The Role of Endothelin in the Progression of Pulmonary Fibrosis-Animal model of Pulmonary Fibrosis induced by in vivo Transfer of Endothelin Gene-

特发性肺纤维化（IPF）是一种高度致命的疾病，以肺泡炎开始，随后发生不可逆的间质纤维化。内皮素（ET）是一类具有血管和支气管收缩作用的生物活性肽，可刺激成纤维细胞的有丝分裂。为了阐明Er在肺纤维化发病机制中的作用，(1)我们测量了有间质性肺疾病（ILD）临床症状患者支气管肺泡灌洗液（BALF）中的ET水平。ILD患者的ET/白蛋白水平高于对照组。BALF中ET/白蛋白水平与ILD患者肺功能参数（%VC和%DLco）之间存在显著相关性。(2)我们评估了ET A型受体拮抗剂BQ-123对博来霉素（BLM）诱导的仓鼠肺纤维化病理表现的影响。在blm治疗的肺中观察到ET水平升高。BLM处理增加了肺胶原蛋白水平，BQ-123抑制了肺胶原蛋白水平。肺光镜观察显示BQ-123治疗动物blm诱导的纤维化改变得到改善。(3)构建了巨细胞病毒启动子（pRc/CMV ET-1）驱动Er-1基因的质粒。阳离子脂质体将pRc/CMV ET-1基因经皮体内转染大鼠肺，可引起明显的肺纤维化。这些发现表明，肺ET水平在介导肺纤维化中起着至关重要的作用。

Idiopathic pulmonary fibrosis (IPF) is a highly lethal disease that begins with alveolitis and irreversible interstitial fibrosis ensues. Endothelins (ET) are a family of bioactive peptides with vaso- and broncho-constrictive effects, and stimulate mitogenesis in fibroblasts. To elucidate the role of Er in the pathogenesis of pulmonary fibrosis, (1) we measured ET levels in bronchoalveolar lavage fluid (BALF) in patients with clinical signs of interstitial lung diseases (ILD). ET/albumin levels in BALF from ILD were higher than those of control subjects. There was a significant correlation between ET/albumin levels in BALF and lung functional parameters (%VC and %DLco) in ILD.(2) We assessed the effect of BQ-123, ET type A receptor antagonist, on pathologic findings in bleomycin (BLM)-induced pulmonary fibrosis in hamsters. The increased ET levels were observed in BLM-treated lungs. BLM treatment increased lung collagen levels, which was inhibited by BQ-123. Light microscopic observation of the lung revealed the amelioration of BLM-induced fibrotic changes in BQ-123 treated animals. (3) We constructed a plasmid which includes Er-1 gene driven by a cytomegalovirus promoter (pRc/CMV ET-1). Percutaneous in vivo gene transfer of pRc/CMV ET-1 with cationic liposome into the rat lung caused remarkable pulmonary fibrosis.These findings suggest that lung ET levels play a crucial role in mediating pulmonary fibrosis.