Time-dependent effects of HJP272, an endothelin receptor antagonist, in bleomycin-induced pulmonary fibrosis

Publication date: Available online 12 June 2017 Source:Pulmonary Pharmacology & Therapeutics Author(s): Xingjian Liu, Nikhil Khadtare, Hardek Patel, Ralph Stephani, Jerome Cantor Using a lipopolysaccharide (LPS) model of acute lung injury, we have previously shown that endothelin-1 (ET-1), a potent mediator of vasoconstriction, may act as a “gatekeeper” for the influx of inflammatory cells into the lung. To further investigate the potential of ET-1 to limit the progression of lung injury, hamsters were treated with an endothelin receptor antagonist (ERA), HJP272, either 1 h prior to intratracheal instillation of bleomycin (BLM) or 24 h afterwards. Lung injury and repair were examined by measuring the following parameters: 1) histopathological changes; 2) neutrophil content in bronchoalveolar lavage fluid (BALF); 3) lung collagen content; 4) tumor necrosis factor receptor 1 (TNFR1) expression by BALF macrophages; 5) BALF levels of: a) transforming growth factor beta-1 (TGF-β1), b) stromal cell-derived factor 1 (commonly referred to as CXCL12), and c) platelet-derived growth factor BB (PDGF-BB); 6) alveolar septal cell apoptosis (as measured by the TUNEL assay). For each of these parameters, animals pretreated with HJP272 showed significant reductions compared to those receiving BLM alone. In contrast, post-treatment with HJP272 was either ineffective or produced only marginally significant changes. The efficacy of a single pretreatment with HJP272 prior t...
Source: Pulmonary Pharmacology and Therapeutics - Category: Respiratory Medicine Source Type: research