Vitamin D attenuates lung injury via stimulating epithelial repair, reducing epithelial cell apoptosis and inhibits TGF-β induced epithelial to mesenchymal transition

Shengxing Zheng,Jingxiang Yang,Xin Hu,Ming Li,Qian Wang,Rachel C.A Dancer,Dhruv Parekh,Fang Gao-Smith,David R Thickett,Shengwei Jin

doi:10.1016/j.bcp.2020.113955

Abstract

Vitamin D regulates cell proliferation, inhibits cytokines release at sites of inflammation and reduces inflammatory responses. In this study, the aim was to investigate whether exogenous vitamin D attenuates LPS-induced lung injury via modulating epithelial cell proliferation, migration, apoptosis and epithelial mesenchymal transition (EMT). Murine and in vitro primary type II alveolar epithelial cell work were included in this study. In vivo, mice were mildly vitamin D deficient, 0.1, 1.5, 10 mg/kg 1,25(OH)2-vitamin D3 or 25(OH)-vitamin D3 was administrated by means of an intra-gastric injection for 14 days pre-intra-tracheal (IT) LPS, which remarkedly promoted alveolar epithelial type II cells proliferation, inhibited ATII cells apoptosis and inhibited EMT, with the outcome of attenuated LPS-induced lung injury. In vitro, vitamin D stimulated epithelial cell scratch wound repair, reduced primary ATII cells apoptosis as well. Vitamin D promoted primary human ATII cells proliferation through the PI3K/AKT signaling pathway and activation of vitamin D receptor (VDR). Moreover, vitamin D inhibited EMT in response to TGF-β, which was vitamin D receptor dependent. In conclusion, vitamin D attenuates lung injury via stimulating ATII cells proliferation and migration, reducing epithelial cell apoptosis and inhibits TGF-β induced EMT. Together, these results suggest that vitamin D has therapeutic potential for the resolution of ARDS.

Highlights

Acute Respiratory Distress syndrome (ARDS) characterized by alveolar epithelial disruption, resulting in influx of protein-rich edema fluid [1] and refractory hypoxia causing acute respiratory failure
ZK159222 and LY294002 blocked the effects of vitamin D on the proliferation of alveolar type II (ATII) cells in vitro, indicating vitamin D promotes ATII cells proliferation through activation of vitamin D receptor, the PI3K/AKT signaling pathway
Vitamin D is hydroxylated by the cytochrome P450 enzymes including CYP2R1, CYP27A1, and CYP2D25 to 25(OH) vitamin D3 [27]. 25(OH)vitamin D3 is the major circulating vitamin D3 metabolite, which is widely used as one of the most reliable biomarkers of vitamin D status [27]. 25(OH)vitamin D3 is hydroxylated by mitochondrial CYP27B1 to 1,25(OH)2D3, active form of vitamin D which mediates the biological actions via the vitamin D receptor (VDR) [28]

Summary

Introduction

Acute Respiratory Distress syndrome (ARDS) characterized by alveolar epithelial disruption, resulting in influx of protein-rich edema fluid [1] and refractory hypoxia causing acute respiratory failure. Many studies suggest that excessive inflammation resulting in profound alveolar epithelial cell injury is central to the pathogenesis of ARDS [2]. This results in extensive alveolar epithelial cell apoptosis and increases in alveolar capillary permeability thought to be mediated by soluble Fas ligand (sFasL) [3]. The timely repair of alveolar epithelium is thought to be pivotal to the resolution phase of ARDS [5]. Disordered repair mechanisms such as epithelial to mesenchymal transition (EMT), may be involved producing the fibroproliferative response seen in some patients with ARDS [6,7]

Methods

Results

Conclusion