Vasoactive intestinal peptide attenuates bleomycin-induced murine pulmonary fibrosis by inhibiting epithelial-mesenchymal transition: Restoring autophagy in alveolar epithelial cells.

Vasoactive intestinal peptide (VIP) is an intrapulmonary neuropeptide with multi-function, including anti-fibrosis. However, the exact role of VIP in pulmonary fibrosis has not been documented. Here, we investigated the protective effect of VIP against pulmonary fibrosis in a murine model induced by bleomycin (BLM). We found that the overexpression of VIP mediated by the adenoviral vector significantly attenuated the lung tissue destruction, reduced the deposition of the extracellular matrix, and inhibited the expression of alpha-smooth muscle actin (α-SMA) in the lungs of mice received BLM. Mechanismly, we found that VIP significantly suppressed the transforming growth factor-beta 1 (TGF-ß1)-induced epithelial-mesenchymal transition (EMT) and inhibited the matrix-producing ability of alveolar epithelial cells in vitro. Furthermore, we found that TGF-ß1 depressed the autophagy and an autophagy inductor partly reversed the TGF-ß1-induced EMT in alveolar epithelial cells. The impaired autophagy was also observed in the lungs of BLM-treated mice, which was restored by VIP treatment. And VIP treatment enhanced autophagy in TGF-ß1-stimulated alveolar epithelial cells, contributing to its anti-EMT effect. In summary, our data, for the first time, show that VIP attenuates BLM-induced pulmonary fibrosis in mice with anti-EMT effect through restoring autophagy in alveolar epithelial cells. This study provides a possibility that inhaled long-acting VIP may be an anti-fibrotic drug in the treatment of pulmonary fibrosis.

Aucubin Alleviates Bleomycin-Induced Pulmonary Fibrosis in a Mouse Model.

Pulmonary fibrosis is a life-threatening disease characterized by progressive dyspnea and worsening of pulmonary function. No effective therapeutic strategy for pulmonary fibrosis has been established. Aucubin is a natural constituent with a monoterpene cyclic ring system. The potency of aucubin in protecting cellular components against inflammation, oxidative stress, and proliferation effects is well documented. In this study, we investigated the protective effect of aucubin against pulmonary fibrosis in mice. A mouse model of pulmonary fibrosis was established by intratracheal injection of bleomycin (BLM), and aucubin was administered for 21 days after BLM injection. We found that aucubin decreased the breathing frequency and increased the lung dynamic compliance of BLM-stimulated mice detected by Buxco pulmonary function testing system. Histological examination showed that aucubin alleviated BLM-induced lung parenchymal fibrotic changes. Aucubin also reduced the intrapulmonary collagen disposition and inflammatory injury induced by BLM. In addition, aucubin reduced the expression of pro-fibrotic protein transforming growth factor (TGF)-ß1 and α-smooth muscle actin (α-SMA) of pulmonary fibrosis mice induced by BLM. Furthermore, the effect of aucubin on the proliferation and differentiation of fibroblast was investigated in vitro. Aucubin inhibited the mRNA and protein expression of Ki67 and proliferating cell nuclear antigen (PCNA) induced by TGF-ß1 and reduced the cell proliferation in a murine fibroblast cell NIH3T3. Aucubin also reduced the collagen syntheses and α-SMA expression induced by TGF-ß1 in fibroblast. Our results indicate that aucubin inhibits inflammation, fibroblast proliferation, and differentiation, exerting protective effects against BLM-induced pulmonary fibrosis in a mouse model. This study provides an evidence that aucubin may be a novel drug for pulmonary fibrosis.