PPARγ基因沉默对细胞炎症反应的调控作用

发布时间：2018-01-10 05:12

本文关键词：PPARγ基因沉默对细胞炎症反应的调控作用　出处：《第三军医大学》2005年博士论文　论文类型：学位论文

【摘要】：炎症,作为与人类多种疾患息息相关的病理过程而备受国际医学界的瞩目,目前仍是临床与基础医学研究的重要课题。业已研究证实,过度炎症反应是创伤后多种并发症,如脓毒症/脓毒性休克、急性呼吸窘迫综合征、多器官功能不全综合征等的重要病理基础。为此,我们已从效应细胞表面膜受体、细胞内信号通路、靶基因表达调控、效应细胞凋亡与炎症反应的关系四方面研究炎症反应的发生机制和关键的调控环节,并在此基础上寻找新的抗炎措施。近五年来,我们不仅在揭示创伤后炎症反应发生机制方面取得一定的进展,同时,研究发现,机体自身的抗炎保护效应机制也是影响炎症发生发展的重要因素。此外,我们研究发现,严重创伤早期,体内单核细胞合成促炎介质能力明显增强,但随后却明显受抑,细胞产生抗炎介质如IL-1Ra、IL-10 无明显减少。基于上述结果,我们认为,炎症应是一个促炎与抗炎反应相互依存、互为拮抗的复杂过程,伴随炎症产生的各种内源性抗炎保护效应机制固然是机体在炎症环境下得以维持内环境稳定的根本需要,但抗炎机制的失调,不仅是促使早期有限性保护性炎症反应转化为破坏性过度炎症反应的重要机制,同时也是造成创伤机体免疫力低下、对感染易感性增加的重要原因。然而,对于机体自身调控抗炎反应的机制,迄今尚鲜见文献报道。近年研究发现,细胞内过氧化物酶体增殖物激活受体(peroxisome proliferator-activated receptors,PPARs)通过反式阻抑机制对细胞的促炎反应具有明显的抑制作用。PPARs 有三种异构体:PPARα、PPARβ/δ和PPARγ,在巨噬细胞、树突细胞、T细胞、B 细胞等广泛表达。早期研究认为,它们在调节脂质代谢方面发挥重要作用。近年研究发现,PPARs 也是调控炎症反应的关键点(checkpoint)。有关PPARγ抗炎作用研究发现:PPARγ激动剂能明显抑制炎性刺激诱导单核/巨噬细胞产生促炎细胞因子(TNFα、IL1、IL6、NO)的产生;PPARγ配体预处理野生型动物,能明显降低组织内促炎细胞因子的表达,减轻炎症局部和远隔部位的组织损伤,对多种实验性炎性疾病,如急性心肌炎、自身免疫性脑脊髓炎、多发性硬化等均显示较好的治疗作用;然而,PPARγ基因敲除可导致胚胎死亡,目前尚无PPARγ缺陷动物,仅有通过同源重组建立的PPARγ+/-嵌合小鼠模型。关于PPARγ对细胞其它抗炎保护效应的
[Abstract]:Inflammation, as a pathological process closely related to a variety of human diseases, has attracted the attention of the international medical community. At present, it is still an important subject in clinical and basic medicine research, which has been confirmed. Excessive inflammatory reaction is an important pathological basis for various post-traumatic complications, such as sepsis / septic shock, acute respiratory distress syndrome, multiple organ dysfunction syndrome and so on. We have studied the mechanism and key regulation of inflammatory reaction from four aspects: membrane receptor, intracellular signal pathway, target gene expression and regulation, and the relationship between apoptosis and inflammatory response. In the last five years, we have not only made some progress in revealing the mechanism of post-traumatic inflammatory response, but also found that. The mechanism of anti-inflammatory protective effect is also an important factor affecting the occurrence and development of inflammation. In addition, we found that in the early stage of severe trauma, the ability of monocytes to synthesize inflammatory mediators was significantly enhanced. But then it was obviously inhibited, and the cell produced anti-inflammatory mediators such as IL-1 Rahl IL-10. Based on the above results, we believe that inflammation should be a pro-inflammatory and anti-inflammatory response is dependent on each other. With the complex process of antagonism, the mechanism of endogenous anti-inflammatory protective effect produced by inflammation is certainly the fundamental need for the body to maintain the stability of the internal environment in the inflammatory environment, but the anti-inflammatory mechanism is out of balance. It is not only an important mechanism to promote the early limited protective inflammatory reaction into destructive excessive inflammatory reaction, but also an important reason for the low immunity of trauma organism and the increase of susceptibility to infection. The mechanism of self-regulation of anti-inflammatory response has been rarely reported. In recent years, peroxisome proliferator-activated receptors, an intracellular peroxisome proliferator activated receptor, has been found. PPARs have obvious inhibitory effect on the pro-inflammatory response of cells through the mechanism of trans-inhibition. PPARs have three isomers: PPAR 伪, PPAR 尾 / 未 and PPAR 纬. They are widely expressed in macrophages, dendritic cells, T cells and B cells. Early studies suggest that they play an important role in regulating lipid metabolism. PPARs is also a key point for regulating inflammation. In the study of anti-inflammatory effect of PPAR 纬, it was found that PPAR 纬 agonist could significantly inhibit the production of proinflammatory cytokine TNF- 伪 in monocytes / macrophages induced by inflammatory stimulation. The production of IL 1, IL 6 and no; Pretreatment with PPAR 纬 ligands can significantly reduce the expression of pro-inflammatory cytokines and reduce the tissue damage in the local and distant areas of inflammation. It can be used to treat many experimental inflammatory diseases, such as acute myocarditis. Autoimmune encephalomyelitis and multiple sclerosis showed good therapeutic effect. However, PPAR 纬 gene knockout can lead to embryo death, and there are no PPAR 纬 deficient animals. PPAR 纬 r-chimeric mouse model was established only by homologous recombination.
【学位授予单位】：第三军医大学
【学位级别】：博士
【学位授予年份】：2005
【分类号】：R363

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