Feasibility of Hemin-Based Therapy in Experimental Acute Pancreatitis

描述（由申请人提供）：Hemin上调血红素氧合酶-1 (HO-1)，这是一种涉及多种损伤保护的应激诱导酶，而其相关异构体HO-2是组成性表达的。hemin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，我们发现从血红素治疗的小鼠分离的腹膜细胞回到胰腺并保护免受胰腺炎。我们的中心假设是直接或间接的血红素暴露保护小鼠免受实验性急性胰腺炎。我们建议用两个具体目标来检验这一假设：确定血红素对急性胰腺炎的保护作用是否由HO-1介导。这一目的将通过使用HO-1杂合型和野生型小鼠比较它们对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。这一目的还需要将腹膜巨噬细胞暴露于指向HO-1的siRNA中，以测试HO-1激活是否对巨噬细胞免受胰腺炎的保护很重要。目标# 2。比较直接血凝素或间接血凝素激活细胞治疗的效果，作为预防或治疗实验性胰腺炎的潜在模式。这一目的将通过评估血红素静脉注射对外周血亚群和胰腺中HO-1诱导的影响来实现。本研究还旨在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hemin与活化腹膜细胞给药的潜在治疗效果。急性胰腺炎即使不是致命疾病，也会使人严重衰弱。大多数治疗方法是支持性的，针对胰腺炎的血流动力学影响，如脱水和去除沉淀因素，可能包括酒精或胆道梗阻结石。我们的建议的意义在于为胰腺炎的潜在治疗奠定基础，并揭示了HO-1或其下游副产品之一（如一氧化碳，铁或胆绿素）在胰腺疾病中的作用，这一点迄今尚未得到重视。

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.