In Focus: The Role of Mediators in Hepatic Dysfunction from Trauma, Ischemia, and Surgical Sepsis

Brian G. Harbrecht, MD
Professor of Surgery
University of Louisville 
Department of Surgery

Brian G. Harbrecht, MD, and his team are focusing on hepatic function and dysfunction after trauma, ischemia, and surgical sepsis.

The immune response to trauma, ischemia, and sepsis involves a series of complex, highly integrated homeostatic responses that, if prolonged and excessive, can lead to organ dysfunction and death. Nitric oxide (NO) synthesis is upregulated in many tissues and is an essential component of the host immune response. Nitric oxide synthesis can be beneficial and improve immune and organ function but if synthesis is excessive and prolonged, NO can promote organ injury, tissue inflammation, and death. NO is produced in hepatocytes by the inducible nitric oxide synthase (iNOS) that is stimulated by cytokines and proinflammatory stimuli.

Going to the Excess
Excessive NO from iNOS produces cellular dysfunction and hepatic injury. Several mediators such as glucagon and cyclic adenosine monophosphate (cAMP) regulate hepatic iNOS expression in vitro and in vivo and, by doing so, decrease NO-mediated hepatic injury. Endogenous hormones such as insulin and estrogen as well as hormone-like compounds found in natural plant products also mediate hepatic function in a variety of disease models.

Understanding the Regulators
In our laboratory, we are investigating how mediators work to regulate hepatocyte iNOS expression, hepatocyte intracellular signaling pathways, and hepatic gene expression in models of infection and ischemia.  We use cultured cells, selected cell lines, and tissues to investigate these mechanisms and provide a framework for understanding the basic pathophysiologic cellular events in shock and sepsis that may lead to novel cellular-based therapies for critically ill patients.