Vitamin-D ameliorates sepsis-induced acute lung injury via augmenting miR-149-5p and downregulating ER stress

Abstract

Acute lung injury is a life-threatening medical problem induced by sepsis or endotoxins and may be associated with enhanced Endoplasmic reticulum stress (ER stress). Vitamin-D (Vit-D) possesses an anti-inflammatory effect; however, this specific mechanism on acute lung injury is still unknown. Here we scrutinize the mechanism of Vit-D on Acute lung injury (ALI) models and explored the Vit-D augmented miRNA's role in regulating the ER stress pathway in ALI. Sepsis was induced by CLP, and Endotoxemia was caused by lipopolysaccharide (LPS). We found that Vit-D alleviates pulmonary edema, improves lung histoarchitecture, infiltration of neutrophils, endothelial barrier in mice, and improves ER stress markers Activating Transcription Factor 6 (ATF6) and CHOP (C/EBP Homologous Protein) expression elevated by CLP/LPS induce ALI. Vit-D decreases the nitric oxide production and ATF6 in macrophages induced by LPS. Vit-D augments miR (miR-149-5p) in LPS-induce macrophages, CLP, and LPS-induced ALI models. Vit-D enhanced miRNA-149-5p when overexpressed, inhibited ER-specific ATF6 inflammatory pathway in LPS-stimulated macrophages, and improved histoarchitecture of the lung in LPS/CLP-induced mice models. This vitro and vivo studies demonstrate that Vit-D could improve ALI induced by CLP/LPS. In this regard, miR-149-5p may play a crucial role in vitamin-D inhibiting LPS/CLP induce ALI. The mechanism might be an association of increased miR-149-5p and its regulated gene target ATF6, and downstream CHOP proteins were suppressed. Thus, these findings demonstrate that the anti-inflammatory effect of Vit-D is achieved by augmentation of miRNA-149-5p expression, which may be a key physiologic mediator in the prevention and treatment of ALI.

Keywords: Acute lung injury; ER stress; Sepsis; Vitamin-D; miRNA-149-5p.