tPA promotes the proliferation of lung fibroblasts and activates the Wnt/beta-catenin signaling pathway in idiopathic pulmonary fibrosis

摘要

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, irreversible and the most common fatal interstitial lung disease, which is characterized by damaged alveolar structure, the massive proliferation of fibroblasts and deposition of extracellular matrix (ECM). While the pathogenesis of IPF remains unclear, it has been clearly established that the excessive proliferation of lung fibroblasts is the most direct cause of fibrogenesis. Numerous proliferating fibroblasts form fibrous foci and secrete a large amount of ECM to aggravate the process of pulmonary fibrosis. Tissue plasminogen activator (tPA) is a kind of serine protease, its main function is to activate zymogens into active enzymes involved in fibrinolysis. Our study found tPA functioned as a cytokine to promote the proliferation of lung fibroblasts through intracellular signaling events involving Erk1/2, p90RSK, GSK-3 beta phosphorylation, and cyclinD1 induction. We also uncovered that tPA indirectly activated the Wnt/beta-catenin signaling pathway by regulating the GSK-3 beta phosphorylation level. It's well-known that Wnt/beta-catenin signaling pathway plays an important role in the pathogenesis of pulmonary fibrosis, in which the accumulation of beta-catenin in the cytoplasm is an important signal of the activation of Wnt/beta-catenin signaling pathway. Our study unveiled that tPA can serve as a cytokine involved in Wnt/beta-catenin signaling pathway and be implicated in pulmonary fibrosis.