title: Role of IL-18 in second-hand smoke-induced emphysema.
abstract: Chronic second-hand smoke (SHS) exposure comprises the main risk factor for nonsmokers to develop chronic obstructive pulmonary disease (COPD). However, the mechanisms behind the chronic inflammation and lung destruction remain incompletely understood. In this study, we show that chronic exposure of Sprague-Dawley rats to SHS results in a significant increase of proinflammatory cytokine IL-18 and chemokine (C-C motif) ligand 5 in the bronchoalveolar lavage fluid (BALF) and a significant decrease of vascular endothelial growth factor (VEGF) in the lung tissue. SHS exposure resulted in progressive alveolar airspace enlargement, cell death, pulmonary vessel loss, vessel muscularization, collagen deposition, and right ventricular hypertrophy. Alveolar macrophages displayed a foamy phenotype and a decreased expression of the natural inhibitor of IL-18, namely, IL-18 binding protein (IL-18BP). Moreover, IL-18 down-regulated the expression of VEGF receptor-1 and VEGFR receptor-2, and induced apoptosis in pulmonary microvascular endothelial cells in vitro. We also observed a trend toward increased concentrations of IL-18 in the BALF of patients with COPD. Our findings suggest that IL-18-mediated endothelial cell death may contribute to vascular destruction and disappearance in SHS-induced COPD. Moreover, IL-18 and IL-18BP are potential new targets for therapeutics.
authors: Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado at Denver, Aurora, CO 80045, USA.
authors: Adelheid
authors: A
authors: Kratzer
authors: Jonas
authors: J
authors: Salys
authors: Claudia
authors: C
authors: Nold-Petry
authors: Carlyne
authors: C
authors: Cool
authors: Martin
authors: M
authors: Zamora
authors: Russ
authors: R
authors: Bowler
authors: Andreas Rembert
authors: AR
authors: Koczulla
authors: Sabina
authors: S
authors: Janciauskiene
authors: Michael G
authors: MG
authors: Edwards
authors: Charles A
authors: CA
authors: Dinarello
authors: Laimute
authors: L
authors: Taraseviciene-Stewart
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D002199:Capillary Permeability; D006332:Cardiomegaly / Q000139:chemically induced / Q000473:pathology; D016923:Cell Death; D002460:Cell Line; D018946:Chemokine CCL5 / Q000276:immunology; D042783:Endothelial Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D019570:Inhalation Exposure / Q000009:adverse effects; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D020382:Interleukin-18 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D016676:Macrophages, Alveolar / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D029424:Pulmonary Disease, Chronic Obstructive / Q000276:immunology / Q000473:pathology; D011656:Pulmonary Emphysema / Q000276:immunology / Q000473:pathology*; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D062789:Tobacco Products / Q000009:adverse effects; D014028:Tobacco Smoke Pollution / Q000009:adverse effects*; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism; D015431:Weight Loss
chemical_list: D018946:Chemokine CCL5; D036341:Intercellular Signaling Peptides and Proteins; D020382:Interleukin-18; D014028:Tobacco Smoke Pollution; D042461:Vascular Endothelial Growth Factor A; C118370:interleukin-18 binding protein; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2
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