Liang Hui, Liu Gaoli, Zeng Wenhui, Fan Qinglu, Nie Zhihao, Hu Haifeng, Zhang Renquan, Xie Songping
Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei, China.
Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei, China.
Int Immunopharmacol. 2023 Oct;123:110727. doi: 10.1016/j.intimp.2023.110727. Epub 2023 Aug 17.
Acute lung injury (ALI) is featured as excessive inflammatory response and oxidative damage, and results in high death rate of septic patients. This research intends to determine the function of multiple EGF like domains 6 (MEGF6) in sepsis-induced ALI.
Mice were intratracheally treated with adenovirus to knock down or overexpress MEGF6 in lung tissues, and then were subjected to cecum ligation and puncture (CLP) operation to induce ALI. Primary peritoneal macrophages were isolated, and were knocked down or overexpressed with MEGF6, and then, were stimulated with lipopolysaccharide (LPS) to confirm its role in vitro.
Serum and lung MEGF6 levels were significantly elevated in septic mice. MEGF6 knockdown exacerbated, while MEGF6 overexpression prevented inflammation, oxidative damage and ALI in CLP mice. Meanwhile, LPS-elicited inflammatory response and oxidative damage in primary macrophages were reduced by MEGF6 overexpression, but were further aggravated by MEGF6 knockdown. Mechanistic studies revealed that MEGF6 reduced cluster of differentiation 38 (CD38) expression and subsequently elevated intracellular nicotinamide adenine dinucleotide levels, thereby activating sirtuin 1 (SIRT1) without affecting the protein expression. SIRT1 suppression or CD38 overexpression with either genetic or pharmacologic methods remarkably blunted the lung protective effects of MEGF6 in CLP mice.
MEGF6 prevents CLP-induced ALI through CD38/SIRT1 pathway, and it might be a valuable therapeutic candidate for the management of sepsis-induced ALI.
急性肺损伤（ALI）的特征为过度的炎症反应和氧化损伤，导致脓毒症患者的高死亡率。本研究旨在确定多表皮生长因子样结构域6（MEGF6）在脓毒症诱导的ALI中的作用。
通过气管内注射腺病毒使小鼠肺组织中MEGF6基因敲低或过表达，然后进行盲肠结扎穿孔（CLP）手术诱导ALI。分离原代腹腔巨噬细胞，使其MEGF6基因敲低或过表达，然后用脂多糖（LPS）刺激以在体外确认其作用。
脓毒症小鼠血清和肺组织中MEGF6水平显著升高。MEGF6基因敲低会加重CLP小鼠的炎症、氧化损伤和ALI，而MEGF6过表达则可预防。同时，MEGF6过表达可降低原代巨噬细胞中LPS诱导的炎症反应和氧化损伤，而MEGF6基因敲低则使其进一步加重。机制研究表明，MEGF6可降低分化簇38（CD38）的表达，随后提高细胞内烟酰胺腺嘌呤二核苷酸水平，从而激活沉默调节蛋白1（SIRT1），且不影响其蛋白表达。采用基因或药理学方法抑制SIRT1或过表达CD38可显著削弱MEGF6对CLP小鼠的肺保护作用。
MEGF6通过CD38/SIRT1途径预防CLP诱导的ALI，可能是脓毒症诱导的ALI治疗的有价值候选药物。
