2020 IARS Mentored Research Award

Michael Bokoch, MD, PhD
University of California, San Francisco
Assistant Professor of Clinical Anesthesia & Perioperative Care
San Francisco, CA

Dr. Bokoch’s Research

Endothelial Activation by Liver Reperfusion Injury in Transplantation

Ischemia-reperfusion (I-R) injury during liver transplantation (LT) is a profound inflammatory phenomenon that injures remote organs and worsens patient outcomes. The rising global need for LT has increased use of marginal quality grafts such as those with steatosis or from donors after cardiac death. Coagulopathy and acute kidney injury often arise after reperfusion of marginal grafts. These observations suggest a mechanism of pathologic endothelial activation downstream of liver I-R. I hypothesize that liver I-R releases endogenous Toll-like receptor (TLR) agonists into the circulation that trigger diffuse endothelial activation and dysfunction. In this translational proposal, human serum collected from LT patients at baseline and following reperfusion of the liver graft will be applied to cultured endothelial cells (ECs). Aim 1 will characterize the in vivo state of inflammation and endothelial activation during LT before and after liver I-R. We’ll measure circulating blood markers and perform histology on native blood vessels collected from liver transplant recipients. Aim 2 tests the ability of sera from LT patients to activate ECs ex vivo. Assays of endothelial permeability will be performed, cytokine production, neutrophil adhesion, and expression of coagulation pathway intermediaries to characterize the phenotype of EC activation. To probe the mechanisms by which liver I-R triggers endothelial dysfunction, innate immune signaling pathways will be disrupted using inhibitors, antibodies, and siRNA knockdown. Specifically, the hypothesis will test that LT serum activates ECs through TLR4 signaling stimulated by high-mobility group box 1, a damage-associated molecular pattern. Successful completion of this work will elucidate mechanisms by which inflammation and I-R injury drive endothelial activation, which is of broad relevance to the fields of anesthesia and critical care in addition to liver transplantation.

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