Mechanisms mediating severity of acute pancreatitis in the aged

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ABSTRACT The objective of this project is to understand the mechanisms leading to the development of severe acute pancreatitis (sAP), a life-threatening illness with high mortality characterized by necrotizing pancreas, severe systemic inflammation, coagulation, multiple organ dysfunction syndrome (MODS). AP is a particularly serious disease among the elderly as both incidence and the likelihood for progression to sAP increases dramatically with advancing age. Despite recognition of this clinical problem, little is known regarding the underlying biological mechanisms of this disease or why progression to sAP is more common among elderly patients. We recently developed an aged mouse model of AP in which only aged mice exhibit sAP that parallels clinical observations including prolonged systemic inflammation, coagulation, MODS, and fatality. Our observations with this mouse model include a dramatic age-dependent increase in tissue damage and cytokine gene expression within visceral adipose tissue, and elevated levels of free fatty acids in the ascitic fluid. Collectively these findings suggest that visceral adipose tissues are key mediators promoting the progression of AP to sAP in the aged. The central hypothesis of this project is that aged animals are more prone to develop sAP due to pronounced visceral adipose tissue inflammation caused by leakage of pancreas-derived digestive enzymes into the peritoneum from the damaged pancreas. AP-induced adipose tissue inflammation results in release of free fatty acids, inflammatory cytokines, and pro-thrombotic factors, all promoting MODS. Our hypothesis will be tested in the following three specific aims: To determine features of visceral adipose tissue inflammation in aged animals with sAP (Aim 1); To demonstrate that increased visceral adipose tissue inflammation promotes the progression of AP to sAP in the aged (Aim 2); and To develop strategies to prevent the progression of AP to sAP in aged animals by suppressing adipose tissue inflammation (Aim 3).