1998 Fiscal Year Final Research Report Summary

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

Research Project

Project/Area Number	09670598
Research Category	Grant-in-Aid for Scientific Research (C)
Allocation Type	Single-year Grants
Section	一般
Research Field	Respiratory organ internal medicine
Research Institution	Yamagata University School of Medicine
Principal Investigator	KATO Shuichi Yamagata University School of Medicine.The First Department Internal Medicine., 医学部, 助手 (90260463)
Co-Investigator(Kenkyū-buntansha)	NAKAMURA Hidenori Yamagata University School of Medicine.The First Department Internal Medicine., 医学部, 講師 (30240675)
Project Period (FY)	1997 – 1998
Keywords	Pulmonary fibrosis / Endothelin / Gene transfer / 遺伝子導入
Research Abstract	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.