Trauma hemorrhagic shock-induced lung injury involves a gut-lymph-induced TLR4 pathway in mice.
Trauma hemorrhagic shock-induced lung injury involves a gut-lymph-induced TLR4 pathway in mice.
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DOI：
10.1371/journal.pone.0014829
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Feinman R
中科院分区：
文献类型：
--
作者：
Reino DC;Pisarenko V;Palange D;Doucet D;Bonitz RP;Lu Q;Colorado I;Sheth SU;Chandler B;Kannan KB;Ramanathan M;Xu DZ;Deitch EA;Feinman R
休克状态下应激状态下肠道释放的有害非微生物因子可导致急性肺损伤(ALI)和多器官功能障碍综合征(MODS)的发生。由于Toll样受体(TLR)既是组织损伤的感受器，也是微生物侵袭的感受器，在脓毒症和非感染性的I/R损伤模型中都存在TLR4信号，我们假设创伤失血性休克(T/HS)后肠系膜淋巴中的因子通过TLR4激活来介导肠源性肺损伤。我们的研究结果证实了T/HS淋巴因子从肠道流出重建ALI的概念，即将从T/HS全局损伤动物身上收集的猪淋巴输注到幼稚野生型(WT)小鼠中导致肺损伤。利用携带TLR4突变的C3H/HeJ小鼠，我们发现TLR4的激活在T/HS猪淋巴液诱导的肺损伤的发生发展中是必需的，这是由伊文氏蓝(EBD)肺通透性和髓过氧化物酶(MPO)水平以及诱导损伤性肺iNOS反应所确定的。TRIF和MyD88缺乏分别完全和部分减弱T/HS淋巴诱导的肺通透性增加。对TLR2缺陷小鼠的进一步研究表明，TLR2激活不参与T/HS淋巴诱导的肺损伤的病理过程。最后，淋巴样本中没有细菌、内毒素和细菌DNA，淋巴通过内毒素去除柱并没有消除T/HS淋巴对幼稚小鼠造成肺损伤的能力。我们的研究结果表明，T/HS后肠系膜淋巴中的非微生物因子能够通过激活TLR4来重建T/HS所致的肺损伤。
Injurious non-microbial factors released from the stressed gut during shocked states contribute to the development of acute lung injury (ALI) and multiple organ dysfunction syndrome (MODS). Since Toll-like receptors (TLR) act as sensors of tissue injury as well as microbial invasion and TLR4 signaling occurs in both sepsis and noninfectious models of ischemia/reperfusion (I/R) injury, we hypothesized that factors in the intestinal mesenteric lymph after trauma hemorrhagic shock (T/HS) mediate gut-induced lung injury via TLR4 activation. The concept that factors in T/HS lymph exiting the gut recreates ALI is evidenced by our findings that the infusion of porcine lymph, collected from animals subjected to global T/HS injury, into naïve wildtype (WT) mice induced lung injury. Using C3H/HeJ mice that harbor a TLR4 mutation, we found that TLR4 activation was necessary for the development of T/HS porcine lymph-induced lung injury as determined by Evan's blue dye (EBD) lung permeability and myeloperoxidase (MPO) levels as well as the induction of the injurious pulmonary iNOS response. TRIF and Myd88 deficiency fully and partially attenuated T/HS lymph-induced increases in lung permeability respectively. Additional studies in TLR2 deficient mice showed that TLR2 activation was not involved in the pathology of T/HS lymph-induced lung injury. Lastly, the lymph samples were devoid of bacteria, endotoxin and bacterial DNA and passage of lymph through an endotoxin removal column did not abrogate the ability of T/HS lymph to cause lung injury in naïve mice. Our findings suggest that non-microbial factors in the intestinal mesenteric lymph after T/HS are capable of recreating T/HS-induced lung injury via TLR4 activation.
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