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Cyclic AMP, Cytokine Modulation and Alcoholic Liver Disease

环磷酸腺苷、细胞因子调节和酒精性肝病

基本信息

批准号：
8509554
负责人：
CRAIG J. MCCLAIN
金额：
$ 36.69万
依托单位：
UNIVERSITY OF LOUISVILLE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-20 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8509554
关键词：
Acute-Phase Reaction Adenylate Cyclase Agonist Alcoholic Hepatitis Alcoholic Liver Cirrhosis Alcoholic Liver Diseases Alcohols Animal Model Animals Anti-Inflammatory Agents Anti-inflammatory Antioxidants Attenuated Biological Models Cause of Death Cell Line Cessation of life Chronic Cirrhosis Clinical Clinical Research Consumption Cyclic AMP Data Depressed mood Development Disease Disease model Endotoxins Epigenetic Process Ethanol Evaluation FDA approved Glutathione Goals Human IL8 gene In Vitro Inflammatory Interleukin-10 Interleukin-18 Isoenzymes Knockout Mice Kupffer Cells Lipopolysaccharides Liver Liver diseases Mediating Metabolism Methionine Misoprostol Modeling Modification Molecular Mus Outcome Oxidative Stress PDE4B Patients Pharmaceutical Preparations Pharmacologic Substance Pharmacotherapy Phosphodiesterase Inhibitors Play Process Production Rattus Reporting Research Role Serum Stomach System Therapeutic Intervention Tumor Necrosis Factor-alpha Whole Blood Work alcohol exposure animal data base bench to bedside chemokine cytokine experience feeding hepatotoxin inhibitor/antagonist liver function liver injury macrophage monocyte novel therapeutic intervention peripheral blood phosphoric diester hydrolase protective effect public health relevance research study volunteer

项目摘要

DESCRIPTION (provided by applicant): Alcoholic Liver Disease (ALD) remains a leading cause of liver-related deaths in the U.S., and there is still no FDA-approved therapy. Abnormal cytokine metabolism is a major feature of ALD. Elevated serum concentrations of tumor necrosis factor (TNF) and TNF-inducible proinflammatory cytokines/chemokines, such as IL-8 and IL-18 have been reported in patients with alcoholic hepatitis and/or cirrhosis, and levels correlated with markers of the acute phase response, liver function, and clinical outcome. Similarly, there are depressed levels of the critical anti-inflammatory cytokine IL-10. Studies in animal models support an etiologic role for cytokines in the liver injury of ALD. The major problem to be investigated in this proposal is the mechanism(s) for this dysregulated cytokine metabolism, and our overall goal is the development of novel therapeutic interventions. ALD is associated with an increase in oxidative stress with a concomitant decrease in cellular antioxidants, such as glutathione (GSH) and importantly, S-adenosyl-L-methionine (SAM), due to subnormal synthesis. Clinical studies have suggested that SAM has beneficial effects in many hepatic disorders including ALD, and numerous animal studies have clearly demonstrated the protective effects of SAM against a variety of hepatotoxins. Previous studies from our group evaluated the role of SAM in positively modulating endotoxin (LPS)-stimulated TNF and IL-10 production related to ALD. We showed that SAM decreased LPS stimulated TNF production and increased LPS stimulated IL-10 production, and that SAM increased cellular levels of cyclic AMP (cAMP), which is known to positively modulate cytokine production. We therefore began an evaluation of the role of cAMP in dysregulated cytokine production in ALD, which is the research focus of this current proposal. We present compelling preliminary data that cAMP is decreased in a macrophage cell line chronically cultured in alcohol, and in Kupffer cells from mice chronically fed ethanol intragastrically. Our working hypothesis is that altered phosphodiesterase 4B (PDE4B) and cAMP metabolism cause abnormal TNF and IL-10 metabolism, which play a critical role in the development and perpetuation of ALD. Specific Objectives for this proposal are to: 1. Document increased PDE4B expression/activity and decreased cAMP in peripheral blood monocytes from patients with alcoholic hepatitis (AH) and alcoholic cirrhosis, and evaluate whether in vitro incubation of monocytes with specific phosphodiesterase inhibitors corrects dysregulated cAMP and cytokine metabolism; 2. Determine whether PDE4 (and specifically, PDE4B) inhibition blocks the development of alcohol-induced liver injury in a murine intra-gastric ethanol-feeding model of chronic ALD and in a murine model of AH; 3. Evaluate potential molecular and epigenetic mechanisms whereby cAMP metabolism is altered in alcoholic liver disease; and 4. Evaluate the effects of combined consumption of a commercially- available adenyl cyclase agonist (Misoprostol - increases cAMP production) and a phosphodiesterase inhibitor (Pentoxyfilline - decreases cAMP breakdown) in normal volunteers and in patients with stable alcoholic cirrhosis. PUBLIC HEALTH RELEVANCE: Alcoholic Liver Disease (ALD) remains a leading cause of death from liver disease in the U.S. and there is still no FDA-approved therapy. Abnormal cytokine metabolism is a major feature of ALD. Elevated serum concentration levels of tumor necrosis factor (TNF) and TNF-inducible proinflammatory cytokines/chemokines, such as IL-8 and IL-18 have been reported in patients with alcoholic hepatitis and/or cirrhosis, and levels correlated with markers of the acute phase response, liver function, and clinical outcome. Similarly, there are depressed levels of the critical anti-inflammatory cytokine IL-10. Studies in animal models support an etiologic role for cytokines in the liver injury of ALD. The major problem to be investigated in this proposal is the mechanism(s) for this dysregulated cytokine metabolism, and our overall goal is the development of novel therapeutic interventions.

描述（由申请人提供）：酒精性肝病（ALD）仍然是美国肝脏相关死亡的主要原因，并且仍然没有 FDA 批准的治疗方法。细胞因子代谢异常是ALD的一大特征。据报道，在酒精性肝炎和/或肝硬化患者中，肿瘤坏死因子 (TNF) 和 TNF 诱导的促炎细胞因子/趋化因子（例如 IL-8 和 IL-18）的血清浓度升高，并且其水平与急性期反应标志物、肝功能和临床结果相关。同样，关键的抗炎细胞因子 IL-10 的水平也降低。动物模型研究支持细胞因子在 ALD 肝损伤中的病因学作用。该提案要研究的主要问题是这种细胞因子代谢失调的机制，我们的总体目标是开发新的治疗干预措施。 ALD 与氧化应激增加相关，同时细胞抗氧化剂（如谷胱甘肽 (GSH) 和重要的 S-腺苷-L-蛋氨酸 (SAM)）因合成异常而减少。临床研究表明，SAM 对包括 ALD 在内的许多肝脏疾病具有有益作用，并且大量动物研究已清楚地证明 SAM 对多种肝毒素的保护作用。我们小组之前的研究评估了 SAM 在正向调节内毒素 (LPS) 刺激的与 ALD 相关的 TNF 和 IL-10 产生中的作用。我们发现，SAM 减少了 LPS 刺激 TNF 的产生，增加 LPS 刺激 IL-10 的产生，并且 SAM 增加了环 AMP (cAMP) 的细胞水平，众所周知，cAMP 可以正向调节细胞因子的产生。因此，我们开始评估 cAMP 在 ALD 细胞因子产生失调中的作用，这是本提案的研究重点。我们提供了令人信服的初步数据，表明长期在酒精中培养的巨噬细胞系以及长期灌胃乙醇的小鼠的库普弗细胞中 cAMP 降低。我们的工作假设是，磷酸二酯酶 4B (PDE4B) 和 cAMP 代谢的改变导致 TNF 和 IL-10 代谢异常，这在 ALD 的发生和持续中发挥着关键作用。该提案的具体目标是： 1. 记录酒精性肝炎 (AH) 和酒精性肝硬化患者外周血单核细胞中 PDE4B 表达/活性的增加和 cAMP 的减少，并评估单核细胞与特定磷酸二酯酶抑制剂的体外孵育是否可以纠正失调的 cAMP 和细胞因子代谢； 2. 确定 PDE4（特别是 PDE4B）抑制是否能在慢性 ALD 小鼠胃内乙醇喂养模型和 AH 小鼠模型中阻断酒精诱导的肝损伤的发展； 3. 评估酒精性肝病中 cAMP 代谢改变的潜在分子和表观遗传机制； 4. 评估在正常志愿者和稳定的酒精性肝硬化患者中联合使用市售腺苷酸环化酶激动剂（米索前列醇 - 增加 cAMP 产生）和磷酸二酯酶抑制剂（喷托菲林 - 减少 cAMP 分解）的效果。公共健康相关性：酒精性肝病 (ALD) 仍然是美国肝病死亡的主要原因，并且仍然没有 FDA 批准的治疗方法。细胞因子代谢异常是ALD的一大特征。据报道，在酒精性肝炎和/或肝硬化患者中，肿瘤坏死因子 (TNF) 和 TNF 诱导的促炎细胞因子/趋化因子（例如 IL-8 和 IL-18）的血清浓度水平升高，并且其水平与急性期反应标志物、肝功能和临床结果相关。同样，关键的抗炎细胞因子 IL-10 的水平也降低。动物模型研究支持细胞因子在 ALD 肝损伤中的病因学作用。该提案要研究的主要问题是这种细胞因子代谢失调的机制，我们的总体目标是开发新的治疗干预措施。