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

Abstract

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-β1)-induced epithelial-mesenchymal transition (EMT) and inhibited the matrix-producing ability of alveolar epithelial cells in vitro. Furthermore, we found that TGF-β1 depressed the autophagy and an autophagy inductor partly reversed the TGF-β1-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-β1-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.

Keywords: Alveolar epithelial cells; Autophagy; Epithelial-mesenchymal transition; Pulmonary fibrosis; Vasoactive intestinal peptide.