPII expression, while caspase inhibition decreased its production, even in transgenic EMAPII mice. These findings may have clinical significance, as both current smokers and ex-smoker chronic obstructive pulmonary disease (COPD) patients had increased levels of secreted EMAPII in the bronchoalveolar lavage fluid compared with that of nonsmokers. In conclusion, we suggest that EMAPII perpetuates the mechanism of CS-induced lung emphysema in mice and, given its secretory nature, is a suitable target for neutralization antibody therapy.
View details for PubMedID 21576822
Periostin regulates goblet cell metaplasia in a model of allergic airway inflammation.
Journal: Journal of immunology (Baltimore, Md. : 1950)
Authors: Sehra S; Yao W; Nguyen ET; Ahyi AN; Tuana FM; Ahlfeld SK; Snider P; Tepper RS; Petrache I; Conway SJ; Kaplan MH;
Publication Date: 2011 Mar 14

Abstract

Periostin is a 90-kDa member of the fasciclin-containing family and functions as part of the extracellular matrix. Periostin is expressed in a variety of tissues and expression is increased in airway epithelial cells from asthmatic patients. Recent studies have implicated a role for periostin in allergic eosinophilic esophagitis. To further define a role for periostin in Th2-mediated inflammatory diseases such as asthma, we studied the development of allergic pulmonary inflammation in periostin-deficient mice. Sensitization and challenge of periostin-deficient mice with OVA resulted in increased peripheral Th2 responses compared with control mice. In the lungs, periostin deficiency resulted in increased airway resistance and significantly enhanced mucus production by goblet cells concomitant with increased expression of Gob5 and Muc5ac compared with wild type littermates. Periostin also inhibited the expression of Gob5, a putative calcium-activated chloride channel involved in the regulation of mucus production, in primary murine airway epithelial cells. Our studies suggest that periostin may be part of a negative-feedback loop regulating allergic inflammation that could be therapeutic in the treatment of atopic disease.
View details for PubMedID 21402898
Mechanisms of lung endothelial barrier disruption induced by cigarette smoke: role of oxidative stress and ceramides.
Journal: American journal of physiology. Lung cellular and molecular physiology
Authors: Schweitzer KS; Hatoum H; Brown MB; Gupta M; Justice MJ; Beteck B; Van Demark M; Gu Y; Presson RG Jr; Hubbard WC; Petrache I;
Publication Date: 2011 Aug 26

Abstract

The epithelial and endothelial cells lining the alveolus form a barrier essential for the preservation of the lung respiratory function, which is, however, vulnerable to excessive oxidative, inflammatory, and apoptotic insults. Whereas profound breaches in this barrier function cause pulmonary edema, more subtle changes may contribute to inflammation. The mechanisms by which cigarette smoke (CS) exposure induce lung inflammation are not fully understood, but an early alteration in the epithelial barrier function has been documented. We sought to investigate the occurrence and mechanisms by which soluble components of mainstream CS disrupt the lung endothelial cell barrier function. Using cultured primary rat microvascular cell monolayers, we report that CS induces endothelial cell barrier disruption in a dose- and time-dependent manner of similar magnitude to that of the epithelial cell barrier. CS exposure triggered a mechanism of neutral sphingomyelinase-mediated ceramide upregulation and p38 MAPK and JNK activation that were oxidative stress dependent and that, along with Rho kinase activation, mediated the endothelial barrier dysfunction. The morphological changes in endothelial cell monolayers induced by CS included actin cytoskeletal rearrangement, junctional protein zonula occludens-1 loss, and intercellular gap formation, which were abolished by the glutathione modulator N-acetylcysteine and ameliorated by neutral sphingomyelinase inhibition. The direct application of ceramide recapitulated the effects of CS, by disrupting both endothelial and epithelial cells barrier, by a mechanism that was redox and apoptosis independent and required Rho kinase activation. Furthermore, ceramide induced dose-dependent alterations of alveolar microcirculatory barrier in vivo, measured by two-photon excitation microscopy in the intact rat. In conclusion, soluble components of CS have direct endothelial barrier-disruptive effects that could be ameliorated by glutathione modulators or by inhibitors of neutral sphingomyelinase, p38 MAPK, JNK, and Rho kinase. Amelioration of endothelial permeability may alleviate lung and systemic vascular dysfunction associated with smoking-related chronic obstructive lung diseases.
View details for PubMedID 21873444
Sphingolipid-mediated inhibition of apoptotic cell clearance by alveolar macrophages.
Journal: The Journal of biological chemistry
Authors: Petrusca DN; Gu Y; Adamowicz JJ; Rush NI; Hubbard WC; Smith PA; Berdyshev EV; Birukov KG; Lee CH; Tuder RM; Twigg HL 3rd; Vandivier RW; Petrache I;
Publication Date: 2010 Oct 18

Abstract

A decreased clearance of apoptotic cells (efferocytosis) by alveolar macrophages (AM) may contribute to inflammation in emphysema. The up-regulation of ceramides in response to cigarette smoking (CS) has been linked to AM accumulation and increased detection of apoptotic alveolar epithelial and endothelial cells in lung parenchyma. We hypothesized that ceramides inhibit the AM phagocytosis of apoptotic cells. Release of endogenous ceramides via sphingomyelinase or exogenous ceramide treatments dose-dependently impaired apoptotic Jurkat cell phagocytosis by primary rat or human AM, irrespective of the molecular species of ceramide. Similarly, in vivo augmentation of lung ceramides via intratracheal instillation in rats significantly decreased the engulfment of instilled target apoptotic thymocytes by resident AM. The mechanism of ceramide-induced efferocytosis impairment was dependent on generation of sphingosine via ceramidase. Sphingosine treatment recapitulated the effects of ceramide, dose-dependently inhibiting apoptotic cell clearance. The effect of ceramide on efferocytosis was associated with decreased membrane ruffle formation and attenuated Rac1 plasma membrane recruitment. Constitutively active Rac1 overexpression rescued AM efferocytosis against the effects of ceramide. CS exposure significantly increased AM ceramides and recapitulated the effect of ceramides on Rac1 membrane recruitment in a sphingosine-dependent manner. Importantly, CS profoundly inhibited AM efferocytosis via ceramide-dependent sphingosine production. These results suggest that excessive lung ceramides may amplify lung injury in emphysema by causing both apoptosis of structural cells and inhibition of their clearance by AM.
View details for PubMedID 20956540
Adipose stem cell treatment in mice attenuates lung and systemic injury induced by cigarette smoking.
Journal: American journal of respiratory and critical care medicine
Authors: Schweitzer KS; Johnstone BH; Garrison J; Rush NI; Cooper S; Traktuev DO; Feng D; Adamowicz JJ; Van Demark M; Fisher AJ; Kamocki K; Brown MB; Presson RG Jr; Broxmeyer HE; March KL; Petrache I;
Publication Date: 2010 Aug 13

Abstract

Adipose-derived stem cells express multiple growth factors that inhibit endothelial cell apoptosis, and demonstrate substantial pulmonary trapping after intravascular delivery.
View details for PubMedID 20709815
Mechanism of alpha-1 antitrypsin endocytosis by lung endothelium.
Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Authors: Sohrab S; Petrusca DN; Lockett AD; Schweitzer KS; Rush NI; Gu Y; Kamocki K; Garrison J; Petrache I;
Publication Date: 2009 May 7

Abstract

The integrity of lung alveoli is maintained by proper circulating levels of alpha-1 antitrypsin (A1AT). Next to cigarette smoking, A1AT deficiency is a major risk factor for lung emphysema development. We recently reported that in addition to neutralizing neutrophil elastases in the extracellular compartment, A1AT is internalized by lung endothelial cells and inhibits apoptosis. We hypothesized that the intracellular uptake of A1AT by endothelial cells may be required for its protective function; therefore, we studied the mechanisms of A1AT internalization by primary rat lung microvascular endothelial cells and the effect of cigarette smoke on this process both in vitro and in vivo (in mice). Purified A1AT was taken up intracellularly by endothelial cells in a time-dependent, dose-dependent, and conformer-specific manner and was detected in the cytoplasm of endothelial cells of nondiseased human lung sections. Despite a critical role for caveoli in endothelial cell endocytosis in general, specific inhibition of clathrin-mediated, but not caveoli-mediated, endocytosis profoundly decreased A1AT internalization and reversed the A1AT's antiapoptotic action. Further more, A1AT associated with clathrin heavy chains, but not with caveolin-1 in the plasma membrane fraction of endothelial cells. Interestingly, cigarette smoke exposure significantly inhibited A1AT uptake both in endothelial cells and in the mouse lung and altered the intracellular distribution of clathrin heavy chains. Our results suggest that clathrin-mediated endocytosis regulates A1AT intracellular function in the lung endothelium and may be an important determinant of the serpin's protection against developing cigarette smoke-induced emphysema.
View details for PubMedID 19423638
Safety and efficacy of alpha-1-antitrypsin augmentation therapy in the treatment of patients with alpha-1-antitrypsin deficiency.
Journal: Biologics : targets & therapy
Authors: Petrache I; Hajjar J; Campos M;
Publication Date: 2009 Jul 13

Abstract

Alpha-1-antitrypsin deficiency (AATD), also known as alpha1-proteinase inhibitor deficiency, is an autosomal co-dominant condition. The genotypes associated with AATD include null, deficient, and dysfunctional alpha-1-antitrypsin (A1AT) variants, which result in low levels of circulating functional A1AT, unbalanced protease activity, and an increased risk of developing lung emphysema, the leading cause of morbidity in these patients. Furthermore, the most common abnormal genotype, Pi*ZZ may also cause trapping of abnormally folded protein polymers in hepatocytes causing liver dysfunction. A major focus of therapy for patients with lung disease due to AATD is to correct the A1AT deficiency state by augmenting serum levels with intravenous infusions of human plasma-derived A1AT. This strategy has been associated with effective elevations of A1AT levels and function in serum and lung epithelial fluid and observational studies suggest that it may lead to attenuation in lung function decline, particularly in patients with moderate impairment of lung function. In addition, an observational study suggests that augmentation therapy is associated with a reduction of mortality in subjects with AATD and moderate to severe lung impairment. More recent randomized placebo-controlled studies utilizing computer scan densitometry suggest that this therapy attenuates lung tissue loss. Augmentation therapy has a relative paucity of side effects, but it is highly expensive. Therefore, this therapy is recommended for patients with AATD who have a high-risk A1AT genotype with plasma A1AT below protective levels (11 microM) and evidence of obstructive lung disease. In this article, we review the published evidence of A1AT augmentation therapy efficacy, side effects, and safety profile.
View details for PubMedID 19707408
Type V collagen-induced oral tolerance plus low-dose cyclosporine prevents rejection of MHC class I and II incompatible lung allografts.
Journal: Journal of immunology (Baltimore, Md. : 1950)
Authors: Yamada Y; Sekine Y; Yoshida S; Yasufuku K; Petrache I; Benson HL; Brand DD; Yoshino I; Wilkes DS;
Publication Date: 2009 Jul 1

Abstract

Autoimmunity to type V collagen (col(V)) is a major risk factor for lung allograft rejection. Although col(V)-induced oral tolerance abrogates rejection of minor histoincompatible lung transplants, its ability to prevent rejection of fully MHC incompatible lung allografts is unknown. Rat lung allografts fully incompatible at MHC class I and II loci (Brown Norway (RT1(n))) were transplanted into untreated Wistar Kyoto rat recipients (WKY, RT1(l)), or WKY rats were fed col(V) pretransplantation. To determine whether col(V) enhanced cyclosporine (CsA)-mediated immune suppression, WKY rats were treated with low-dose CsA (5 mg/kg), posttransplant, or oral col(V) plus CsA. The data showed that in contrast to col(V) or CsA, col(V) plus low-dose CsA significantly prevented rejection pathology, down-regulated alloantigen-induced production of IFN-gamma and IL-17A, and suppressed chemotaxis for lung macrophages in allograft bronchoalveolar lavage fluid that was associated with lower local levels of MCP-1 (CCL2). Col(V) plus CsA was associated with alloantigen-induced expression of IL-10 in mediastinal lymph node or splenic T cells, intragraft expression of IL-10 and Foxp3 in perivascular and peribronchiolar mononuclear cells, and constitutive production of IL-10 from allograft alveolar macrophages. These data demonstrate that col(V) enhances low-dose CsA-mediated immune suppression, and suggest a role for oral col(V) in immune modulation in lung transplantation.
View details for PubMedID 19542435
CFTR regulation of intracellular pH and ceramides is required for lung endothelial cell apoptosis.
Journal: American journal of respiratory cell and molecular biology
Authors: Noe J; Petrusca D; Rush N; Deng P; VanDemark M; Berdyshev E; Gu Y; Smith P; Schweitzer K; Pilewsky J; Natarajan V; Xu Z; Obukhov AG; Petrache I;
Publication Date: 2009 Jan 23

Abstract

The functional significance of the expression of cystic fibrosis transmembrane regulator (CFTR) on endothelial cells has not yet been elucidated. Since CFTR has been implicated in the regulation of intracellular sphingolipid levels, which are important regulators of endothelial cell apoptosis in response to various insults, we investigated the role of CFTR in the apoptotic responses of lung endothelial cells. CFTR was detected as a functional chloride channel in primary lung endothelial cells isolated from both pulmonary arteries (human or mouse) and bronchial arteries (sheep). Both specific CFTR inhibition with 2-(phenylamino) benzoic acid diphenylamine-2-carboxylic acid, 5-[(4-carboxyphenyl)methylene]-2-thioxo-3-[(3-trifluoromethyl)phenyl-4-thiazolidinone (CFTR(inh)-172), or 5-nitro-2-(3-phenylpropylamino)benzoic acid and CFTR knockdown significantly attenuated endothelial cell apoptosis induced by staurosporine or H(2)O(2). CFTR(inh)-172 treatment prevented the increases in the ceramide:sphingosine-1 phosphate ratio induced by H(2)O(2) in lung endothelial cells. Replenishing endogenous ceramides via sphingomyelinase supplementation restored the susceptibility of CFTR-inhibited lung endothelial cells to H(2)O(2)-induced apoptosis. Similarly, the anti-apoptotic phenotype of CFTR-inhibited cells was reversed by lowering the intracellular pH, and was reproduced by alkalinization before H(2)O(2) challenge. TUNEL staining and active caspase-3 immunohistochemistry indicated that cellular apoptosis was decreased in lung explants from patients with cystic fibrosis compared with those with smoking-induced chronic obstructive lung disease, especially in the alveolar tissue and vascular endothelium. In conclusion, CFTR function is required for stress-induced apoptosis in lung endothelial cells by maintaining adequate intracellular acidification and ceramide activation. These results may have implications in the pathogenesis of cystic fibrosis, where aberrant endothelial cell death may dysregulate lung vascular homeostasis, contributing to abnormal angiogenesis and chronic inflammation.
View details for PubMedID 19168702
Stimulation of sphingosine 1-phosphate signaling as an alveolar cell survival strategy in emphysema.
Journal: American journal of respiratory and critical care medicine
Authors: Diab KJ; Adamowicz JJ; Kamocki K; Rush NI; Garrison J; Gu Y; Schweitzer KS; Skobeleva A; Rajashekhar G; Hubbard WC; Berdyshev EV; Petrache I;
Publication Date: 2009 Dec 3

Abstract

Vascular endothelial growth factor receptor (VEGFR) inhibition increases ceramides in lung structural cells of the alveolus, initiating apoptosis and alveolar destruction morphologically resembling emphysema. The effects of increased endogenous ceramides could be offset by sphingosine 1-phosphate (S1P), a prosurvival by-product of ceramide metabolism.
View details for PubMedID 19965812
A monoclonal rat anti-mouse EMAP II antibody that functionally neutralizes pro- and mature-EMAP II in vitro.
Journal: Journal of immunological methods
Authors: Rajashekhar G; Mitnacht-Kraus R; Ispe U; Garrison J; Hou Y; Taylor B; Petrache I; Vestweber D; Clauss M;
Publication Date: 2009 Aug 14

Abstract

EMAP II is an endothelial cell and monocyte activating proinflammatory cytokine, which has been demonstrated to induce endothelial cell apoptosis. In order to analyze its role in disease models linked to inflammation and endothelial cell death, we aimed to develop a neutralizing antibody against mouse EMAP II. Therefore, we generated rat monoclonal anti-mouse EMAP II antibodies by immunization with recombinant full length, mouse pro-EMAP II protein. We could identify by ELISA, hybridoma clones from fusion with mouse myeloma SP2/0 cells which produced antibodies recognizing both full length and mature EMAP II. We further characterized one antibody, M7/1 and demonstrated its ability to detect both EMAP II forms in Western blotting and to neutralize EMAP II directed migration of human peripheral blood monocytes as well as EMAP II induced apoptosis of tumor and endothelial cells. We conclude that this antibody can be useful to both target and analyze murine disease models, in which EMAP II may be involved.
View details for PubMedID 19683532
Anti-type V collagen humoral immunity in lung transplant primary graft dysfunction.
Journal: Journal of immunology (Baltimore, Md. : 1950)
Authors: Iwata T; Philipovskiy A; Fisher AJ; Presson RG Jr; Chiyo M; Lee J; Mickler E; Smith GN; Petrache I; Brand DB; Burlingham WJ; Gopalakrishnan B; Greenspan DS; Christie JD; Wilkes DS;
Publication Date: 2008 Oct 15

Abstract

Primary graft dysfunction (PGD) is a major complication following lung transplantation. We reported that anti-type V collagen (col(V)) T cell immunity was strongly associated with PGD. However, the role of preformed anti-col(V) Abs and their potential target in PGD are unknown. Col(V) immune serum, purified IgG or B cells from col(V) immune rats were transferred to WKY rat lung isograft recipients followed by assessments of lung pathology, cytokines, and PaO(2)/FiO(2), an index of lung dysfunction in PGD. Immune serum, purified IgG, and B cells all induced pathology consistent with PGD within 4 days posttransfer; up-regulated IFN-gamma, TNF-alpha, and IL-1beta locally; and induced significant reductions in PaO(2)/FiO(2). Depleting anti-col(V) Abs before transfer demonstrated that IgG2c was a major subtype mediating injury. Confocal microscopy revealed strong apical col(V) expression on lung epithelial, but not endothelial cells; which was consistent with the ability of col(V) immune serum to induce complement-dependent cytotoxicity only in the epithelial cells. Examination of plasma from patients with or without PGD revealed that higher levels of preformed anti-col(V) Abs were strongly associated with PGD development. This study demonstrates a major role for anti-col(V) humoral immunity in PGD, and identifies the airway epithelium as a target in PGD.
View details for PubMedID 18832733
HIV associated pulmonary emphysema: a review of the literature and inquiry into its mechanism.
Journal: Thorax
Authors: Petrache I; Diab K; Knox KS; Twigg HL 3rd; Stephens RS; Flores S; Tuder RM;
Publication Date: 2008 May

Abstract

Chronic lung diseases are increasingly recognised complications of the human immunodeficiency virus (HIV) infection and acquired immune deficiency syndrome (AIDS). Of these, pulmonary emphysema, characterised by permanent destruction of the lung parenchyma distal to the terminal bronchioles accompanied by various degrees of inflammation, is emerging as a distinct source of morbidity for patients infected with HIV. Similarly, HIV is now frequently cited as a susceptibility factor for the development of emphysema, independent of cigarette smoking status. The presence of common coexistent confounding factors that may predispose patients to chronic lung injury such as drugs, opportunistic infections and malnutrition, limits the scope of studies of direct mechanisms involved in HIV associated emphysematous lung disease. We review the clinical studies supporting a direct association between HIV infection and emphysema. Recent developments in the basic understanding of HIV infection and emphysema are also reviewed, since they may aid in understanding the pathobiology of HIV associated emphysema. The authors emphasise how HIV infection may affect cytotoxic lymphocyte activation, lung capillary endothelial cell injury and apoptosis, sphingolipid imbalance and oxidative stress in the lung. A better understanding of the pathogenesis of HIV associated pulmonary emphysema may provide clues and therapeutic targets that have broader application in this disease, including cigarette smoke induced emphysema.
View details for PubMedID 18443163
Tissue transglutaminase protects epithelial ovarian cancer cells from cisplatin-induced apoptosis by promoting cell survival signaling.
Journal: Carcinogenesis
Authors: Cao L; Petrusca DN; Satpathy M; Nakshatri H; Petrache I; Matei D;
Publication Date: 2008 Jul 29

Abstract

Tissue transglutaminase (TG2), an enzyme involved in protein cross-linking and overexpressed in ovarian tumors, has antiapoptotic effects in cancer cells and may play a role in response to chemotherapy. In this study, we investigated the role of TG2 in the sensitivity of ovarian cancer cells to cisplatin. By using stable knockdown and overexpression strategies, we demonstrate that the level of expression of TG2 regulates apoptosis induced by cisplatin in SKOV3 and OV-90 ovarian cancer cells. Interestingly, not only TG2 knockdown but also a TG2 enzymatic inhibitor (KCC009) sensitized SKOV3 cells to cisplatin. To understand the mechanism by which TG2 exerts its antiapoptotic role, we examined the effects of protein kinase B (Akt) and nuclear factor-kappa B (NF-kappaB), two survival pathways commonly involved in development of drug resistance. Overexpression of the constitutively active p65 subunit of NF-kappaB, but not constitutively active Akt, rescued cells with diminished TG2 expression from cisplatin-induced apoptosis. This implicates activation of NF-kappaB as the main cisplatin resistance mechanism downstream of TG2. Indeed, NF-kappaB activity is decreased and the level of the inhibitory subunit I kappaB alpha is increased in ovarian cancer cells engineered to express diminished levels of TG2 or treated with the enzymatic inhibitor, KCC009. Our data show that TG2 prevents apoptosis induced by cisplatin by activating the NF-kappaB survival pathway in ovarian cancer cells.
View details for PubMedID 18667446
Superoxide dismutase protects against apoptosis and alveolar enlargement induced by ceramide.
Journal: American journal of physiology. Lung cellular and molecular physiology
Authors: Petrache I; Medler TR; Richter AT; Kamocki K; Chukwueke U; Zhen L; Gu Y; Adamowicz J; Schweitzer KS; Hubbard WC; Berdyshev EV; Lungarella G; Tuder RM;
Publication Date: 2008 Apr 25

Abstract

The molecular events leading to emphysema development include generation of oxidative stress and alveolar cell apoptosis. Oxidative stress upregulates ceramides, proapoptotic signaling sphingolipids that trigger further oxidative stress and alveolar space enlargement, as shown in an experimental model of emphysema due to VEGF blockade. As alveolar cell apoptosis and oxidative stress mutually interact to mediate alveolar destruction, we hypothesized that the oxidative stress generated by ceramide is required for its pathogenic effect on lung alveoli. To model the direct lung effects of ceramide, mice received ceramide intratracheally (Cer(12:0) or Cer(8:0); 1 mg/kg) or vehicle. Apoptosis was inhibited with a general caspase inhibitor. Ceramide augmentation shown to mimic levels found in human emphysema lungs increased oxidative stress, and decreased, independently of caspase activation, the lung superoxide dismutase activity at 48 h. In contrast to their wild-type littermates, transgenic mice overexpressing human Cu/Zn SOD were significantly protected from ceramide-induced superoxide production, apoptosis, and air space enlargement. Activation of lung acid sphingomyelinase in response to ceramide treatment was abolished in the Cu/Zn SOD transgenic mice. Since cigarette smoke-induced emphysema in mice is similarly ameliorated by the Cu/Zn SOD overexpression, we hypothesized that cigarette smoke may induce ceramides in the mouse lung. Utilizing tandem mass spectrometry, we documented increased lung ceramides in adult mice exposed to cigarette smoke for 4 wk. In conclusion, ceramide-induced superoxide accumulation in the lung may be a critical step in ceramide's proapoptotic effect in the lung. This work implicates excessive lung ceramides as amplifiers of lung injury through redox-dependent mechanisms.
View details for PubMedID 18441093
Ceramide causes pulmonary cell apoptosis and emphysema: a role for sphingolipid homeostasis in the maintenance of alveolar cells.
Journal: Proceedings of the American Thoracic Society
Authors: Petrache I; Natarajan V; Zhen L; Medler TR; Richter A; Berdyshev EV; Tuder RM;
Publication Date: 2006 Aug