Sun Hua-Dong, Liu Yong-Jun, Chen Juan, Chen Min-Ying, Ouyang Bin, Guan Xiang-Dong
Department of SICU, The First Affiliated Hospital of Sun Yat-Sen University, PR China; The Key Laboratory of Asisted Circulation, Ministry of Health, PR China.
Department of SICU, The First Affiliated Hospital of Sun Yat-Sen University, PR China.
Biomed Pharmacother. 2017 Jul;91:476-484. doi: 10.1016/j.biopha.2017.04.103. Epub 2017 May 4.
Hypoxia inducible factor-1α (HIF-1α) plays an essential role in hypoxia and inflammatory response. Oxygen metabolic dysfunction and cascade amplification of inflammatory response are prominent pathophysiological characteristics in sepsis induced acute lung injury (ALI). In this study, we started with septic mesenteric lymph injection model to investigate whether HIF-1α played a role in the pathogenesis of ALI induced by septic lymph. The data demonstrated that rats injected with septic lymph showed a significant higher Lung Injury Scale and MPO(myeloperoxidase) levels than that of rats injected with normal saline/lymph. ALI was associated with a higher degree of HIF-1α expression in the lungs infused by septic lymph. Intratracheal delivery of YC-1(3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole) significantly attenuated lung inflammatory damages. Furthermore, in vitro studies, human alveolar type II epithelial cell (A549)/human pulmonary microvascular endothelial cell (HPMEC) incubated by septic lymph showed dramatically decreased cell viability, higher levels of inflammatory cytokines (TNF-α, IL-6 and IL-1β) and excitation of HIF-1α expression (Immunofluorescence localization/RT-PCR test) simultaneously. Nevertheless, compared with the non-silencing cell lines, A549/HPMEC with HIF-1α gene silencing manifested increased viability and restrained cytokines' expression after incubation with septic lymph. These results indicate that HIF-1α expression can be induced and activated in rats during the acute lung inflammatory damages triggered by septic lymph injection and that lung inflammatory injuries occur via a HIF-1α-dependent pathway.
缺氧诱导因子-1α（HIF-1α）在缺氧和炎症反应中起关键作用。氧代谢功能障碍和炎症反应的级联放大是脓毒症诱导的急性肺损伤（ALI）突出的病理生理特征。在本研究中，我们以脓毒症肠系膜淋巴注射模型入手，研究HIF-1α在脓毒症淋巴诱导的ALI发病机制中是否发挥作用。数据表明，注射脓毒症淋巴的大鼠肺损伤评分和髓过氧化物酶（MPO）水平显著高于注射生理盐水/淋巴的大鼠。ALI与脓毒症淋巴灌注的肺中更高程度的HIF-1α表达相关。气管内给予YC-1（3-（5'-羟甲基-2'-呋喃基）-1-苄基吲唑）可显著减轻肺部炎症损伤。此外，在体外研究中，经脓毒症淋巴孵育的人II型肺泡上皮细胞（A549）/人肺微血管内皮细胞（HPMEC）显示细胞活力显著降低、炎症细胞因子（TNF-α、IL-6和IL-1β）水平升高以及HIF-1α表达同时被激活（免疫荧光定位/逆转录-聚合酶链反应检测）。然而，与非沉默细胞系相比，HIF-1α基因沉默的A549/HPMEC在经脓毒症淋巴孵育后活力增加且细胞因子表达受到抑制。这些结果表明，在脓毒症淋巴注射引发的急性肺炎症损伤过程中，大鼠体内的HIF-1α表达可被诱导和激活，且肺部炎症损伤通过HIF-1α依赖途径发生。
