肾脏固有细胞及炎症细胞在肾脏缺血/再灌注损伤中作用机制的研究进展

肾脏缺血/再灌注(L/R)损伤是急性肾功能衰竭(ARF)的主要原因之一.近年来认为,炎症反应是L/R损伤形成的重要因素之一,炎症反应与肾脏的固有细胞以及炎症细胞浸润有重要的关系,参与了这一损伤的过程.本文对近年来相关的研究作一综述,以进一步了解肾脏L/R损伤的机制.     

TLR2和TLR4在缺血/再灌注中的研究进展

缺血/再灌注(I/R)损伤是器官功能衰竭的主要原因之一,临床上常见于术后、严重创伤、心肌梗死、器官移植等.目前认为I/R损伤与TLRs中的TLR2和TLR4有重要的关系.本文对近年来TLR2和TLR4与心脏、肾脏、脑、肝脏等器官I/R损伤相关的研究作一综述,以进一步防治I/R损伤.     

肠缺血再灌注损伤发病机制及防治

肠缺血再灌注(Ischemia and Reperfusion,I/R)损伤是严重创伤、烧伤和休克后常见的病理生理过程,肠I/R不仅可引起肠道局部组织损伤和炎症反应,而且可致肠道细菌和内毒素移位,大量肠源性炎症介质和细胞因子释放,引发全身性炎症反应,甚至脓毒症和多器官功能障碍.     

HO-1/CO系统在缺血/再灌注中的保护机制

缺血/再灌注(ischemia/reperfusion,I/R)损伤是心肌梗死等许多疾病的病理生理基础,也是手术、创伤、休克以及器官移植导致器官功能和结构损伤的原因之一.在已知的I/R损伤的众多病理机制中已经明确氧化应激产生的活性氧自由基和炎症反应具有重要的作用.血色素氧合酶-1(heme oxygenase-1,HO-1)能催化血色素降解生成胆绿素、一氧化碳(carbon monoxide,CO),并释放Fe2+离子.近年来的研究已经证明HO-1及其催化产物CO具有抗氧化应激和抗炎作用,在正规损伤中能够发挥对组织器官的保护作用.现就I/R损伤中HO-1/CO系统的保护作用进行综合阐述.     

炎症反应在心肌缺血/再灌注损伤中作用的研究进展

背景 心肌缺血/再灌注损伤(ischemia/reperfusion injury,I/RI)是指在缺血心肌恢复血流灌注后,细胞代谢功能障碍和结构破坏反而加重的现象,并且伴随有以炎症细胞浸润和细胞因子产生为特征的炎症反应.目前认为,炎症反应是I/RI的重要病理机制之一,再灌注诱发的炎症反应及其介质可加重心肌I/RI,而...     

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<正>抗原特异性T细胞如何参与缺血-再灌注损伤(IRI)?本刊特邀中国工程院院士、南京医科大学第一附属医院肝脏外科研究所所长王学浩教授就T淋巴细胞在缺血-再灌注损伤中的重要作用作一述评。王教授在文中阐明了T淋巴细胞在IRI中的活化机制、辅助性T17细胞与调节性T细胞在IRI中的作用。T淋巴细胞参与多种器官IRI发病过程,且在不同组织和疾病的不同阶段发挥不同的生物学功能。精准的T淋巴细胞     

Janus激酶/信号转导与转录激活因子信号通路在肠缺血再灌注损伤中的研究进展

缺血再灌注（I/R）是指组织因各种原因引起缺血,一段时间后恢复血供,引起组织细胞再次损伤的临床症状。肠道是I/R损伤发生的常见器官,其发生具有突然性及多样性,临床难以精准预测及有效预防,因此目前研究多集中于再灌注期的症状缓解及组织保护策略上。多种信号通路参与肠I/R损伤的过程,本研究综述Janus激酶/信号转导与转录激活因子（JAKSTAT）信号通路在肠I/R损伤过程中的作用,以期为肠I/R相关治疗提供思路。     

内源性一氧化碳在大鼠肢体缺血再灌注致远隔多脏器氧化性损伤中的作用

目的　探讨内源性一氧化碳 (CO)在大鼠肢体缺血再灌注 (I/ R)致远隔多器官氧化性损伤中的作用机制。方法　将 6 4只大鼠随机分为 4组 :假手术 (Sham )组 ;Sham 特异性血红素氧化酶阻断剂—锌原卟啉 (Zn PP)组 ;肢体缺血 2小时和再灌注 4小时 (I/ R)组 ;I/ R Zn PP组。测定各组心、肺、肝和肾组织匀浆中丙二醛 (MDA )含量、超氧化物歧化酶 (SOD)活性及血液内碳氧血红蛋白 (COHb)的变化 ,观察动物 2 4小时存活率。结果　与 Sham组相比 ,I/ R组各脏器 MDA含量及血液内 COHb水平均显著增高 ,组织中 SOD活性和动物 2 4小时存活率显著降低 ,有统计学意义(P<0 .0 5 ) ;I/ R Zn PP组与 I/ R组相比各脏器 MDA含量进一步增高 ,血液内 COHb水平、组织中 SOD活性和动物的2 4小时存活率显著降低 ,也有统计学意义 (P<0 .0 5 )。结论　肢体缺血再灌注可导致多器官的氧化性损伤 ,并使 CO产生增多 ,后者在大鼠抗缺血再灌注所致的远隔多器官损伤中具有重要作用。     

肝细胞生长因子对肝缺血再灌注损伤的治疗作用

肝缺血再灌注损伤(Ischaemic Reperfusion Injury．I／R iniury)是肝胆外科实践中常见的组织器官损伤之一．在严重感染、创伤、休克、心肺功能不全、器官移植等疾患的病理演变中起重要作用。I／R损伤使肝脏组织发生一系列代谢、结构和功能的损伤,甚至导致肝功能衰竭,是影响疾病预后、手术成败和病人存活的主要因素之一。因此探讨I／R损伤的发     

线粒体DNA释放在肠缺血再灌注损伤中作用的研究进展

肠缺血再灌注(I/R)损伤是指肠缺血一定时间后再恢复血供所引起的损伤。肠组织缺血可由失血性休克、绞窄性肠梗阻和急性肠系膜缺血等引发, 当肠组织再灌注后虽然血氧水平恢复, 但活性氧(ROS)的大量产生, 直接促进中性粒细胞浸润缺血肠组织并加重组织损伤, 这是造成肠I/R损伤患者肠坏死和高死亡率的主要原因[1]。肠I/R损伤主要有两个阶段:首先是肠组织发生缺血, 此时有氧代谢障碍, ATP合成减少, 而无氧代谢生成大量乳酸, 细胞内电解质紊乱, 线粒体功能障碍, 导致细胞死亡, 上皮细胞屏障功能破坏, 血管通透性增加[2,3]。由于长时间缺血, 肠组织恢复血流后, 富含氧气的血液进入肠组织, 产生大量氧自由基、细菌易位、炎症反应, 最终导致细胞死亡、组织损伤、器官衰竭[4]。肠I/R损伤的发生会破坏肠壁的屏障功能[5], 一旦引起肠壁屏障破坏超过其代偿能力, 肠道菌群和毒素可进入血液循环, 导致全身炎症反应综合征(SIRS)[6], 甚至导致多器官功能衰竭(MODS)和死亡[7]。人体肠组织富含线粒体, 它参与了能量的产生、免疫应答、细胞代谢、死亡等一系列过程。当细胞受到损伤或应激时, 线...     

Resident Macrophages are Involved in Intestinal Transplantation-Associated Inflammation and Motoric Dysfunction of the Graft Muscularis

Gut manipulation and ischemia/reperfusion evoke an inflammatory response within the intestinal muscularis that contributes to dysmotility. We hypothesize that resident macrophages play a key role in initiating the inflammatory cascade. Isogenic small bowel transplantation was performed in Lewis rats. The impact of recovery of organs on muscularis inflammation was investigated by comparing cold whole-body perfusion after versus prior to recovery. The role of macrophages was investigated by transplantation of macrophage-depleted gut. Leukocytes were counted using muscularis whole mounts. Mediator expression was determined by real-time RT-PCR. Contractility was assessed in a standard organ bath. Both organ recovery and ischemia/reperfusion induced leukocyte recruitment and a significant upregulation in IL-6, MCP-1, ICAM-1 and iNOS mRNAs. Although organ recovery in cold ischemia prevented early gene expression, peak expression was not changed by modification of the recovery technique. Compared to controls, transplanted animals showed a 65% decrease in smooth muscle contractility. In contrast, transplanted macrophage-depleted isografts exhibited significant less leukocyte infiltration and only a 19% decrease in contractile activity. In summary, intestinal manipulation during recovery of organs initiates a functionally relevant inflammatory response within the intestinal muscularis that is massively intensified by the ischemia reperfusion injury. Resident muscularis macrophages participate in initiating this inflammatory response.     

Tissue factor and thrombin mediate myocardial ischemia-reperfusion injury

Reperfusion of the ischemic heart is necessary to prevent irreversible injury of the myocardium, which leads to permanent organ dysfunction. However, reperfusion in itself leads to myocardial ischemia/reperfusion (I/R) injury, which is characterized by an acute inflammatory response mediated by activated inflammatory cells, chemokines, cytokines, and adhesion molecules. The molecular mechanisms of myocardial I/R injury are not completely known. Tissue factor (TF) and thrombin, two potent procoagulant and proinflammatory mediators, are recognized to play significant roles in myocardial I/R injury. To investigate the role of TF and thrombin in myocardial I/R injury, we used rabbit and murine in situ coronary artery ligation models. Increased TF mRNA, antigen, and activity were found in ischemic cardiomyocytes. Administration of an inhibitory antirabbit TF monoclonal antibody before or during the onset of ischemia resulted in a significant reduction in infarct size. Functional inhibition of thrombin with hirudin also reduced the infarct size. However, defibrinogenating rabbits with ancrod had no effect on infarct size, suggesting a requirement of thrombin generation but not fibrin deposition in myocardial I/R injury.     

Alloimmune Activation Enhances Innate Tissue Inflammation/Injury in a Mouse Model of Liver Ischemia/Reperfusion Injury

The deleterious sensitization to donor MHC Ags represents one of the most challenging problems in clinical organ transplantation. Although the role of effector/memory T cells in the rejection cascade has been extensively studied, it remains unknown whether and how these ‘Ag‐specific’ cells influence host innate immunity, such as tissue inflammation associated with ischemia and reperfusion injury (IRI). In this study, we analyzed how allogeneic skin transplant (Tx) affected the sequel of host's own liver damage induced by partial warm ischemia and reperfusion. Our data clearly showed that allo‐Tx recipients had increased inflammatory response against IR insult in their native livers, as evidenced by significantly more severe hepatocelluar damage, compared with syngeneic Tx recipient controls, and determined by serum ALT levels, liver histology (Suzuki's score) and intrahepatic proinflammatory gene inductions (TNF‐α, IL‐1β and CXCL10). The CD4 T cells, but neither CD8 nor NK cells, mediated the detrimental effect of allo‐Ag sensitization in liver IRI. Furthermore, CD154, but not IFN‐γ, was the key mechanism in allo‐Tx recipients to facilitate IR‐triggered liver damage. These results provide new evidence that alloreactive CD4 T cells are capable of enhancing innate tissue inflammation and organ injury via an Ag‐nonspecific CD154‐dependent but IFN‐γ independent mechanism.     

The role of mitochondria in ischemia/reperfusion injury

In organ transplantation, ischemia/reperfusion injury is a multifactorial process that leads to organ damage and primary graft dysfunction. Injury to the organ is mediated by a complex chain of events that involves depletion of energy substrates, alteration of ionic homeostasis, production of reactive oxygen species, and cell death by apoptosis and necrosis. There is increasing evidence that mitochondria play a role in this process because of the profound changes experienced during ischemia and reperfusion. Understanding the mechanisms that lead to mitochondrial damage may be important for developing strategies aimed at improving graft outcome. In this review, we examine the role of mitochondria in ischemia/reperfusion injury and the possible mechanisms that may contribute to organ dysfunction.     

Ischemia-Reperfusion Injury

Abstract The term ischemia-reperfusion injury describes the experimentally and clinically prevalent finding that tissue ischemia with inadequate oxygen supply followed by successful reperfusion initiates a wide and complex array of inflammatory responses that may both aggravate local injury as well as induce impairment of remote organ function. Conditions under which ischemia-reperfusion injury is encountered include the different forms of acute vascular occlusions (stroke, myocardial infarction, limb ischemia) with the respective reperfusion strategies (thrombolytic therapy, angioplasty, operative revascularization) but also routine surgical procedures (organ transplantation, free-tissue-transfer, cardiopulmonary bypass, vascular surgery) and major trauma/shock. Since the first recognition of ischemia-reperfusion injury during the 1970s, significant knowledge has accumulated and the purpose of this review is to present an overview over the current literature on the molecular and cellular basis of ischemia-reperfusion injury, to outline the clinical manifestations and to compile contemporary treatment and prevention strategies. Although the concept of reperfusion injury is still a matter of debate, it is corroborated by recent and ongoing clinical trials that demonstrated ischemic preconditioning, inhibition of sodium-hydrogen-exchange and administration of adenosine to be effective in attenuating ischemia-reperfusion injury.     

肠缺血/再灌注损伤时中性粒细胞呼吸爆发活性的变化

目的:研究肠缺血/再灌注(I/R)时中性粒细胞(PMN)呼吸爆发活性的变化.方法:30只成年雄性Wistar大鼠,按照随机数字表法分为假手术,缺血45 min,缺血45 min再灌注60min、120min、360min等5组.阻断肠系膜上动脉血流45min后复流,复制I/R模型:假手术组只进行同样的手术操作但不阻断肠系膜上动脉血流.在各时间点分别取门静脉血测定白细胞计数,并分离PMN进行化学发光(CL)测定.结果:肠I/R损伤过程中,缺血组与假手术组比较,PMN的CL峰值无明显差异(P＞0.05),再灌注组PMN的CL峰值均明显升高(P＜0.01).肠缺血组白细胞数量较假手术组降低,再灌注后开始回升,再灌注360 min时白细胞计数最高.PMN化学发光峰值变化和血白细胞计数的变化趋势呈显著正相关(r=0.748,P＜0.05).结论:肠I/R损伤可激活循环中的PMN,使血中的PMN数量增加,PMN的呼吸爆发化学发光活性明显升高,可能是引起全身炎症反应和器官损害的因素之一.     

Rip1 (receptor-interacting protein kinase 1) mediates necroptosis and contributes to renal ischemia/reperfusion injury

Loss of kidney function in renal ischemia/reperfusion injury is due to programmed cell death, but the contribution of necroptosis, a newly discovered form of programmed necrosis, has not been evaluated. Here, we identified the presence of death receptor-mediated but caspase-independent cell death in murine tubular cells and characterized it as necroptosis by the addition of necrostatin-1, a highly specific receptor-interacting protein kinase 1 inhibitor. The detection of receptor-interacting protein kinase 1 and 3 in whole-kidney lysates and freshly isolated murine proximal tubules led us to investigate the contribution of necroptosis in a mouse model of renal ischemia/reperfusion injury. Treatment with necrostatin-1 reduced organ damage and renal failure, even when administered after reperfusion, resulting in a significant survival benefit in a model of lethal renal ischemia/reperfusion injury. Unexpectedly, specific blockade of apoptosis by zVAD, a pan-caspase inhibitor, did not prevent the organ damage or the increase in urea and creatinine in vivo in renal ischemia/reperfusion injury. Thus, necroptosis is present and has functional relevance in the pathophysiological course of ischemic kidney injury and shows the predominance of necroptosis over apoptosis in this setting. Necrostatin-1 may have therapeutic potential to prevent and treat renal ischemia/reperfusion injury.     

Contribution of T lymphocytes to rat renal ischemia/reperfusion injury

BACKGROUND: This study aimed to elucidate the early involvement of T lymphocytes in renal ischemia/reperfusion injury. METHODS: Athymic nude rats (F344/N_Jcl-nu) and control F344/Jcl were subjected to 45 min unilateral renal ischemia. To determine whether the observed differences might be derived from the T lymphocyte presence, T lymphocytes from the spleens of F344/Jcl were injected into F344/N_Jcl-nu via tail vein at the initiation of reperfusion. Immunohistochemical analysis was performed for CD3, the proliferative cell nuclear antigen (PCNA), vimentin, and E-cadherin. T lymphocytes were obtained from the green fluorescent protein transgenic (GFP) rats, and transplanted to F344/N_Jcl-nu 10 min before reperfusion. The animals were euthanized 15 min after reperfusion. RESULTS: F344/N_Jcl-nu showed less retention of both Cr and BUN at 24 and 48 h after reperfusion, compared with F344/Jcl. F344/N_Jcl-nu received T lymphocyte transplantation showed significantly higher retention of both Cr and BUN 24, 48, and 72 h after reperfusion than those without T lymphocyte. A rapid infiltration of T lymphocytes into proximal tubular epithelial cells and tubular lumen was observed using T lymphocytes with green fluorescent protein. In contrast, T lymphocytes were observed with much less frequency 24 h after ischemia. The number of PCNA-positive proximal tubular cells 24 h after the initiation of reperfusion was significantly smaller in the T lymphocyte transplantation group compared with the non-transplantation group. The vimentin positivity and cytoplasmic staining of E-cadherin were also more prominent in the transplantation group. CONCLUSION: These findings demonstrate a rapid renal T lymphocyte infiltration, which propagate renal functional deterioration.     

缺血后处理与线粒体通透性转运孔

背景 缺血后处理(ischemic postconditioning,IPo)能明显减轻器官缺血/再灌注损伤(ischemia/reperfusion injury,I/RI),动物实验和临床研究均已经得到证实,其机制可能与增强组织抗氧化能力和抑制细胞凋亡有关.然而近些年提出线粒体通透性转换孔(mitochondria...     

Lecithinized superoxide dismutase reduces cold ischemia-induced chronic allograft dysfunction

BACKGROUND: Chronic renal allograft failure (CAF) is influenced by both allo-dependent and independent factors and is a major cause of graft loss in clinical renal transplantation. We evaluated a novel membrane-bound free radical scavenger, lecithinized superoxide dismutase (lec-SOD), to determine its potential in limiting the harmful effects of ischemia/reperfusion injury on CAF. METHODS: Fisher rat kidneys were stored for either 1 hour or 18 hours in cold Marshall's preservation solution either with or without lec-SOD and transplanted into Lewis recipients. RESULTS: Within 3 days of transplantation, an early inflammatory response involving granulocytes and macrophages was detected in renal allografts exposed to 18 hours cold ischemia that was significantly reduced by preservation with lec-SOD. By 24 weeks post-transplantation, elevated proteinuria and detection of apoptotic cells was observed in kidneys exposed to 18 hours of cold ischemia, that was attenuated by preservation with lec-SOD (P < 0.05). However, up-regulated expression of intracellular adhesion molecule-1 (ICAM-1) and major histocompatibility complex (MHC) Class II together with a T lymphocyte infiltration were observed at 24 weeks that was not prevented by preservation with lec-SOD. CONCLUSIONS: These results demonstrate that ischemia/reperfusion injury, apoptotic cell death and allo-immune responses may be exacerbated by cold ischemia and accelerate the development of CAF. Preservation with lec-SOD may protect against the early damage induced by cold ischemia and reperfusion injury.