Hobart W. Harris, M.D., M.P.H.

Biography

Dr. Hobart W. Harris is Chief of the Division of General Surgery, Vice-Chair of the Department of Surgery, and a Professor of Surgery at the University of California, San Francisco. Dr. Harris is also a Principal Investigator in the UCSF Surgical Research Laboratory at San Francisco General Hospital.

Dr. Harris is an expert in treating surgical infections and diseases of the pancreas and biliary system. His areas of expertise include pancreas and bile duct cancer, acute and chronic pancreatitis, gallstone disease, intra-abdominal sepsis and serious infections of the skin and soft tissue.

Dr. Harris earned his undergraduate, medical and public health degrees at Harvard University, then completed an internship and residency in surgery at UCSF. After residency training, he completed a fellowship in heptobiliary surgery at the University of Hong Kong, Queen Mary Hospital and joined UCSF in 1994.

His research focuses on surgical infections, innate immunity and inflammatory diseases of the pancreas. His laboratory work is supported by an NIH grant to study the role of triglyceride-rich lipoproteins in the innate host response to endotoxins, such as those released by the Gram-negative bacteria that cause the most deadly form of sepsis.

Dr. Harris is a fellow of the American College of Surgeons and is a member of numerous surgical and scientific societies including the American Surgical Association and the International Hepato-Pancreato-Biliary Association.

Research Summary

Gram negative sepsis is initiated by host exposure to endotoxin (LPS), which triggers both pro-inflammatory and regulatory responses. Whereas neutrophils and macrophages are stimulated to release cytokines (TNF, IL-1), nitric oxide and other promoters of inflammation, sepsis also induces the acute phase response, wherein hepatocytes secrete substances designed to limit the extent and severity of the inflammatory reaction. Therefore, the balance between these opposing responses defines the difference between a healthy, protective reaction versus a pathologic, potentially fatal one. Despite increasing insight into the pathophysiology of gram negative infection, sepsis remains a significant problem in Medicine, annually effecting 750,000 patients and causing over 175,000 deaths. Unfortunately, recent clinical trials employed a strategy of inhibiting a single inflammatory mediator with anti-endotoxin or anti-cytokine agents, and have been largely unsuccessful.

Efforts in the laboratory have focused on understanding the molecular basis of the "lipemia of sepsis," a facet of the acute phase response resulting from the increased production of triglyceride (TG)-rich lipoproteins by the liver. Dr. Harris hypothesizes that chylomicrons (CM) and VLDL are components of an innate host immune response to infection. Specifically, CM and VLDL bind LPS forming lipoprotein-LPS complexes that are capable of regulating the hepatocellular response to inflammatory stimuli.

Current studies examine how the CM-LPS complexes are internalized and the impact of this cytoplasmic LPS on hepatocellular function. Specifically, the research group is a) using their recently developed cell culture system to delineate the mechanisms by which CM-bound LPS is internalized by and inhibits the response of hepatocytes to cytokines, b) determining the effect of CM-bound LPS on the response of hepatocytes to acute cellular stressors, and c) examining whether CM-bound LPS inhibits cytokine-induced activation of hepatocytes by interrupting intracellular signal transduction. Whereas the acute inflammatory response is critical for the host to combat bacterial infections, this defensive response must be tightly regulated or it can culminate in shock, multiple organ failure and death. Understanding how CM protect against LPS and contribute to host homeostasis is central to the understanding of the host response to infection, and the future development of a novel therapeutic strategy based on manipulating the response of target cells to pro-inflammatory stimuli rather than blocking individual inflammatory mediators.

In addition, Dr. Harris' research group is actively investigating the role of apolipoprotein E (apoE) as an immunomodulatory agent. Specifically, they are examining how apoE modulates the response to infection through the CD1-mediated activation of Natural Killer T lymphocytes in a rodent model of polymicrobial sepsis. These studies may provide additional evidence in support of our global hypothesis that triglyceride-rich lipoproteins are integral components of the host immune response to infection.