Mutsaers S E, Foster M L, Chambers R C, Laurent G J, McAnulty R J
Centre for Cardiopulmonary Biochemistry and Respiratory Medicine, University College London Medical School, Rayne Institute, London.
Am J Respir Cell Mol Biol. 1998 May;18(5):611-9. doi: 10.1165/ajrcmb.18.5.2898.
Endothelin-1 (Et-1) has been implicated in the pathogenesis of pulmonary fibrosis with increased levels in the lung tissue of patients with pulmonary fibrosis and profibrotic effects in vitro. In this study we have investigated the temporal changes in lung Et-1 levels and immunohistochemical localization in relation to collagen deposition during the development of bleomycin-induced pulmonary fibrosis in rats. Lung Et-1 content doubled by 3 d following the intratracheal instillation of bleomycin, and continued to increase up to 7 d when values were about threefold greater than controls. Thereafter, the values for bleomycin-treated animals remained constant up to 21 d. There was no change in collagen content at 3 d but after 7 d there was a 25% increase and by 21 d levels were almost double those of the controls. In normal lung, Et-1 was predominantly associated with epithelial cells of conducting and nonconducting airways. Following bleomycin administration, intense staining of macrophages and conducting airway and alveolar epithelial cells was observed with marked staining of perivascular, peribronchiolar, and alveolar septal connective tissue, as well as the venular and arterial intima and media. These results demonstrate elevation of Et-1 levels prior to an increase in collagen content which, along with its localization within developing fibrotic lesions, provides further evidence of a profibrotic role for Et-1 in the pathogenesis of pulmonary fibrosis.
内皮素-1（Et-1）与肺纤维化的发病机制有关，肺纤维化患者肺组织中其水平升高，且在体外具有促纤维化作用。在本研究中，我们调查了博来霉素诱导的大鼠肺纤维化发展过程中肺Et-1水平的时间变化以及与胶原沉积相关的免疫组化定位。气管内滴注博来霉素后3天，肺Et-1含量增加一倍，并持续增加至7天，此时其值比对照组高约三倍。此后，博来霉素处理组动物的值在21天内保持恒定。3天时胶原含量无变化，但7天后增加了25%，到21天时水平几乎是对照组的两倍。在正常肺中，Et-1主要与传导性和非传导性气道的上皮细胞相关。给予博来霉素后，观察到巨噬细胞、传导性气道和肺泡上皮细胞强烈染色，血管周围、细支气管周围和肺泡间隔结缔组织以及小静脉和动脉内膜及中膜有明显染色。这些结果表明，在胶原含量增加之前Et-1水平升高，连同其在正在形成的纤维化病变中的定位，为Et-1在肺纤维化发病机制中的促纤维化作用提供了进一步证据。
