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物-1（HO-1），这是一种应激诱导的酶，涉及对多种损伤的保护，而其相关同种型HO-2是组成型表达的。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尚不清楚。在初步的实验中，我们发现从氯化血红素处理的小鼠中分离的腹膜细胞可以回到胰腺并防止胰腺炎。我们的中心假设是，直接或间接的氯化血红素暴露保护小鼠免受实验性急性胰腺炎。我们建议使用两个具体目标来测试这个假设：目标1。确定血红素相关的急性胰腺炎保护作用是否由HO-1介导。这一目的将通过使用HO-1杂合型和野生型小鼠来比较它们对由两种已建立的实验性胰腺炎模型产生的胰腺损伤的易感性来解决。该目的还需要将腹膜巨噬细胞暴露于针对HO-1的siRNA，以测试HO-1活化对于巨噬细胞保护免受胰腺炎是否重要。目标2。比较直接氯高铁血红素或间接氯高铁血红素活化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。这一目的将通过评估氯化血红素静脉内给药对外周血亚群和胰腺中HO-1诱导的影响来实现。该目的还旨在确定腹膜细胞内赋予对胰腺炎的保护作用的特定细胞亚群，并比较诱导胰腺炎后氯化血红素与活化腹膜细胞给药的潜在治疗作用。急性胰腺炎可以严重衰弱，如果不是致命的疾病在人类。大多数治疗是支持性的，针对胰腺炎的血流动力学效应，如脱水，同时清除可能包括酒精或胆道梗阻结石的促发因素。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（例如一氧化碳、铁或胆绿素）在胰腺疾病中的参与，迄今为止尚未被认识到。

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.