Project Grant R21AI178204

THE ROLE OF C/EBPSS IN SEPSIS ASSOCIATED ACUTE-ON-CHRONIC LIVER FAILURE - PROJECT SUMMARY ACUTE-ON-CHRONIC LIVER FAILURE (ACLF) IS A CLINICAL SYNDROME IN WHICH THERE IS RAPID DEVELOPMENT OF LIVER AND MULTI- ORGAN SYSTEM FAILURE IN A PATIENT WITH PREVIOUSLY STABLE CIRRHOSIS. THERE ARE TWO DIFFERENT TYPES OF ACLF. IN THE FIRST, THE PRECIPITATING INSULT DIRECTLY INJURES THE LIVER AND LIVER FAILURE IS A DIRECT CONSEQUENCE OF THIS INJURY. IN THE SECOND, THE PRECIPITATING EVENT IS TYPICALLY SEPSIS, AND THIS UNEXPECTEDLY RESULTS IN THE SUDDEN LOSS OF LIVER FUNCTION WITHOUT MASSIVE LIVER CELL DEATH AND ITS MECHANISM IS UNKNOWN. THERE HAVE BEEN VERY FEW MECHANISTIC STUDIES OF ACLF TO DATE DUE TO THE LACK OF AN APPROPRIATE ANIMAL MODEL. RECENTLY WE DEVELOPED A MOUSE MODEL OF SEPSIS RELATED ACLF. WE FOUND THAT SEPSIS INDUCTION IN MICE WITH ADVANCED LIVER FIBROSIS RESULTS IN HIGH MORTALITY AND A RAPID DECREASE IN LIVER FUNCTION, ASSOCIATED WITH A DECREASE IN DIFFERENTIATION MARKERS, SUCH AS ALB, AND AN INCREASE IN HEPATOCYTE EXPRESSION OF C/EBPB PRELIMINARY DATA INDICATE THAT THE KEY MECHANISM RESPONSIBLE FOR LOSS OF LIVER FUNCTION IS LINKED TO ENDOTHELIAL CELL DYSREGULATION MEDIATED BY ANGIOPOIETIN IMBALANCE AND C/EBPB SIGNALING IN HEPATOCYTES. ANGIOPOIETIN-1 AND -2 ARE KEY REGULATORS OF ENDOTHELIAL CELL FATE AND FUNCTION, DYNAMIC CHANGES IN ANGIOPOIETINS CONTROL BOTH REGENERATIVE RESPONSE AFTER LIVER INJURY AND ENSUING RETURN TO HOMEOSTATIC STATE. INCREASED ANG-2/ANG-1 RATIO IS A WELL-KNOWN FEATURE OF ACLF. PRELIMINARY EXPERIMENTS INDICATED THAT ANGIOPOIETINS PROFOUNDLY ALTERED ENDOTHELIAL CELL-HEPATOCYTE CROSSTALK. WHILE ANG-1 PROMOTED HEPATOCYTE ALBUMIN PRODUCTION, ANG-2 SUPPRESSED HEPATOCYTE DIFFERENTIATION WHILE INCREASING C/EBPB EXPRESSION AND CELL PROLIFERATION. HOWEVER, THE MEDIATORS OF THIS ENDOTHELIAL CELL-HEPATOCYTE CROSSTALK ARE NOT KNOWN. C/EBPB IS A TRANSCRIPTION FACTOR THAT REGULATES THE EXPRESSION OF GENES INVOLVED IN THE ACUTE PHASE RESPONSE, METABOLIC FUNCTIONS, AND CELL CYCLE PROGRESSION. C/EBPB IS TRANSIENTLY ACTIVATED DURING LIVER REGENERATION. HOWEVER, SUSTAINED ACTIVATION IS HARMFUL BECAUSE IT MAY PREVENT RE-DIFFERENTIATION. PRELIMINARY DATA INDICATED THAT C/EBPB IS ACTIVATED IN ACLF MICE AND IN HUMAN ACLF SAMPLES. ACTIVATED C/EBPB PROMOTED SUSTAINED SUPPRESSION OF METABOLIC AND HEPATOCYTE DIFFERENTIATION GENES. HEPATOCYTE SPECIFIC CEBPB KNOCKOUT INCREASED GENE EXPRESSION OF HEPATOCYTE DIFFERENTIATION MARKERS AND PREVENTED MORTALITY IN ACLF MODEL. TAKEN TOGETHER, WE HYPOTHESIZE THAT ENDOTHELIAL DYSFUNCTION MEDIATED BY SEPSIS IN THE PRESENCE OF LIVER FIBROSIS PROMOTES SUSTAINED ACTIVATION OF C/EBPB IN HEPATOCYTES THAT IN TURN PROMOTES LOSS OF HEPATOCYTE DIFFERENTIATION AND LIVER FAILURE IN ACLF. WE PROPOSE TO STUDY C/EBPB-MEDIATED LOSS OF LIVER FUNCTION IN ACLF USING MOUSE MODELS AND HUMAN LIVER TRANSPLANT EXPLANTS; AND FIND THE LINK BETWEEN ENDOTHELIAL DYSFUNCTION AND C/EBPB ACTIVATION. THE RESULTS OF THIS PROJECT WILL DEFINE IF C/EBPB PROMOTES LIVER FAILURE IN ACLF AND WILL SET STAGE FOR FUTURE STUDIES DEFINING C/EBPB FUNCTION AND ULTIMATELY IDENTIFYING NEW THERAPEUTIC TARGETS OF SEPSIS ACLF.