Ursodeoxycholic acid stimulates alveolar fluid clearance in LPS‐induced pulmonary edema via ALX/cAMP/PI3K pathway

Abstract

This study aims to examine the impact of ursodeoxycholic acid (UDCA) on pulmonary edema and explore the underlying molecular mechanisms. The effects of UDCA on pulmonary edema were assessed through hematoxylin and eosin (H&E) staining, lung dry/wet (W/D) ratio, TNF-α/IL-1β levels of bronchoalveolar lavage fluid (BALF), protein expression of epithelial sodium channel (ENaC), and Na + /K + -ATPase. Besides, the detailed mechanisms were explored in primary rat alveolar type (AT) II epithelial cells by determining the effects of BOC-2 (ALX [lipoxin A4 receptor] inhibitor), Rp-cAMP (cAMP inhibitor), LY294002 (PI3K inhibitor), and H89 (PKA inhibitor) on the therapeutic effects of UDCA against lipopolysaccharide (LPS)-induced changes. Histological examination suggested that LPS-induced lung injury was obviously attenuated by UDCA. BALF TNF-α/IL-1β levels and lung W/D ratios were decreased by UDCA in LPS model rats. UDCA stimulated alveolar fluid clearance (AFC) though the upregulation of ENaC and Na + /K + -ATPase. BOC-2, Rp-cAMP, and LY294002 largely suppressed the therapeutic effects of UDCA. Significant attenuation of pulmonary edema and lung inflammation was revealed in LPS-challenged rats after the UDCA treatment. The therapeutic efficacy of UDCA against LPS was mainly achieved through the ALX/cAMP/PI3K pathway. Our results suggested that UDCA might be a potential drug for the treatment of pulmonary edema induced by LPS. K E Y W O R D S alveolar fluid clearance, epithelial sodium channel, Na + /K + -ATPase, pulmonary edema, ursodeoxycholic acid

Lipopolysaccharide Inhibits Alpha Epithelial Sodium Channel Expression via MiR-124-5p in Alveolar Type 2 Epithelial Cells

“…e active transport of Na + by AT2 cells provides a major driving force for the removal of fluid from the alveolar space. Previous studies revealed that AFC strongly depends on the function of ENaC on the apical surface and Na + /K + -ATPase on the basolateral surface of alveolar epithelial cells [25].…”

Bone marrow mesenchymal stem cells derived miRNA-130b enhances epithelial sodium channel by targeting PTEN

“…The discovery of novel and effective therapeutic targets for ALI is of great significance for improving the life quality of patients, and MSCs may be a promising alternative for ALI treatment, as a cell-based therapy [ 33 ]. Research data have shown that MSCs reversed ALI-induced decrease of AFC, foremostly contributed by ENaC-mediated fluid transport [ 34 , 35 ]. In this study, we first found that the expression of ENaC protein and mRNA in AT2 cells increased after the administration of BMSCs, contrary to the effects of LPS alone.…”

Bone Marrow Mesenchymal Stem Cells Derived miRNA-130b Enhances Epithelial Sodium Channel by Targeting PTEN

“…The discovery of novel and effective therapeutic targets for ALI is of great significance for improving the life quality of patients, and MSCs may be a promising alternative for ALI treatment, as a cell-based therapy [33]. Research data have shown that MSCs reversed ALI-induced decrease of AFC, foremostly contributed by ENaC-mediated fluid transport [34,35].…”