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，尤其是在重症患者中。 疾病。尽管有疾病负担，但治疗充其量仍是支持性的，同时还会移除 诱发因素可能包括酒精或胆道梗阻性结石。我们表现出了一种保护作用 氯化血红素的治疗作用(上调血红素氧合酶-1，HO-1的血红蛋白假体部分) 在实验性AP中，通过向胰腺募集HO-1+F4/80+细胞。此外，我们还澄清了 HO-1下游效应子的有益作用机制。鉴于这些结果，我们建议测试 与急性胰腺炎相比，认为在急性胰腺炎恢复过程中免疫反应发生转变的假说 AP的各个阶段，我们建议在此了解这些机制，以便改进我们的 了解促进炎症恢复和消退的免疫途径。这个 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的分辨率与增强的适应性和降低的 单核/巨噬细胞募集与AP急性期比较。目标2：移动通信中的串扰 急性胰腺炎的发病机制。在这里，我们将检验激活胰腺星状细胞的假设 细胞分泌因子，将AP急性期招募的促炎巨噬细胞转化为 促进恢复的抑制性巨噬细胞。目标3：先天免疫激活和细胞损伤 胰腺炎中的相关信号。在这里，我们将检验这一假说，与急性白血病中的巨噬细胞不同 AP时相，恢复期巨噬细胞通过抑制T细胞活化和 扩散。然而，在急性胰腺炎的严重或急性期，巨噬细胞感觉到细胞损伤。 成分和激活途径，使促炎细胞因子的释放永久化。由此得出的结论 该项目将使人们能够更好地了解与急性胰腺炎相关的免疫反应和渗透。 AP和恢复阶段。除了对免疫机制的了解外， 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开发，可以改变临床 在没有积极治疗方法的疾病中行医。

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.