Judith Hellman, MD

Professor & Vice Chair for Research
Department of Anesthesia and Perioperative Care
hellmanj@anesthesia.ucsf.edu

Summary: My research program is focused on basic and translational research on sepsis and other forms of inflammation-associated acute organ failure. 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 projects in the laboratory:

i.  The role of TLR2 expressed by endothelial cells and monocytes/macrophages in bacterial sepsis and organ injury: My lab has been investigating the bacterial lipoproteins in the context of sepsis for over a decade. 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. 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. 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. We are continuing to explore the role of these TLR2 signaling intermediaries in the development of coagulopathy and vascular leak in vitro, and more specifically the role of endothelial-specific TLR2 in bacterial sepsis and inflammatory critical illness.

ii. ERK5 in inflammatory critical illness: We recently made the novel discovery that extracellular signal-regulated kinase 5 (ERK5, aka: Big MAP kinase 1) mediates inflammatory activation of leukocytes and endothelial cells by multiple inflammatory agonists, and participates in inflammation in sepsis and lung ischemia reperfusion injury models. We are now characterizing ERK5 pathways and defining the role of ERK5 in sepsis-induced coagulopathy, vascular leak, and organ injury.

iii. 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. 

Primary Thematic Area: 
Immunology
Secondary Thematic Area: 
Vascular & Cardiac Biology
Research Summary: 
Innate Immune Pathways and the Endothelium in Inflammatory Critical Illness

Websites

Featured Publications: 

Vascular endothelial cell Toll-like receptor pathways in sepsis.

Innate immunity

Khakpour S, Wilhelmsen K, 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

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

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