自噬与免疫相关性自噬的研究进展

自噬是细胞内的长寿命蛋白和大分子蛋白成分利用溶酶体进行降解的过程,是真核细胞所特有的分解代谢途径,在能量代谢循环、促进细胞存活中都起到相当重要的作用。随着生命科学领域相互交叉学科的迅速发展,自噬在免疫、炎症、肿瘤等方面的地位也越来越多地受到人们的关注,而自噬与炎症感染、机体免疫及自身免疫反应之间的联系也逐渐成为了研究的焦点。研究发现,通过自噬诱导适度的机体免疫对稳定生物体的正常机能状态具有非常重要的生理意义。本文对自噬与免疫相关性自噬方面的研究进展进行综述。     

细胞自噬的调控与自噬程序性死亡的研究进展

自噬(autophagy)是一种溶酶体依赖性降解途径,涉及细胞内长寿蛋白和受损伤细胞器的降解,其既是细胞保守的自我防御机制,又是一种程序性细胞死亡机制(PCD),与机体的多种疾病有密切关系.自噬具有独特的形态改变和特有的调控通路,自噬的调控涉及到多种机制、如翻译后修饰等.凋亡是研究最清楚的程序性细胞死亡机制,凋亡与细胞自噬程序性死亡之间存在着复杂的关系.对哺乳动物细胞自噬的分子调控机制,自噬程序性细胞死亡过程及其与凋亡的关系等方面进行探讨很有意义.     

线粒体自噬与肺部疾病的研究进展

线粒体自噬是选择性自噬的重要形式之一,可通过调控生物体内线粒体质量影响肺部疾病发生发展。线粒体自噬在不同的肺部疾病中发挥着不同的作用。如在特发性肺纤维化与急性肺损伤中,线粒体自噬水平过高或过低都可加重病情;而在肺动脉高压中,线粒体自噬水平过高时会产生损害效应。除此之外,在慢性阻塞性肺疾病中,线粒体自噬可调节细胞坏死以及控制细胞炎性反应。因此,深入了解线粒体自噬调控机制对肺部疾病的防治具有重要意义。     

脂肪组织炎性反应的研究进展

本文探讨了与脂肪组织炎性反应相关的脂质介质,促炎介质:环氧合酶衍生的二十烷类化合物(如前列腺素);促炎性反应消退介质:由ω-6-多不饱和脂肪酸产生的脂氧素,以及由ω-3-多不饱和脂肪酸产生的消退素等。炎性反应的治疗不应局限于急性级联拮抗剂或抑制剂的使用,而应扩大到考虑炎性反应消退阶段诱导剂或激动剂的巨大治疗潜力。     

自噬的分子机制与病理生理意义

自噬是以细胞质空泡化为特征的溶酶体依赖性的降解途径。自噬可以降解胞质内受损的结构,并产生氨基酸、游离脂肪酸等物质以供蛋白质和能量的合成,使细胞能够适应缺氧和饥饿等环境。自噬的过程受一系列复杂的信号分子的调控,调控机制的失效与肿瘤、神经退行性疾病、衰老等有重要的联系。     

自噬与肿瘤关系的研究进展

自噬是细胞适应环境变化、防御病原微生物侵袭、维持内环境稳定的重要机制.在多种人类肿瘤中存在有自噬活性的改变,自噬在肿瘤的发生发展过程中起到了促进和抑制的双重作用.对自噬研究的不断深入,不仅进一步揭示了真核生物自身调控的复杂性和多样性,更为肿瘤的基因治疗及克服肿瘤耐药性提供了新的思路.现将自噬与肿瘤的发生、发展的研究进展做一综述.     

自噬与卵巢癌的研究进展

细胞自噬(autophagy)是将细胞内受损、变性或衰老的蛋白质以及细胞器运输到溶酶体进行消化降解的过程。近期研究发现自噬不仅对细胞内自我平衡调节起着重要作用,而且在肿瘤的发生发展中起着双刃剑的作用。研究自噬的分子机制以及自噬与卵巢癌的关系对卵巢癌防治有重大意义。     

细胞自噬与肝细胞癌的研究进展

细胞自噬是真核生物维持内环境稳态的一种保护性机制.同时,在维持肿瘤细胞存活及能量代谢方面具有重要作用,并通过不同机制影响肝癌的治疗效果.如肝细胞通过自噬维持肝内稳态,自噬引起肝癌细胞产生耐药性,以及自噬抑制剂和天然提取物通过自噬途径发挥抗肝癌作用.对深入探讨自噬在肝癌预防和治疗中的调控具有重大意义.     

细胞自噬与动脉粥样硬化关系的研究进展

自噬是一种降解病原体和相关细胞器尤其是损伤的线粒体的分子机制,自噬也可清除其他的细胞成分,例如炎症和细胞因子,这为抗炎症提供了重要的途径.相关研究发现,自噬的产生或降解能够影响动脉粥样硬化斑块的发展过程.因此,在疾病出现时,自噬的调节对于疾病治疗的靶点具有重要的意义.然而,在正常情况和炎症反应时,自噬的调节方式是多方面的.这些错综复杂的改变是通过炎症和环境刺激所产生的,这对于了解和揭示自噬调节的炎症和提供相应的治疗方案是必不可少的.因而人了解自噬的分子机制,以及血管内皮细胞、血管平滑肌细胞、巨噬细胞自噬在动脉粥样硬化中起到的作用对于疾病的发展和靶向治疗具有重要意义.     

体外循环后全身炎性反应

全身炎性反应(SIRS)是体外循环手术后的常见并发症.体外循环中由于血液与体外循环装置中的气体界面及管道的作用,启动三个相交的血浆蛋白酶旁路的激活,这些旁路包括激肽-激肽释放酶系统、凝血-纤溶系统、补体系统,通过一系列的蛋白分解产生活化的致炎性介质,激活白细胞、内皮细胞及血小板,促使血管扩张及通透性增加.激活的细胞成分能分泌炎性介质包括细胞因子,增强这一反应过程,最终导致组织损伤及器官功能失调.     

Mouse models of intestinal inflammation as tools to understand the pathogenesis of inflammatory bowel disease

Mouse models of intestinal inflammation resemble aspects of inflammatory bowel disease in humans. These models have provided important insights into mechanisms that control intestinal homeostasis and regulation of intestinal inflammation. This viewpoint discusses themes that have emerged from mouse models of intestinal inflammation including bacterial recognition, autophagy, the IL‐23/Th‐17 axis of inflammation as well as the role of negative regulators. Many of the pathways highlighted by model systems have been identified in recent genome‐wide association studies in human validating the relevance of mouse models to human inflammatory bowel disease. Understanding of the complex biological mechanisms that lead to intestinal inflammation in mouse models may help to define targets for treatment of human diseases.     

The granuloma in Crohn's disease. A bioptical study

Serial sections of 1434 colonic and rectal biopsies of 347 patients with Crohn's disease were performed. The relationship between the incidence of granulomas and the inflammatory alterations of the mucosa and some clinical parameters was studied. The presence of granulomas depends on the severity of inflammatory alterations and not on the site of the biopsy. The number of granulomas per mm3 increases from caecum to rectum. The incidence of granulomas decreases with age, duration of illness and under a conservative therapy. If several biopsies, taken at the same or at different times, are studied, granulomas can be found in 40-50% of these patients.     

Increased expression of receptor activator of NF-kappaB ligand (RANKL), its receptor RANK and its decoy receptor osteoprotegerin in the colon of Crohn's disease patients

Crohn's disease (CD) is associated with low bone mass due to chronic inflammation and other factors. Receptor activator of NF-kappaB ligand (RANKL), its receptor RANK and its decoy receptor osteoprotegerin (OPG) are potentially involved in this process as they regulate osteoclastogenesis and are influenced by pro-inflammatory cytokines. The aim of this study was to determine the levels of soluble RANKL (sRANKL), RANK and OPG expression both in the serum and in the colon of CD patients. Levels of sRANKL and OPG were assessed in the serum and the supernatants of cultured colonic biopsies in patients with CD and controls by ELISA. RANK expression was explored by immunostaining and immunofluorescence of fixed colonic samples. OPG and sRANKL levels were higher in the serum of CD patients as compared to age- and sex-matched controls. Levels of sRANKL and OPG were significantly enhanced in cultured colonic biopsies from CD, and OPG levels correlated with histological inflammation, and pro- and anti-inflammatory cytokine levels. No significant correlation was found for sRANKL. RANK+ cells were increased in the colon of CD, particularly in inflamed areas. These cells were positive for CD68 or S100 protein. We conclude that serum and local levels of sRANKL and OPG are increased in CD. Moreover, RANK is expressed in the colonic mucosa by subpopulations of activated macrophages or dendritic cells at higher levels in CD compared to normal colon.     

Identification of serum and tissue micro‐RNA expression profiles in different stages of inflammatory bowel disease

The altered expression of micro‐RNA (miRNA) has been associated with Crohn's disease (CD) and ulcerative colitis (UC). The aim of this study was to establish specific miRNA expression patterns in the serum and mucosa of inflammatory bowel disease (IBD) patients (UC and CD with colonic involvement) at different stages of the disease. Serum and biopsies from nine active CD (aCD), nine inactive CD (iCD), nine active UC (aUC) and nine inactive UC (iUC) and serum from 33 healthy subjects were collected. Up to 700 miRNAs were evaluated by the TaqMan® human miRNA array. The ΔCt values were obtained using the mean expression values of all expressed miRNAs in a given sample as a normalization factor for miRNA real‐time quantitative polymerase chain reaction data. The levels of serum miRNAs in CD and UC patients were different to healthy subjects. Thirteen serum miRNAs were expressed commonly in CD and UC patients. Two miRNAs were higher and four miRNAs were lower in the serum of aCD than iCD. No serum miRNA was regulated exclusively in aUC compared with iUC patients. Four miRNAs were higher and three miRNAs were lower in the mucosa of aCD than iCD. Two miRNAs were higher and three miRNAs were lower in the mucosa of aUC than iUC. No serum miRNAs coincided with tissue miRNAs in aCD and aUC patients. Our results suggest the existence of specific miRNA expression patterns associated with IBD and their different stages and support the utility of miRNA as possible biomarkers. This pilot study needs to be validated in a large prospective cohort.     

肥胖状态下不同组织细胞与自噬关系的研究进展

近年来越来越多的关注投向肥胖与自噬之间关系的研究,肥胖状态下机体不同组织细胞中的自噬发挥不同的作用.脂肪细胞特异性自噬基因Atg7和Atg5被敲除后脂滴积累减少,胰岛素抵抗得到改善;肝细胞中增加自噬可以提高其代谢功能:胰岛β-细胞中自噬缺陷可损伤细胞功能:适宜的自噬水平对维持骨骼肌内环境的稳态至关重要.     

细胞自噬在血管新生中作用的研究进展

自噬(autophagy)是细胞利用溶酶体降解自身受损的细胞器和大分子物质的过程,在稳定细胞内环境中发挥着重要作用。在血管新生的病理生理过程中,细胞自噬作用持续存在。从自噬的角度探索血管新生的发生发展进程,能够为临床治疗血管相关疾病提供新的思路。     

Regulation of galectin-3 function in mucosal fibroblasts: potential role in mucosal inflammation

Recently we identified galectin-3 (gal-3), which is secreted by colonic epithelial cells (CEC), to be a strong activator of colonic lamina propria fibroblasts (CLPF). Modulation of CLPF function may play a role during stricture and fistula formation in inflammatory bowel disease (IBD). Therefore, we investigated further the expression of gal-3 and effects on CLPF. The aim of this study is to perform a direct comparison of gal-3 between tissue from healthy controls and from patients with either Crohn's disease (CD) or ulcerative colitis (UC). CEC, CLPF and intestinal macrophages (IMAC) were isolated from control and IBD colonic tissue. Interleukin-8 secretion as a readout of CLPF activation was quantified by enzyme-linked immunosorbent assay. Gal-3 in cell cultures and tissue samples was evaluated by Western blot, immunofluorescence and immunohistochemistry. CLPF-migration was assayed in the 48-well modified Boyden chamber. Gal-3 expression was found in all segments of the colon. In the terminal ileum, less gal-3 was found compared with the colon. Immunohistochemistry and immunofluorescence revealed a homogenous distribution of gal-3 in CEC and IMAC of control mucosa and UC. However, significantly less gal-3 was found in IMAC from CD patients. In CD fistulae and stenoses, gal-3 expression was reduced significantly and barely detectable. In co-incubation studies lactose reduced significantly the CLPF-stimulatory potential of gal-3, indicating that the C-terminal domain of gal-3 is responsible for CLPF activation. Gal-3 stimulated CLPF migration in CLPF derived from fistulae. In conclusion, gal-3 expression is down-regulated in CD-fistulae and stenoses as well as in IMAC in CD patients. Gal-3 induces migration of CLPF derived from fistulae. Its role for stricture and fistula formation warrants further investigation.     

Activation of cytokines corroborate with development of inflammation and autoimmunity in thromboangiitis obliterans patients

Thromboangiitis obliterans (TAO) is a segmental inflammatory occlusive disorder that affects the arm and leg arteries of young smokers. The immune system seems to play a critical role in the aetiology of TAO; however, knowledge of the aspects involved in the progression of vascular tissue inflammation and, consequently, the evolution of this disease is still limited. This study was carried out to investigate the cytokine levels of tumour necrosis factor (TNF)‐α, interleukin (IL)‐1β, IL‐4, IL‐17 and IL‐23 in the plasma of TAO patients presenting with acute clinical manifestations. The study included 20 TAO patients (n = 10 women; n = 10 men) aged 38–59 years under clinical follow‐up, classified into two groups: (i) TAO former smokers (n = 11) and (ii) TAO active smokers (n = 9); the control groups included normal volunteer non‐smokers (n = 10, active smokers (n = 10) and former smokers (n = 10). Patients' plasma samples were measured using the sandwich enzyme‐linked immunosorbent assay. Statistical analyses were performed using the non‐parametric Mann–Whitney U‐test, with parameters significant at P < 0·05. The activities of all cytokines were different in groups of TAO patients when compared with normal controls, and decreased for control smokers. Increased levels of TNF‐α, IL‐1β, IL‐4, IL‐17 and IL‐23 were significant in patients with TAO when compared to the controls (P < 0·005, all parameters). The results presented here indicate an increased production of cytokines in TAO, possibly contributing to the inflammatory response observed in the patients' vascular levels. In addition, the increased levels of IL‐17 and IL‐23 suggest that the disturbance of TAO is involved with mechanisms of autoimmunity. Thus, the discovery of IL‐17 and its association with inflammation and autoimmune pathology has reshaped our viewpoint regarding the pathogenesis of TAO, which was based previously on the T helper type 1 (Th1)–Th2 paradigm.