Judith Hellman, MD

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-1β (IL1R), and TNFα (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 TNFα, 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-κB 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.