Wendel Martina, Petzold Anna, Koslowski Roland, Kasper Michael, Augstein Antje, Knels Lilla, Bleyl Jörg-Uwe, Koch Thea
Department of Anesthesiology, University Hospital Dresden, Fetscherstrasse 74, 01307 Dresden, Germany.
Histochem Cell Biol. 2004 Nov;122(5):507-17. doi: 10.1007/s00418-004-0708-7. Epub 2004 Oct 5.
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.
肺纤维化的特征是细胞外基质过度沉积，同时气体交换单位丧失，内皮素-1（ET-1）被认为参与了其发病机制。在肺纤维化患者以及气管内注射博来霉素后的动物模型中，已报道组织和支气管肺泡灌洗中ET-1水平升高。我们通过免疫组织化学法对博来霉素诱导的大鼠肺纤维化中肺泡ET受体的细胞分布进行了表征，并确定了博来霉素对分离的肺泡巨噬细胞和大鼠肺成纤维细胞中ET受体mRNA表达的调节作用。我们发现，与第28天和对照动物相比，第7天的成纤维细胞和巨噬细胞数量显著增加。在成纤维细胞和浸润的单核细胞上观察到ET（B）受体免疫反应性。分离的成纤维细胞表达ET（A）和ET（B）受体mRNA，博来霉素可上调ET（A）受体mRNA。分离的驻留肺泡巨噬细胞既不表达ET（A）受体mRNA也不表达ET（B）受体mRNA，博来霉素也不能诱导其表达。我们得出结论，虽然在博来霉素诱导的肺损伤过程中，ET（B）受体对募集的成纤维细胞和单核细胞的刺激对成纤维细胞胶原蛋白合成具有拮抗作用，但体内观察到的成纤维细胞数量增加以及体外博来霉素对成纤维细胞ET（A）受体mRNA的上调表明，ET受体参与的促纤维化作用占主导地位。
