Wei Ke, Luo Jie, Cao Jun, Peng Lihua, Ren Li, Zhang Fan
Department of Anesthesiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, People's Republic of China.
Department of Anesthesiology, Jianyang People's Hospital, Jianyang, Sichuan 641400, People's Republic of China.
Diabetes Metab Syndr Obes. 2020 Nov 5;13:4179-4190. doi: 10.2147/DMSO.S278684. eCollection 2020.
Endoplasmic reticulum (ER) stress seems to mediate the obesity-induced susceptibility to acute lung injury (ALI). The present study was designed to evaluate the role of ER stress in adiponectin (APN)-induced lung protection in an obese rat model treated with lipopolysaccharide (LPS).
Four-week-old male Sprague-Dawley rats fed either a normal chow diet or a high-fat diet for 12 weeks were randomly assigned to one of the following groups: lean rats, diet-induced obesity rats, lean rats with ALI, obese rats with ALI, obese rats pretreated with 4-phenylbutyric acid (4-PBA) before ALI or obese rats pretreated with APN before ALI. At 24 h after instillation of LPS into the lungs, cell counts in the bronchoalveolar lavage fluid (BALF) were determined. Lung tissues were separated to assess the degree of inflammation, pulmonary oedema, epithelial apoptosis and the expression of ER stress marker proteins.
The 78-kDa glucose-regulated protein (GRP78) and C/EBP homologous protein (CHOP) expression in the lung tissues of obese rats was upregulated before ALI, as well as the elevated apoptosis in epithelial cells. During ALI, the expression of ER stress marker proteins was similarly increased in both lean and obese rats, while significant downregulation of Mitofusin 2 (MFN2) was detected in obese epithelial cells. The lung tissues of obese rats showed higher concentrations of tumor necrosis factor-alpha (TNF-α), Interleukin 6 (IL-6) and IL-10, enhanced neutrophil counts and elevated wet/dry weight ratios. APN and 4-PBA decreased the degree of ER stress and suppressed LPS-induced lung inflammation, pulmonary oedema and epithelial apoptosis.
APN may exert protective effects against the exacerbated lung injuries in obese rats by attenuating ER stress, which operates as a key molecular pathway in the progression of ALI.
内质网（ER）应激似乎介导了肥胖诱导的急性肺损伤（ALI）易感性。本研究旨在评估ER应激在脂多糖（LPS）处理的肥胖大鼠模型中脂联素（APN）诱导的肺保护作用中的作用。
将4周龄雄性Sprague-Dawley大鼠分为正常饮食组或高脂饮食组，喂养12周，然后随机分为以下几组：瘦大鼠、饮食诱导肥胖大鼠、ALI瘦大鼠、ALI肥胖大鼠、ALI前用4-苯基丁酸（4-PBA）预处理的肥胖大鼠或ALI前用APN预处理的肥胖大鼠。在向肺内滴注LPS后24小时，测定支气管肺泡灌洗液（BALF）中的细胞计数。分离肺组织以评估炎症程度、肺水肿、上皮细胞凋亡以及ER应激标记蛋白的表达。
ALI前，肥胖大鼠肺组织中78-kDa葡萄糖调节蛋白（GRP78）和C/EBP同源蛋白（CHOP）的表达上调，上皮细胞凋亡也增加。在ALI期间，瘦大鼠和肥胖大鼠中ER应激标记蛋白的表达同样增加，而在肥胖上皮细胞中检测到线粒体融合蛋白2（MFN2）显著下调。肥胖大鼠的肺组织显示肿瘤坏死因子-α（TNF-α）、白细胞介素6（IL-6）和IL-10浓度更高，中性粒细胞计数增加，湿/干重比升高。APN和4-PBA降低了ER应激程度，并抑制了LPS诱导的肺部炎症、肺水肿和上皮细胞凋亡。
APN可能通过减轻ER应激对肥胖大鼠加重的肺损伤发挥保护作用，ER应激是ALI进展中的关键分子途径。
