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. Previously we showed a protective efect 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. More recently, we showed that Panhematin (PH, an FDA-approved water soluble formulation of hemin) induces rapid HO-1+ cell recruitment and treats ongoing experimental AP. Given these results, we propose to test the hypothesis that HO-1 downstream effectors and hemin primed cell- based transfers offer alternative therapeutic means for treating AP. Furthermore, we propose to define the source, characteristics, and mechanisms for monocyte recruitment and acinar cell protection.
The specific aims of our proposal are:
Aim 1 : Determine the therapeutic role of HO-1 downstream effectors and evaluate the role for cell-based therapy in experimental acute pancreatitis. We propose to define the therapeutic role of HO-1 downstream effectors and PH-primed cells in treating AP.
Aim 2 : Characterize HO-1+ monocytes/macrophages recruitment to the inflamed pancreas following hemin treatment. We propose to characterize the monocytes recruited to the pancreas following PH treatment and ases their polarization into macrophages using phenotypic and functional assays.
Aim 3 : Define the mechanism of HO-1+ monocyte protection against pancreatic acinar cell injury. We propose here to determine mechanisms via which HO-1+ monocytes interact and protect against acinar cell injury.
Aim 4 : Characterize molecular and cellular determinants via which HO-1+ monocytes are recruited to the inflamed pancreas. In this aim, we propose to define trafficking molecule expression and then assess their functional role using blocking antibodies and/or mice genetically deficient in specified trafficking receptors. Evaluation of PH/HO-1 downstream effectors and interaction of PH-primed monocytes with acinar cells should help define PH's mechanism of action and offer alternate means of treating AP. Relative to lymphocyte trafficking, monocyte recruitment to various inflammatory sites is not as well-defined, and even less so to the pancreas. Findings from this project could lead to a better understanding of disease pathogenesis and mechanisms for immune cell recruitment to the inflamed pancreas.
Acute pancreatitis can follow a severe course that leads to 10-30% mortality in high-risk patients and, in the United States alone, it accounts for over 220,000 hospital admissions every year. Alcohol abuse and gallstones remain the most important risk factors for the disease. Thus the relevance of this project to pancreatic diseases such as acute pancreatitis, where no active (other than supportive) therapy is available, is tremendous. Findings from this project could lead to effective therapy and a better understanding of disease pathogenesis and mechanisms for immune cell recruitment to the inflamed pancreas.
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