Intestinal Epithelial TLR-4 Activation Is Required for the Development of Acute Lung Injury after Trauma/Hemorrhagic Shock via the Release of HMGB1 from the Gut.
Intestinal Epithelial TLR-4 Activation Is Required for the Development of Acute Lung Injury after Trauma/Hemorrhagic Shock via the Release of HMGB1 from the Gut.
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DOI：
10.4049/jimmunol.1402490
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发表时间：
2015-05-15
期刊：
影响因子：
--
通讯作者：
Hackam DJ
中科院分区：
文献类型：
--
作者：
Sodhi CP;Jia H;Yamaguchi Y;Lu P;Good M;Egan C;Ozolek J;Zhu X;Billiar TR;Hackam DJ
The mechanisms leading to the development of remote lung injury after trauma remain unknown, although a central role for the gut in the induction of lung injury has been postulated. We hypothesize that the development of remote lung injury after trauma/hemorrhagic shock requires activation of Toll Like Receptor-4 (TLR4) in the intestinal epithelium and sought to determine the mechanisms involved. We now show that trauma/hemorrhagic shock caused lung injury in wild-type mice but not in mice lacking TLR4 in the intestinal epithelium, confirming the importance of intestinal TLR4 activation in the process. Activation of intestinal TLR4 after trauma led to increased endoplasmic reticulum (ER) stress, enterocyte apoptosis and the release of circulating HMGB1, while inhibition of ER stress attenuated apoptosis, reduced circulating HMGB1, and decreased lung injury severity. Neutralization of circulating HMGB1 led to reduced severity of lung injury after trauma, and mice lacking HMGB1 in the intestinal epithelium were protected from the development of lung injury, confirming the importance of the intestine as the source of HMGB1, whose release of HMGB1 induced a rapid pkc-zeta-mediated internalization of surface tight junctions in the pulmonary epithelium. Strikingly, the use of a novel small molecule TLR4 inhibitor reduced intestinal ER stress, decreased circulating HMGB1, and preserved lung architecture after trauma. Thus, intestinal epithelial TLR4 activation leads to HMGB1 release from the gut and the development of lung injury, while strategies that block upstream TLR4 signaling may offer pulmonary protective strategies after trauma.
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