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Billiar Lab



Location

NW607 MUH

Principal Investigator

Research Description

Dr. Billiar has had a long-standing interest in the mechanisms involved in acute cellular and organ injury in inflammatory states such as shock, trauma, and sepsis. His laboratory focuses research in two main areas. The first area investigates innate immune mechanisms leading to activation of inflammation following acute cellular and organ damage. There is a special emphasis on damage associated molecular pattern molecules (DAMPs) and pattern recognition receptors (PRR) in this response. Model systems include organ ischemia and reperfusion, as well as systemic insults such as shock and tissue trauma. Analysis includes markers of inflammation, the immunological consequences of injury and inflammation, mechanisms of organ injury and genome wide studies.

The second area of investigation includes examining pathways leading to cell death in hepatocytes. This work stems from Dr. Billiar’s long-standing interest in the actions of nitric oxide in the liver, and has led to an interest in understanding how cells such as hepatocytes regulate responses to both protective and damaging stimuli. The work involves both in vitro and in vivo systems. Dr. Billiar is also credited with initially cloning the human nitric oxide synthase gene.

Dr. Billiar’s laboratory is currently funded by the NIH to investigate both research areas, including a Trauma Center Grant and a T32 training grant. Dr. Billiar’s lab is a prime example of a productive and well-funded lab with both PhDs and MDs working together in a coordinated fashion for the pursuit of knowledge and the advancement of science. He also holds seven U.S. patents associated with his research. The goal of all his research is to define mechanisms and identify therapeutic targets.

Lab Members

Publications

Vogel S, Bodenstein R, Chen Q, Feil S, Feil R, Rheinlaender J, Schäffer TE, Bohn E, Frick JS, Borst O,Münzer P, Walker B, Markel J, Csanyi G, Pagano PJ, Loughran P, Jessup ME, Watkins SC, Bullock GC, Sperry JL, Zuckerbraun BS, Billiar TR, Lotze MT, Gawaz M, Neal MD.  Platelet derived HMGB1 is a critical mediator of thrombosis.  Journal of Clinical Investigation. In press

INF/IR-12: EARLY DYNAMICS OF SYSTEMIC INFLAMMATION ARE AFFECTED BY SEVERE EXTREMITY INJURY AND ARE ASSOCIATED WITH WORSE OUTCOMES IN POLYTRAUMA PATIENTS. Almahmoud K, Abboud AN, Namas RA, Abdul-Malak O, Zaaqoq A, Zamora R, Sperry J, Peitzman AB, Pape HC, Billiar TR, Vodovotz Y. Shock. 2015 Oct;44 Suppl 2:10. doi: 10.1097/01.shk.0000472034.95062.1e.PMID: 26375092

The HIV protease inhibitor saquinavir inhibits HMGB1 driven inflammation by targeting the interaction of cathepsin V with TLR4/MyD88. Pribis JP, Al-Abed Y, Yang H, Gero D, Xu H, Montenegro MF, Bauer EM, Kim S, Chavan SS, Cai C, Li T, Szoleczky P, Szabo C, Tracey KJ, Billiar TR.Mol Med. 2015 Sep 2. doi: 10.2119/molmed.2015.00197. [Epub ahead of print]PMID: 26349060 

Impact of Injury Severity on Dynamic Inflammation Networks Following Blunt Trauma. Almahmoud K, Namas RA, Abdul-Malak O, Zaaqoq AM, Zamora R, Zuckerbraun BS, Sperry J, Peitzman AB, Billiar TR, Vodovotz Y. Shock. 2015 Aug;44(2):101-9. doi: 10.1097/SHK.0000000000000395.PMID: 26009819

Trauma in silico: Individual-specific mathematical models and virtual clinical populations. Brown D, Namas RA, Almahmoud K, Zaaqoq A, Sarkar J, Barclay DA, Yin J, Ghuma A, Abboud A, Constantine G, Nieman G, Zamora R, Chang SC, Billiar TR, Vodovotz Y. Sci Transl Med. 2015 Apr 29;7(285):285ra61. doi: 10.1126/scitranslmed.aaa3636.PMID: 25925680

Intestinal Epithelial TLR-4 Activation Is Required for the Development of Acute Lung Injury after Trauma/Hemorrhagic Shock via the Release of HMGB1 from the Gut. Sodhi CP, Jia H, Yamaguchi Y, Lu P, Good M, Egan C, Ozolek J, Zhu X, Billiar TR, Hackam DJ. J Immunol. 2015 May 15;194(10):4931-9. doi: 10.4049/jimmunol.1402490. Epub 2015 Apr 10.PMID: 25862813

Prehospital Hypotension Is Associated With Altered Inflammation Dynamics and Worse Outcomes Following Blunt Trauma in Humans. Almahmoud K, Namas RA, Zaaqoq AM, Abdul-Malak O, Namas R, Zamora R, Sperry J, Billiar TR, Vodovotz Y. Crit Care Med. 2015 Jul;43(7):1395-404. doi: 10.1097/CCM.0000000000000964. PMID: 25803650

Myocyte TLR4 enhances enteric and systemic inflammation driving late murine endotoxic ileus. Buchholz BM, Shapiro RA, Vodovotz Y, Billiar TR, Sodhi CP, Hackam DJ, Bauer AJ. Am J Physiol Gastrointest Liver Physiol. 2015 May 15;308(10):G852-62. doi: 10.1152/ajpgi.00211.2014. Epub 2015 Mar 6. PMID: 25747352

The early evolving sex hormone environment is associated with significant outcome and inflammatory response differences after injury. Zolin SJ, Vodovotz Y, Forsythe RM, Rosengart MR, Namas R, Brown JB, Peitzman AP, Billiar TR, Sperry JL. J Trauma Acute Care Surg. 2015 Mar;78(3):451-7; discussion 457-8. doi: 10.1097/TA.0000000000000550. PMID: 25710413

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. Ruan X, Darwiche SS, Cai C, Scott MJ, Pape HC, Billiar TR. Mediators Inflamm. 2015;2015:458626. doi: 10.1155/2015/458626. Epub 2015 Jan 29.PMID: 25709155

Cytosolic HMGB1 controls the cellular autophagy/apoptosis checkpoint during inflammation. Zhu X, Messer JS, Wang Y, Lin F, Cham CM, Chang J, Billiar TR, Lotze MT, Boone DL, Chang EB. J Clin Invest. 2015 Mar 2;125(3):1098-110. doi: 10.1172/JCI76344. Epub 2015 Feb 2. PMID: 25642769

Shedding of the tumor necrosis factor (TNF) receptor from the surface of hepatocytes during sepsis limits inflammation through cGMP signaling. Deng M, Loughran PA, Zhang L, Scott MJ, Billiar TR. Sci Signal. 2015 Jan 27;8(361):ra11. doi: 10.1126/scisignal.2005548. PMID: 25628461

MD-2 is required for disulfide HMGB1-dependent TLR4 signaling. Yang H, Wang H, Ju Z, Ragab AA, Lundbäck P, Long W, Valdes-Ferrer SI, He M, Pribis JP, Li J, Lu B, Gero D, Szabo C, Antoine DJ, Harris HE, Golenbock DT, Meng J, Roth J, Chavan SS, Andersson U, Billiar TR, Tracey KJ, Al-Abed Y. J Exp Med. 2015 Jan 12;212(1):5-14. doi: 10.1084/jem.20141318. Epub 2015 Jan 5. PMID: 25559892

Temporal Patterns of Circulating Inflammation Biomarker Networks Differentiate Susceptibility to Nosocomial Infection Following Blunt Trauma in Humans. Namas RA, Vodovotz Y, Almahmoud K, Abdul-Malak O, Zaaqoq A, Namas R, Mi Q, Barclay D, Zuckerbraun B, Peitzman AB, Sperry J, Billiar TR. Ann Surg. 2014 Nov 3. [Epub ahead of print] PMID: 25371118

Injury-induced MRP8/MRP14 stimulates IP-10/CXCL10 in monocytes/macrophages. Wang J, Vodovotz Y, Fan L, Li Y, Liu Z, Namas R, Barclay D, Zamora R, Billiar TR, Wilson MA, Fan J, Jiang Y. FASEB J. 2015 Jan;29(1):250-62. doi: 10.1096/fj.14-255992. Epub 2014 Oct 23. PMID: 25342131

Neutrophils counteract autophagy-mediated anti-inflammatory mechanisms in alveolar macrophage: role in posthemorrhagic shock acute lung inflammation. Wen Z, Fan L, Li Y, Zou Z, Scott MJ, Xiao G, Li S, Billiar TR, Wilson MA, Shi X, Fan J. J Immunol. 2014 Nov 1;193(9):4623-33. doi: 10.4049/jimmunol.1400899. Epub 2014 Sep 29. PMID: 25267975

X chromosome-linked IRAK-1 polymorphism is a strong predictor of multiple organ failure and mortality postinjury. Sperry JL, Zolin S, Zuckerbraun BS, Vodovotz Y, Namas R, Neal MD, Ferrell RE, Rosengart MR, Peitzman AB, Billiar TR.Ann Surg. 2014 Oct;260(4):698-703; discussion 703-5. doi: 10.1097/SLA.0000000000000918. PMID: 25203887

Toll-like receptor 4 regulates platelet function and contributes to coagulation abnormality and organ injury in hemorrhagic shock and resuscitation. Ding N, Chen G, Hoffman R, Loughran PA, Sodhi CP, Hackam DJ, Billiar TR, Neal MD. Circ Cardiovasc Genet. 2014 Oct;7(5):615-24. doi: 10.1161/CIRCGENETICS.113.000398. Epub 2014 Jul 21. PMID: 25049041

PKM2 regulates the Warburg effect and promotes HMGB1 release in sepsis. Yang L, Xie M, Yang M, Yu Y, Zhu S, Hou W, Kang R, Lotze MT, Billiar TR, Wang H, Cao L, Tang D. Nat Commun. 2014 Jul 14;5:4436. doi: 10.1038/ncomms5436. PMID: 25019241

Delayed neutralization of interleukin 6 reduces organ injury, selectively suppresses inflammatory mediator, and partially normalizes immune dysfunction following trauma and hemorrhagic shock. Zhang Y, Zhang J, Korff S, Ayoob F, Vodovotz Y, Billiar TR. Shock. 2014 Sep;42(3):218-27. doi: 10.1097/SHK.0000000000000211. PMID: 24978887

Full listing of publications