Feasibility of Hemin-Based Therapy in Experimental Acute Pancreatitis

描述(由申请人提供)：氯化血红素上调血红素氧合酶-1(HO-1)，这是一种压力诱导酶，涉及对各种损伤的保护，而其相关的亚型HO-2是结构性表达的。氯化血红素或HO-1在胰腺中的作用及其对胰腺损伤的潜在调节作用尚不清楚。在初步实验中，我们发现从氯化血红素处理的小鼠身上分离出的腹膜细胞可以安放在胰腺中，从而保护胰腺免受胰腺炎的侵袭。我们的中心假设是，直接或间接接触氯化血红素可以保护小鼠免受实验性急性胰腺炎的影响。我们建议使用两个特定的目标来检验这一假说：目的1.确定氯化血红素对急性胰腺炎的保护作用是否由HO-1介导。为了达到这一目的，将使用HO-1杂合子和野生型小鼠来比较它们对两种已建立的实验性胰腺炎模型所造成的胰腺损伤的敏感性。这一目的还需要将针对HO-1的siRNA暴露于腹膜巨噬细胞，以测试HO-1的激活是否对巨噬细胞预防胰腺炎具有重要作用。目的#2.比较直接氯化血红素或间接氯化血红素激活的细胞疗法作为预防或治愈实验性胰腺炎的潜在模式的效果。这一目标将通过评估静脉注射氯化血红素对外周血亚群和胰腺中HO-1诱导的影响来实现。本研究的目的还在于确定腹膜细胞中对胰腺炎具有保护作用的特定细胞亚群，并比较诱导胰腺炎后给予氯化血红素和活化腹膜细胞的潜在治疗效果。急性胰腺炎对人类来说即使不是致命的疾病，也可能是严重虚弱的。大多数治疗都是支持性的，并针对胰腺炎的血流动力学影响，如脱水，以及清除可能包括酒精或胆道梗阻性结石的沉淀因素。我们的建议的意义在于为胰腺炎的潜在治疗奠定基础，并揭示HO-1或其下游副产物之一(如一氧化碳、铁或胆绿素)在胰腺疾病中的参与，这些疾病到目前为止还没有得到重视。

DESCRIPTION (provided by applicant): Hemin upregulates heme oxygenates-1 (HO-1), the stress induced enzyme implicated in protection from a variety of injuries, while its related isoform HO-2 is constitutively expressed. The role of hemin or HO-1 in the pancreas and their potential modulation of pancreatic injury are unknown. In preliminary experiments we find that peritoneal cells isolated from hemin-treated mice home to the pancreas and protect from pancreatitis. Our central hypothesis is that direct or indirect hemin exposure protects mice from experimental acute pancreatitis. We propose to test this hypothesis using two specific aims: Aim #1. Determine if the hemin-associated protection from acute pancreatitis is mediated by HO-1. This aim will be addressed by using HO-1 heterozygous and wild type mice to compare their susceptibility to pancreatic injury produced by two established models of experimental pancreatitis. This aim also entails exposing peritoneal macrophages to siRNA directed towards HO-1 in order to test if HO-1 activation is important for macrophage protection from pancreatitis. Aim #2. Compare the effects of direct hemin, or indirect hemin-activated cell-based therapy, as potential modes of prevention or cure of experimental pancreatitis. This aim will be carried out by assessing the effect of hemin intravenous administration on HO-1 induction in peripheral blood subpopulations and in the pancreas. This aim also seeks to identify the specific cell subpopulation within peritoneal cells that imparts the protective effect towards pancreatitis, and to compare the potential therapeutic effects of hemin versus activated peritoneal cell administration after induction of pancreatitis. Acute pancreatitis can be severely debilitating, if not lethal disease in humans. Most therapies are supportive and target the hemodynamic effects of pancreatitis such as dehydration together with removal of precipitating factors that may include alcohol or biliary obstructing calculi. The significance of our proposal pertains to laying the foundation to a potential therapeutic for pancreatitis, and bringing to light the involvement of HO-1 or one of its down stream by-products (eg carbon monoxide, iron or biliverdin) in pancreatic disease which hitherto has not been appreciated.