Ursolic acid alleviates heat stress-induced lung injury by regulating endoplasmic reticulum stress signaling in mice

Abstract

Acute lung injury has been reported to be associated with heat stress in various animals. Ursolic acid is a natural pentacyclic triterpenoid compound with multiple bioactivities. However, it remains unknown whether ursolic acid supplementation alleviates heat stress-induced lung injury. In the present study, male Institute of Cancer Research mice were left untreated under a normal temperature condition (23±1°C), receiving orally administrated with vehicle (phosphate buffered saline) or ursolic acid (40 mg/kg BW^-1·d^-1 for 2 d), and then were subjected to high temperature (41±1°C) for 2 h. Histological alterations, activities of antioxidative enzymes, apoptosis, generation of reactive oxygen species, abundance of inflammatory cytokines, and endoplasmic reticulum stress-related proteins were analyzed. Compared with the controls, heat stress treatment led to enhanced apoptosis, increased H₂O₂ production, and upregulated protein levels of inflammatory cytokines in the serum, including tumor necrosis factor alpha, interleukin-6, and interleukin-1 beta. Activities of malondialdehyde, lactate dehydrogenase, and myeloperoxidase were increased, while the activities for superoxide dismutase and catalase were reduced in lung tissues of mice. All these alterations were significantly prevented by ursolic acid administration. Further study showed that heat stress led to activation of protein kinase-like ER kinase eukaryotic initiation factor 2 alpha -the transcription factor CCAAT-enhancer-binding protein homologous protein (CHOP) signaling, which was attenuated by ursolic acid supplementation. These findings indicated that ursolic acid pretreatment protected lung tissues against heat stress-induced injury by regulating inflammatory cytokines and unfolded protein response in mice. Ursolic acid supplementation might be a therapeutic strategy to alleviate high temperature-induced lung injury in humans and animals.

Keywords: Apoptosis, Heat stress; ER stress, Unfolded protein response; Lung injury; Ursolic acid.