University of Michigan Medical School, Department of Molecular & Integrative Physiology, Ann Arbor, Michigan, USA.
Gut. 2011 May;60(5):671-9. doi: 10.1136/gut.2010.217208. Epub 2010 Dec 15.
Acute pancreatitis (AP) can result in pancreatic necrosis and inflammation, with subsequent multi-organ failure. AP is associated with increased neutrophil recruitment and a rise in pro-inflammatory cytokines such as TNFα. Pretreatment with haemin, results in recruitment of haem-oxygenase-1 (HO-1)(+) macrophages and protects against experimental pancreatitis. It is not clear whether modulation of HO-1 after onset of disease has a protective role. In this study, we tested the utility of Panhematin, a water-soluble haemin formulation, in activating and inducing pancreatic HO-1, and as a therapeutic agent in treating mouse acute pancreatitis.
We defined the distribution of radiolabelled haemin, then used in vivo HO-1-luciferase bioluminescence imaging and the CO-release assay to test Panhematin-induced upregulation of HO-1 transcription and activity, respectively. Using two well-defined AP murine models, we tested the therapeutic benefit of Panhematin, and quantified cytokine release using a luminex assay.
Intravenously administered Panhematin induces rapid recruitment of HO-1(+) cells to the pancreas within 2 h and de novo splenic HO-1 transcription by 12 h. Despite high baseline spleen HO-1 activity, the pancreas is particularly responsive to Panhematin-mediated HO-1 induction. Panhematin-treated mice, at various time points after AP induction had significant reduction in mortality, pancreatic injury, together with upregulation of HO-1 and downregulation of pro-inflammatory cytokines and CXCL1, a potent neutrophil chemoattractant.
Despite AP-associated mortality and morbidity, no effective treatment other than supportive care exists. We demonstrate that Panhematin leads to: (i) rapid induction and activation of pancreatic HO-1 with recruitment of HO-1(+) cells to the pancreas, (ii) amelioration of AP even when given late during the course of disease, and (iii) a decrease in leucocyte infiltration and pro-inflammatory cytokines including CXCL1. The utility of Panhematin at modest doses as a therapeutic in experimental pancreatitis, coupled with its current use and safety in humans, raises the potential of its applicability to human pancreatitis.
急性胰腺炎（AP）可导致胰腺坏死和炎症，随后发生多器官功能衰竭。AP 与中性粒细胞募集增加和 TNFα 等促炎细胞因子水平升高有关。血红素预先处理可导致血红素加氧酶-1（HO-1）（+）巨噬细胞募集，并预防实验性胰腺炎。目前尚不清楚疾病发作后 HO-1 的调节是否具有保护作用。在这项研究中，我们测试了 Panhematin（一种水溶性血红素制剂）在激活和诱导胰腺 HO-1 中的作用，并作为治疗急性胰腺炎的药物。
我们确定了放射性标记血红素的分布，然后使用体内 HO-1-荧光素酶生物发光成像和 CO 释放测定分别测试 Panhematin 诱导的 HO-1 转录和活性上调。使用两种明确的 AP 小鼠模型，我们测试了 Panhematin 的治疗益处，并使用 Luminex 测定法定量细胞因子释放。
静脉内给予 Panhematin 可在 2 小时内迅速将 HO-1（+）细胞募集到胰腺，并在 12 小时内使新的脾脏 HO-1 转录。尽管基础脾脏 HO-1 活性较高，但胰腺对 Panhematin 介导的 HO-1 诱导特别敏感。在 AP 诱导后不同时间点给予 Panhematin 的小鼠，死亡率、胰腺损伤均显著降低，HO-1 上调，促炎细胞因子和 CXCL1（一种有效的中性粒细胞趋化因子）下调。
尽管 AP 相关的死亡率和发病率很高，但除了支持性治疗外，尚无其他有效治疗方法。我们证明 Panhematin 导致：（i）胰腺 HO-1 的快速诱导和激活，并将 HO-1（+）细胞募集到胰腺，（ii）即使在疾病过程中晚期给予也能改善 AP，以及（iii）白细胞浸润和包括 CXCL1 在内的促炎细胞因子减少。Panhematin 在适度剂量下作为实验性胰腺炎的治疗药物的实用性，加上其在人类中的当前用途和安全性，提高了其在人类胰腺炎中的应用潜力。
