The pivotal role of HIF-1α in lung inflammatory injury induced by septic mesenteric lymph
The pivotal role of HIF-1α in lung inflammatory injury induced by septic mesenteric lymph
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DOI：
10.1016/j.biopha.2017.04.103
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发表时间：
2017-07-01
影响因子：
7.5
通讯作者：
Guan, Xiang-Dong
中科院分区：
文献类型：
--
作者：
Sun, Hua-Dong;Liu, Yong-Jun;Guan, Xiang-Dong
缺氧诱导因子-1 α（HIF-1 α）在缺氧和炎症反应中起重要作用。氧代谢紊乱和炎症反应级联放大是脓毒症所致急性肺损伤（acute lung injury，ALI）的重要病理生理特征，本研究从脓毒症肠系膜淋巴液注射模型入手，探讨HIF-1 α在脓毒症淋巴液所致ALI发病机制中的作用。数据表明，与注射生理盐水/淋巴液的大鼠相比，注射脓毒症淋巴液的大鼠显示出显著更高的肺损伤评分和MPO（髓过氧化物酶）水平。在脓毒症淋巴液灌注的肺中，ALI与HIF-1 α的高表达相关。YC-1的肠内递送此外，体外研究发现，脓毒症淋巴液孵育的人肺泡Ⅱ型上皮细胞（A549）/人肺微血管内皮细胞（HPMEC）的细胞活力显著降低，炎性细胞因子水平升高，（TNF-α、IL-6和IL-1 β）和激发HIF-1 α表达（免疫荧光定位/RT-PCR测试）。与未沉默的细胞相比，HIF-1 α基因沉默的A549/HPMEC细胞在感染性淋巴液中存活率提高，细胞因子的表达受到抑制，提示感染性淋巴液诱导的急性肺炎症损伤可诱导和激活HIF-1 α的表达，肺炎症损伤是通过HIF-1 α依赖性途径发生的。(C)2017 Elsevier Masson SAS。All rights reserved.
Hypoxia inducible factor-1 alpha (HIF-1 alpha) 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-1 alpha 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-1 alpha 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-alpha, IL-6 and IL-1 beta) and excitation of HIF-1 alpha expression (Immunofluorescence localization/RT-PCR test) simultaneously. Nevertheless, compared with the non-silencing cell lines, A549/HPMEC with HIF-1 alpha gene silencing manifested increased viability and restrained cytokines' expression after incubation with septic lymph.These results indicate that HIF-1 alpha 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-1 alpha-dependent pathway. (C) 2017 Elsevier Masson SAS. All rights reserved.