SCF in liver repair after hepatectomy or toxic injury

描述(申请人提供)衰竭的肝脏是我们唯一无法获得药物或机械支持的重要器官。肝脏也是独一无二的，因为它可以再生正常的功能性细胞团，以应对许多损伤，而不是大多数器官修复自己的非功能性疤痕。肝功能衰竭是一种重要的临床问题，发生在各种毒性、创伤性和感染性的侮辱之后。肝功能衰竭偶尔也会伴随着肿瘤的主要肝脏切除。更重要的是，当根治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，通常不会进行肝切除。在美国，20%的急性肝衰竭病例是由意外和故意过量的扑热息痛引起的。扑热息痛中毒会导致直接的肝细胞损伤，患者的生存在很大程度上取决于肝脏从损伤中恢复和再生的能力。扑热息痛所致的肝损伤有很好的特点，然而，肝脏保护、修复和再生的机制还没有得到充分的研究。这项建议研究了一种特殊的细胞因子，干细胞因子(SCF)，在扑热息痛诱导的肝毒性期间以及70%的肝切除后，对肝细胞的保护和再生。SCF是一种重要的白细胞造血因子，参与多种白细胞亚群的增殖和成熟，尤其是肥大细胞。最近，它被证明是正常结构细胞发育的一个重要因素，如肝细胞。我们将利用扑热息痛中毒和70%肝切除两种小鼠模型来研究SCF在肝损伤后的作用。我们假设SCF通过两种机制发挥作用，既有抗细胞凋亡的保护作用，又有增强肝细胞再生反应的作用。为了验证这一假设，我们将着眼于以下特定目标的SCF相关肝修复机制：1)检测70%肝切除或对乙酰氨基酚诱导的肝损伤后SCF的表达、产生和细胞来源；2)在毒性或创伤性肝损伤的背景下，检测跨膜与可溶性SCF及其受体c-kit的调节；3)研究SCF对中毒性或创伤性肝损伤后肝细胞凋亡和增殖的影响及其作用机制(S)；4)探讨SCF和IL-6在毒性或创伤性肝损伤恢复过程中的相互作用。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.