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

Abstract

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.

Innate immune responses to trauma

“…5). Consequently, IECs respond by releasing DAMPs and cytokines, which attract inflammatory leukocytes and induce remote organ injury (ALI) 159 . In hemorrhagic shock, locally and systemically activated complement can also contribute to the recruitment and activation of leukocytes, together with the deposition of complement and opsonization of damaged cells 160 .…”

Endoplasmic Reticulum Stress in Sepsis

“…Jian et al have demonstrated the role of ER stress and subsequent activation of the UPR and the elevated apoptosis in a murine model of trauma and hemorrhage [9]. Sodhi et al investigated the involvement of ER stress in trauma/hemorrhage induced lung injury [104]. In this study they reported that activation of epithelial TLR4 and HMGB1 enhance the lung injury and inhibition of TLR4 signaling by TLR4 inhibitor reduced the ER stress, decreased the HMGB1 and protected lung injury.…”

High Mobility Group Box Protein 1 (HMGB1): The Prototypical Endogenous Danger Molecule

“…In the absence of infection, hemorrhagic shock stimulated a systemic release of HMGB1. Intestinal epithelial cells were recently identified as the main source for the detrimental HMGB1 release in an experimental model of hemorrhagic-induced systemic inflammation (15). Stroke patients also express increased circulating HMGB1 levels within hours after the ischemic tissue damage (16).…”