免疫细胞在心肌重塑中的作用

心肌重塑几乎与所有类型的心脏疾病的发生发展相关,是一个重要的全球性健康问题.这种病理性重塑过程包括心室扩张、心肌炎症反应和心肌细胞肥大,最终导致心力衰竭的发生.在各种类型的心肌损伤后,心脏从纤维细胞转化为肌成纤维细胞,随后并沉积在细胞外基质中,这是心肌纤维化的重要病理机制.同时免疫细胞的激活及其介导的炎症反应也参与了心肌重塑的发生与发展,因而了解免疫细胞导致心肌重塑的可能病理机制可为临床防治和逆转心肌重塑提供新的靶点.     

高迁移率族蛋白B1(HMGB-1)与器官纤维化研究进展

高迁移率族蛋白B1(HMGB1)作为一种重要的晚期炎症因子和促炎因子,可以通过损伤/坏死细胞被动释放,也可由活化状态的细胞主动分泌至胞外介导炎症反应.一直以来,HMGB1在各种急慢性炎症中的作用研究备受关注.器官组织纤维化为持续慢性炎症的后期病理变化,近年来,HMGB1在各种器官纤维化中的作用研究越来越多.许多研究结果显示,HMGB1在肝、肺、肾、心脏等器官纤维化的发生发展中发挥重要作用.     

自然杀伤T细胞通过IL-10拮抗高血压心肌重塑

<正>目的:炎症和免疫细胞的活化参与心肌重塑的发生,已表明恒定自然杀伤T细胞(invariant natural killer T cells,iNKT细胞)产生炎症因子,调节组织的炎症反应。然而,目前iNKT细胞在心肌重塑中的作用还不清楚。方法:血管紧张素Ⅱ(1 000ng·kg-1·min-1)灌注诱导心肌重塑的发生,植入缓释泵之前,给予自然杀伤T细胞的激动剂α-Galce。结果:血管紧张素Ⅱ     

Th2相关的Kupffer细胞活化促进肝纤维化但不引起局部炎症反应

肝纤维化的最终结局是肝硬化。Kupffer细胞介导的炎症反应会加重肝脏的损伤和纤维化。活化的巨噬细胞能控制慢性炎症的结局和触发肝功能恢复的过程。为了了解Kupffer细胞的选择性活化在肝损害中的作用,研究人员用四氯化碳诱导的肝损害的小鼠模型平估选择性活化的Kupffer细胞在肝脏炎症和纤维化中的作用。对BALBc/AnN雌性小鼠接种20条肥头     

CD4+T淋巴细胞在炎症性心脏重构中的作用

心肌纤维化是指心肌细胞外基质进行性累积,导致心室僵硬和舒张充盈受损,是心衰患者临床预后不良的指标.多种原因导致的心肌纤维化均经历过炎症过程,炎症与心肌纤维化常并存于病变心肌.T淋巴细胞通过与心肌成纤维细胞相互作用而影响胶原及基质金属蛋白酶表达,参与炎症性心肌纤维化的调控.对于不同T淋巴细胞亚群如Th1、Th2、Th17...     

间充质干细胞在T细胞免疫反应中的调节作用

间充质干细胞(MSCs)独特的免疫调节作用以T细胞为主,在混合淋巴细胞反应中,通过周期阻滞抑制T细胞增殖,但不引起T细胞凋亡增加、活化受抑。同时MSCs还能降低反应体系中的CD8+T细胞和Th1细胞,升高Th2细胞以抑制炎症反应,从而在T细胞介导的自身免疫性疾病中发挥治疗作用。     

细胞焦亡在肾间质纤维化中的作用机制北大核心CSCD

细胞焦亡是由caspase蛋白酶介导,经GSDMD切割细胞膜成孔,引起细胞破裂死亡、活性促炎因子释放的一种新型的细胞促炎性程序性死亡方式。细胞焦亡分为caspace-1相关的经典途径与caspase-4/5/11相关的非经典途径。细胞焦亡是肾间质纤维化的重要参与者,多种信号刺激激活炎性小体,诱发细胞焦亡,引起炎症反应和免疫细胞、肾固有细胞的相关应答,三者串联形成“焦亡-炎症-纤维化”轴,共同参与肾间质纤维化的发生;细胞焦亡还与自噬相互作用,影响纤维化进程。本文就细胞焦亡的分子机制及其在肾间质纤维化中的作用机制进行概述。     

腹腔注射人免疫球蛋白对压力超负荷心力衰竭大鼠心肌纤维化的影响北大核心CSCD

心肌纤维化是高血压病、冠心病、心肌炎等多种心脏疾病最终走向心力衰竭的病理改变,它还可引起心律失常、心源性猝死等严重并发症,因此如何减缓或逆转心肌纤维化已日益成为临床治疗中的关键。心肌纤维化形成的机制与多种因素有关,其中慢性炎症被认为是心肌纤维化进程中重要的因素之一,炎性因子的释放及炎性细胞的聚集可以导致组织损伤、血管再生以及胶原沉积,参与了慢性心力衰竭的病理过程。而免疫球蛋白是临床常用的免疫调节剂,它可能通过调节炎性细胞因子、抑制炎症反应等作用干预心肌纤维化的形成。因此,本研究旨在探讨免疫球蛋白是否能延缓在压力超负荷心力衰竭情况下心肌纤维化的进程,为今后临床工作中开展应用免疫球蛋白治疗心肌纤维化提供依据。     

趋化因子RANTES及其受体与哮喘

嗜酸性粒细胞在哮喘变应性炎症发生中作为一种效应细胞 ,参与介导气道内各种炎性细胞的生存、趋化和活化等 ,对气道变应性炎症的发生起重要作用。哮喘患者支气管粘膜的慢性非特异性炎症反应 ,涉及多种炎症介质细胞 ,其中趋化因子家族及其对各种炎症细胞的特异性趋化和激活功能在哮喘非特异性炎症中的作用正受到重视。RANTES(活化正常T细胞表达和分泌的调节物 )是CC类趋化因子 ,RANTES及其受体CCR3、CCR1和CCR5等在诱导嗜酸性粒细胞募集中起到重要作用。本文就CC类趋化因子RANTES及其受体与哮喘的研究进展作一综述     

p38MAPK信号通路及其在全身炎症反应中的作用

分裂原激活的蛋白激酶（ＭＡＰＫ）级联是细胞内主要的信号转导系统。细胞运用这一系统将细胞外信号传递细胞核，介导细胞产生反应。近年来发现一类新的ＭＡＰＫ通路——ｐ３８ＭＡＰＫ信号通路，对其结构和功能以及在全身炎症反应中的作用机制已有所了解，在信号通路水平阻断和调控ｐ３８ＭＡＰＫ的表达和活性、治疗过度炎症反应性疾病可能成为急性炎症反应新的治疗途径。     

Cardiovascular lipid accumulation with Coxsackie B virus infection in mice

The authors used a myocarditic coxsackievirus B3 infection in Balb/c mice to investigate cardiovascular lipid accumulation and whether a cholesterol-enriched diet influences the development of the myocardial inflammatory reaction. It was found that, seven days after CB3 infection, the accumulation of 14C-cholesterol increased by 75% (P less than 0.001) in the heart and by 92% (P less than 0.001) in the aorta. This infection also caused extensive inflammatory lesions (4.5% of tissue section area) and lipid accumulation in the myocardium seven days after inoculation. Seven weeks on a 1% cholesterol-enriched diet did not affect the myocardial area damaged (3.9%), the lethality, or immune cell activity (T, B, and natural killer [NK] cells). The response pattern of myocardial lymphocyte subpopulations was studied with an immune histochemical staining technique. The number of Mac 2+ (macrophages), class II expressing cells, or the T cytotoxic, suppressor/T helper cell ratio was not changed by the cholesterol diet. The number of class II cells tended to increase (38%) with cholesterol and was positively correlated (P less than 0.001) with the Mac 2 expression regardless of the cholesterol diet. Although moderate diet-induced hypercholesterolemia did not alter host response to viral infection, these results support the idea that virus and immune cells may cooperate and play a role in arterial and myocardial lipid accumulation, possibly acting as initiating factors for atherosclerosis.     

The role of inflammation in the pathophysiology of CF lung disease

Cystic fibrosis (CF) lung disease is characterized by a self-perpetuating cycle of airway obstruction, chronic bacterial infection, and vigorous inflammation that results in structural damage to the airway. CF patients have a predilection for infection with a limited spectrum of distinctive bacteria that initiate a vigorous inflammatory response which is more harmful than protective. The airway epithelial cell, which normally expresses the cystic fibrosis transmembrane conductance regulator (CFTR), directs the inflammatory response. Defects in CFTR are associated with increased production of proinflammatory mediators including IL-8, a potent neutrophil chemoattractant that stimulates the influx of massive numbers of neutrophils into the airways. These neutrophils are the primary effector cells responsible for the pathological manifestations of CF lung disease. Documented deficiencies in immuno regulatory molecules such as IL-10 likely contribute to the generation of the excessive and persistent inflammatory response. Since inflammation is a key contributor to the pathogenesis of CF lung disease, anti-inflammatory therapy must assume a larger role in CF until a cure is discovered. To date, attention has focused primarily on the therapeutic potential of systemic and inhaled corticosteroids and the non-steroidal anti-inflammatory drug (NSAID) ibuprofen. Development of new anti-inflammatory therapies that impact intracellular signaling pathways and cell-cell communication molecules likely will have the greatest impact on limiting the excessive production of the inflammatory mediators in the CF lung, thereby slowing the decline in lung function and improving survival.     

Regulation of gap junctional communication by a pro-inflammatory cytokine in cystic fibrosis transmembrane conductance regulator-expressing but not cystic fibrosis airway cells

Airway inflammation is orchestrated by cell-cell interactions involving soluble mediators and cell adhesion molecules. Alterations in the coordination of the multicellular process of inflammation may play a major role in the chronic lung disease state of cystic fibrosis (CF). The aim of this study was to determine whether direct cell-cell interactions via gap junctional communication is affected during the inflammatory response of the airway epithelium. We have examined the strength of intercellular communication and the activation of nuclear factor-kappaB (NF-kappaB) in normal (non-CF) and CF human airway cell lines stimulated with tumor necrosis factor-alpha (TNF-alpha). TNF-alpha induced maximal translocation of NF-kappaB into the nucleus of non-CF as well as CF airway cells within 20 minutes. In non-CF cells, TNF-alpha progressively decreased the extent of intercellular communication. In contrast, gap junctional communication between CF cells exposed to TNF-alpha remained unaltered. CF results from mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Interestingly, transfer of wild-type CFTR into CF cells by adenovirus-mediated infection was associated with the recovery of TNF-alpha-induced uncoupling. These results suggest that expression of functional CFTR is necessary for regulation of gap junctional communication by TNF-alpha. Gap junction channels close during the inflammatory response, therefore limiting the intercellular diffusion of signaling molecules, and thereby the recruitment of neighboring cells. Defects in this mechanism may contribute to the excessive inflammatory response of CF airway epithelium.     

Unregulated inflammation shortens human functional longevity

Systemic inflammation, represented in large part by the production of pro-inflammatory cytokines, is the response of humans to the assault of the non-self on the organism. Three distinct types of human ailments - namely autoimmunity, presenile dementia (Alzheimer's disease), or atherosclerosis - are initiated or worsened by systemic inflammation. Autoimmunity is unregulated hyperimmunity to organ-specific proteins, inducing rapid turnover of antigen-specific T cells of the acquired immune system with ultimate exhaustion and loss of acquired immunity IL-2 and IFN-gamma production and proliferative decline, conforming to the limited capacity of clonal division (Hayflick phenonmenon). In Alzheimer's disease (AD), the primary degenerative process of amyloid-beta (AJ3) protein precedes a cascade of events that ultimately leads to a local "brain inflammatory response". Unregulated systemic immune processes are secondary but important as a driving-force role in AD pathogenesis. Atherosclerosis, an underlying cause of myocardial infarction, stroke, and other cardiovascular diseases, consists of focal plaques characterized by cholesterol deposition, fibrosis, and inflammation. The presence of activated T lymphocytes and macrophages indicate a local immunologic activation in the atherosclerotic plaque that may be secondary to unregulated pro-inflammatory cytokines too. The premature hyperimmunity of autoimmunity, the local "brain inflammatory response" to A/3 protein in AD, and the immune response to fatty changes in vessels in atherosclerosis all signal the critical importance of unregulated systemic inflammation to common neurological and cardiovascular disease that shortens the nominal longevity of humans.     

Evidence for an active inflammatory process in the hibernating human myocardium

Myocardial hibernation refers to a state of prolonged impairment of left ventricular function in the presence of coronary artery disease, which may be reversed by revascularization. In this study we present evidence for a local inflammatory reaction in hibernating myocardial segments from patients undergoing coronary revascularization. We obtained transmural myocardial biopsies guided by transesophageal echocardiography from patients with ischemic ventricular dysfunction undergoing bypass surgery. Among the 28 biopsied segments included in the study, 23 showed evidence of systolic dysfunction. The majority of dysfunctional segments (85.7%) were viable ((201)Tl uptake >/= 60%). The samples were stained with markers for mast cells, mature resident macrophages, and the monoclonal antibody Mac387 that labels newly recruited myeloid cells. Dysfunctional segments showed more extensive fibrosis and higher macrophage density than normal segments. Among the 23 dysfunctional segments, 12 recovered function as assessed with echocardiograms 3 months after revascularization. Segments with postoperative functional recovery had comparable macrophage and mast cell density with those showing persistent dysfunction. However, biopsied segments that subsequently recovered function contained significantly higher numbers of newly recruited Mac387-positive leukocytes (18.7 +/- 3.1 cells/mm(2), n = 12 versus 8.6 +/- 0.9 cells/mm(2), n = 11; P = 0.009). In addition, monocyte chemotactic protein-1, a potent mononuclear cell chemoattractant, was predominantly expressed in segments with recovery of function. Myocardial hibernation is associated with an inflammatory response leading to active leukocyte recruitment. Dysfunctional myocardial segments that show an active inflammatory reaction have a greater potential for recovery of function after revascularization. We postulate that revascularization may promote resolution of the ongoing inflammation, preventing further tissue injury and fibrosis.     

Roles of T lymphocytes in pulmonary fibrosis

Infiltration of T lymphocytes in the lungs is common in patients with and in animal models of pulmonary fibrosis. The role of these cells in regulating the accumulation of extracellular matrix, particularly collagen, is not understood completely. Research literature provides evidence for a profibrotic, an antifibrotic, or no significant role of T lymphocytes in pulmonary fibrosis. This review offers a discussion of such evidence with the focus on phenotypes of pulmonary T lymphocytes and related profibrotic and antifibrotic mechanisms. It appears unlikely that T lymphocytic infiltration per se is the central driving force in most cases of pulmonary fibrosis. Instead, evidence suggests that T lymphocytes may modulate the inflammatory and healing responses in the lungs in a profibrotic or antifibrotic manner, depending on their phenotype. Phenotypic reshaping, rather than elimination of the infiltrating pulmonary T lymphocytes, may be a promising approach to improving outcomes in patients with pulmonary fibrosis.     

IL-17 Producing γδ T Cells are Required for a Controlled Inflammatory Response after Bleomycin-induced Lung Injury

BACKGROUND: gammadelta T cells play a key role in the regulation of inflammatory responses in epithelial tissue, and in adaptive immunity, as gammadelta T cell deficient mice have a severely impaired capacity to clear lung pathogens. gammadelta T cells regulate the initial inflammatory response to microbial invasion and thereby protect against tissue injury. Here we examined the response of gammadelta T cells to lung injury induced by bleomycin, in an effort to study the inflammatory response in the absence of any adaptive immune response to a pathogen. RESULTS: After lung injury by bleomycin, we localized the gammadelta T cells to the lung lesions. gammadelta T cells were the predominant source of IL-17 (as detected by flow cytometry and real-time PCR). Moreover, gammadelta T cell knockout mice showed a significant reduction in cellular infiltration into the airways, reduced expression of IL-6 in the lung, and a significant delay in epithelial repair. CONCLUSION: Mouse gammadelta T cells produce IL-17 in response to lung injury and are required for an organized inflammatory response and epithelial repair. The lack of gammadelta T cells correlates with increased inflammation and fibrosis.     

Experimental Trypanosoma cruzi cardiomyopathy in BALB/c mice. The potential role of intravascular platelet aggregation in its genesis

In male BALB/c mice aged 5-6 weeks inoculated three times at intervals of 15 days with 1 X 10(7) epimastigote forms of the PF strain of Trypanosoma cruzi and challenged 30 days after the last inoculation with 2 X 10(4) trypomastigote forms of the Colombia strain of T cruzi (the mice were sacrificed 80-100 days after the challenge) a cardiomyopathy very similar to that observed in the chronic phase of Chagas' disease in man develops. The cardiac syndrome is characterized grossly by cardiomegaly with hypertrophy, dilatation of ventricular chambers, and thinning of the apex of the left ventricle (apical aneurysm) and microscopically by focal areas of myocytolytic necrosis and myocardial degeneration with an inflammatory response composed of mononuclear cells (predominantly macrophages and a few lymphocytes) with concurrent interstitial fibrosis and occasional myofibers containing pseudocysts. In addition, aggregated platelets and occlusive thrombi were found in small epicardial and intramyocardial vessels of infected mice as compared with controls. The potential role of intravascular platelet aggregation in the causation of focal myocardial necrosis and degeneration and apical aneurysm in experimental T cruzi cardiomyopathy in BALB/c mice is discussed.