交感神经系统与肝纤维化

肝纤维化是各种不同致病因子引起慢性肝病进而发展为肝硬化的共有病理改变和必经途径,研究肝纤维化的发生机制,进而逆转肝纤维化是治疗各种慢性肝病、预防其向肝硬化发展的关键所在。交感神经系统参与心血管、内分泌、泌尿、消化等多个系统的功能调节。近年来,交感神经系统与肝脏疾病的关系受到越来越多的关注。有关研究表明,交感神经系统过度活化可能参与了肝脏损伤后修复和纤维化的调节[1],本文就此方面的研究作一综述。1肝脏内交感神经纤维的分布交感神经分布广泛,几乎全身所有脏器都受其支配,已证实肝脏实质内同样存在交感神经纤维分布…     

自噬参与肝纤维化的机制

自噬是细胞依赖溶酶体的一种代谢过程,通过分解细胞内蛋白质、脂质等成分,循环再利用分解产物,使细胞适应不利的生活环境,是机体维持内环境稳态的重要机制.肝纤维化是指肝组织内细胞外基质成分过度增生与异常沉积,导致肝脏结构和功能异常的病理变化,肝纤维化见于多数不同病因的慢性肝脏疾病中.本文总结了自噬参与肝纤维化的作用以及与肝纤维化相关的自噬信号通路,进一步阐述细胞自噬参与肝纤维化的机制.     

肝纤维化的免疫相关性

肝脏是人体最大的消化器官,虽然不属于免疫系统,但由于其特殊的解剖位置和血管系统,使肝脏在免疫细胞的激活和分化、机体的局部和全身性免疫反应、以及免疫调节等方面具有重要作用.免疫应答导致的肝损伤是许多肝脏疾病的发病机制,同时也参与各种病因引起的肝纤维化发生.     

肝脏巨噬细胞及其在肝损伤中的作用

肝脏巨噬细胞来源和功能复杂,包括肝脏固有巨噬细胞和单核细胞来源的浸润巨噬细胞,在宿主防御机制及维持机体内环境稳定中起着重要作用,也是参与肝脏损伤和修复的主要细胞成分.解析不同来源肝脏巨噬细胞在不同病因导致肝损伤过程中表型分化、生物学作用的动态变化及其分子机制,对理解肝损伤的病理过程,探索以肝脏巨噬细胞为靶点预防和治疗肝损伤以及肝纤维化的方案具有重要意义.     

肝纤维化形成机制的研究进展

肝纤维化是不同病因(病毒、乙醇等)引起慢性肝脏损害后修复过程的1种代偿性反应;以胶原为主的细胞外基质(ECM)在肝内过分沉积为病理特征。肝纤维化和其他部位的纤维化一样都被认为是机体对损伤的1种修复作用,它是可逆性病变,若进一步发展引起小叶改建,假小叶和结节形成则进入肝硬化,肝硬化则是不可逆转的。     

Th17/Treg免疫失衡在血吸虫病肝纤维化中的作用

血吸虫病肝纤维化是宿主感染血吸虫后发生免疫反应所致的一种严重病理性损害。肝脏的免疫应答状态决定了肝纤维化的进程。近期研究发现,Th17和Treg细胞是CD4+T细胞的2个亚群。Th17细胞主要参与炎症反应;Treg细胞主要介导负向调控。Th17/Treg细胞的分化相互抑制、功能反向调节,在正常状况下两者保持平衡。Th17、Treg细胞及其免疫平衡在维持机体内环境的稳定、参与炎症反应、组织损伤、纤维化及多种疾病的发生发展方面发挥着重要的作用。本文就Th17/Treg细胞及其免疫失衡在血吸虫病肝纤维化中的作用进行综述。     

Wnt/β-catenin通路与肝星状细胞的活化、增殖

肝纤维化是指各种致病因子导致肝细胞炎症、坏死,肝脏中胶原蛋白等细胞外基质(extracellular matrix)降解与沉积失衡,进而导致肝脏内结缔组织异常增生的病理状态.在肝纤维化的形成过程中,肝星状细胞为主要效应细胞.肝星状细胞的激活、分泌细胞外基质、过度的细胞外基质的沉积是形成肝纤维化的中心环节.Wnt/β-catenin通路参与器官纤维化的机制并没有被明确,但已有文献报道Wnt信号通路参与到器官纤维化和肝纤维化的过程中.国内外也均有研究证实Wnt/β-catenin通路与肝星状细胞的活化增殖、肝纤维化存在着一定的关系.     

肝窦内皮细胞在肝纤维化发生发展中的机制及相关治疗策略

肝窦内皮细胞不仅是保护肝脏免受损伤的第一道防线,也在慢性肝损伤导致的纤维化和肝硬化中伴有重要角色。它主要通过介导肝脏炎症反应、参与肝窦毛细血管化和血管再生、激活肝星状细胞、分泌多种促炎细胞因子、参与细胞外基质生成以及介导肝脏微循环障碍等参与肝纤维化。阐明这些机制,有助于探索肝纤维化治疗的新靶点和方案。     

过氧化物酶体增殖物激活受体α、γ调控长链酰基辅酶A合成酶1对肝纤维化进程的影响

在肝纤维化的发生发展进程中,过氧化物酶体增殖物激活受体(PPAR)α、γ具有调控脂代谢、脂肪酸代谢和抗肝纤维化等生物学功能,并与调控脂肪代谢的相关酶类关系密切。长链酰基辅酶A合成酶1(ACSL1)作为脂肪代谢的关键酶之一,在肝脏中参与脂质的合成与分解代谢,可引起肝脏内脂质沉积、炎症反应,并在肝脏中直接或间接促进肝纤维化进程。回顾了PPARα、γ和ACSL1各自的生物学功能与作用;简述了PPARα、γ对ACSL1的转录调控机制;从肝脏脂代谢和肝星状细胞活化等两个方面分析了PPARα、γ对ACSL1的调控作用,进而影响肝纤维化进程。从而指出在肝脏中PPARα、γ通过调控ACSL1直接或间接参与肝纤维化进程。     

过氧化物酶体增殖物激活受体α、γ调控长链酰基辅酶A合成酶1对肝纤维化进程的影响

在肝纤维化的发生发展进程中,过氧化物酶体增殖物激活受体(PPAR)α、γ具有调控脂代谢、脂肪酸代谢和抗肝纤维化等生物学功能,并与调控脂肪代谢的相关酶类关系密切。长链酰基辅酶A合成酶1(ACSL1)作为脂肪代谢的关键酶之一,在肝脏中参与脂质的合成与分解代谢,可引起肝脏内脂质沉积、炎症反应,并在肝脏中直接或间接促进肝纤维化进程。回顾了PPARα、γ和ACSL1各自的生物学功能与作用;简述了PPARα、γ对ACSL1的转录调控机制;从肝脏脂代谢和肝星状细胞活化等两个方面分析了PPARα、γ对ACSL1的调控作用,进而影响肝纤维化进程。从而指出在肝脏中PPARα、γ通过调控ACSL1直接或间接参与肝纤维化进程。     

Autonomic Nervous System and the Liver

The liver is innervated by both the sympathetic and the parasympathetic nerve systems. These nerves are derived from the splanchnic and vagal nerves that surround the portal vein, hepatic artery, and bile duct. The afferent fiber delivers information regarding osmolality, glucose level, and lipid level in the portal vein to the central nervous system (CNS). In contrast, the efferent fiber is crucial in the regulation of metabolism, blood flow, and bile secretion. Furthermore, liver innervation has been associated with hepatic fibrosis, regeneration, and circadian rhythm. Knowledge of these mechanisms can be applied for potential liver disease treatment.     

The role of the autonomic nervous system in liver regeneration and apoptosis--recent developments

Hepatocytes have a great replicative capacity and are capable of repopulating the liver. Previous studies have suggested that the autonomic nervous system regulates liver regeneration and apoptosis. Moreover, the central nervous system modulates them through the autonomic nervous system. The lateral hypothalamus (LH) area and the ventromedial hypothalamus (VMH) nucleus have been studied for their role in the integration of neurohumoral information. The LH is part of the parasympathetic system, while the VMH belongs to the sympathetic system. Lesions of the LH reportedly induced an increase in sympathetic nerve activity, while those in the VMH produced facilitation of vagus nerve activity. Moreover, VMH or LH lesions facilitate hepatic regeneration after partial hepatectomy. Furthermore, the hypothalamus mediates hepatic apoptosis through the autonomic nervous system. Although further studies are needed to define the role clearly, the autonomic nervous system is one of the important factors that regulate liver regeneration and apoptosis.     

Hepatic fibrogenesis requires sympathetic neurotransmitters

BACKGROUND AND AIMS: Hepatic stellate cells (HSC) are activated by liver injury to become proliferative fibrogenic myofibroblasts. This process may be regulated by the sympathetic nervous system (SNS) but the mechanisms involved are unclear. METHODS: We studied cultured HSC and intact mice with liver injury to test the hypothesis that HSC respond to and produce SNS neurotransmitters to promote fibrogenesis. RESULTS: HSC expressed adrenoceptors, catecholamine biosynthetic enzymes, released norepinephrine (NE), and were growth inhibited by alpha- and beta-adrenoceptor antagonists. HSC from dopamine beta-hydroxylase deficient (Dbh(-/-)) mice, which cannot make NE, grew poorly in culture and were rescued by NE. Inhibitor studies demonstrated that this effect was mediated via G protein coupled adrenoceptors, mitogen activated kinases, and phosphatidylinositol 3-kinase. Injury related fibrogenic responses were inhibited in Dbh(-/-) mice, as evidenced by reduced hepatic accumulation of alpha-smooth muscle actin(+ve) HSC and decreased induction of transforming growth factor beta1 (TGF-beta1) and collagen. Treatment with isoprenaline rescued HSC activation. HSC were also reduced in leptin deficient ob/ob mice which have reduced NE levels and are resistant to hepatic fibrosis. Treating ob/ob mice with NE induced HSC proliferation, upregulated hepatic TGF-beta1 and collagen, and increased liver fibrosis. CONCLUSIONS: HSC are hepatic neuroglia that produce and respond to SNS neurotransmitters to promote hepatic fibrosis.     

肝窦内皮细胞调控肝脏微环境影响肝纤维化的研究进展

肝窦内皮细胞不仅是血液和肝细胞进行物质交换的重要中介细胞,也是慢性肝损伤因素导致肝纤维化和肝硬化的重要肝非实质细胞。它主要通过与肝星状细胞、肝细胞、Kupffer细胞的相互作用和介导肝脏硬度、肝脏血管再生从而调控肝脏微循环,参与肝纤维化的发展。阐明这些机制,有助于探索肝纤维化治疗的新靶点和方案。     

Sympathetic nervous system inhibition increases hepatic progenitors and reduces liver injury

Recovery from liver damage might be enhanced by encouraging repopulation of the liver by endogenous hepatic progenitor cells. Oval cells are resident hepatic stem cells that promote liver regeneration and repair. Little is known about the mediators that regulate the accumulation of these cells in the liver. Parasympathetic nervous system inhibition reduces the number of oval cells in injured livers. The effect of sympathetic nervous system (SNS) inhibition on oval cell number is not known. Adrenergic inhibition mobilizes hematopoietic precursors into the circulation and has also been shown to promote liver regeneration. Thus, we hypothesized that SNS inhibition would promote hepatic accumulation of oval cells and reduce liver damage in mice fed antioxidant-depleted diets to induce liver injury. Our results confirm this hypothesis. Compared with control mice that were fed only the antioxidant-depleted diets, mice fed the same diets with prazosin (PRZ, an alpha-1 adrenoceptor antagonist) or 6-hydroxydopamine (6-OHDA, an agent that induces chemical sympathectomy) had significantly increased numbers of oval cells. Increased oval cell accumulation was accompanied by less hepatic necrosis and steatosis, lower serum aminotransferases, and greater liver and whole body weights. Neither PRZ nor 6-OHDA affected the expression of cytokines, growth factors, or growth factor receptors that are known to regulate progenitor cells. In conclusion, stress-related sympathetic activity modulates progenitor cell accumulation in damaged livers and SNS blockade with alpha-adrenoceptor antagonists enhances hepatic progenitor cell accumulation.     

去甲肾上腺素对大鼠肝星状细胞作用的实验研究

目的 探讨交感神经系统在肝纤维化发生和发展中的作用. 方法采用免疫荧光和RT-PCR检测体外培养的肝星状细胞(HSC)中α1、β2-肾上腺素能受体的表达;用四甲基偶氮唑盐法检测不同浓度的去甲肾上腺素(NE)对HSC增殖活性的影响.同时用RT-PCR检测受NE作用后HSC的活化指标胶原蛋白-1、转化生长因子β(TGF β)及α-平滑肌动蛋白(α-SMA)的表达.用高效液相色谱-电化学法测定活化的HSC中交感神经递质NE的水平. 结果α1和β2-肾上腺素能受体表达于HSC的胞膜和胞质内;NE可呈剂量依赖性地促进HSC增殖,在浓度为100μmol/L时达到最大效应,F=140.464,P<0.05,差异有统计学意义.以NE 100 μmol/L作用细胞24h后,可显著促进反应HSC活化的指标上升,胶原蛋白-1表达为0.3022±0.0610,TGF β表达为2.2080±0.2151,α-SMA mRNA表达为0.5469±0.0108,与对照组胶原蛋白-1(0.1040±0.0556)、TGF β(1.1190±0.0070)、α-SMA mRNA表达(0.0759±0.0449)比较,t值分别为-4.160、-8.763和-17.651,P值均<0.05,差异均有统计学意义.HSC可以合成并释放NE,且受血小板衍生生长因子(10ng/ml)刺激后HSC中NE含量为(14.24±0.21)ng/ml,对照组为(11.34±0.15)ng/ml,两组比较,t=-32.907,P<0.05,差异有统计意义.结论 抑制交感神经系统使HSC活性降低对临床上治疗肝纤维化有一定的指导意义.     

New insights into sympathetic regulation of glucose and fat metabolism

The autonomic nervous system modulates glucose and fat metabolism through both direct neural effects and hormonal effects. This review presents recent concepts on the sympathetic regulation of glucose and fat metabolism. Focally released norepinephrine from sympathetic nerves is likely to increase glucose uptake in skeletal muscle and adipose tissues independent of insulin but norepinephrine does not contribute so much as epinephrine to hepatic glucose production. Epinephrine increases hepatic glucose production and inhibits insulin secretion and the glucose uptake by tissues that is induced by insulin. Additionally, catecholamines can increase thermogenesis and lipolysis, leading to increased energy expenditure and decreased fat stores. It is likely that β-(β3)-adrenergic receptors mediate these responses. Alterations of central neurotransmission and environmental factors can change the relative contribution of sympathetic outflow to the pancreas, liver, adrenal medulla and adipose tissues, leading to the modulation of glucose and fat metabolism. Recent studies have proposed that leptin, an adipocyte hormone, affects the central nervous system to increase sympathetic outflow independent of feeding. The effects of leptin on glucose and fat metabolism could be in part mediated by the sympathetic nervous system. Studies using mice with a genetic disruption of serotonin 5-HT2 c receptor indicate that central neural mechanisms in the regulation of sympathetic outflow and satiety could be dissociated. Abnormalities of sympathetic effects, including disturbances of leptin and β3-adrenergic receptor signalling, are likely to cause obesity and impaired glucose tolerance in rodents and humans. These findings indicate that dysfunction of the sympathetic nervous system could predispose to obesity and Type II (non-insulin-dependent) diabetes mellitus. [Diabetologia (2000) 43: 533–549]     

Epithelial-mesenchymal transition in the liver

Epithelial-mesenchymal transition (EMT) is a physiological process occuring in the embryo. In adult organism, EMT could be involved in disease development. In the liver, the possibility that EMT of liver epithelial cells participate to liver fibrosis is increasingly discussed. Furthermore, the involvement of hepatocyte EMT to liver cancer biology has also been documented over the past few years. In this review, we will first describe how EMT participates to embryological development. We will then discuss the involvement of hepatocytes and biliary epithelial cells in liver fibrosis. Finally, we will describe how EMT may impact the metastatic process and resistance to therapy in hepatocellular carcinoma.     

Stress, acute hyperglycemia, and hyperlipidemia role of the autonomic nervous system and cytokines.

Stress is accompanied by metabolic alterations that could contribute to the etiology of diabetes mellitus, arteriosclerosis, and cardiovascular diseases; however, the mechanisms by which stress affects glucose and lipid metabolism remain to be resolved. Stress-induced effects on neurotransmission and interleukin-1 (IL-1) signaling rapidly produce hyperglycemia by increasing sympathetic outflow. Activation of the sympathetic nervous system can also rapidly stimulate lipolysis and hepatic triglyceride secretion. Furthermore, stress increases serum interleukin-6 (IL-6) and nerve growth factor (NGF) levels by activating neuroendocrine systems. IL-6 and NGF can rapidly increase lipolysis and hepatic triglyceride secretion without inducing hyperglycemia. The sympathetic nervous system does not mediate cytokine-induced hypertriglyceridemia. Thus, the central nervous system plays an important role in regulation of hepatic glucose and lipid metabolism via the sympathetic nervous system and cytokines. (Trends Endocrinol Metab 1997;8:192-197). (c) 1997, Elsevier Science Inc.     

肝硬化腹水和肝性胸水的治疗

腹水和肝性胸水是肝硬化失代偿期的并发症,其产生主要是由于门脉压升高、激活交感神经系统、肾素-血管紧张素-醛固酮系统、血浆胶体渗透压降低等因素有关,肝性胸水还有膈肌破裂形成裂孔等有关。治疗上多采用利尿剂、排放腹腔积液、输注白蛋白、腹水浓缩静脉回输、外科手术,甚至肝移植等综合治疗措施。