Judith Hellman, MD

Professor
Anesthesia
+1 415 476-5950

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.

Publications: 

Elevated Gut Microbiome-Derived Propionate Levels Are Associated With Reduced Sterile Lung Inflammation and Bacterial Immunity in Mice.

Frontiers in microbiology

Tian X, Hellman J, Horswill AR, Crosby HA, Francis KP, Prakash A

Part III: Minimum Quality Threshold in Preclinical Sepsis Studies (MQTiPSS) for Fluid Resuscitation and Antimicrobial Therapy Endpoints.

Shock (Augusta, Ga.)

Hellman J, Bahrami S, Boros M, Chaudry IH, Fritsch G, Gozdzik W, Inoue S, Radermacher P, Singer M, Osuchowski MF, Huber-Lang M

Premise for Standardized Sepsis Models.

Shock (Augusta, Ga.)

Remick DG, Ayala A, Chaudry IH, Coopersmith CM, Deutschman C, Hellman J, Moldawer L, Osuchowski MF

The Response to the Letter to the Editor Titled: "Is Triple Self-plagiarism "OK" If Only Made Transparent?" by Volker R Jacobs, MD, MBA.

Shock (Augusta, Ga.)

Osuchowski MF, Hellman J, Huber-Lang M, Libert C, Remick DG, Thiemermann C, Zingarelli B

NF-?B/MAPK activation underlies ACVR1-mediated inflammation in human heterotopic ossification.

JCI insight

Barruet E, Morales BM, Cain CJ, Ton AN, Wentworth KL, Chan TV, Moody TA, Haks MC, Ottenhoff TH, Hellman J, Nakamura MC, Hsiao EC

Correction to: Minimum Quality Threshold in Pre-Clinical Sepsis Studies (MQTiPSS): an international expert consensus initiative for improvement of animal modeling in sepsis.

Infection

Osuchowski MF, Ayala A, Bahrami S, Bauer M, Boros M, Cavaillon JM, Chaudry IH, Coopersmith CM, Deutschman C, Drechsler S, Efron P, Frostell C, Fritsch G, Gozdzik W, Hellman J, Huber-Lang M, Inoue S, Knapp S, Kozlov AV, Libert C, Marshall JC, Moldawer LL, Radermacher P, Redl H, Remick DG, Singer M, Thiemermann C, Wang P, Wiersinga WJ, Xiao X, Zingarelli B

Minimum Quality Threshold in Pre-Clinical Sepsis Studies (MQTiPSS): An International Expert Consensus Initiative for Improvement of Animal Modeling in Sepsis.

Shock (Augusta, Ga.)

Osuchowski MF, Ayala A, Bahrami S, Bauer M, Boros M, Cavaillon JM, Chaudry IH, Coopersmith CM, Deutschman CS, Drechsler S, Efron P, Frostell C, Fritsch G, Gozdzik W, Hellman J, Huber-Lang M, Inoue S, Knapp S, Kozlov AV, Libert C, Marshall JC, Moldawer LL, Radermacher P, Redl H, Remick DG, Singer M, Thiemermann C, Wang P, Wiersinga WJ, Xiao X, Zingarelli B

Minimum Quality Threshold in Pre-Clinical Sepsis Studies (MQTiPSS): an international expert consensus initiative for improvement of animal modeling in sepsis.

Infection

Osuchowski MF, Ayala A, Bahrami S, Bauer M, Boros M, Cavaillon JM, Chaudry IH, Coopersmith CM, Deutschman C, Drechsler S, Efron P, Frostell C, Fritsch G, Gozdzik W, Hellman J, Huber-Lang M, Inoue S, Knapp S, Kozlov AV, Libert C, Marshall JC, Moldawer LL, Radermacher P, Redl H, Remick DG, Singer M, Thiemermann C, Wang P, Wiersinga WJ, Xiao X, Zingarelli B

Minimum quality threshold in pre-clinical sepsis studies (MQTiPSS): an international expert consensus initiative for improvement of animal modeling in sepsis.

Intensive care medicine experimental

Osuchowski MF, Ayala A, Bahrami S, Bauer M, Boros M, Cavaillon JM, Chaudry IH, Coopersmith CM, Deutschman C, Drechsler S, Efron P, Frostell C, Fritsch G, Gozdzik W, Hellman J, Huber-Lang M, Inoue S, Knapp S, Kozlov AV, Libert C, Marshall JC, Moldawer LL, Radermacher P, Redl H, Remick DG, Singer M, Thiemermann C, Wang P, Wiersinga WJ, Xiao X, Zingarelli B

N-Arachidonoyl Dopamine Modulates Acute Systemic Inflammation via Nonhematopoietic TRPV1.

Journal of immunology (Baltimore, Md. : 1950)

Lawton SK, Xu F, Tran A, Wong E, Prakash A, Schumacher M, Hellman J, Wilhelmsen K

20.

Potentiation and tolerance of toll-like receptor priming in human endothelial cells.

Translational research : the journal of laboratory and clinical medicine

Koch SR, Lamb FS, Hellman J, Sherwood ER, Stark RJ

Gut Microbiota-Induced Immunoglobulin G Controls Systemic Infection by Symbiotic Bacteria and Pathogens.

Immunity

Zeng MY, Cisalpino D, Varadarajan S, Hellman J, Warren HS, Cascalho M, Inohara N, Núñez G

Vascular endothelial cell Toll-like receptor pathways in sepsis.

Innate immunity

Khakpour S, Wilhelmsen K, Hellman J

Lung Ischemia-Reperfusion is a Sterile Inflammatory Process Influenced by Commensal Microbiota in Mice.

Shock (Augusta, Ga.)

Prakash A, Sundar SV, Zhu YG, Tran A, Lee JW, Lowell C, Hellman J

Extracellular signal-regulated kinase 5 promotes acute cellular and systemic inflammation.

Science signaling

Wilhelmsen K, Xu F, Farrar K, Tran A, Khakpour S, Sundar S, Prakash A, Wang J, Gray NS, Hellman J

Intravenous immunoglobulin skews macrophages to an anti-inflammatory, IL-10-producing activation state.

Journal of leukocyte biology

Kozicky LK, Zhao ZY, Menzies SC, Fidanza M, Reid GS, Wilhelmsen K, Hellman J, Hotte N, Madsen KL, Sly LM

Dual orientation of the outer membrane lipoprotein Pal in Escherichia coli.

Microbiology (Reading, England)

Michel LV, Shaw J, MacPherson V, Barnard D, Bettinger J, D'Arcy B, Surendran N, Hellman J, Pichichero ME

The endocannabinoid/endovanilloid N-arachidonoyl dopamine (NADA) and synthetic cannabinoid WIN55,212-2 abate the inflammatory activation of human endothelial cells.

The Journal of biological chemistry

Wilhelmsen K, Khakpour S, Tran A, Sheehan K, Schumacher M, Xu F, Hellman J

Alveolar macrophages and Toll-like receptor 4 mediate ventilated lung ischemia reperfusion injury in mice.

Anesthesiology

Prakash A, Mesa KR, Wilhelmsen K, Xu F, Dodd-o JM, Hellman J

Identification of hemopexin as an anti-inflammatory factor that inhibits synergy of hemoglobin with HMGB1 in sterile and infectious inflammation.

Journal of immunology (Baltimore, Md. : 1950)

Lin T, Sammy F, Yang H, Thundivalappil S, Hellman J, Tracey KJ, Warren HS

Bacterial lipoprotein TLR2 agonists broadly modulate endothelial function and coagulation pathways in vitro and in vivo.

Journal of immunology (Baltimore, Md. : 1950)

Shin HS, Xu F, Bagchi A, Herrup E, Prakash A, Valentine C, Kulkarni H, Wilhelmsen K, Warren S, Hellman J

Resilience to bacterial infection: difference between species could be due to proteins in serum.

The Journal of infectious diseases

Warren HS, Fitting C, Hoff E, Adib-Conquy M, Beasley-Topliffe L, Tesini B, Liang X, Valentine C, Hellman J, Hayden D, Cavaillon JM

Upregulation of PD-L1 on monocytes and dendritic cells by HIV-1 derived TLR ligands.

AIDS (London, England)

Meier A, Bagchi A, Sidhu HK, Alter G, Suscovich TJ, Kavanagh DG, Streeck H, Brockman MA, LeGall S, Hellman J, Altfeld M

Activation of Toll-like receptor 2 impairs hypoxic pulmonary vasoconstriction in mice.

American journal of physiology. Lung cellular and molecular physiology

Petersen B, Bloch KD, Ichinose F, Shin HS, Shigematsu M, Bagchi A, Zapol WM, Hellman J

MyD88-dependent immune activation mediated by human immunodeficiency virus type 1-encoded Toll-like receptor ligands.

Journal of virology

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

Toll-like receptor 2 activation by bacterial peptidoglycan-associated lipoprotein activates cardiomyocyte inflammation and contractile dysfunction.

Critical care medicine

Zhu X, Bagchi A, Zhao H, Kirschning CJ, Hajjar RJ, Chao W, Hellman J, Schmidt U

MyD88-dependent and MyD88-independent pathways in synergy, priming, and tolerance between TLR agonists.

Journal of immunology (Baltimore, Md. : 1950)

Bagchi A, Herrup EA, Warren HS, Trigilio J, Shin HS, Valentine C, Hellman J

Passive immunization to outer membrane proteins MLP and PAL does not protect mice from sepsis.

Molecular medicine (Cambridge, Mass.)

Valentine CH, Hellman J, Beasley-Topliffe LK, Bagchi A, Warren HS

Increased leakage of sarcoplasmic reticulum Ca2+ contributes to abnormal myocyte Ca2+ handling and shortening in sepsis.

Critical care medicine

Zhu X, Bernecker OY, Manohar NS, Hajjar RJ, Hellman J, Ichinose F, Valdivia HH, Schmidt U

Bacterial peptidoglycan-associated lipoprotein: a naturally occurring toll-like receptor 2 agonist that is shed into serum and has synergy with lipopolysaccharide.

The Journal of infectious diseases

Liang MD, Bagchi A, Warren HS, Tehan MM, Trigilio JA, Beasley-Topliffe LK, Tesini BL, Lazzaroni JC, Fenton MJ, Hellman J

Protective efficacy of CAP18106-138-immunoglobulin G in sepsis.

The Journal of infectious diseases

Warren HS, Matyal R, Allaire JE, Yarmush D, Loiselle P, Hellman J, Paton BG, Fink MP

Outer membrane protein A, peptidoglycan-associated lipoprotein, and murein lipoprotein are released by Escherichia coli bacteria into serum.

Infection and immunity

Hellman J, Loiselle PM, Tehan MM, Allaire JE, Boyle LA, Kurnick JT, Andrews DM, Sik Kim K, 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.

The Journal of infectious diseases

Hellman J, Loiselle PM, Zanzot EM, Allaire JE, Tehan MM, Boyle LA, Kurnick JT, Warren HS

Antiendotoxin strategies.

Infectious disease clinics of North America

Hellman J, Warren HS

Antiserum against Escherichia coli J5 contains antibodies reactive with outer membrane proteins of heterologous gram-negative bacteria.

The Journal of infectious diseases

Hellman J, Zanzot EM, Loiselle PM, Amato SF, Black KM, Ge Y, Kurnick JT, Warren HS