Role of hemeoxygenase-1 in experimental acute pancreatitis

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Acute pancreatitis (AP) remains a challenging clinical problem, particularly in patients with severe disease. Despite its disease burden, therapy remains supportive at best coupled with removal of precipitating factors that may include alcohol or biliary obstructing calculi. We showed a protective effect and therapeutic role of hemin (hemoglobin prosthetic moiety that upregulates hemeoxygenase-1, HO-1) in experimental AP via recruitment of HO-1+ F4/80+ cells to the pancreas. Moreover, we also elucidated mechanism for beneficial effects of HO-1 downstream effectors. Given these results, we propose to test the hypothesis that there is shift in immune response during recovery from AP as compare to acute phases of AP and we propose here to understand these mechanisms in order to improve our understanding of immune pathways that promote recovery and resolution of the inflammation. The specific aims of our proposal are: Aim 1: Phenotypic and functional assessment. Here we will test the hypothesis that resolution of AP is associated with an increased adaptive and decreased monocyte/macrophage recruitment as compared to acute phase of AP. Aim 2: Cellular cross talk in the pathogenesis of acute pancreatitis. Here we will test the hypothesis that activated pancreatic stellate cells secrete factors that alter pro-inflammatory macrophages recruited during acute phase of AP into suppressive macrophages that promote recovery. Aim 3: Innate immune activation and cell damage associated signals in pancreatitis. Here we will test the hypothesis that unlike macrophages in acute phase of AP, macrophages during recovery mediate recovery by suppressing T cell activation and proliferation. During severe or acute phase of AP however, macrophages sense cellular damage components and activate pathways that perpetuate pro-inflammatory cytokine release. Findings from this project will allow for a better understanding of immune responses and infiltrates associated with acute phases of AP and recovery. In addition to the gained understanding of immune mechanisms that mediate and/or allow progression of AP and recovery, the potential impact of this project is of great clinical significance, as our studies may lead to the development of novel therapies that can alter clinical practice in a disease for which no active therapy is available.