Hemorrhagic shock (HS) resulting from severe trauma promotes the development of systemic inflammatory response syndrome (SIRS) by activating and priming the inflammatory process through as of yet unclear mechanisms. Acute lung injury (ALI) is a major component of SIRS and often serves as a direct cause of death to patients. The lung vascular endothelium is an active organ and plays a central role in the development of ALI through synthesis and release of a number of inflammatory mediators. IL-12 is a key cytokine with multiple effects on lung inflammatory processes. Lung endothelial cells (EC) are one important source of IL-12 in response to HS insult. Conversely, lung EC is targets of IL-12, causing the production of a range of inflammatory molecules, including IL-12 itself, in response to IL-12 stimulation. Thus, lung EC through interacting with IL-12 forms a feedback mechanism to amplify lung inflammation in HS. The production of active IL-12 is tightly controlled by Inflammasome. Despite the central role of IL-12 in the development of SIRS, anti-IL-12 therapy aimed at blocking IL-1 receptor has not been successful. Targeting at inflammasome, however, may present a novel anti-IL-12 strategy for post-trauma SIRS. However, the mechanism underlying HS initiation of inflammasome in the lung and EC is unclear. We have observed two receptor cross-talk mechanisms that might mediate HS activation and priming of inflammasome. We found that TLR4 signaling upregulates type I IL-1 receptor (IL-1RI), and thereby sensitizing the cells to IL-12 stimulation;and HS enhances Toll-like receptor (TLR)4 signaling upregulation of TLR2 in lung EC, which in turn augments IL-12 release in response to TLR2 ligands. In the proposed study we will test the hypotheses that: 1) HS through targeting lung EC inflammasome promotes the development of ALI;2) cross-talk of TLR4- IL-1RI is a novel feedback mechanism amplifying lung inflammation in HS;and 3) cross-talk of TLR4-TLR2 serves as an important mechanism mediating HS-primed inflammasome activation.

Public Health Relevance

The burden of disease related to trauma is considerable. Acute lung injury (ALI) is a major component of post- trauma SIRS. However, few specific targets have yet been identified that predispose to SIRS and ALI. Since lung endothelial cells (EC) and IL-12 play important and roles in hemorrhagic shock (HS)-induced inflammation, and inflammasome sits at the center in controlling the IL-12 process, an insight of the mechanisms of HS initiation of EC inflammasome will provide us novel targets for therapeutic interventions of post-HS SIRS and ALI. We propose to study the mechanisms underlying HS-induced lung EC inflammasome activation and priming. In a broader sense, the studies will contribute to a greater understanding of the pathogenesis of a number of human diseases in which EC are involved in the inflammatory process.

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
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Wen, Zongmei; Fan, Liyan; Li, Yuehua et al. (2014) Neutrophils counteract autophagy-mediated anti-inflammatory mechanisms in alveolar macrophage: role in posthemorrhagic shock acute lung inflammation. J Immunol 193:4623-33
Xu, J; Jiang, Y; Wang, J et al. (2014) Macrophage endocytosis of high-mobility group box 1 triggers pyroptosis. Cell Death Differ 21:1229-39
Sun, Qian; Gao, Wentao; Loughran, Patricia et al. (2013) Caspase 1 activation is protective against hepatocyte cell death by up-regulating beclin 1 protein and mitochondrial autophagy in the setting of redox stress. J Biol Chem 288:15947-58
Liu, Zheng; Jiang, Yong; Li, Yuehua et al. (2013) TLR4 Signaling augments monocyte chemotaxis by regulating G protein-coupled receptor kinase 2 translocation. J Immunol 191:857-64
Xu, Peng; Wen, Zongmei; Shi, Xueyin et al. (2013) Hemorrhagic shock augments Nlrp3 inflammasome activation in the lung through impaired pyrin induction. J Immunol 190:5247-55
Xiang, Meng; Yuan, Youzhong; Fan, Liyan et al. (2012) Role of macrophages in mobilization of hematopoietic progenitor cells from bone marrow after hemorrhagic shock. Shock 37:518-23
Xiang, Meng; Yin, Lianhua; Li, Yuehua et al. (2011) Hemorrhagic shock activates lung endothelial reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase via neutrophil NADPH oxidase. Am J Respir Cell Mol Biol 44:333-40
Xiang, Meng; Shi, Xiaolian; Li, Yuehua et al. (2011) Hemorrhagic shock activation of NLRP3 inflammasome in lung endothelial cells. J Immunol 187:4809-17
Xiang, Meng; Fan, Jie (2010) Pattern recognition receptor-dependent mechanisms of acute lung injury. Mol Med 16:69-82
Kaczorowski, David J; Afrazi, Amin; Scott, Melanie J et al. (2010) Pivotal advance: The pattern recognition receptor ligands lipopolysaccharide and polyinosine-polycytidylic acid stimulate factor B synthesis by the macrophage through distinct but overlapping mechanisms. J Leukoc Biol 88:609-18

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