Severe trauma and hemorrhage renders the patient more susceptible to a second inflammatory stimulus, the so-called """"""""two-hit"""""""" model. The post-trauma inflammation can lead to severe multi-organ failure (MOF) and death. Studies have suggested that cell priming caused by a first hit is the mechanism for enhanced response of the cell to a second hit. Acute lung injury (ALl) is an important part of the MOF, and often serves as a direct cause of death. The accumulation of polymorphonuclear neutrophils (PMN) in the lung vasculature, interstitium, and alveolar space is considered a critical event in ALI and has been the target of various preventative strategies. However, the mechanisms that prime PMN migration remain unclear. Endothelial cells play a critical role in initiating PMN migration through directly interacting with PMN by expression of cytokines, chemokines, and adhesion molecules. We have reported that endothelial cells express a low level of Toll-like receptor (TLR) 2, the receptor for a variety of microbial products, which could be up-regulated by UPS through TLR4 signaling, suggesting a receptor cross-talk mechanism of inducible cell sensitivity to infection. We have further shown that oxidants amplify LPS-induced TLR2 expression in endothelial cells and which are functionally associated with an increased ICAM-1 expression and enhanced PMN migration in response to TLR2 agonist. Based on the findings we hypothesize that: (I) pulmonary endothelial cell priming is responsible for the enhanced post-trauma PMN migration in the lungs, (II) TLR2 up-regulation serves a role in the endothelial cell priming through increasing cell susceptibility to pathogens, and (III) hemorrhage/ resuscitation-induced generation of oxidants contributes to enhanced TLR2 upregulation in the endothelial cells. We will pursue these hypotheses in three interrelated Aims: 1) to determine the effect of hemorrhagic shock on LPS/TLR4 regulation of TLR2 in the lung and pulmonary endothelial cells; 2) to determine the role of TLR2 in hemorrhagic shock-induced endothelial cell priming; and 3) to determine the role of TLR2 in priming for lung inflammation following hemorrhage shock. We will use in vivo, ex vivo, and in vitro models to fully address the role of TLR2 in shock-induced cell priming and lung injury. Insights gained from these studies should significantly enhance our understanding of cell priming in post-trauma MOF.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Surgery, Anesthesiology and Trauma Study Section (SAT)
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Harabin, Andrea L
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University of Pittsburgh
Schools of Medicine
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