SCF in liver repair after hepatectomy or toxic injury

描述（由申请人提供）衰竭的肝脏是我们唯一没有药物或机械支持手段的重要器官。肝脏的独特之处还在于，它可以在许多损伤后再生出正常功能的细胞团，而不是像大多数器官那样用无功能的疤痕进行自我修复。肝功能衰竭是一个重要的临床问题，发生在各种毒性、创伤性和感染性损伤之后。肝衰竭也偶有因肿瘤而切除肝脏的情况。更重要的是，当治疗性切除会留下数量不足的功能性肝组织，最终导致患者死亡时，往往会排除肝切除。在美国，20%的急性肝衰竭病例是由于意外和故意过量服用对乙酰氨基酚造成的，对乙酰氨基酚中毒会导致肝细胞直接损伤，患者的生存在很大程度上依赖于肝脏从损伤中恢复和再生的能力。对乙酰氨基酚引起的肝损伤有很好的特征，然而，肝脏保护、修复和再生的机制尚未得到充分的研究。本研究研究了一种特定的细胞因子，干细胞因子（SCF），在对乙酰氨基酚诱导的肝毒性期间和70%肝切除术后肝细胞保护和再生中的作用。SCF是一种重要的白细胞造血因子，参与多种白细胞亚群，尤其是肥大细胞的增殖和成熟。最近，它已被证明是正常结构细胞（如肝细胞）发育的重要因素。我们将利用对乙酰氨基酚中毒和70%肝切除术两种小鼠模型来研究SCF对肝损伤的影响。我们假设SCF通过两种机制起作用，具有抗凋亡保护作用，以及增强肝细胞再生反应。为了验证这一假设，我们将重点研究scf相关的肝脏修复机制，具体目标如下：1)研究70%肝切除术或对乙酰氨基酚损伤后肝SCF的表达、生成和细胞来源；2)研究中毒性或外伤性肝损伤时跨膜与可溶性SCF及其受体c-kit的调节；3)研究中毒性或外伤性肝损伤后SCF对肝细胞凋亡和增殖的影响及其作用机制。4)探讨SCF和IL-6在中毒性或创伤性损伤后肝脏恢复中的相互作用。这些研究将有助于阐明scf在临床相关肝切除和毒性模型中介导的肝细胞保护和再生的新机制。

DESCRIPTION (provided by applicant)The failing liver is the only vital organ for which we have no means of pharmacologic or mechanical support. The liver is also unique in that it can regenerate a normal functional cellular mass in response to many injuries, as opposed to most organs which repair themselves with non-functional scar. Liver failure is an important clinical problem that occurs after a variety of toxic, traumatic, and infectious insults. Liver failure also occasionally follows major hepatic resections for tumor. More importantly, hepatic resection is often precluded when a curative resection will leave an inadequate amount of functioning hepatic tissue, ultimately resulting in the death of the patient. Accidental and purposeful acetaminophen overdose accounts for 20 percent of acute liver failure cases in the U.S. Acetaminophen poisoning causes direct hepatocyte damage and patient survival relies heavily upon the liver's ability to recover from the damage and regenerate. Acetaminophen-induced liver injury is well characterized, however, the mechanisms of liver protection, repair, and regeneration have not been fully examined. This proposal examines a specific cytokine, stem cell factor (SCF), in hepatocyte protection and regeneration during acetaminophen-induced liver toxicity, as well as following 70 percent hepatectomy. SCF is well-known as an important leukocyte hematopoietic factor, involved in the proliferation and maturation of multiple leukocyte subsets, especially mast cells. More recently, it has been shown to be an important factor in the development of normal structural cells, such as hepatocytes. We will utilize two murine models, acetaminophen poisoning and 70 percent hepatectomy, to investigate SCF's effects following liver injury. We hypothesize that SCF functions via two mechanisms, having anti-apoptotic protective effects, as well as enhancing the hepatocyte regenerative response. To test this postulate, we will focus on mechanisms of SCF-associated liver repair utilizing the following specific aims: 1) To examine the expression, production, and cellular source of hepatic SCF following 70 percent hepatectomy or acetaminophen-induced injury, 2) To examine the regulation of transmembrane versus soluble SCF and its receptor, c-kit, in the setting of toxic or traumatic hepatic injury, 3) To investigate SCF's effects and mechanism(s) of action on hepatocyte apoptosis and proliferation after toxic or traumatic hepatic injury, and 4) To investigate the interactions of SCF and IL-6 in the liver's recovery from toxic or traumatic injury. These studies will help to elucidate novel mechanisms in SCF-mediated hepatocyte protection and regeneration in a clinically relevant liver resection and toxicity model.