氧自由基在急性肺损伤发病中的作用

自由基是具有不配对电子的原子和原子团的总称，在体内分布广泛，它在介导脂质过氧化、蛋白质和DNA损伤、改变信号传导通路、刺激转录因子活化、诱导细胞凋亡中有重要而广泛的生物学效应，对急性肺损伤／急性呼吸窘迫综合征的发生、发展和转归有着重要的影响。     

自由基与缺血性脑血管病

脑缺血损伤中各种学说，已受到广泛关注，成为研究热点。本文对自由基的产生、脑缺血时自由基对脑组织的损伤机制以及抗氧化剂的研究进展作一综述，以期提高对自由基与脑缺血关系的认识，更好地指导临床治疗。     

活性氧自由基系统对氟中毒的影响及抗氧化剂的作用

氟中毒是以损害牙齿和骨骼的硬组织为主的全身中毒性疾病，氟除有亲骨的特性外，氟能引起全身广泛的组织损伤，目前尚无成熟的理论解释，氧自由基损伤可能是一重要理论。氧自由基损伤理论在氟中毒防治科研领域中日益为人们重视，当氟在体内作用于组织和细胞后，诱发产生氧自由基，并随之引起一系列的生物化学反应，从而造成广泛的组织损伤。     

上皮损伤和肺纤维化

肺纤维化是以肺实质炎症和进行性肺间质纤维化为特征的疾病，其发病机制复杂涉及多方面因素。肺上皮损伤是引起肺纤维化的重要因素之一，近年来人们对上皮 损伤在肺纤维化中的作用进行了广泛研究，取得了一定进展。     

线粒体与肝细胞损伤的关系

在肝脏组织中,线粒体不但为肝细胞的物质代谢提供了能量,同时还广泛参与了肝细胞损伤甚至凋亡的过程,在与肝细胞损伤、凋亡密切相关的肝炎、肝纤维化、肝癌癌前病变及肝癌的病理过程中也发挥了重要的作用。从线粒体膜通透性的改变在肝细胞损伤中的重要作用、ATP合成障碍及消耗加速肝细胞损伤以及肝细胞线粒体Ca 2+稳态异常与肝细胞损伤关系等方面阐述了线粒体与肝细胞损伤之间的关系,以期以线粒体为靶点,为防治肝细胞损伤引起的慢性肝脏疾病提供理论依据。     

细胞周期调控与肾小球疾病

肾小球疾病是引起慢性肾脏疾病与终末期肾脏疾病的重要原因。构成肾小球的三大固有细胞包括系膜细胞（mesangial cell，MC）、足细胞及内皮细胞，它们各自对损伤机制产生的不同反应决定了肾小球损伤的不同病理类型，包括增生、分化、肥大、老化、凋亡及坏死，而这些反应类型又取决于细胞周期水平的调控差异。细胞周期调控蛋白之间的相互作用决定了细胞周期的进展。这些蛋白最初被认为主要参与调节细胞周期的进展与增生，然而近来研究表明，它们具有更广泛的细胞生物学作用，包括调节发育、分化、肥大及凋亡等生物学过程。本文对细胞周期调节蛋白在肾小球固有细胞损伤反应中的意义作一综述。了解这些蛋白在肾脏固有细胞损伤反应中的调节机制对于阐明肾小球的损伤机制，乃至了解肾小球硬化和肾功能衰竭都具有重要意义。     

亚低温状态行机械通气治疗患者的护理(附26例报告)

亚低温治疗是近年来广泛应用于重型颅脑损伤以及危重患者脑保护的一项新技术，而机械通气则是保证亚低温治疗顺利进行的重要辅助手段。机械通气不仅能保证亚低温期间患者的通气、换气，同时有助于降低颅内压、改善脑部血供和氧供，对于促进患者脑功能恢复以及降低病死率有重要意义。2000年10月～2003年8月，我们共对26例危重患者在亚低温治疗过程行机械通气辅助呼吸，效果满意。现将护理体会报告如下。     

非甾体类抗炎药物相关性小肠疾病

非甾体类抗炎药(NSAID)是临床上应用最为广泛的抗炎药物之一，主要用于治疗风湿、类风湿性关节炎、骨关节疾病，以及对血管疾病的预防。据估计每天全世界约有3000万人在服用，因此该类药物引起的副作用不容忽视，尤其是胃肠道的不良反应最为突出。NSAID对胃十二指肠黏膜损伤和引起医源性上消化道溃疡的副作用已经非常肯定，并得到临床广泛重视。     

肝吸虫感染致胆管损伤及胆管癌的相关研究进展

[摘要]　肝吸虫是一种重要的食源性寄生虫，包括华支睾吸虫、后睾吸虫和肝片吸虫等，其成虫寄生在肝胆管或胆管内，可引起以肝胆管损伤为主要病变的肝脏疾病。肝吸虫已被WHO明确列为胆管癌的I类致癌物。在我国广泛流行的主要是华支睾吸虫，因此本文将以华支睾吸虫为例，结合最新研究进展，分别从虫体（虫体机械刺激和排泄分泌物毒性损伤作用）和宿主（免疫应答反应、胆汁淤积、肠肝循环障碍、肠道菌群失衡等）两方面系统阐述肝吸虫感染致胆管系统病变以及胆管癌发生发展的致病机制。     

氧自由基对大鼠海马及皮层的损伤作用

目的　探讨氧自由基对大鼠海马和皮层的损伤作用。方法　制备海马和皮层氧自由基损伤的大鼠模型 ,分析氧自由基代谢变化 ,核DNA损伤情况 ,蛋白质和脂质的损伤情况 ,以及组织结构变化等。结果　氧自由基可造成组织细胞核 DNA损伤 (DNA单链断裂增加 )、蛋白质损伤(羰基增加、ATPase活性下降、无活性或 /和低活性 SOD增加 )和脂质损伤 (LPO增加、自由基总量增加 )以及组织细胞结构损伤。结论　氧自由基可造成广泛的脑组织损伤。     

Oxidative stress and congestive heart failure

Oxygen free radicals, produced by the reduction of oxygen during many cellular reactions, have been implicated in the pathogenesis of a variety of cardiovascular diseases. Extremely reactive, free radicals damage many cellular structures and interfere with multiple cell functions. Clinically, free radicals have been associated with coronary atherosclerosis, ischemia, and reperfusion injury (“stunning”), and other processes related to chronic myocardial dysfunction. Several studies have reported elevated markers of free radical mediated injury in patients with congestive heart failure (CHF), and the link between oxidative stress and the genesis and progression of chronic CHF is being increasingly explored. This review briefly highlights free radical biology and examines the rationale and evidence for the role of oxidative stress in chronic heart failure. (c)1999 by CHF, Inc.     

Oxygen free radicals and cardiac reperfusion abnormalities.

Oxygen free radicals are highly reactive compounds causing peroxidation of lipids and proteins and are thought to play an important role in the pathogenesis of reperfusion abnormalities including myocardial stunning, irreversible injury, and reperfusion arrhythmias. Free radical accumulation has been measured in ischemic and reperfused myocardium directly using techniques such as electron paramagnetic resonance spectroscopy and tissue chemiluminescence and indirectly using biochemical assays of lipid peroxidation products. Potential sources of free radicals during ischemia and reperfusion have been identified in myocytes, vascular endothelium, and leukocytes. In several different experimental models exogenous free radical-generating systems have been shown to produce alterations in cardiac function that resemble the various reperfusion abnormalities described above. Injury to processes involved in regulation of the intracellular Ca2+ concentration may be a common mechanism underlying both free radical-induced and reperfusion abnormalities. Direct effects of free radicals on each of the known Ca(2+)-regulating mechanisms of the cell as well as the contractile proteins and various ionic membrane currents have been described. Free radicals also inhibit critical enzymes in anaerobic and aerobic metabolic pathways, which may limit the metabolic reserve of reperfused myocardium and contribute to intracellular Ca2+ overload. Inhibiting free radical accumulation during myocardial ischemia/reperfusion with free radical scavengers and inhibitors has been demonstrated to reduce the severity of myocardial stunning, irreversible injury, and reperfusion arrhythmias in many, but not all, studies. This evidence strongly implicates free radical accumulation during myocardial ischemia/reperfusion as an important pathophysiological mechanism of reperfusion abnormalities, although many issues remain unresolved.     

血浆谷胱甘肽过氧化物酶与脑梗死

氧自由基在脑梗死的重要危险因素--动脉粥样硬化的形成中起着重要作用,并且是脑梗死后缺血再灌注损伤的主要因素之一.谷胱甘肽过氧化物酶(GPx)是一种重要的抗氧化酶,其主要作用是清除新陈代谢和氧化应激时产生的过多氧自由基.GPx缺乏将会增高脑梗死风险.文章对GPx的生物学特性及与脑梗死的相关性做了综述.     

Deleterious effects of oxygen radicals in ischemia/reperfusion. Resolved and unresolved issues

Oxygen free radicals are known to be generated during periods of ischemia followed by reperfusion. There is still some controversy, however, concerning the use of electron paramagnetic resonance spectroscopy to accurately detect and identify the free radical species that are formed. There is no doubt that oxygen radicals are deleterious to the myocardium; free radicals cause left ventricular dysfunction and structural damage to myocytes and endothelial cells in both in vitro and in vivo preparations. Potential sources of these cytotoxic oxygen species include the xanthine oxidase pathway, activated neutrophils, mitochondria, and arachidonate metabolism, yet the crucial source of free radicals in the setting of ischemia and reperfusion is unresolved. There is little doubt that oxygen radicals play a role in the phenomenon of stunned myocardium induced by brief periods of ischemia followed by reperfusion; numerous studies have consistently observed that pretreatment with free radical scavengers and antioxidants enhances contractile function of stunned, postischemic tissue. Whether oxygen free radical scavengers administered only during reperfusion enhance recovery of stunned myocardium in models of brief ischemia remains to be determined. In models of prolonged ischemia (2 hours) followed by reperfusion, we have not observed a beneficial effect of scavengers on stunned myocardium. The issue of whether oxygen free radical scavengers are capable of reducing so-called irreversible or lethal reperfusion injury remains, in our opinion, unresolved. Although some studies have observed that agents such as superoxide dismutase and catalase reduce infarct size in ischemia and reperfusion models, many others have reported negative results. Additional studies will be needed to resolve this ongoing controversy. Oxygen free radicals may also contribute to reperfusion-induced arrhythmias in rodent heart preparations; however, less data are available in other animal models. The concept of reperfusion injury should not be considered a deterrent to reperfusion for the treatment of acute myocardial infarcts in the clinical setting. Thrombolytic therapy reduces myocardial infarct size, enhances recovery of left ventricular function, and improves survival. Whether incremental beneficial effects on these parameters will be obtained when oxygen radical-scavenging agents are used as adjuvant therapy to thrombolysis in patients remains to be determined.     

Measurement of endothelial cell free radical generation: evidence for a central mechanism of free radical injury in postischemic tissues.

Oxygen free radicals have been demonstrated to be important mediators of postischemic reperfusion injury in a broad variety of tissues; however, the cellular source of free radical generation is still unknown. In this study, electron paramagnetic resonance measurements with the spin trap 5,5'-dimethyl-1-pyrroline-N-oxide (DMPO) demonstrate that bovine endothelial cells subjected to anoxia and reoxygenation become potent generators of superoxide and hydroxyl free radicals. A prominent DMPO-OH signal aN = aH = 14.9 G is observed on reoxygenation after 45 min of anoxic incubation. Quantitative measurements of this free radical generation and the time course of radical generation are performed. Both superoxide dismutase and catalase totally abolish this radical signal, suggesting that O2 is sequentially reduced from O2-. to H2O2 to OH.. Addition of ethanol resulted in trapping of the ethoxy radical, further confirming the generation of OH.. Endothelial radical generation was shown to cause cell death, as evidenced by trypan blue uptake. Radical generation was partially inhibited and partially scavenged by the xanthine oxidase inhibitor allopurinol. Marked inhibition of radical generation was observed with the potent xanthine oxidase inhibitor oxypurinol. These studies demonstrate that endothelial cells subjected to anoxia and reoxygenation, conditions observed in ischemic and reperfused tissues, generate a burst of superoxide-derived hydroxyl free radicals that in turn cause cell injury and cell death. Most of this free radical generation appears to be from the enzyme xanthine oxidase. Thus, endothelial cell free radical generation may be a central mechanism of cellular injury in postischemic tissues.     

Neutrophil-derived, oxygen free radical-mediated cardiovascular dysfunction

Oxygen free radicals and their metabolites generated from activated neutrophils have been implicated in mediating the cardiovascular dysfunction of such diverse etiologies as myocardial ischemia and reperfusion injury, Gram negative sepsis, myocarditis and acute cardiac allograft rejection, but a direct demonstration of neutrophil derived oxygen free radical mediation of cardiovascular dysfunction has not been accomplished. In this study, we have demonstrated that activation of the canine neutrophil system, in vivo, results in the generation of oxygen free radicals that are capable of disrupting cardiovascular function producing a significant decrease in mean arterial pressure and cardiac index without any significant effect on the conduction system of the myocardium. Neutrophil depletion or pretreatment with superoxide dismutase and catalase inhibited the effects of activated neutrophils. This study provides evidence that neutrophil-derived reduced oxygen intermediates are able to induce severe cardiovascular dysfunction.     

Oxygen-derived free radicals related injury in the heart during ischemia and reperfusion

It has been suggested recently that oxygen-derived free radicals may play an important role in the genesis of reperfusion injury and arrhythmias. Free radicals have a very short half-life (ranging from mili- to microseconds), hence almost all the reports supporting the free radical hypothesis of reperfusion cell injury have been indirect. We have applied electrone spin resonance spectrometry to measure directly the amount of free radicals generated during ischemia and reperfusion. The concentration of free radicals in mitochondria increased significantly during ischemia (for 20 and 40 min). The concentration of free radicals after reperfusion was higher than that during ischemia, and a large amount of free radical generation occurred within the first 60 sec of reperfusion and returned to the level of prereperfusion at 5 min after reperfusion. The concentration of free radicals in the reperfusion-induced ventricular fibrillation group was significantly higher than that in the non-occurrence group. The administration of liposomal superoxide dismutase reduced the incidence of reperfusion-induced ventricular fibrillation and that prevented the free radical generation during reperfusion. This study showed that enhanced generation of free radicals occurred at the onset of ventricular fibrillation and that free radical scavenger prevented the development of arrhythmias and free radical generation during reperfusion. We have obtained more circumstantial evidence for an involvement of free radicals in the genesis of reperfusion injury and arrhythmias.     

Pathobiology and Clinical Impact of Reperfusion Injury

Reperfusion injury refers to cellular death or dysfunction caused by restoration of blood flow to previously alchemic tissue. This should be differentiated from the normal reparative processes that follow an ischemic insult. Four types of reperfusion injury have been described in the literature: (1) lethal reperfusion injury, (2) nonlethal reperfusion injury, (myocardial stunning), (3) reperfusion arrhythmias, and (4) vascular injury (including the "no-reflow" phenomenon). There is continued debate whether reperfusion itself is capable of killing viable myocytes, which otherwise would have survived the ischemic insult. However, there is firm evidence for the existence of myocardial stunning following various ischemic syndromes, including reperfusion therapy for acute myocardial infarction, unstable angina pectoris, vasospastic angina, effort-induced ischemia, coronary artery bypass surgery, and cardiac transplantation. Reperfusion arrhythmia is more common after short ischemic episodes than after long ischemic periods. Thus, while reperfusion arrhythmias in the setting of acute myocardial infarction are relatively rare, reperfusion arrhythmias may be an important cause of sudden death. The "no-reflow" phenomenon has been described following reperfusion in patients with acute myocardial infarction. Three major components have been proposed as mediators of reperfusion injury: (1) oxygen free radicals, (2) the complement system, and (3) neutrophils. Numerous experimental studies have shown short-term benefit by blocking various stages of the postischemic inflammatory response. Oxygen free radicals scavengers, complement inhibition, leukocyte depletion, and the use of antibodies against various adhesion molecules have shown a reduction of infarct size in many ischemic/reperfusion experimental models. However, many of these agents failed to show a benefit in the clinical setting. Moreover, the long-term benefit of such intervention is still unknown.     

Neutrophil-induced myocardial cell damage and active oxygen metabolites.

Free radicals derived from polymorphonuclear leukocytes (PMN) have been suggested to play an important role in myocardial ischemia-reperfusion injury. To define the mechanism by which activated PMN exacerbate ischemic myocardial damage, we investigated the extent of cell injury, free radical generation and lipid peroxidation in embryo mouse myocardial cells co-incubated with activated PMN. The generation of free radicals derived from PMN correlated with the extent of myocardial cell injury. Among the cell sheets preconditioned with hypoxic and glucose free medium, PMN-adhered myocardial cells were initially injured after adding PMN activator, extending to adjacent cells. Chemiluminescence emission and thiobarbituric acid reactive substance in the co-incubated cells were markedly increased and sustained compared with those in each cell monoincubation. The augmented lipid peroxidation was related to the progression of myocardial cell injury. These results indicate that PMN-derived free radicals cause membrane disruption, contributing to the progression of myocardial injury.     

Allopurinol attenuates caerulein induced acute pancreatitis in the rat.

Oxygen derived free radicals have been implicated in the pathogenesis of acute pancreatitis in numerous animal models of the disease. The xanthine oxidase inhibitor allopurinol has been shown to attenuate pancreatic damage in canine and mouse models of acute pancreatitis presumably by preventing the generation of cytotoxic superoxide anions. We therefore examined whether allopurinol could attenuate pancreatic injury in conscious rats with caerulein induced acute pancreatitis. A continuous intravenous infusion of allopurinol (20 mg/kg/h) for six hours along with an acute pancreatitis producing dose of caerulein (10 micrograms/kg/h) reduced pancreas weights by approximately 45% and serum amylase concentrations by approximately 60% compared with rats intravenously infused with either caerulein alone or caerulein plus a lower dose (10 mg/kg/h) of allopurinol. We conclude that the generation of oxygen derived free radicals via pancreatic xanthine oxidase represents an early and perhaps pivotal mechanism in the pathogenesis of acute pancreatitis.