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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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      Abstract

      The mechanisms that lead 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 hypothesized that the development of remote lung injury after trauma/hemorrhagic shock requires activation of TLR4 in the intestinal epithelium, and we sought to determine the mechanisms involved. We show that trauma/hemorrhagic shock caused lung injury in wild-type mice, but not in mice that lack 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, whereas 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 that lack 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 protein kinase C ζ-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, whereas strategies that block upstream TLR4 signaling may offer pulmonary protective strategies after trauma.

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      Affiliations
      [1 ] Division of General Pediatric Surgery, Department of Surgery, Johns Hopkins University, Baltimore, MD 21287;
      [2 ] Division of Newborn Medicine, Children's Hospital of Pittsburgh, Pittsburgh, PA 15213; Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261;
      [3 ] Division of Pathology, Children's Hospital of Pittsburgh, Pittsburgh, PA 15224; Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261;
      [4 ] Department of Medicine, Gastroenterology, Hepatology and Nutrition, University of Chicago, Chicago, IL 60637; and.
      [5 ] Division of Trauma and General Surgery, Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213.
      [6 ] Division of General Pediatric Surgery, Department of Surgery, Johns Hopkins University, Baltimore, MD 21287; Dhackam1@jhmi.edu.
      Journal
      J. Immunol.
      Journal of immunology (Baltimore, Md. : 1950)
      1550-6606
      0022-1767
      May 15 2015
      : 194
      : 10
      25862813 jimmunol.1402490 10.4049/jimmunol.1402490 4417407 NIHMS674167
      Copyright © 2015 by The American Association of Immunologists, Inc.

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