Hemorrhagic shock (HS), as a result of major trauma, promotes the development of systemic inflammatory response syndrome (SIRS) by activating and priming the innate immune system for an exaggerated inflammatory response through as of yet unclear mechanisms. HS-induced pro-inflammatory cytokines secretion plays an important role in the development of SIRS. Interleukin-lbeta (IL-lbeta) is one of the key pro? inflammatory mediators, and its processing and secretion is tightly controlled in the settings of HS, trauma, and infection. It has been shown that inflammasome, a multiprotein complex, is a molecular platform triggering activation of inflammatory caspase and processing of pro-IL-lbeta and IL-18. Our preliminary studies have revealed that HS not only induces IL-lbeta secretion from alveolar macrophages (AM) but also primes for an enhanced IL-lbeta release from AM in response to stimulations of bacterial products LPS and peptidoglycan (PGN) through inflammasome/caspase-1-dependent mechanisms, suggesting an important regulatory role of HS in inflammasome activation. Furthermore, we observed that Toll-like receptor (TLR)2 signaling, which was up? regulated by LPS/TLR4 signal and enhanced by HS, triggers pro-lL-lbeta processing in AM independent of the "typical" potassium efflux pathway, suggesting that TLR2 signaling is a novel pathway in HS regulation of inflammasome activation. Based on these observations, we hypothesize that I) inflammasome is a major target of HS in developing post-traumatic SIRS;II) the mechanisms underlying HS-induced inflammasome activation are diverse, which include "activating" and "priming" mechanisms;III) cross-talk of TLRs serves as a novel mechanism mediating HS-primed pro-IL-lbeta processing. We will pursue these hypotheses in three interrelated Aims: 1) to define the danger signal that transduces HS insult to cell activation of inflammasome;2) to determine the intracellular signaling that mediates HS activation of inflammasome;and 3) to determine the mechanism of HS-primed activation of inflammasome by upregulated TLR2 signaling. To achieve the stated goals, multidisciplinary models, such as in vivo mouse HS model and gene overexpression or knockdown chimeric mouse model, as well as ex vivo AM-neutrophil co-culture system, will be applied to the studies.
lL-1beta plays important and broad roles in HS-induced inflammation, and inflammasome sits at the center in controlling IL-1 beta process. An insight of the mechanisms of HS regulation of inflammasome will provide us novel target for preventive and therapeutic interventions of post-HS SIRS. In a broader sense the study will contribute to a greater understanding of other human diseases where innate immunity plays a role.
|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|
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