Abstract Rationale Pulmonary fibrosis comprises a group of progressive and irreversible lung diseases characterized by a complex and dynamic fibrotic process and underlying mechanisms involving multiple cell types, including epithelial-mesenchymal transition (EMT), endothelial-mesenchymal transition (EndoMT), and fibroblast-to-myofibroblast differentiation (FMD) that collectively drive pathological fibrogenesis. Previous studies have reported that bone morphogenetic protein (BMP10), primarily synthesized in the right atrium and secreted into the circulation, plays a pivotal role in cardiac development and the maintenance of cardiac function by preventing cardiomyocyte apoptosis and fibrosis. Nevertheless, its potential role and underlying mechanisms in mitigating pulmonary fibrosis remain poorly understood. Methods Pulmonary fibrosis was induced in male C57BL/6 mice via intratracheal instillation of bleomycin (BLM). Recombinant murine BMP10 was administered intraperitoneally once daily, five days per week, for two consecutive weeks. In parallel, human alveolar basal epithelial adenocarcinoma cells (A549), pulmonary microvascular endothelial cells (HPMECs), and pulmonary fibroblasts (WI-38) were used as in vitro models to assess the effects of recombinant human BMP10 on BLM-induced EMT, EndoMT, and FMD. Histopathological and molecular analyses, including hematoxylin and eosin (H&E) staining, Masson’s trichrome staining, immunohistochemistry (IHC), immunofluorescence (IF), and Western blotting, were performed to evaluate murine lung tissues and cultured cells. Results Masson’s trichrome staining revealed extensive collagen deposition in the lungs of BLM-treated mice, which was markedly diminished after BMP10 administration, indicating attenuation of pulmonary fibrosis. IHC staining and Western blot analyses of murine lung tissues showed that BLM exposure upregulated the expression of collagen I, α-SMA, and vimentin, while reducing VE-cadherin and E-cadherin levels. These alterations were effectively reversed by BMP10 treatment. Similarly, IF staining and Western blotting of BLM-stimulated A549, HPMECs, and WI-38 cells showed increased expression of EMT-, EndoMT-, and FMD-related proteins, all of which were significantly suppressed by BMP10 treatment. Furthermore, IHC and IF staining of murine lung tissues, together with Western blot analyses of murine lung homogenates, A549, HPMECs, and WI-38 cells, demonstrated that BLM stimulation increased the expression of transforming growth factor-beta (TGF-β) and phospho-Smad2 (pSmad2)—key mediators of fibrogenesis—while BMP10 treatment significantly suppressed these protein expressions. Conclusions BMP10 markedly mitigates BLM-induced pulmonary fibrosis through suppressing EMT, EndoMT, and FMD. These findings shed new light on the key mechanisms underlying the therapeutic effects of BMP10 and suggest its potential as a novel strategy for the treatment of pulmonary fibrosis. This abstract is funded by: None
Yu et al. (Fri,) studied this question.