Each year, when the American Society of Anesthesiologists chooses a recipient for our Excellence in Research Award, we look for impact. The reason is simple: Because the award is the highest honor an individual investigator can receive from our group, his or her work must substantially advance science in the service of saving lives.
Physician-scientist Judith Hellman, MD, the William L. Young Endowed Professor and Vice Chair for Research in the UCSF Department of Anesthesia & Perioperative Care, has spent her career tracking how the interactions between microorganisms and the body’s innate immune system lead to shock and organ dysfunction in sepsisand inflammatory critical illness. Given the role of sepsis in so many ICU deaths and our ongoing struggles to diagnose the condition and help our patients recover from its effects, it is hard to imagine more important work.
Dr. Hellman’s path to this work was not a straight line, but it was all of a piece. She grew up in New York City, before her family’s San Francisco roots eventually drew her to UC Berkeley where she majored in microbiology. She then attended medical school at Columbia University, where she decided to become an ICU physician – and then completed residencies in internal medicine at Oregon Health Sciences University and in anesthesia at Massachusetts General Hospital. At the latter, her department chair discovered her microbiology background and referred her to the lab of H. Shaw Warren, MD, an infectious disease physician and sepsis researcher.
That’s where Dr. Hellman connected the dots between her interests in microbiology, intensive care and sepsis. After completing an intensive care fellowship, also at Mass General, she moved on to do post-doctoral work in Warren’s lab on a T-32 training grant and began making her own mark on our understanding of sepsis.
Her initial research path was unusually fruitful. She demonstrated that bacteria shed commonly expressed bacterial lipoproteins into the circulation of septic animals and into human serum [1-5]; that bacterial lipoproteins induce inflammation and lethality in mice; that E. colilacking the bacterial lipopeptide, peptidoglycan-associated lipoprotein (PAL) have reduced lethality in sepsis; and that TLR2 agonists synergistically induce inflammation with other TLR agonists [4-6]. In addition, she found that bacterial lipopeptide causes respiratory dysfunction and contributed to the understanding of the effects of TLR2 activation on cardiomyocyte function [7-9].
In these same years, while continuing to provide clinical care in ICUs, Dr. Hellman observed the complex bleeding and clotting derangements that occur in patients with sepsis. Motivated by that observation, she began to explore whether the processes that occur in the endothelium, which is important in coagulation homeostasis and is activated in sepsis, might be at the heart of sepsis-induced organ failure – a condition that occurs in roughly half of patients who succumb to septic shock. Ultimately, Dr. Hellman became the first to define the broad spectrum of effects of TLR2 activation on endothelial cells, including showing that TLR2 activation up-regulates inflammatory mediators, increases endothelial-neutrophil adhesion, and modulates endothelial permeability and the expression of coagulation pathway intermediaries [10-12].
Next, Dr. Hellman turned her attention to defining the role of the Extracellular Signal Regulated Kinases (ERKs) 1/2 and ERK5 in acute inflammation and sepsis. That research path has led her to identify novel roles for ERKs1, 2 and 5, in activation of leukocytes and endothelial cells by microbial and endogenous inflammatory agonists. Moreover, while mapping out endothelial TLR2 signaling pathways, she and her team uncovered a previously unrecognized role for ERK5 in mediating TLR2-dependent activation of endothelial cells and leukocytes [13]. She then identified a role for ERK5 in inflammatory activation of cells by agonists of other TLRs, and by endogenous inflammatory agonists including IL-1band TNFa[14]– and found that ERK5 mediates inflammation in mice with sepsis or with lung ischemia-reperfusion injury [14]. Finally, her work suggests that ERK1/2 activation plays divergent roles in the inflammatory activation of human endothelial cells versusleukocytes [13].
Moreover, Dr. Hellman’s novel discoveries on immune modulation by the endocannabinoid and endovanilloid systems could eventually lead to important therapeutic targets for sepsis and acute inflammation. She has published two papers on the anti-inflammatory effects of the endogenous lipid, N-arachidonoyl dopamine (NADA), which activates cannabinoid receptors as well as the pain receptor, TRPV1. She and her team discovered that NADA has potent anti-inflammatory effects in vitro on leukocytes and endothelial cells,and in vivo in endotoxemic and septic mice [15, 16]. She also found that NADA down-regulates acute inflammation in mice TRPV1 expressed by non-hematopoietic cells [16]. In as yet unpublished work, she found that another acyl-dopamine TRPV1 agonist, N-oleoyl dopamine (OLDA), as well as the phytocannabinoid, THC, also have potent anti-inflammatory effects in vitroand in vivo.
In connected research, Dr. Hellman has made important contributions to understanding lung ischemia-reperfusion (IR) injury. She collaborated with Dr. Arun Prakash, a K08-funded anesthesiologist for whom she is the primary mentor, to find that alveolar macrophages, TLR4, and the NLRP3 inflammasome mediate inflammation in lung IR; that manipulation of the intestinal microbiome affects IR-induced lung inflammation; and that lung IR affects bacterial containment in mice with E. colipneumonia [17-19]. Her group has also made important contributions to understanding other aspects of immune modulation. They have shown that rats with metabolic syndrome have impaired bacterial clearance and exaggerated lung inflammation during S. aureusinfection [20]and Dr. Hellman has contributed to studies that show how the intestinal microbiome regulates lung injury and systemic infection [18, 21].
This is extraordinarily important work, yet Dr. Hellman’s influence goes far beyond her own research program. She has served as a reviewer for multiple publications, as well as an editor, associate editor or section editor for journals that include the Journal of ImmunologyandSHOCK. Andfor more than two decades, she has contributed substantially to research training and mentoring in anesthesia and critical care at the institutional and national levels.
To wit: As our department’s vice chair for research since 2013, she is responsible for everything from the education of research trainees through the recruitment of faculty, fellows, and residents. As director of the department's research training program, she trains and mentors students, residents, post-doctoral fellows, and junior faculty. In addition, she is the program director for the Anesthesia NIH T32 training grant and helped establish and now runs the department's Pathway to Scientific Independence program, which facilitates the research training of anesthesiologist physician-scientists.
Similarly, in her own research lab, Dr. Hellman trains medical students, graduate students, post-doctoral fellows and junior faculty. In clinical settings, she has taught medical students and house officers at the bedside and in lectures. She has served as the primary research advisor/mentor for many, served on multiple Research Advisory Committees and been a short-term mentor for a number of undergraduate and medical students doing summer research projects. In 2018, she received the Fellows' Leadership and Advocacy Group Mentorship Award by the UCSF Pediatrics Department.
All this in addition to serving in numerous leadership roles and on important committees for the Society of Critical Care Medicine, the American Association of Immunologists, the Shock Society – andthe American Society of Anesthesiologists.
Dr. Hellman’s cumulative impact on our specialty and on an essential area for medical research is hard to quantify, but it is considerable and rare. We are honored to have her as a colleague and thrilled to see her receive an honor that is so richly deserved.
Previous recipients of the ASA Excellence in Research Award from the UCSF Department of Anesthesia and Perioperative Care include: Daniel Sessler, MD (2002), Mervyn Maze, MB ChB (2003), and William L. Young (2009).
References
1. Hellman J, Loiselle PM, Tehan MM, Allaire JE, Boyle LA, Kurnick JT, et al. Outer membrane protein A, peptidoglycan-associated lipoprotein, and murein lipoprotein are released by Escherichia coli bacteria into serum. Infect Immun. 2000;68(5):2566-72. PubMed PMID: 10768945; PubMed Central PMCID: PMC97460.
2. Hellman J, Loiselle PM, Zanzot EM, Allaire JE, Tehan MM, Boyle LA, et al. 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;181(3):1034-43. doi: 10.1086/315302. PubMed PMID: 10720528.
3. 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. PubMed PMID: 11521086.
4. Liang MD, Bagchi A, Warren HS, Tehan MM, Trigilio JA, Beasley-Topliffe LK, et al. 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;191(6):939-48. Epub 2005/02/18. doi: 10.1086/427815. PubMed PMID: 15717270.
5. Hellman J, Roberts JD, Jr., 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;277(16):14274-80. doi: 10.1074/jbc.M109696200. PubMed PMID: 11830585.
6. Bagchi A, Herrup EA, Warren HS, Trigilio J, Shin HS, Valentine C, et al. MyD88-dependent and MyD88-independent pathways in synergy, priming, and tolerance between TLR agonists. J Immunol. 2007;178(2):1164-71. Epub 2007/01/05. PubMed PMID: 17202381.
7. Petersen B, Bloch KD, Ichinose F, Shin HS, Shigematsu M, Bagchi A, et al. Activation of Toll-like receptor 2 impairs hypoxic pulmonary vasoconstriction in mice. Am J Physiol Lung Cell Mol Physiol. 2008;294(2):L300-8. doi: 10.1152/ajplung.00243.2007. PubMed PMID: 18055842.
8. Zhu X, Bernecker OY, Manohar NS, Hajjar RJ, Hellman J, Ichinose F, et al. Increased leakage of sarcoplasmic reticulum Ca2+ contributes to abnormal myocyte Ca2+ handling and shortening in sepsis. Crit Care Med. 2005;33(3):598-604. Epub 2005/03/09. PubMed PMID: 15753753.
9. Zhu X, Bagchi A, Zhao H, Kirschning CJ, Hajjar RJ, Chao W, et al. Toll-like receptor 2 activation by bacterial peptidoglycan-associated lipoprotein activates cardiomyocyte inflammation and contractile dysfunction. Crit Care Med. 2007;35(3):886-92. Epub 2007/01/27. doi: 10.1097/01.CCM.0000256723.37586.A2. PubMed PMID: 17255871.
10. Shin HS, Xu F, Bagchi A, Herrup E, Prakash A, Valentine C, et al. Bacterial lipoprotein TLR2 agonists broadly modulate endothelial function and coagulation pathways in vitro and in vivo. J Immunol. 2011;186(2):1119-30. Epub 2010/12/21. doi: 10.4049/jimmunol.1001647. PubMed PMID: 21169547; PubMed Central PMCID: PMC3482611.
11. 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;18(4):602-16. Epub 2011/12/22. doi: 10.1177/1753425911429336. PubMed PMID: 22186927; PubMed Central PMCID: PMC3444510.
12. Khakpour S, Wilhelmsen K, Hellman J. Vascular endothelial cell Toll-like receptor pathways in sepsis. Innate Immun. 2015;21(8):827-46. Epub 2015/09/26. doi: 10.1177/1753425915606525. PubMed PMID: 26403174.
13. 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;287(32):26478-94. Epub 2012/06/19. doi: 10.1074/jbc.M112.359489. PubMed PMID: 22707717.
14. Wilhelmsen K, Xu F, Farrar K, Tran A, Khakpour S, Sundar S, et al. Extracellular signal-regulated kinase 5 promotes acute cellular and systemic inflammation. Sci Signal. 2015;8(391):ra86. Epub 2015/08/27. doi: 10.1126/scisignal.aaa3206. PubMed PMID: 26307013.
15. Wilhelmsen K, Khakpour S, Tran A, Sheehan K, Schumacher M, Xu F, et al. 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;289(19):13079-100. Epub 2014/03/20. doi: 10.1074/jbc.M113.536953. PubMed PMID: 24644287; PubMed Central PMCID: PMC4036321.
16. Lawton SK, Xu F, Tran A, Wong E, Prakash A, Schumacher M, et al. N-Arachidonoyl Dopamine Modulates Acute Systemic Inflammation via Nonhematopoietic TRPV1. J Immunol. 2017;199(4):1465-75. doi: 10.4049/jimmunol.1602151. PubMed PMID: 28701511; PubMed Central PMCID: PMCPMC5544930.
17. 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;117(4):822-35. Epub 2012/08/15. doi: 10.1097/ALN.0b013e31826a4ae3. PubMed PMID: 22890118; PubMed Central PMCID: PMC3477877.
18. Prakash A, Sundar SV, Zhu YG, Tran A, Lee JW, Lowell C, et al. Lung Ischemia-Reperfusion is a Sterile Inflammatory Process Influenced by Commensal Microbiota in Mice. Shock (Augusta, Ga. 2015;44(3):272-9. Epub 2015/07/22. doi: 10.1097/SHK.0000000000000415. PubMed PMID: 26196836; PubMed Central PMCID: PMCPMC4537678.
19. Tian X, Sun H, Casbon AJ, Lim E, Francis KP, Hellman J, et al. NLRP3 Inflammasome Mediates Dormant Neutrophil Recruitment following Sterile Lung Injury and Protects against Subsequent Bacterial Pneumonia in Mice. Front Immunol. 2017;8:1337. Epub 2017/11/23. doi: 10.3389/fimmu.2017.01337. PubMed PMID: 29163464; PubMed Central PMCID: PMCPMC5671513.
20. Feng X, Maze M, Koch LG, Britton SL, Hellman J. Exaggerated acute lung injury and impaired antibacterial defenses during Staphylococcus aureusinfection in rats with the Metabolic Syndrome. PLoS One. 2015;10(5):e0126906. Epub 2015/05/16. doi: 10.1371/journal.pone.0126906. PubMed PMID: 25978669.
21. Zeng MY, Cisalpino D, Varadarajan S, Hellman J, Warren HS, Cascalho M, et al. Gut Microbiota-Induced Immunoglobulin G Controls Systemic Infection by Symbiotic Bacteria and Pathogens. Immunity. 2016;44(3):647-58. Epub 2016/03/06. doi: 10.1016/j.immuni.2016.02.006. PubMed PMID: 26944199; PubMed Central PMCID: PMCPMC4794373.