Controlling inflammation and cellular damage is the key to preventing and treating multiple organ failure (MOF) following trauma. However, many of the mechanisms that regulate inflammation and cell death in specific organs remain unknown. This means that despite advances in supportive measures for patients with MOF, there have been few advances in MOF treatments, or in our ability to adequately prevent the onset of MOF. Our overarching goal is to ultimately develop new therapeutics for trauma patients based on regulating the inflammatory response and its effects on cellular death and survival pathways following trauma and hemorrhagic shock (HS). In this proposal we will continue to investigate molecular pathways following HS that lead to activation of caspase-1 in end-organs, particularly liver. We will also determine how caspase-1 activation regulates autophagy and apoptosis, which in turn determines organ cell survival. Knowing how these cell-signaling pathways function and interact may help us to find future therapeutic targets for prevention and treatment of MOF after trauma. Our preliminary data suggest novel roles for caspase-1 in the liver during trauma/HS and during oxidative stresses. We have found that caspase-1 is a central regulator of autophagy in the liver following trauma/HS. Importantly, we have shown that caspase-1 activation is hepatoprotective after trauma/HS, in a manner independent of caspase-1-activated cytokines (IL1b/IL18) or a main inflammasome component, NLRP3. These findings challenge the paradigm that activation of caspase-1 by danger signals such as reactive oxygen species (ROS) occurs via the NLRP3-inflammasome. These preliminary findings lead us to our main hypothesis that caspase-1 activation occurs by cell-type specific mechanisms, and that caspase-1 function also differs in these cell types. We have shown that caspase-1 is central to the regulation of liver cell survival pathways during oxidative stress induced by HS. Without caspase-1, or where caspase-1 activation is inhibited, hepatocytes are less able to initiate cell survival strategies such as autophagy in response to HS. This results in increased apoptotic or necrotic cell death and increased levels of organ damage and failure. We expect to show that caspase-1 activation pathways differ after HS and are cell-type dependent. We also expect to show that caspase-1 has multiple novel functions in cells where production of IL1b/IL18 inflammatory cytokines is not the primary response to trauma. Understanding these novel pathways of inflammatory activation and function in individual cell types and organs may help us find new ways to treat and prevent MOF in trauma patients in the future.

Public Health Relevance

Trauma and shock activate pathways of inflammation that can lead to organ failure and death. The mechanisms of activation of inflammation in different organs and cell-types is not well understood, but knowing how organs respond to shock may improve our future ability to prevent and treat organ failure in trauma patients. Our research investigates organ-specific inflammation pathways after shock and may lead to the identification of future treatment targets that may improve survival in severely injured patients.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
Project #
Application #
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Somers, Scott D
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Pittsburgh
Schools of Medicine
United States
Zip Code
Sun, Qian; Wang, Qingde; Scott, Melanie J et al. (2016) Immune Activation in the Liver by Nucleic Acids. J Clin Transl Hepatol 4:151-7
Sun, Qian; Scott, Melanie J (2016) Caspase-1 as a multifunctional inflammatory mediator: noncytokine maturation roles. J Leukoc Biol 100:961-967
Li, Z; Scott, M J; Fan, E K et al. (2016) Tissue damage negatively regulates LPS-induced macrophage necroptosis. Cell Death Differ 23:1428-47
Scott, Melanie J; Billiar, Timothy R; Stoyanovsky, Detcho A (2016) N-tert-butylmethanimine N-oxide is an efficient spin-trapping probe for EPR analysis of glutathione thiyl radical. Sci Rep 6:38773
Scott, Melanie J (2015) Purposeful Repurposing: Unexpected but Not Necessarily Unwelcome Effects of Dexmedetomidine. Crit Care Med 43:2043-5
Ruan, Xiangcai; Darwiche, Sophie S; Cai, Changchun et al. (2015) Anti-HMGB1 monoclonal antibody ameliorates immunosuppression after peripheral tissue trauma: attenuated T-lymphocyte response and increased splenic CD11b (+) Gr-1 (+) myeloid-derived suppressor cells require HMGB1. Mediators Inflamm 2015:458626
Yang, Qin; Stevenson, Heather L; Scott, Melanie J et al. (2015) Type I interferon contributes to noncanonical inflammasome activation, mediates immunopathology, and impairs protective immunity during fatal infection with lipopolysaccharide-negative ehrlichiae. Am J Pathol 185:446-61
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
Chen, Christine; Deng, Meihong; Sun, Qian et al. (2014) Lipopolysaccharide stimulates p62-dependent autophagy-like aggregate clearance in hepatocytes. Biomed Res Int 2014:267350

Showing the most recent 10 out of 14 publications