Localization of endothelin receptors in bleomycin-induced pulmonary fibrosis in the rat.

Abstract

Pulmonary fibrosis is characterized by excessive extracellular matrix deposition with concomitant loss of gas exchange units, and endothelin-1 (ET-1) has been implicated in its pathogenesis. Increased levels of ET-1 from tissues and bronchoalveolar lavage have been reported in patients with pulmonary fibrosis and in animal models after intratracheal bleomycin. We characterized the cellular distribution of alveolar ET receptors by immunohistochemistry in bleomycin-induced pulmonary fibrosis in the rat and determined the regulation by bleomycin of ET receptor mRNA expression in isolated alveolar macrophages and rat lung fibroblasts. We found significant increases in the numbers of fibroblasts and macrophages at day 7 compared to day 28 and control animals. ET(B) receptor immunoreactivity was observed on fibroblasts and invading monocytes. Isolated fibroblasts expressed both ET(A) and ET(B) receptor mRNA, and ET(A) receptor mRNA was upregulated by bleomycin. Isolated resident alveolar macrophages expressed neither ET(A) nor ET(B) receptor mRNA which were also not induced by bleomycin. We conclude that, while ET(B) receptor stimulation of fibroblasts and monocytes recruited during bleomycin-induced lung injury exerts antagonistic effects on fibroblast collagen synthesis, the observed increase in the number of fibroblasts in vivo and upregulation of fibroblast ET(A) receptor mRNA by bleomycin in vitro point to a predominance of the profibrotic effects of ET receptor engagement.