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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\u20131 and VEGFR receptor\u20132, 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\u2013mediated 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.<\/jats:p>","DOI":"10.1165\/rcmb.2012-0173oc","type":"journal-article","created":{"date-parts":[[2013,2,8]],"date-time":"2013-02-08T03:59:29Z","timestamp":1360295969000},"page":"725-732","source":"Crossref","is-referenced-by-count":42,"title":["Role of IL-18 in Second-Hand Smoke\u2013Induced Emphysema"],"prefix":"10.1093","volume":"48","author":[{"given":"Adelheid","family":"Kratzer","sequence":"first","affiliation":[{"name":"Division of Pulmonary Sciences and Critical Care Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonas","family":"Salys","sequence":"additional","affiliation":[{"name":"Division of Pulmonary Sciences and Critical Care Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Nold-Petry","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Medicine, University of Colorado at Denver, 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