Yuan Zhai, M.D., Ph.D.

Professor
Department: Surgery
Programs: Cellular Injury, Inflammation, Fibrosis, End Organ Disease

 

 

Research Interests:

Liver ischemia-reperfusion injury (IRI) remains a major clinical problem in both hepatic tumor resection (warm) and liver transplantation (warm+cold), leading to organ dysfunction and rejection. Although there are differences in the histopathology of warm and cold IRI, the underlying mechanism is common, i.e., innate immune-dominated tissue inflammation. The danger-associated molecular pattern (DAMP) activates liver immune cells via pattern recognition receptors to initiate the inflammatory cascade. Although significant progress has been made in our mechanistic understanding of the inflammatory response in liver IR, the picture is incomplete. The majority of studies have analyzed only the activation without examining the resolution of liver IRI. Tissue inflammation resolution impacts not only the severity and duration of tissue injuries but also its long-term outcome. It is an active and dynamic process consisting of at least three key steps, including the following: (1) the cessation of neutrophil infiltration and their clearance, (2) infiltrating MФ (iMФ) reprogramming from pro-inflammatory to regulatory/reparative phenotype, and (3) tissue repair/regeneration. Each of these steps involves complex molecular and cellular pathways in distinctive cell populations, which are often initiated by or overlapped with the immune activation process. Thus, simple anti-inflammatory therapies may potentially interfere with the resolution, leading to chronic inflammatory diseases. A “pro-resolution” therapeutic strategy has emerged recently as an improved alternative, which aims to truly restore IR-stressed liver tissue homeostasis. Dr. Zhai’s laboratory seeks to understand inflammation resolution mechanisms in liver IRI and identify novel pro-resolving therapeutic targets. They take advantage of recently established mouse genetic tools to elucidate KC-specific function in both partial warm ischemia and liver transplantation models. They are testing the hypothesis that embryonic (em)-KCs are the most effective reparative MФs in the resolution of liver IRI in a MerTK/TIM-4 dependent manner via Liver X Receptor (LXR) - and lipoxygenase (LOX) -mediated effector pathways. Enhancement of pro-resolution function of KCs protects the liver from IRI and inhibits allo-immune activation (promotes tolerance).

Dr. Zhai is also examining the role of glycogen synthase kinase 3b (Gsk3b) and how it differentially regulates pro- and anti-inflammatory gene programs in MФs upon innate stimulations. They have shown in a murine liver partial warm ischemia model that both Gsk3 inhibitors in WT hosts and myeloid Gsk3b deficiency protect livers from IRI via an AMPK- IL-10-dependent mechanism. They have also shown that Gsk3b regulates liver inflammatory immune activation and resolution by targeting distinctive populations of liver MФs.

Publications:

PubMed Collection