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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL079669-09
Application #
8602849
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Harabin, Andrea L
Project Start
2004-12-01
Project End
2015-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
9
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Surgery
Type
Schools of Medicine
DUNS #
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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