肝脏微循环障碍在慢性乙型肝炎发生发展中的作用

一般认为 ,慢性乙型肝炎 (下称慢乙肝 )的发病与免疫反应有关。70年代末有学者提出 ,肝功能减退是由于肝脏结构异常所致 ,此即完整肝细胞学说 [1]。肝脏微循环是肝脏结构的一个重要组成部分 ,研究证实 ,病毒性肝炎、肝硬化存在肝微循环障碍[2、3 ] ,但对肝微循环障碍在慢性肝病中的地位、作用 ,尚缺乏深入细致的研究。我们对 5 1例慢乙肝患者的肝脏微循环状态进行了观察 ,旨在探讨其在慢乙肝发生发展中的作用。1　资料与方法1 .1　一般资料　本组男 40例、女 1 1例 ,年龄 1 6～6 7岁 ,经血清乙肝病毒指标检测证实为乙型肝炎。1 .2　方法　患…     

一氧化氮和血管紧张素Ⅱ在原发性高血压中的作用

目的：探讨一氧化氮（NO）和血管紧张素Ⅱ（AngⅡ）与原发性高血压（EH）的关系。方法：分别选择EH合并左室肥厚（LVH）患者（EH＋LVH组）、EH无LVH患者（EH组）及正常人（正常对照组）各30例,检测NO、AngⅡ水平,并进行组间比较分析。结果：（1）EH＋LVH组NO水平明显低于EH组、正常对照组[（37.24±11.27）μmol/L比（51.79±20.04）μmol/L比（80.25±20.58）μmol/L],且EH组NO水平明显低于正常对照组（P均〈0.01）;EH＋LVH组AngⅡ水平明显高于EH组、正常对照组[（198.37±93.54）ng/L比（139.87±56.39）ng/L比（57.34±18.85）ng/L],且EH组AngⅡ水平明显高于正常对照组（P〈0.05～〈0.01）;（2）直线相关分析显示收缩压、舒张压与NO呈负相关（r=-0.448、P=0.000;r=-0.249,P=0.018）,与AngⅡ呈正相关（r=0.491,P=0.000;r=0.265,P=0.012）,NO与AngⅡ呈负相关（r=-0.555,P=0.000）。结论：一氧化氮、血管紧张素Ⅱ参与了原发性高血压发病的病理生理过程。     

CO在肝脏微循环中的调节作用

CO与NO一样具有扩血管作用,参与血液循环的调节和神经冲动的传导,被认为是继NO之后又一新的气体信使物质,在机体的生理和病理生理过程中起很重要的作用。本文就CO在肝脏微循环中的作用作一综述。     

血管活性物质在肝脏微循环障碍中的作用

肝脏微循环障碍是各种急慢性肝病中重要的病理生理变化。肝脏在病毒、酒精及化学等作用下产生多种血管活性介质，这些介质作用于肝脏各种间质细胞，出现肝脏微循环障碍；微循环障碍进一步导致内毒素血症的发生，刺激肝脏间质细胞、中性粒细胞及组织细胞等释放多种血管活性物质，诸如肿瘤坏死因子、一氧化氮、一氧化碳、内皮素、白细胞介素、细胞因子、氧自由基、血小板激活因子、前列腺素E、血栓素等，进一步加重微循环障碍。本文就其中发挥主要作用的血管活性物质在肝脏微循环障碍中的作用作一综述。     

一氧化氮缺乏在高血压及心血管重构中的作用

目的:探讨一氧化氮(NO)缺乏所致高血压、心血管重构的作用及机理.方法:Wistar大鼠,经饮水给予不同药物,如下分组:对照组(C组):仅给予饮水;NO合酶抑制剂组(L组):L-NAME 50 mg/kg.d-1;大剂量培哚普利组(L+HA组):L-NAME 50 mg/kg.d-1+培哚普利4 mg/kg.d-1 ;小剂量培哚普利组(L+LA组):L-NAME 50 mg/kg.d-1+培哚普利0.4 mg/kg.d-1.每两周监测血压一次(尾袖法).8周后,颈动脉插管测定动脉压、采血样、摘取心脏,测定心脏湿重及室壁厚度,用病理及体视学方法测定心肌细胞大小、血管中膜厚度、血管周围纤维化程度、管壁厚度/腔径比、管壁面积/腔径等心血管重构指标.测定血浆及组织中NO、内皮素-1(ET-1)、血管紧张素AngⅠ、 AngⅡ、血管紧张素转换酶(ACE)含量或活性.结果:L组大鼠血压明显升高、心血管系统出现明显重构改变,血浆中NO含量降低,ET、Ang I 含量增高;心肌组织中NO含量降低,ACE活性、AngⅡ、AngⅠ含量增高.经大剂量培哚普利(4 mg/kg.d-1)干预后,血压得到控制,心血管重构及血液、心肌中的生化指标得到改善,与对照组相比无明显差异.小剂量培哚普利(0.4 mg/kg.d-1)对血压无明显影响,但心室重构得到一定程度的改善.结论:本研究证实,抑制NO合成可引起血压升高和心血管重构.血管紧张素转化酶抑制剂(ACEI)能使心血管重构得到改善,说明在该模型中,心肌局部组织中的肾素-血管紧张素-醛固酮系统(RAS)参与了心血管重构的形成过程.     

血浆一氧化氮和血管紧张素Ⅱ在原发性高血压及左室肥厚中的作用

目的探讨血浆一氧化氮（NO）和血管紧张素Ⅱ（AngⅡ）在原发性高血压（EH）患者中的变化,以及与左室肥厚（LVH）的相关性。方法分别选取EH伴LVH患者、EH不伴LVH患者及正常人各30例,检测血浆NO、AngⅡ水平及左室重量（LVM）,进行组间比较及相关分析。结果（1）EH伴LVH组血NO水平低于EH不伴LVH组、正常对照组俨〈0．01）,EH不伴LVH组NO水平低于正常对照组（P〈0．01）;（2）三组之间血AngⅡ水平与室间隔舒张末期厚度（IVS）、左室后壁舒张末期厚度（LVPW）、LVM呈正相关（P〈0．01或0．05）;（3）血压、LVM与NO呈负相关、与AngⅡ、LVM呈正相关（P〈0．01或0．05）。结论研究结果提示：血浆NO、AngⅡ参与了EH及LVH形成的病理生理过程。     

血管紧张素Ⅱ对肝星状细胞的作用及分子机制

研究表明肝纤维化与局部肾素血管紧张素系统(RAS)的激活有关,血管紧张素Ⅱ(AngⅡ)是 RAS中的核心效应分子,与肝星状细胞表面的相应受体ATl结合后,通过信号传导,发挥生物学效应,促进活化HSC的收缩和增殖,刺激TGF-β1 的大量表达,促进细胞外基质的生成,抑制其降解,并减少HSC凋亡,参与肝纤维化发生、发展的病理生理过程。现就AngⅡ对肝星状细胞作用的分子机制作一综述。     

肠源性内毒素血症所致肝微循环障碍在肝损伤中的作用

目的　探讨肠源性内毒素血症诱导的肝微循环障碍在肝损伤中的作用。方法　用硫代乙酰胺(TAA)构建肠源性内毒素血症大鼠模型。25只雄性Wistar大鼠分为4组生理盐水组,肝素对照组,TAA组,TAA+肝素组。采用生化检测方法　、组织化学方法　和电镜技术,检测实验各组血浆内毒素、丙氨酸转氨酶(ALT)和丙二醛(MDA)水平的变化及肝组织形态学改变。结果　TAA组血浆内毒素为(0.1899±0.0540)EU/ml、ALT为(1006.80±9182)U/L、MDA为(636±1.96)nmol/ml;对照组分别为(0.0911±0.0068)EU/ml、(31.15±10.58)U/L、(366±0.86)nmol/ml,两组相比TAA组明显升高(P<0.05);TAA+肝素组与TAA组相比,内毒素(0.1597±0.0357)略有下降(P＞005),ALT(586.69±221.97)和MDA(3.64±0.95)显著降低(P＜005)。肝组织形态学改变,苏木精-伊红染色显示TAA组肝坏死面积达50%,纤维素染色TAA组肝窦及微血管内可见大量蓝色丝状团块样的微血栓;电镜结果　显示TAA组窦腔内红细胞聚集、白细胞粘附贴壁,肝窦内皮细胞窗孔数目减少,而TAA+肝素组上述改变明显减轻。结论　肠源性内毒素血症可诱导肝微循环障碍导致缺血、缺氧性肝损伤,肝素可明显改善肠源性内毒素血症所致的肝微循环障碍,从而使缺血、缺氧所致的肝损伤明显减轻。     

血管紧张素Ⅱ调控大鼠肝星状细胞血管紧张素Ⅱ受体表达及其功能的影响

国内外学者在心、肾、肺等脏器纤维化实验研究中发现，血管紧张素Ⅱ(AngⅡ)能刺激这些脏器组织间质成纤维细胞胶原分泌，证实AngⅡ参与组织纤维化的形成。现已证实AngⅡ调节血压、水电解质平衡和细胞生长都是通过AngⅡⅠ型受体(AT1R)发挥作用。在肝纤维化发生过程中，肝星状细胞(HSC)是否也表达AT1R和AT2R，为此我们观察了AngⅡ对大鼠HSC表达AngⅡ受体(ATR)及前胶原基因的调控情况，旨在探讨AngⅡ对HSC功能的影响及其机制。     

Superoxide,NO and CO in liver microcirculation: Physiology and pathophysiology

Superoxide anion (O₂ ^?), nitric oxide (NO), and carbon monoxide (CO) are metabolites of molecular oxygen endogenously generated through oxygen activation by a variety of oxidases and oxygenases such as xanthine oxidase and NADPH oxidase, NO synthase, and heme oxygenase, respectively. There is an increasing body of evidence showing that these active oxygen metabolites not only exert their cytotoxic properties but also play a modulatory role in regulation of cell function in and around hepatic sinusoidal vessels. Among them, CO generated by heme oxygenase is a novel vasodilatory mediator which can upregulate cGMP in fatstoring Ito cells, liver-specific microvascular pericytes which encircle sinusoidal walls, and thereby control the microvascular tone under control conditions. When exposed to endotoxemia, Kupffer cells and hepatocytes can express inducible NO synthase activity which serves as a NO-dependent cytotoxic mechanisms involving peroxynitrite formation. Disclosure of the whole picture of NO- and CO-dependent mechanisms for regulation of hepatic microcirculation gives a clue to understanding the physiology and pathophysiology of liver function.     

Role of nitric oxide in the regulation of the hepatic microcirculation in vivo

Background/Aims: Nitric oxide (NO) is an important mediator in the regulation of vascular tone. However no data exist on the physiological role of NO in the regulation of the hepatic microcirculation. This tudy was designed to evaluate the role of NO in the hepatic microcirculation in vivo under physiological conditions.Methods: The hepatic microcirculation was investigated in anesthetized rats by intravital fluorescence microscopy after injection of fluorescein-isothiocyanate-labeled erythrocytes. Following assessment of baseline sinusoidal perfusion, animals were randomly treated with L-NMMA (n=6), L-arginine (n=6), nitroprusside sodium (NPS, n=5) or a comparable volume of NaCl (n=4). Drugs were given through a portal vein catheter at three doses (Dx), each followed by intravital microscopy. L-NMMA was given: 5 mg/kg (D1), 25 mg/kg (D2), 50 mg/kg (D3); L-arginine 30 mg/kg (D1), 150 mg/kg (D2), 300 mg/kg (D3); and NPS continuously 80 μ·kg⁻¹·h⁻¹.Results: L-NMMA, induced a significant increase of mean arterial blood pressure (MAP) (114 vs. 129 mm Hg; p<0.05). In contrast, MAP of NPS-treated animals decreased (107 vs. 91 mm Hg; p<0.01) whereas MAP of animals receiving L-arginine did not significantly differ. Sinusoidal blood flow revealed dose-dependent changes: L-NMMA significantly decreased perfusion of sinusoids (D1: 65%, D2: 57%, D3: 50% of baseline, p<0.05). Injection of L-arginine increased the sinusoidal flow even with the lowest dose (D1: 137%, D2: 133%, D3: 123%, p<0.05). Continuous infusion of NPS had little effect on sinusoidal blood flow at the first and second times of microscopy but sinusoidal blood flow was significantly increased at the third time (D1: 103%, D2: 106%, D3: 122%).Conclusions: Inhibition of NOS results in a dose-dependent disturbance of the hepatic microcirculation despite significantly increased MAP, whereas L-arginine increases the sinusoidal blood flow. The results indicate an important role for NO in the regulatory mechanisms of hepatic sinusoidal perfusion under physiological conditions.     

Hemorheological disorders in the microcirculation following hemorrhage

We analysed hemorheological disorders in the microcirculation of intestinal mesenterium of adult laboratory rats following massive exsanguinations when the mean arterial pressure dropped and then the hemorrhagic shock developed in the animals. The mesenteric microcirculation was analysed by the Texture Analysis System (Leitz, Wetzlar): (a) diameters of the afferent arterioles, capillaries, and efferent venules; (b) the blood flow velocity; (c) microvascular blood flow changes (during the RBC aggregation); (d) local microvascular hematocrit; and (e) the transformation of capillaries into plasmatic microvessels. During development of the hemorrhagic shock we found that the blood flow velocity decreased in all microvessels, there was an increased RBC aggregation which gradually enhanced in the mesenteric microvessels' lumen causing blood flow slowing down till appearance of stases. A part of the capillaries transformed into plasmatic vessels. Therefore the microcirculation demonstrated a significant decrease, this being related both to the lowered pressure gradient and to specific hemorheological disorders in the capillary networks.     

Role of microcirculation in transplantation

Microcirculatory derangements in organ transplantation, characterized by capillary perfusion failure and inflammation-associated leukocyte recruitment, are major determinants for the manifestation of graft dysfunction and destruction. Although preservation/cold storage, posttransplant reperfusion, and rejection have to be considered as individual factors that contribute to injury, recent studies have indicated that ischemia-reperfusion-associated events may trigger immune-response-mediated late rejection. There is major evidence that the microcirculatory derangements induced by cold preservation and reperfusion involve oxygen radicals, complement, phospholipase A2, leukotrienes, thromboxane, platelet-activating factor, and endothelin-1 as well as the activation and function of leukocytic and endothelial selectins, beta 2-integrins, and ICAM-1. This view is based on the fact that blockade or neutralization of these inflammatory mediators and adhesion molecules results in significant amelioration of microvascular graft dysfunction. In parallel, rejection-mediated microcirculatory derangements may not only be ameliorated by immunosuppressive agents, such as cyclosporin, deoxyspergualin, or RS61443, but may, in addition, effectively be inhibited by counteracting oxygen radicals, complement, platelet-activating factor, and adhesion molecules. The introduction of novel techniques for the study of the microcirculation in men, such as thermodiffusion and orthogonal polarization spectral imaging, may in the future assist in improving both early diagnosis of microcirculatory derangements and monitoring of appropriateness of therapy in clinical transplantation surgery.     

Age-related changes in the hepatic microcirculation in mice

Aging of the liver is associated with impaired metabolism of drugs, adverse drug interactions, and susceptibility to toxins. Since reduced hepatic blood flow is suspected to contribute this impairment, we examined age-related alterations in hepatic microcirculation. Livers of C57Bl/6 mice were examined at 0.8 (pre-pubertal), 3 (young adult), 14 (middle-aged), and 27 (senescent) months of age using in vivo and electron microscopic methods. The results demonstrated a 14% reduction in the numbers of perfused sinusoids between 0.8 and 27 month mice associated with 35% reduction in sinusoidal blood flow. This was accompanied by an inflammatory response evidenced by a fivefold increase in leukocyte adhesion in 27 month mice, up-regulated expression of ICAM-1, and increases in intrahepatic macrophages. Sinusoidal diameter decreased 6-10%. Liver sinusoidal endothelial cell (LSEC) dysfunction was seen as early as 14 months when there was a threefold increase in the numbers of swollen LSEC. The endocytotic capacity of LSEC also was found to be reduced in older animals. The sinusoidal endothelium in 27 month old mice exhibited pseudocapillarization. In conclusion, the results suggest that leukocyte accumulation in the sinusoids and narrowing of sinusoidal lumens due to pseudocapillarization and dysfunction of LSEC reduce sinusoidal blood flow in aged livers.     

Role of microcirculation in hypertension

A large share of the pressure gradient in the vascular system is situated in the microcirculation. Most of the mechanisms resulting in an increase of peripheral resistances during hypertension are also located in this network. Experimental studies have shown that the functional characteristics of arterioles are profoundly modified in most hypertension models. The sensitivity to vasoconstrictor agonists is increased. The activity of the angiotensin-converting enzyme, situated in the arteriolar wall, is considerably greater in genetically hypertensive animals than in control animals. Endothelium-dependent vasodilator mechanisms are also decreased in these animals, while endothelium-derived vasoconstrictor factors are responsible for an increased smooth muscle response. These functional disorders are associated with structural modifications of the microvascular network. Changes of wall thickness are observed only inconstantly, but an initially functional then anatomical rarefaction of arterioles and capillaries has been observed in most experimental models of hypertension and in several clinical studies. This phenomenon reduces the capacities of adaptation of perfusion condition to changes in metabolic requirements of the various organs, reflecting the fact that the microcirculation is a target of hypertensive disease. Antihypertensive drugs should therefore be assessed not only in terms of the reduction of blood pressure figures, but also in terms of their capacity to prevent or correct structural changes of the microvascular network.     

Regulatory mechanisms of hepatic microcirculation

Hepatic microvasculature receives blood from two types of afferent vessels: the terminal portal venule (TPVn) and the terminal hepatic arteriole (THAo). The TPVns directly connect with the capillary bed in the liver parenchyma, which is referred to as sinusoids. Hepatic arterial blood pours into the hepatic sinusoids not only indirectly via the anastomosis between the THAo and the portal venule (PVn), but also directly through the THAo or the capillaries derived from the arterial capillary network around the bile duct. From a regulatory point of view, the hepatic arterial system is considered to be supplementary, but hepatic arterial flow is essential for supplying oxygen to sinusoidal blood flow as well as to the bile ducts, portal venules and nerves in the portal tract. The main regulators of hepatic sinusoidal blood flow are present in the portal venous system. By intravital and scanning electron microscopy, it is evident that a potent vasoconstrictor endothelin (ET)-1 causes a contraction of the SEF via the ET_B receptors, as well as a significant contraction of the PVn and TPVn, resulting in an increase in sinusoidal and pre-sinusoidal microvascular resistance. This phenomenon implies that the TPVn, particularly the transitional part to the sinusoid, would provide an essential regulatory site for hepatic sinusoidal blood flow as an inlet sphincter-like function. The endothelial cell linings along the hepatic sinusoids are characterized by the presence of a large number of sieve plate-like pores, 100 nm in diameter, i.e. the sinusoidal endothelial fenestrae (SEF). The SEF are dynamic structures, forming the racemose invaginations of the endothelial plasma membrane across the endothelium, and regulating not only the permeability of hepatic sinusoids, but also the sinusoidal blood flow by the Ca++ -actomyosin-mediated contraction and dilatation of the SEF. Our recent immunoelectron microscopic and Western blot studies have revealed that caveolin-1, i.e. the principal structural protein of caveolae, and endothelial nitric oxide synthase (eNOS) co-exist in the plasma membrane of the SEF, implying that the SEF may correspond to a permanent (stationary) type of fused and interconnected caveolae, thus contributing to the local control of hepatic sinusoidal blood flow by the regulation of NO synthesis.     

Significance of hemodynamics and hemorheology in microcirculation disorders

The angioarchitecture of the terminal vascular system and the rheologic properties of the flowing blood lead to its inhomogeneous distribution in the so-called microcirculation. Together with the spatial disproportion in the vascular pattern, a temporal inhomogeneity becomes quantitatively and qualitatively measurable with the help of intravital microscopy in animal experiments. Vasomotion in the precapillary vessels of resistance and further local regulation mechanisms are discussed, particularly the factors caused by blood fractions and their fluidity. The correlation between blood fractions, plasma and vascular wall is quantifiable by capillary microscopy with the help of dynamic morphometry. Useful consequences for prophylaxis and therapy are summarized in surveys.     

Impairment of hepatic microcirculation in fatty liver

Fatty liver or hepatic steatosis, which is the result of the abnormal accumulation of triacylglycerol within the cytoplasm of hepatocytes, is a common histological finding in human liver biopsy specimens that is attributed to the effects of alcohol excess, obesity, diabetes, or drugs. There is a general consensus that fatty liver compromises hepatic microcirculation, the common exchange network upon which hepatic arterial and portal inflows converge, regardless of underlying etiology. A significant reduction in hepatic microcirculation has been observed in human fatty donor livers and in experimental models of hepatic steatosis. There is an inverse correlation between the degree of fat infiltration and both total hepatic blood flow and flow in microcirculation. Fatty accumulation in the cytoplasm of the hepatocytes is associated with an increase in the cell volume that reduces the size of the hepatic sinusoid space by 50% compared with a normal liver and may result in partial or complete obstruction of the hepatic sinusoid space. As a result of impaired hepatic microcirculation, the hepatocytes of the fatty liver have reduced tolerance against ischemia-reperfusion injury, which affects about 25% of the donors for liver transplantation because severe steatosis is associated with a high risk of primary nonfunction after liver transplantation.