Abstract
Systemic sclerosis (SSc) is a systemic autoimmune disease that causes inflammation, vasculopathy, and fibrosis of the skin and internal organs. One of the most severe complications of SSc involves the development of pulmonary fibrosis. Endothelial cell injury precedes the development of fibrosis, and is believed to be an initiating event. Therefore, we aimed to characterize the role of endothelial cells in the progression of pulmonary fibrosis, using a well-established bleomycin (BLM) model of pulmonary fibrosis. Endothelial cells were isolated by cell sorting, and the analysis of gene expression was performed with quantitative RT-PCR. Endothelial injury was induced between the first and second week, as shown by the elevated expression of the vascular injury markers matrix metallopeptidase-12 and von Willebrand factor. After injury, endothelial activation was indicated by the up-regulation of selectins, CCL chemokines, and inflammatory mediators, including complement anaphylatoxin receptors (C3aR and C5aR), oncostatin M, and leukemia inhibitory factor. The endothelial cell overexpression of fibrotic mediators, including connective tissue growth factor, plasminogen activator inhibitor-1, osteopontin, fibronectin, and fibroblast specific protein-1, was observed in the second and fourth weeks. This study suggests that endothelial cells actively contribute to the disease process via multiple mechanisms, including the recruitment of inflammatory cells and the establishment of a profibrotic environment during the development of BLM-induced pulmonary fibrosis.