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Judith Hellman, MD

TitleProfessor
InstitutionUniversity of California San Francisco
DepartmentAnesthesia
Address500 Parnassus Avenue
San Francisco CA 94117
Phone415-476-5950
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    Collapse Biography 
    Collapse Education and Training
    Columbia UniversityM.D.1989School of Medicine

    Collapse Overview 
    Collapse Overview
    My research program is focused on basic and translational research on sepsis and other forms of inflammation-driven acute organ failure ("Inflammatory Critical Illness"). Sepsis and multiple organ failure are leading causes of death in the Intensive Care Unit. These processes result from a complex inflammatory response that is initiated through the innate immune system by interactions between host cells and microbes or endogenous host factors that are released during injury or cell death. The family of Toll-like receptors (TLRs) recognize different microbial components and endogenous host factors, and are critical in initiating inflammatory responses to infection. The Hellman Group studies TLR-dependent pathways expressed by macrophages as well as non-conventional inflammatory cells, including endothelial cells, in Inflammatory Critical Illness, focusing on their roles in coagulopathy, vascular permeability, neutrophil trafficking to organs, and organ injury and failure.

    Major Ongoing Projects:
    1. The role of cell-specific extracellular signal-regulated kinases (ERK1/2 and ERK5) in sepsis and inflammatory critical illness. We reported that extracellular signal-regulated kinase 5 (ERK5) mediates the TLR2-dependent activation of human endothelial cells and monocytes (Wilhelmsen et al, JBC 2012). Subsequently we found that ERK5 promotes endothelial activation by a broad range of microbial and host agonists, including LPS (TLR4), IL-1ß (IL1R), and TNFa (TNFR) (Wilhelmsen et al, Science Signaling 2015). Furthermore, we observed that treatment with ERK5 inhibitor reduces inflammation, coagulopathy, and mortality in LPS-treated mice, but conversely increases mortality and bacteremia in a cecal ligation and puncture model of sepsis. Finally, we made the intriguing observation in vitro that ERK1/2 activation reduces endothelial inflammation induced by LPS and TNFa, in contrast to its role in promoting leukocyte inflammation. We are now further exploring these observations, testing the basic hypotheses that ERK1/2 and ERK5 regulate TLR-dependent and TLR-independent activation of endothelial inflammatory pathways and contribute to endothelial dysfunction in septic shock and organ failure.
    2. The immunomodulatory role of the endocannabinoid system in inflammatory activation of endothelial cells and leukocytes: We recently discovered that the endocannabinoid N-arachidonoyl dopamine (NADA) can negatively regulate endothelial cell activation by a variety of inflammatory agonists. We hypothesize that the endothelial endocannabinoid system may represent a novel regulatory system to therapeutically manipulate in order to ameliorate the manifestations of a variety of inflammatory disorders, including sepsis. We plan to pursue these studies further by identifying other endocannabinoids that regulate EC inflammation, and determining the mechanism by which NADA exerts its effects in ECs. We will also investigate the role of NADA, and the other components of the endocannabinoid system, in vivo using mouse models of infectious and non-infectious inflammation.
    3. The role of TLR2 in bacterial sepsis and organ injury: My lab has been investigating the bacterial lipoproteins in the context of sepsis for over a decade. In our early studies we found that bacterial lipoprotein TLR2 agonists are shed by bacteria into human serum in vitro and into the blood of septic mice and rats in vivo. We have characterized the effects of bacterial lipoproteins on monocytes, macrophages, and endothelial cells, and have done extensive work on the effects of TLR2 activation on coagulation and permeability in vitro and in vivo. We have recently found that TLR2 participates, in a complex fashion, in Staph aureus invasion of organs in a bacteremia model. We are continuing to explore TLR2 pathways in gram-positive and gram-negative sepsis. The goals are to further delineate the downstream pathways leading to coagulopathy and organ failure, and identify potential therapeutic targets to mitigate these deleterious outcomes without negatively impacting bacterial clearance.
    4. The effects of TLR2 activation on the vascular endothelium, including on endothelial inflammatory responses, leucocyte trafficking, coagulation pathways and permeability: Endothelial cell (EC) activation, coagulopathy, and vascular leak contribute to sepsis-induced organ failure. We have found TLR2-dependent activation of endothelial inflammatory pathways, as well as pathways involved in coagulopathy and vascular leak in vitro and in vivo. Thus TLR2 pathways may be important in sepsis-induced coagulopathy and vascular leak. We have defined the roles of several MAPKs (p38, JNK, ERK1/2, ERK5) and of NF-?B in TLR2-dependent signaling to inflammation, and have newly identified ERK5 as a key mediator of TLR2-dependent signaling in endothelial cells and human monocytes. We are continuing to explore the role of these TLR2 signaling intermediaries in the development of coagulopathy and vascular leak in vitro.
    5. The effects of TLR2 activation on coagulation in vivo: We recently found that challenge with bacterial lipopeptides or Staph aureus bacteria TLR2-dependently modulates plasma levels of coagulation pathway factors and coagulation times, and that TLR2 activation increases fibrin deposition in the lungs of mice. We are exploring the mechanisms and functional consequences of these effects, and will expand studies to look at different aspects of coagulation in vivo.
    6. The role of microbial components and endothelial cells in sepsis-induced endothelial and organ dysfunction: We previously found that activation of TLR2 has physiological effects on the lung, including reduced blood arterial blood oxygenation and impaired lung vasoconstrictive responses to alveolar hypoxia. In the future we will further explore the functional significance of activation of TLR2 and other TLRs, in particular TLR4 and TLR9, in sepsis-induced organ failure.
    7. Cellular and molecular mechanisms of lung ischemia-reperfusion injury.


    Collapse Research 
    Collapse Research Activities and Funding
    TLR2 in Sepsis-Induced Coagulopathy, Endothelial Leak, and Pulmonary Dysfunction
    NIH/NIAID R01AI058106Dec 1, 2003 - May 31, 2012
    Role: Principal Investigator
    BACTERIAL SURFACE PROTEINS: POTENTIAL TARGETS FOR SEPSIS
    NIH/NIAID K08AI001722Jun 1, 2000 - May 31, 2005
    Role: Principal Investigator
    Comprehensive Anesthesia Research Training
    NIH/NIGMS T32GM008440Jul 1, 1995 - Jun 30, 2022
    Role: Principal Investigator

    Collapse ORNG Applications 
    Collapse Featured Publications
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    Collapse Bibliographic 
    Collapse Publications
    Publications listed below are automatically derived from MEDLINE/PubMed and other sources, which might result in incorrect or missing publications. Researchers can login to make corrections and additions, or contact us for help.
    List All   |   Timeline
    1. Remick DG, Ayala A, Chaudry I, Coopersmith CM, Deutschman C, Hellman J, Moldawer L, Osuchowski M. Premise for Standardized Sepsis Models. Shock. 2018 Jun 05. PMID: 29877959.
      View in: PubMed
    2. Tian X, Sun H, Casbon AJ, Lim E, Francis KP, Hellman J, Prakash A. NLRP3 Inflammasome Mediates Dormant Neutrophil Recruitment following Sterile Lung Injury and Protects against Subsequent Bacterial Pneumonia in Mice. Front Immunol. 2017; 8:1337. PMID: 29163464.
      View in: PubMed
    3. Lawton SK, Xu F, Tran A, Wong E, Prakash A, Schumacher M, Hellman J, Wilhelmsen K. N-Arachidonoyl Dopamine Modulates Acute Systemic Inflammation via Nonhematopoietic TRPV1. J Immunol. 2017 08 15; 199(4):1465-1475. PMID: 28701511.
      View in: PubMed
    4. Guan Z, Hellman J, Schumacher M. Contemporary views on inflammatory pain mechanisms: TRPing over innate and microglial pathways. F1000Res. 2016; 5. PMID: 27781082.
      View in: PubMed
    5. Koch SR, Lamb FS, Hellman J, Sherwood ER, Stark RJ. Potentiation and tolerance of toll-like receptor priming in human endothelial cells. Transl Res. 2017 02; 180:53-67.e4. PMID: 27567430.
      View in: PubMed
    6. Zeng MY, Cisalpino D, Varadarajan S, Hellman J, Warren HS, Cascalho M, Inohara N, Núñez G. Gut Microbiota-Induced Immunoglobulin G Controls Systemic Infection by Symbiotic Bacteria and Pathogens. Immunity. 2016 Mar 15; 44(3):647-658. PMID: 26944199.
      View in: PubMed
    7. Hellman J. Addressing the Complications of Ebola and Other Viral Hemorrhagic Fever Infections: Using Insights from Bacterial and Fungal Sepsis. PLoS Pathog. 2015 Oct; 11(10):e1005088. PMID: 26425845; PMCID: PMC4591006.
    8. Khakpour S, Wilhelmsen K, Hellman J. Vascular endothelial cell Toll-like receptor pathways in sepsis. Innate Immun. 2015 Nov; 21(8):827-46. PMID: 26403174.
      View in: PubMed
    9. Prakash A, Sundar SV, Zhu YG, Tran A, Lee JW, Lowell C, Hellman J. Lung Ischemia-Reperfusion is a Sterile Inflammatory Process Influenced by Commensal Microbiota in Mice. Shock. 2015 Sep; 44(3):272-9. PMID: 26196836; PMCID: PMC4537678.
    10. Wilhelmsen K, Xu F, Farrar K, Tran A, Khakpour S, Sundar S, Prakash A, Wang J, Gray NS, Hellman J. Extracellular signal-regulated kinase 5 promotes acute cellular and systemic inflammation. Sci Signal. 2015 Aug 25; 8(391):ra86. PMID: 26307013.
      View in: PubMed
    11. Kozicky LK, Zhao ZY, Menzies SC, Fidanza M, Reid GS, Wilhelmsen K, Hellman J, Hotte N, Madsen KL, Sly LM. Intravenous immunoglobulin skews macrophages to an anti-inflammatory, IL-10-producing activation state. J Leukoc Biol. 2015 Dec; 98(6):983-94. PMID: 26216934.
      View in: PubMed
    12. Feng X, Maze M, Koch LG, Britton SL, Hellman J. Exaggerated Acute Lung Injury and Impaired Antibacterial Defenses During Staphylococcus aureus Infection in Rats with the Metabolic Syndrome. PLoS One. 2015; 10(5):e0126906. PMID: 25978669.
      View in: PubMed
    13. Michel LV, Shaw J, MacPherson V, Barnard D, Bettinger J, D'Arcy B, Surendran N, Hellman J, Pichichero ME. Dual orientation of the outer membrane lipoprotein Pal in Escherichia coli. Microbiology. 2015 Jun; 161(6):1251-9. PMID: 25808171.
      View in: PubMed
    14. Wilhelmsen K, Khakpour S, Tran A, Sheehan K, Schumacher M, Xu F, Hellman J. The endocannabinoid/endovanilloid N-arachidonoyl dopamine (NADA) and synthetic cannabinoid WIN55,212-2 abate the inflammatory activation of human endothelial cells. J Biol Chem. 2014 May 09; 289(19):13079-100. PMID: 24644287; PMCID: PMC4036321.
    15. Wilhelmsen K, Farrar K, Hellman J. Quantitative in vitro assay to measure neutrophil adhesion to activated primary human microvascular endothelial cells under static conditions. J Vis Exp. 2013 Aug 23; (78):e50677. PMID: 23995778; PMCID: PMC3856291.
    16. Prakash A, Mesa KR, Wilhelmsen K, Xu F, Dodd-o JM, Hellman J. Alveolar macrophages and Toll-like receptor 4 mediate ventilated lung ischemia reperfusion injury in mice. Anesthesiology. 2012 Oct; 117(4):822-35. PMID: 22890118; PMCID: PMC3477877.
    17. Lin T, Sammy F, Yang H, Thundivalappil S, Hellman J, Tracey KJ, Warren HS. Identification of hemopexin as an anti-inflammatory factor that inhibits synergy of hemoglobin with HMGB1 in sterile and infectious inflammation. J Immunol. 2012 Aug 15; 189(4):2017-22. PMID: 22772444; PMCID: PMC3426910.
    18. Wilhelmsen K, Mesa KR, Lucero J, Xu F, Hellman J. ERK5 protein promotes, whereas MEK1 protein differentially regulates, the Toll-like receptor 2 protein-dependent activation of human endothelial cells and monocytes. J Biol Chem. 2012 Aug 03; 287(32):26478-94. PMID: 22707717; PMCID: PMC3410990.
    19. Wilhelmsen K, Mesa KR, Prakash A, Xu F, Hellman J. Activation of endothelial TLR2 by bacterial lipoprotein upregulates proteins specific for the neutrophil response. Innate Immun. 2012 Aug; 18(4):602-16. PMID: 22186927; PMCID: PMC3444510.
    20. Shin HS, Xu F, Bagchi A, Herrup E, Prakash A, Valentine C, Kulkarni H, Wilhelmsen K, Warren S, Hellman J. Bacterial lipoprotein TLR2 agonists broadly modulate endothelial function and coagulation pathways in vitro and in vivo. J Immunol. 2011 Jan 15; 186(2):1119-30. PMID: 21169547; PMCID: PMC3482611.
    21. Prakash A, Hellman J. Editorial: Pattern recognition receptors and factor B: "complement"ary pathways converge. J Leukoc Biol. 2010 Oct; 88(4):605-7. PMID: 20884653.
      View in: PubMed
    22. Warren HS, Fitting C, Hoff E, Adib-Conquy M, Beasley-Topliffe L, Tesini B, Liang X, Valentine C, Hellman J, Hayden D, Cavaillon JM. Resilience to bacterial infection: difference between species could be due to proteins in serum. J Infect Dis. 2010 Jan 15; 201(2):223-32. PMID: 20001600; PMCID: PMC2798011.
    23. Meier A, Bagchi A, Sidhu HK, Alter G, Suscovich TJ, Kavanagh DG, Streeck H, Brockman MA, LeGall S, Hellman J, Altfeld M. Upregulation of PD-L1 on monocytes and dendritic cells by HIV-1 derived TLR ligands. AIDS. 2008 Mar 12; 22(5):655-8. PMID: 18317010; PMCID: PMC2810187.
    24. Petersen B, Bloch KD, Ichinose F, Shin HS, Shigematsu M, Bagchi A, Zapol WM, Hellman J. Activation of Toll-like receptor 2 impairs hypoxic pulmonary vasoconstriction in mice. Am J Physiol Lung Cell Mol Physiol. 2008 Feb; 294(2):L300-8. PMID: 18055842.
      View in: PubMed
    25. Meier A, Alter G, Frahm N, Sidhu H, Li B, Bagchi A, Teigen N, Streeck H, Stellbrink HJ, Hellman J, van Lunzen J, Altfeld M. MyD88-dependent immune activation mediated by human immunodeficiency virus type 1-encoded Toll-like receptor ligands. J Virol. 2007 Aug; 81(15):8180-91. PMID: 17507480; PMCID: PMC1951290.
    26. Zhu X, Bagchi A, Zhao H, Kirschning CJ, Hajjar RJ, Chao W, Hellman J, Schmidt U. Toll-like receptor 2 activation by bacterial peptidoglycan-associated lipoprotein activates cardiomyocyte inflammation and contractile dysfunction. Crit Care Med. 2007 Mar; 35(3):886-92. PMID: 17255871.
      View in: PubMed
    27. Bagchi A, Herrup EA, Warren HS, Trigilio J, Shin HS, Valentine C, Hellman J. MyD88-dependent and MyD88-independent pathways in synergy, priming, and tolerance between TLR agonists. J Immunol. 2007 Jan 15; 178(2):1164-71. PMID: 17202381.
      View in: PubMed
    28. Valentine CH, Hellman J, Beasley-Topliffe LK, Bagchi A, Warren HS. Passive immunization to outer membrane proteins MLP and PAL does not protect mice from sepsis. Mol Med. 2006 Sep-Oct; 12(9-10):252-8. PMID: 17225874; PMCID: PMC1770012.
    29. Zhu X, Bernecker OY, Manohar NS, Hajjar RJ, Hellman J, Ichinose F, Valdivia HH, Schmidt U. Increased leakage of sarcoplasmic reticulum Ca2+ contributes to abnormal myocyte Ca2+ handling and shortening in sepsis. Crit Care Med. 2005 Mar; 33(3):598-604. PMID: 15753753.
      View in: PubMed
    30. Liang MD, Bagchi A, Warren HS, Tehan MM, Trigilio JA, Beasley-Topliffe LK, Tesini BL, Lazzaroni JC, Fenton MJ, Hellman J. Bacterial peptidoglycan-associated lipoprotein: a naturally occurring toll-like receptor 2 agonist that is shed into serum and has synergy with lipopolysaccharide. J Infect Dis. 2005 Mar 15; 191(6):939-48. PMID: 15717270.
      View in: PubMed
    31. Warren HS, Matyal R, Allaire JE, Yarmush D, Loiselle P, Hellman J, Paton BG, Fink MP. Protective efficacy of CAP18106-138-immunoglobulin G in sepsis. J Infect Dis. 2003 Nov 01; 188(9):1382-93. PMID: 14593598.
      View in: PubMed
    32. Hellman J, Tehan MM, Warren HS. Murein lipoprotein, peptidoglycan-associated lipoprotein, and outer membrane protein A are present in purified rough and smooth lipopolysaccharides. J Infect Dis. 2003 Jul 15; 188(2):286-9. PMID: 12854085.
      View in: PubMed
    33. Hellman J, Roberts JD, Tehan MM, Allaire JE, Warren HS. Bacterial peptidoglycan-associated lipoprotein is released into the bloodstream in gram-negative sepsis and causes inflammation and death in mice. J Biol Chem. 2002 Apr 19; 277(16):14274-80. PMID: 11830585.
      View in: PubMed
    34. Hellman J, Warren HS. Outer membrane protein A (OmpA), peptidoglycan-associated lipoprotein (PAL), and murein lipoprotein (MLP) are released in experimental Gram-negative sepsis. J Endotoxin Res. 2001; 7(1):69-72. PMID: 11521086.
      View in: PubMed
    35. Hellman J, Loiselle PM, Tehan MM, Allaire JE, Boyle LA, Kurnick JT, Andrews DM, Sik Kim K, Warren HS. Outer membrane protein A, peptidoglycan-associated lipoprotein, and murein lipoprotein are released by Escherichia coli bacteria into serum. Infect Immun. 2000 May; 68(5):2566-72. PMID: 10768945; PMCID: PMC97460.
    36. Hellman J, Loiselle PM, Zanzot EM, Allaire JE, Tehan MM, Boyle LA, Kurnick JT, Warren HS. Release of gram-negative outer-membrane proteins into human serum and septic rat blood and their interactions with immunoglobulin in antiserum to Escherichia coli J5. J Infect Dis. 2000 Mar; 181(3):1034-43. PMID: 10720528.
      View in: PubMed
    37. Hellman J, Warren HS. Antiendotoxin strategies. Infect Dis Clin North Am. 1999 Jun; 13(2):371-86, ix. PMID: 10340172.
      View in: PubMed
    38. Hellman J, Zanzot EM, Loiselle PM, Amato SF, Black KM, Ge Y, Kurnick JT, Warren HS. Antiserum against Escherichia coli J5 contains antibodies reactive with outer membrane proteins of heterologous gram-negative bacteria. J Infect Dis. 1997 Nov; 176(5):1260-8. PMID: 9359727.
      View in: PubMed
    39. Sen K, Hellman J, Nikaido H. Porin channels in intact cells of Escherichia coli are not affected by Donnan potentials across the outer membrane. J Biol Chem. 1988 Jan 25; 263(3):1182-7. PMID: 2447086.
      View in: PubMed