Role of hemeoxygenase-1 in experimental acute pancreatitis

描述（由申请人提供）：急性胰腺炎（AP）仍然是一个具有挑战性的临床问题，特别是在重症患者中。尽管有疾病负担，但治疗最多仍是支持性的，同时去除沉淀因素可能包括酒精或胆道梗阻结石。先前我们通过将HO-1+ F4/80+细胞募集到胰腺，证明了血红蛋白（血红蛋白假体片段，可上调血红素加氧酶-1，HO-1）在实验性AP中的保护作用。最近，我们发现泛血红素（PH，一种fda批准的血红素水溶性制剂）诱导HO-1+细胞快速募集并治疗正在进行的实验性AP。鉴于这些结果，我们建议验证HO-1下游效应物和血红素引发的细胞转移为治疗AP提供了替代治疗手段的假设。此外，我们建议确定单核细胞募集和腺泡细胞保护的来源、特征和机制。我们建议的具体目的是：目的1：确定HO-1下游效应物的治疗作用，并评估细胞治疗在实验性急性胰腺炎中的作用。我们建议确定HO-1下游效应物和ph启动细胞在治疗AP中的治疗作用。目的2：表征血红素治疗后HO-1+单核细胞/巨噬细胞向炎症胰腺的募集。我们建议对PH处理后募集到胰腺的单核细胞进行表征，并利用表型和功能分析将其极化为巨噬细胞。目的3：明确HO-1+单核细胞对胰腺腺泡细胞损伤的保护机制。我们在此提出确定HO-1+单核细胞相互作用和保护免受腺泡细胞损伤的机制。目的4：表征HO-1+单核细胞被募集到炎症胰腺的分子和细胞决定因素。为此，我们建议定义运输分子的表达，然后使用阻断抗体和/或特定运输受体基因缺陷的小鼠来评估它们的功能作用。评估PH/HO-1下游效应物以及PH引发的单核细胞与腺泡细胞的相互作用，应该有助于确定PH的作用机制，并提供治疗AP的替代方法。相对于淋巴细胞运输，单核细胞募集到各种炎症部位的情况并不明确，胰腺的情况就更不明确了。这个项目的发现可以更好地理解疾病的发病机制和免疫细胞募集到炎症胰腺的机制。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.