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.

据报道，各种动物的急性肺损伤与热应激有关。熊果酸是一种天然五环三萜类化合物，具有多种生物活性。然而，补充熊果酸是否能减轻热应激引起的肺损伤仍不清楚。在本研究中，雄性癌症研究所小鼠在常温条件下（23±1°C）不进行处理，接受口服赋形剂（磷酸盐缓冲盐水）或熊果酸（40 mg/kg BW ^-1 ·d） ^-1持续2d)，然后经受高温(41±1℃)2h。分析组织学改变、抗氧化酶活性、细胞凋亡、活性氧的产生、炎症细胞因子的丰度和内质网应激相关蛋白。与对照组相比，热应激治疗导致细胞凋亡增强，H ₂ O ₂产生增加，血清中炎性细胞因子的蛋白水平上调，包括肿瘤坏死因子α、白细胞介素6和白细胞介素1β。小鼠肺组织中丙二醛、乳酸脱氢酶、髓过氧化物酶活性升高，超氧化物歧化酶、过氧化氢酶活性降低。给予熊果酸可以显着防止所有这些改变。进一步的研究表明，热应激导致蛋白激酶样 ER 激酶真核起始因子 2 α 的激活，即转录因子 CCAAT 增强子结合蛋白同源蛋白 (CHOP) 信号传导，而补充熊果酸可减弱这种信号传导。 这些发现表明，熊果酸预处理通过调节小鼠炎症细胞因子和未折叠蛋白反应，保护肺组织免受热应激引起的损伤。补充熊果酸可能是减轻人类和动物高温引起的肺损伤的一种治疗策略。