chiniofon and Acute-Lung-Injury

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 to induction of lung injury suggests that subsequent features of the disease are determined at a very early stage. This may explain why ERAs are not an effective treatment for human pulmonary fibrosis. Nevertheless, our findings suggest that they may be useful as prophylactic agents when given in combination with drugs that have fibrogenic potential.

Topics: Acute Lung Injury; Animals; Bleomycin; Bronchoalveolar Lavage Fluid; Cricetinae; Disease Models, Animal; Endothelin-1; Female; Humans; Hydroxyquinolines; In Situ Nick-End Labeling; Lipopolysaccharides; Macrophages; Mesocricetus; Neutrophils; Pulmonary Fibrosis; Time Factors

Previous studies from this laboratory indicate that endothelin-1 (ET-1), a potent vasoconstrictor, may play an important role in lipopolysaccharide (LPS)-induced release of neutrophils from the pulmonary microvasculature. To further test this concept, Syrian hamsters were treated with a novel endothelin receptor A (ETA) antagonist (HJP272) prior to intratracheal instillation of LPS.. The effect of HJP272 on the LPS-induced inflammatory reaction was determined by measuring: (1) lung histopathological changes, (2) total neutrophils in bronchoalveolar lavage fluid (BALF), (3) expression of tumor necrosis factor receptor 1 (TNFR1) by BALF macrophages, and (4) alveolar septal cell apoptosis.. Treatment with HJP272 significantly reduced each of these parameters during a 24-hr period following LPS instillation, supporting the concept that limiting the activity of ET-1 may reduce the extent of lung injury. This hypothesis was further tested by giving ET-1 prior to LPS instillation, which resulted in a marked enhancement of LPS-induced lung inflammation, as measured by BALF neutrophils and TNFR1-positive macrophages. Furthermore, the increase in neutrophils resulting from treatment with ET-1 was significantly reduced by HJP272, again demonstrating the ability of ETA receptor antagonists to limit the influx of these cells into the lung.. These findings suggest a potential therapeutic role for these agents in diseases where neutrophils are a significant cause of lung injury, such as bronchopneumonia, respiratory distress syndrome, and chronic obstructive pulmonary disease.

Topics: Acute Lung Injury; Animals; Apoptosis; Bronchoalveolar Lavage Fluid; Cytoprotection; Disease Models, Animal; Endothelin A Receptor Antagonists; Endothelin-1; Female; Hydroxyquinolines; Lipopolysaccharides; Lung; Macrophages; Mesocricetus; Neutrophil Infiltration; Neutrophils; Receptor, Endothelin A; Receptors, Tumor Necrosis Factor, Type I; Signal Transduction; Time Factors