Hellman Lab

About

Immune Mechanisms and Immunomodulation in Sepsis and Injury

Sepsis and multiple organ failure are leading causes of death in the Intensive Care Unit. They result from a complex inflammatory response that is initiated by activation of the innate immune system by interactions between host cells and microbes or endogenous host factors that are released during injury or cell death. Non-infectious processes can also cause tissue injury, dysfunction, and long-term complications, such as chronic pain, through the activation of innate immune signaling and inflammation. The Hellman laboratory uses in vitro and in vivo system to define immunologic mechanisms and to explore immunomodulation in sepsis and in acute and non-acute injury. Current research focuses include understanding the role of Toll-like receptor (TLR) signaling in different cell populations (e.g.: endothelial cells, leukocytes) in sepsis and injury, defining the mechanisms of endothelial activation and dysfunction in sepsis and critical illness, and delineating the immune and functional effects of activation of the endocannabinoid and endovanilloid systems in sepsis, acute inflammation and pain.

Research

I. INNATE IMMUNE ACTIVATION AND SIGNALING IN SEPSIS AND INFLAMMATION 

Bacterial lipoproteins and TLR2. TLR2 recognizes bacterial lipoproteins, which are expressed by gram-positive and gram-negative bacteria. TLR2 participates in host defenses against bacterial infections. We found that gram-negative bacteria shed commonly expressed bacterial lipoproteins, including peptidoglycan-associated lipoprotein (Pal), into models of sepsis and into human serum. Bacterial lipoproteins activate multiple cell lineages, including leukocytes and non-leukocyte populations, such as endothelial cells and cardiomyocytes. We showed that bacterial TLR2 agonists induce systemic, cardiac and lung inflammation, and cause respiratory dysfunction in mice. We found that TLR2 agonists synergistically induce inflammation with other TLR agonists based on signaling of the TLR agonists via TRIF and MyD88.

The Extracellular Signal Regulated Kinases (ERKs) in innate immunity. Mitogen-activated protein kinases (MAPK’s) play key roles in inflammatory signaling. Studies by ours and other groups have implicated ERK1/2 and ERK5 in TLR-dependent signaling. We identified novel roles for ERK1/2 and ERK5, in the activation of leukocytes and endothelial cells by bacterial TLR agonists and host inflammatory factors (e.g.:TNF⍺, IL-1β). Our work suggests that ERK1/2 activation plays divergent roles in the inflammatory activation of human endothelial cells versus leukocytes by TLR2 and TLR4 agonists.

Endothelial inflammatory pathways and dysfunction in sepsis and injury. The human body contains more than one trillion endothelial cells, which are uniquely situated to sense and respond to invading pathogens. Microvascular endothelial cells play a substantial role in the pathophysiology of sepsis and injuries such as ischemia reperfusion injury. Endothelial dysfunction contributes to vascular leak, coagulopathy, shock, and organ injury during acute inflammation. We described the broad endothelial effects of TLR2 activation, showing that direct activation of TLR2 expressed by human lung microvascular endothelial cells (HMVEC) upregulates their production of cytokines, chemokines, and coagulation intermediaries, promotes neutrophil-HMVEC adhesion, and increases HMVEC permeability. Consistent with these in vitro effects, we found that bacterial lipopeptide causes coagulopathy and vascular leak in mice. These data suggest that the activation of endothelial TLR2 may contribute to outcomes of sepsis, such as multiple organ failure. Our recent work points to substantial differences in TLR signaling between endothelial cells and leukocytes, and also differences in the signaling pathways leading to TLR-dependent permeability versus cytokine production. We observe that ERK1/2 inhibition augments IL-6 production by HMVEC, but it reduces IL-6 production by monocytes. Furthermore, we have found that despite augmenting LPS-induced IL-6production, ERK1/2 inhibition reduces LPS-induced permeability of HMVEC. Similarly, NF-κB inhibition or siRNA knock down reduces cytokine production, but they do not affect HMVEC permeability induced by TLR2 and TLR4 agonists. These findings raise the possibility of developing therapies that preferentially target specific responses in sepsis and injury.

Current Projects: We are currently exploring the roles of activation of TLR2 expressed by endothelial cells and leukocytes, and similarly, of ERK1/2 and ERK5 expressed by these two populations, on immune responses and functional outcomes of sepsis and injury. We are investigating the role of microvascular endothelial cell innate immune signaling in shock and organ dysfunction caused by sepsis and injury. Conversely, we are also investigating the contribution of microvascular endothelial immune responses to beneficial host responses to sepsis and injury. We are elucidating the intracellular signaling pathways that mediate endothelial permeability versus cytokine production induced by TLR agonists.

II. IMMUNE MODULATION BY CANNABINOIDS, CANNIBINOID RECEPTORS (CBRs), AND THE TRANSIENT RECEPTOR POTENTIAL VANILLOID 1 (TRPV1).

The endocannabinoid system is composed of endocannabinoids, cannabinoid receptors (CBRs), and the transient receptor potential vanilloid 1 (TRPV1). TRPV1, a non-selective cation channel, regulates pain and thermosensation. The endocannabinoid system is postulated to restore homeostasis in a variety of systems, including the nervous system. The role of the endocannabinoid system outside of the nervous system is not well understood. Although there are large gaps in the understanding the effects of cannabinoids on key host systems, such as the immune system,emerging evidence suggests that cannabinoids can profoundly affect inflammation, and that CBRs and TRPV1 play substantial immunomodulatory roles in sepsis and injury.

In 2014 we reported that NADA reduces pro-inflammatory cytokine production by human endothelial cells and leukocytes induced by bacterial lipopeptide, LPS, and TNF⍺. Subsequently we found that NADA strongly increases blood levels ofthe anti-inflammatory cytokine,IL-10, while decreasing IL-6 and CCL2, and that NADA’s anti-inflammatory effects are mediated by TRPV1 expressed by non-myeloid cells. We recently reported that Δ-9-tetrahydrocannbinol (THC) strongly induces IL-10 and reduces pro-inflammatory cytokines, and that THC improves functional outcomes and lung inflammation at 24 hours in endotoxemic mice. We determined that monocytes mediate the anti-inflammatory effects, and that monocyte-derived suppressor cells are the source of IL-10 in THC-treated endotoxemic mice. We identified CB1R as the receptor responsible for the anti-inflammatory and improved functional outcomes in THC-treated endotoxemic mice, in contrast to our studies showing that TRPV1 mediates NADA’s anti-inflammatory effects in mice. In recent studies we have found that another endocannabinoid, N-oleoyl dopamine (OLDA) also has potent TRPV1-dependentanti-inflammatory effects in endotoxemic mice.

Current Projects: We are continuing to explore the immune effects of cannabinoids, including NADA and OLDA, and phytocannabinoids, including THC, cannabidiol (CBD), and several minor cannabinoids. We are studying the roles of CBRs and TRPV1 in regulating immune responses during sepsis and IR injury, and in acute and chronic pain. We are elucidating the mechanisms by which THC, NADA, and OLDA strongly upregulate systemic IL-10 in acute inflammation (endotoxemia) and bacterial sepsis. Studies are also focused on understanding the role of IL-10 upregulation in determining functional outcomes of sepsis, acute inflammation and pain.

 
Publications

Publications: 

Joffre J, Hellman J. Oxidative stress and endothelial dysfunction in sepsis and acute inflammation. Antioxid Redox Signal. 2021 Apr 09.

Coopersmith CM, Antonelli M, Bauer SR, Deutschman CS, Evans LE, Ferrer R, Hellman J, Jog S, Kesecioglu J, Kissoon N, Martin-Loeches I, Nunnally ME, Prescott HC, Rhodes A, Talmor D, Tissieres P, De Backer D. The Surviving Sepsis Campaign: Research Priorities for Coronavirus Disease 2019 in Critical Illness. Crit Care Med. 2021 04 01; 49(4):598-622.

Joffre J, Lloyd E, Wong E, Chung-Yeh C, Nguyen N, Xu F, Legrand M, Hellman J. Catecholaminergic Vasopressors Reduce Toll-Like Receptor Agonist-Induced Microvascular Endothelial Cell Permeability But Not Cytokine Production. Crit Care Med. 2021 03 01; 49(3):e315-e326.

Michel LV, Gallardo L, Konovalova A, Bauer M, Jackson N, Zavorin M, McNamara C, Pierce J, Cheng S, Snyder E, Hellman J, Pichichero ME. Ampicillin triggers the release of Pal in toxic vesicles from Escherichia coli. Int J Antimicrob Agents. 2020 Dec;56(6):106163.

Wong E, Xu F, Joffre J, Nguyen N, Wilhelmsen K, Hellman J. ERK1/2 has Divergent Roles in LPS-Induced Microvascular Endothelial Cell Cytokine Production and Permeability. Shock. 2021 Mar 01; 55(3):349-356.

Michel LV, Gallardo L, Konovalova A, Bauer M, Jackson N, Zavorin M, McNamara C, Pierce J, Cheng S, Snyder E, Hellman J, Pichichero ME. Ampicillin triggers the release of Pal in toxic vesicles from Escherichia coli. Int J Antimicrob Agents. 2020 Dec; 56(6):106163.

Joffre J, Hellman J, Ince C, Ait-Oufella H. Endothelial Responses in Sepsis. Am J Respir Crit Care Med. 2020 Aug 01; 202(3):361-370.

Deutschman CS, Hellman J, Ferrer Roca R, De Backer D, Coopersmith CM. The Surviving Sepsis Campaign: Basic/Translational Science Research Priorities. Crit Care Med. 2020; 48(8):1217-1232 // Intensive Care Med Exp. 2020; 8(1):31.

Joffre J, Yeh CC, Wong E, Thete M, Xu F, Zlatanova I, Lloyd E, Kobzik L, Legrand M, Hellman J. Activation of CB1R Promotes Lipopolysaccharide-Induced IL-10 Secretion by Monocytic Myeloid-Derived Suppressive Cells and Reduces Acute Inflammation and Organ Injury. J Immunol. 2020 Jun 15; 204(12):3339-3350.

Tian X, Hellman J, Horswill AR, Crosby HA, Francis KP, Prakash A. Elevated Gut Microbiome-Derived Propionate Levels Are Associated With Reduced Sterile Lung Inflammation and Bacterial Immunity in Mice. Front Microbiol. 2019; 10:159. Corrigendum in: Front Microbiol. 2019; 10:518.

Hellman J, Bahrami S, Boros M, Chaudry IH, Fritsch G, Gozdzik W, Inoue S, Radermacher P, Singer M, Osuchowski MF, Huber-Lang M. Part III: Minimum Quality Threshold in Preclinical Sepsis Studies (MQTiPSS) for Fluid Resuscitation and Antimicrobial Therapy Endpoints. Shock. 2019 01; 51(1):33-43.

Remick DG, Ayala A, Chaudry IH, Coopersmith CM, Deutschman C, Hellman J, Moldawer L, Osuchowski MF. Premise for Standardized Sepsis Models. Shock. 2019 01; 51(1):4-9.

Barruet E, Morales BM, Cain CJ, Ton AN, Wentworth KL, Chan TV, Moody TA, Haks MC, Ottenhoff TH, Hellman J, Nakamura MC, Hsiao EC. NF-?B/MAPK activation underlies ACVR1-mediated inflammation in human heterotopic ossification. JCI Insight. 2018 11 15; 3(22).

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. Shock. 2018 10; 50(4):377-380 // Infection. 2018; 46(5):687-69 // Intensive Care Med Exp. 2018; 6(1):26.

Coopersmith CM, De Backer D, Deutschman CS, Ferrer R, Lat I, Machado FR, Martin GS, Martin-Loeches I, Nunnally ME, Antonelli M, Evans LE, Hellman J, Jog S, Kesecioglu J, Levy MM, Rhodes A. Surviving Sepsis Campaign: Research Priorities for Sepsis and Septic Shock. Crit Care Med. 2018 08; 46(8):1334-1356 // Intensive Care Med. 2018; 44(9):1400-1426.

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.

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.

Guan Z, Hellman J, Schumacher M. Contemporary views on inflammatory pain mechanisms: TRPing over innate and microglial pathways. F1000Res. 2016; 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.

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.

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.

Khakpour S, Wilhelmsen K, Hellman J. Vascular endothelial cell Toll-like receptor pathways in sepsis. Innate Immun. 2015 Nov; 21(8):827-46.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Prakash A, Hellman J. Editorial: Pattern recognition receptors and factor B: "complement"ary pathways converge. J Leukoc Biol. 2010 Oct; 88(4):605-7.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Judith Hellman, H. Shaw Warren. Antibodies against bacterial membrane proteins. Innate Immunity. 1999 Aug 1; 5(4):213-215.

Hellman J, Warren HS. Antiendotoxin strategies. Infect Dis Clin North Am. 1999 Jun; 13(2):371-86, ix.

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.

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.

 

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People

Judith Hellman, M.D.
Principal Investigator
Professor, Vice Chair for Research
Department of Anesthesia and Critical Care

Judith Hellman, M.D., the William L Young MD Endowed Professor and Vice Chair for Research in the UCSF Department of Anesthesia and Critical Care, is a critical care physician-scientist. She trained in Internal Medicine, Anesthesiology, and Critical Care Medicine, and does basic and translational research on sepsis, injury and critical illness. As a post-doctoral research fellow, Dr. Hellman studied the shedding and inflammatory effects of bacterial lipoproteins into human serum and in sepsis models. This launched her early work on Toll-like receptors (TLRs), and a long-term interest in the immunologic mechanisms of sepsis, critical illness, and injury. Dr. Hellman’s current research is focused on innate immunity and inflammatory signaling in sepsis and injury, on endothelial cell inflammation and dysfunction, and on immune modulation by cannabinoids and their receptors, the cannabinoid receptors (CBRs) and the transient receptor potential vanilloid 1 (TRPV1) in sepsis, injury and pain.

 

Fengyun Xu, Ph.D.
Lab Manager

Dr. Xu obtained her Ph.D. in Pharmacology from Beijing University Health Science Center in China. Her graduate research was focused on the effect of thyroid dysfunction on drug metabolism and pharmacokinetics. She joined the Department of Pharmaceutical Sciences at UCSF as a postdoc researching the role of cytochrome P450 derived eicosanoids in blood pressure regulation and inflammation. A few years later she joined Hellman Lab. Dr. Xu is the Hellman Lab manager and is in charge of lab safety and major equipment maintenance. She is also doing research on the role of TLR2, MAP kinases, and cannabinoids in endothelial permeability, inflammation and organ injury in sepsis.

 

Erika Wong, M.D.
Assistant Adjunct Professor

Dr. Wong is a pediatric critical care physician and basic scientist whose research vision involves understanding the innate immune pathways that are activated during sepsis, in particular, the innate immune pathways activated in endothelial cells. It is the global endothelial cell activation in sepsis that contributes to the body’s overwhelming response to infection, and ultimately can lead multi-organ failure and death. Besides defining these signaling pathways, Dr. Wong has been studying a variety of drugs that can modulate inflammatory signaling pathways to dampen the acute inflammatory response that occurs in sepsis. Dr. Wong’s vast experience in handling primary endothelial cell cultures, endothelial cell permeability assays, and barrier function assays allows her to study these mechanistic pathways in detail, with hopes to gain insight into the role of the endothelium in the host immune response.

 

Che-Chung Yeh, Ph.D.
Senior Specialist

Dr. Yeh’s research interests include the application of in vivo animal models and in vitro cell systems to study the mechanisms of anti-inflammation and inflammation. Dr. Yeh’s current projects include (1) regulation of the innate immune response by cannabinoid related receptors, (2) anti-inflammatory and pain-relief activity of minor cannabinoids and (3) transcriptional regulation of cytokine genes by cannabinoids.

 

 

Jérémie Joffre, M.D., Ph.D.
Visiting Postdoctoral Scholar

Jérémie Joffre graduated from Paris Descartes University School of Medicine in 2008. He completed a residency in cardiology with a qualification in Critical care medicine at Paris-Sorbonne University. Then he practiced two years as an attending in Medical intensive care at the Saint-Antoine University Hospital. (http://reanimation-sat.aphp.fr/). Dr. Joffre obtained a Ph.D. in cell biology in2016. During his Ph.D., at the Paris Cardiovascular Research Center in the team “Immuno-metabolic Mechanisms of Cardiovascular Diseases”, he discovered the role of TREM-1 during atherosclerosis and deciphered its mechanism of action. (http://parcc.inserm.fr/). Dr. Joffre joined the Hellman Lab team in 2018. As a cardiologist and intensivist interested in microvascular failure and immunity, he joined the team to apply his knowledge in immunology and vascular biology to study septic shock, and mechanism of organ failure.

Dr. Joffre is currently working on two major research projects:
The role of the microvascular endothelium in response to infection and the regulation of different facets of sepsis-induced endotheliopathy such as inflammation, permeability, and leukocyte adhesion.
The regulation of the immune response associated with sepsis by the nervous system and the role of the cannabinoid and vanilloid system.

During homeostasis (Left part), a heparan sulfate-rich layer of glycosaminoglycans and proteoglycans called glycocalyx (GCX), coats all healthy vascular endothelium, maintains local osmolarity and high reflection capability for albumin and leukocytes. During sepsis (Right part): The GCX endures qualitative and quantitative alterations (1), adherent junctions are impaired because of VE-cadherin endocytosis after phosphorylation (2), causing exudation and capillary leak syndrome (3). Activated endothelial cells (ECs) produce a large amount of pro-inflammatory cytokine and chemokines (IL-6, IL-8 (CXCL8), CCL-2) (4) leading to local and systemic inflammatory response amplification and promoting monocytes and polymorphonuclears (PMNs) recruitment. Integrin family glycoprotein, including CD 62E/P VCAM-1, PECAM, ICAM-1/2 are upregulated, and leukocyte adhesion, rolling and crawling (5) followed by transendothelial trans-or para-cellular migration (6) towards tissues is increased. EC anticoagulant functions are impaired, and ECs apoptosis and MPS release lead to amplify the procoagulant state (7-8). Defect in fibrinolysis leads to fibrin accumulation and microvascular immuno-thrombosis, involving platelets, NETs, and red blood cells (RBC) (9). The variable intensity of these alterations defines the sepsis-induced endotheliopathy participating in organ failure and septic shock.

 

Nina Nguyen, B.A.
Staff Research Associate

Nina is currently a Staff Research Associate in the Hellman Lab. She originally joined the lab as a summer intern while studying Molecular and Cell Biology as an undergraduate at UC Berkeley. She has enjoyed learning about the different roles of innate immune pathways in inflammatory critical illness while assisting with a few of the lab's projects. However, she is now particularly interested in studying the molecular mechanisms underlying permeability of the vasculature as well as the blood-brain barrier. In the future, Nina plans to attend medical school and hopes to continue to participate in research.

 

Elliot Lloyd, B.A.
Volunteer
 

Elliot Lloyd is a volunteer Research Assistant with the Hellman Lab. Elliot grew up in San Francisco and attended UC Berkeley, where he obtained a B.A. in Molecular and Cellular Biology and minors in Chemistry and Global Public Health. Following graduation, he sought an opportunity to expand his practical experience with laboratory techniques. His current research efforts are focused on investigating the effects of catecholaminergic and non-catecholaminergic vasopressors on microvascular endothelial permeability following inflammatory insult and assessing effects of endocannabinoids on inflammatory profiles during septic shock. In the future, he hopes to pursue either an M.D. or Ph.D., and will continue to be a contributor to biological research and innovation.

Contact

Judith Hellman, M.D. 
William L. Young, MD. Endowed Professor 
Vice Chair for Research

Department of Anesthesia and Perioperative Care

513 Parnassus Ave, MSB
San Francisco, CA 94117
415-476-5950
[email protected]
 

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