Role of hemeoxygenase-1 in experimental acute pancreatitis

急性胰腺炎（AP）仍然是一个具有挑战性的临床问题，特别是在重症胰腺炎患者中， 疾病尽管有疾病负担，但治疗最多仍是支持性的，再加上去除肿瘤。 诱发因素可能包括酒精或胆道梗阻结石。我们表现出了保护作用 和血红素（上调血红素加氧酶-1，HO-1的血红蛋白辅基）的治疗作用 在实验性AP中，通过将HO-1+ F4/80+细胞募集到胰腺。此外，我们还阐明了 HO-1下游效应物的有益作用的机制。根据这些结果，我们建议测试 与急性AP相比，在从AP恢复期间免疫应答发生变化 AP的阶段，我们建议在这里了解这些机制，以提高我们的 了解促进炎症恢复和消退的免疫途径。的 我们建议的具体目标是：目标1：表型和功能评估。在这里，我们将测试 假设AP的分辨率与增加的适应性和减少的 与AP的急性期相比，单核细胞/巨噬细胞募集。目的2：在细胞中的串扰 急性胰腺炎的发病机制。在这里，我们将测试的假设，激活胰腺星状 细胞分泌因子，改变AP急性期募集的促炎巨噬细胞， 抑制性巨噬细胞，促进恢复。目的3：先天免疫激活和细胞损伤 胰腺炎的相关信号。在这里，我们将测试的假设，不同的巨噬细胞在急性 在AP期，恢复期间的巨噬细胞通过抑制T细胞活化介导恢复， 增殖然而，在AP的严重或急性期，巨噬细胞感知细胞损伤 组分和激活使促炎细胞因子释放永久化的途径。时发现的问题 该项目将有助于更好地了解与急性胰腺炎相关的免疫反应和浸润 AP和恢复阶段。除了对免疫机制的理解， 调解和/或允许AP和恢复的进展，该项目的潜在影响是巨大的 临床意义，因为我们的研究可能导致新疗法的发展，可以改变临床 在没有有效治疗方法的疾病中的实践。

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.