Development of cytoprotective therapy against septic multiple organ damage

脓毒症中过度的全身炎症反应会导致严重的组织损伤，导致包括肝脏在内的多器官衰竭，肝脏是脓毒症的靶器官，也是炎症介质的来源。白细胞介素-11 （Interleukin-11, IL-11）是一种多效性细胞因子，可通过下调多种促炎介质来抑制炎症。我们之前报道过用IL-11治疗大鼠通过其抗炎特性改善内毒素血症大鼠模型的肝损伤。然而，IL-11抗炎作用背后的确切机制尚不清楚，尚未确定。最近，有报道称，用IL-11处理体外培养的肝细胞可诱导血红素加氧酶-1 （HO-1）。HO-1是血红素分解代谢中的限速酶，由氧化应激诱导，被认为对氧化组织损伤具有保护作用。因此，在本研究项目中，我们给IL-11腹腔注射四氯化碳（CCI_4）引起的急性肝衰竭大鼠模型，并观察其对肝损伤和炎症的影响。我们发现IL-11处理大鼠在肝脏中高度特异性地诱导HO-1 mRNA及其蛋白。IL-11治疗也能显著改善cci_4诱导的氧化性肝损伤和炎症。相比之下，给IL-11处理过的动物注射一种特异性竞争性HO活性抑制剂锡-中卟啉（SnMP）完全消除了IL-11的细胞保护作用。因此，我们的研究结果表明，IL-11通过其在肝脏中诱导HO-1的能力，对ccl_4诱导的肝损伤具有高度保护作用。因此，IL-11诱导肝脏HO-1可能是抗氧化性肝损伤（包括CCl_4中毒）的有效治疗手段。

Excessive systemic inflammatory responses in sepsis cause severe tissue injuries leading to multiple organ failures including that of liver, the target organ as well as a source of inflammatory mediators in sepsis. Interleukin-11 (IL-11) is a pleiotropic cytokine that can suppress inflammation through the down-regulation of multiple pro-inflammatory mediators. We previously reported that treatment of rats with IL-11 ameliorated hepatic injury in a rat model of endotoxemia by its anti-inflammatory property. However, the precise mechanism behind the anti-inflammatory effect of IL-11 is unclear and yet be determined. Recently, it has been reported that treatment of cultured hepatocytes with IL-11 induces heme oxygenase-1 (HO-1) in vitro. HO-1, the rate-limiting enzyme in heme catabolism, is induced by oxidative stress and is thought to confer protection against oxidative tissue injuries. Thus, in the present research project, we administered IL-11 to a rat model of acute liver failure produced by intraperitoneal injection of carbon tetrachloride (CCI_4) and examined its effect on hepatic injury and inflammation. We found that IL-11 treatment of rats induces both HO-1 mRNA and its protein highly specifically in the liver. IL-11 treatment also markedly ameliorated CCI_4-induced oxidative hepatic injury and inflammation. In contrast, administration of tin-mesoporphyrin (SnMP), a specific competitive inhibitor of HO activity, to IL-11-treated animals completely abolished the cytoprotective effect of IL-11. Our findings thus indicate that treatment with IL-11 highly protective against the CCl_4-induced hepatic injury by virtue of its ability to induce HO-1 in the liver. Induction of hepatic HO-1 by IL-11 treatment thus may be a useful therapeutic means against oxidative liver injuries, including CCl_4 intoxication.