Severe trauma leads to the activation a systemic inflammatory response that when excessive, contributes to both end-organ dysfunction and immune dysregulation. The goal of this project is to define molecular mechanisms for the initiation and propagation of inflammation following severe injury. We hypothesize that tissue damage and/or ischemia leads to the release of endogenous molecules that then trigger inflammatory signaling through pattern recognition receptors of the innate immune system. We have compelling evidence that two pattern recognition receptors, toll-like receptors 4 and 9 (TLR4 and 9) and the nuclear protein and TLR4 ligand, high mobility group box-1 (HMGB1), play critical roles in initiating inflammation following injury. We will more fully characterize the function of TLR4 and 9 and HMGB1 in the injury response in three Aims.
Under Aim 1, we will define the relative roles of TLR4 and TLR9 to the systemic and organ-specific responses. We will also use a TLR4-loxP mouse recently developed in our lab to define cell-type specific roles for TLR4.
Under Aim II, we will use gene knockout mice to establish the major TLR-dependent signaling pathways involved in trauma-induced inflammatory response.
Under Aim 1 11, we will define the cell types that mobilize and release HMGB1 following systemic injury and the mechanisms leading to HMGB1 release. To accomplish these aims, we will utilize our well-characterized mouse models of hemorrhagic shock and peripheral tissue trauma. It is expected that the completion of this work will both advance our understanding of how the immune system becomes activated after injury and define potential targets for therapeutic intervention to limit the excessive inflammation in severely injured patients.

Public Health Relevance

Trauma is the most common cause of death and morbidity in peopl under the age of 50 in the USA. Much of the morbidity and mortality are due to an excessive inflammatory response. The research described in this proposal is aimed at understanding how trauma induces an inflammatory response at the molecular level with the long-term goal identifying strategies to modify this response and improve survival.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Specialized Center (P50)
Project #
5P50GM053789-17
Application #
8522287
Study Section
Special Emphasis Panel (ZGM1-PPBC-5)
Project Start
Project End
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
17
Fiscal Year
2013
Total Cost
$237,198
Indirect Cost
$81,009
Name
University of Pittsburgh
Department
Type
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
An, Gary; Kulkarni, Swati (2015) An agent-based modeling framework linking inflammation and cancer using evolutionary principles: description of a generative hierarchy for the hallmarks of cancer and developing a bridge between mechanism and epidemiological data. Math Biosci 260:16-24
Mathew, Shibin; Bartels, John; Banerjee, Ipsita et al. (2014) Global sensitivity analysis of a mathematical model of acute inflammation identifies nonlinear dependence of cumulative tissue damage on host interleukin-6 responses. J Theor Biol 358:132-48
Good, Misty; Sodhi, Chhinder P; Hackam, David J (2014) Evidence-based feeding strategies before and after the development of necrotizing enterocolitis. Expert Rev Clin Immunol 10:875-84
Aerts, Jean-Marie; Haddad, Wassim M; An, Gary et al. (2014) From data patterns to mechanistic models in acute critical illness. J Crit Care 29:604-10
Lu, Peng; Sodhi, Chhinder P; Hackam, David J (2014) Toll-like receptor regulation of intestinal development and inflammation in the pathogenesis of necrotizing enterocolitis. Pathophysiology 21:81-93
Lu, Peng; Sodhi, Chhinder P; Jia, Hongpeng et al. (2014) Animal models of gastrointestinal and liver diseases. Animal models of necrotizing enterocolitis: pathophysiology, translational relevance, and challenges. Am J Physiol Gastrointest Liver Physiol 306:G917-28
Zaaqoq, Akram M; Namas, Rami; Almahmoud, Khalid et al. (2014) Inducible protein-10, a potential driver of neurally controlled interleukin-10 and morbidity in human blunt trauma. Crit Care Med 42:1487-97
Peer, Xavier; An, Gary (2014) Agent-based model of fecal microbial transplant effect on bile acid metabolism on suppressing Clostridium difficile infection: an example of agent-based modeling of intestinal bacterial infection. J Pharmacokinet Pharmacodyn 41:493-507
Emr, Bryanna; Sadowsky, David; Azhar, Nabil et al. (2014) Removal of inflammatory ascites is associated with dynamic modification of local and systemic inflammation along with prevention of acute lung injury: in vivo and in silico studies. Shock 41:317-23
Zhang, Yong; Zhang, Jinxiang; Korff, Sebastian et al. (2014) Delayed neutralization of interleukin 6 reduces organ injury, selectively suppresses inflammatory mediator, and partially normalizes immune dysfunction following trauma and hemorrhagic shock. Shock 42:218-27

Showing the most recent 10 out of 237 publications