Sirt1在脓毒血症继发的急性肺和肾损伤中的保护作用
[Abstract]:Sepsis is a potentially fatal systemic inflammatory response, also known as systemic inflammatory response syndrome (SIRS), a refractory disease with high morbidity and mortality from severe infections. Sepsis can also be considered an excess from infection to multiple organ dysfunction syndrome. Sepsis can cause organ dysfunction of failure type. Clinical observation shows that patients with sepsis have a high risk of developing acute lung injury (ALI) and acute kidney injury (AKI). Acute Respiratory Distress Syndrome (ARDS), a severe form of ARDS, often leads to multiple organ failure (MOF) with a clinical mortality rate of about 30% - 50%. In addition, as a natural blood filtration system, the kidney becomes a direct target for organ damage in systemic inflammatory reactors. The expression of Sirt1 was decreased in the elderly. It was also reported that the expression of Sirt1 was decreased in patients with chronic obstructive pulmonary disease (COPD), so we speculated that Sirt1 might play a role in the regulation of inflammation. We used cecum ligation puncture (CLP) and lipopolysaccharide (LPS) to induce sepsis, respectively. To study the effect and mechanism of Sirt1 on lung and kidney injury.
Sirtuin 1 (Sirt1), a member of the Sirtuin family, is a deacetylase first discovered in yeast. Unlike the classical histone deacetylation pathway, Sirt1 exerts its deacetylation function by deacetylating lysine residues to regulate other protein functions, such as nuclear transcription factors kB and p53. Sirt1 has been found to play an important role in inflammation, apoptosis, anti-stress, metabolism, differentiation and aging, while the role of Sirt1 in sepsis has not been well understood. In this study, we used Sirt1 knockout mice to study its role in acute lung and kidney injury induced by sepsis and to further clarify its regulation. Our experiments showed that Sirt1 knockout mice were more susceptible to ALI and AKI induced by sepsis.
In the first part of the experiment, we mainly studied the effect and mechanism of Sirt1 on ALI secondary to sepsis. In the experiment, we performed CLP on the wild type mice with Sirt1 gene knockout and its homology, and successfully induced sepsis model in mice. To understand the infiltration of neutrophils, we examined the activity of myeloperoxidase (MPO) in lung tissue homogenate 24 hours after CLP. Then we used kits to detect IL-6 in serum and lung tissue 6 hours and 24 hours after CLP. In order to further understand the mechanism of Sirt1 regulating pulmonary inflammation, we used Western blot to detect the expression of Sirt1-regulated direct and indirect target proteins in the lung. Our study demonstrated that the activation of NF-kB in the lungs of Sirt1 knockout mice was enhanced, and the downstream adhesion molecule-intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) were fine. The expression of extracellular regulated kinase 1/2 (ERK1/2), signal transduction activator 3 (stat3), caspase 3, and caspase 7 were significantly increased. The above results demonstrated that Sirt1 knockout enhanced lung injury by triggering excessive inflammation and related inflammatory complex pathways.
In the second part of the experiment, we mainly studied the role and mechanism of Sirt1 in regulating renal injury secondary to sepsis. We established sepsis model in LPS-induced mice. First, the detection of BUN and KIM-1 in serum showed that renal function was significantly impaired in sepsis. Histological examination revealed that sepsis also caused renal tubular injury and inflammation. Increased inflammation and the production of pro-inflammatory mediators were closely related to the up-regulation of adhesion molecules (such as ICAM-1 and VCAM-1). These early inflammatory reactions caused infiltration of inflammatory cells during renal injury, whereas excessive infiltration of inflammatory cells could be induced. NF-kB regulates the transcription of various inflammatory factors during the regulation of inflammatory factors, thereby affecting the process of inflammation. Sirt1 knockout leads to the activation of NF-kB, and subsequently activated NF-kB leads to the increase of cytokines including IL-6 and TNF-alpha, which is the result of AKI. Significant markers. Cytokines can also activate signaling pathways, such as the cascade of Stat3 and ERK1/2. These experiments have shown that Sirt1 has a protective effect on AKI induced by sepsis and produces its protective mechanism by regulating the activation of NF-kB.
To sum up, Sirt1 plays a protective role in acute lung and kidney injury induced by sepsis. Sirt1 exerts its protective function mainly by regulating the activation of nuclear transcription factors, which in turn leads to the activation of inflammatory pathways such as Stat3, ERK1/2 and caspase. Therapeutic targets for injury.
【学位授予单位】:吉林大学
【学位级别】:博士
【学位授予年份】:2014
【分类号】:R459.7
【相似文献】
相关期刊论文 前10条
1 张惠珍,朱玲t ;慢性肉芽肿1例报告[J];临床儿科杂志;1991年04期
2 杜隽铭;一氧化氮延迟吸入法保护革兰阴性脓毒血症猪肺泡毛细血管膜完整性[J];国外医学.骨科学分册;1997年04期
3 邓烈华,姚华国,邵义明;血必净对脓毒血症患者前降钙素影响的临床观察[J];实用医技杂志;2005年12期
4 林玲,蔡秀军;脓毒血症患者外周血白细胞凋亡与病情及预后关系[J];中国急救医学;2005年11期
5 朱志云;李凌;叶纪录;;早期中心静脉血氧饱和度监测在严重脓毒血症与感染性休克中的意义[J];现代医药卫生;2008年20期
6 盛虹;曹伟新;;鱼油在脓毒血症中的应用[J];上海交通大学学报(医学版);2010年01期
7 金杰波;周军;陈双;;甲亢治疗后继发脓毒血症合并肠外瘘1例报道[J];岭南现代临床外科;2010年02期
8 赵湛元;肖倩霞;张志刚;;血乳酸动态监测对脓毒血症预后的临床意义[J];临床医药实践;2010年14期
9 宋红梅;张泰标;;血必净注射液治疗脓毒血症临床观察[J];中国中医急症;2010年08期
10 闵安如;王伟明;龙连圣;;重型颅脑伤并发肠源性脓毒血症的临床分析[J];南京部队医药;2000年05期
相关会议论文 前10条
1 王春亭;孟玫;蒋进皎;张继承;任宏生;楚玉峰;曾娟;孟冲;郄国强;于结滨;;连续性高容量血液滤过对脓毒血症可溶性黏附分子的影响[A];第三届重症医学大会论文汇编[C];2009年
2 崔微艳;陆洁;邹静蓉;何玉峰;;63例重症脓毒血症的临床分析[A];“2008灾害创伤与急救新进展”学术交流会学术论文集[C];2008年
3 卢中秋;李景荣;卢才教;程俊彦;黄唯佳;周铁丽;李秉熙;陈雷;;弧菌性脓毒血症的早期临床诊断与治疗[A];中华医学会急诊医学分会第十次全国复苏中毒学术论文交流会论文汇编[C];2004年
4 冯思霞;汪杨;李玉香;王峰;;瘤型麻风合并脓毒血症1例[A];第二届传染病诊治高峰论坛暨2009年浙江省感染病、肝病学术年会论文汇编[C];2009年
5 刘小彭;高新;周祥福;温星桥;狄金明;蒲小勇;王德娟;司徒杰;;输尿管急性梗阻伴脓毒血症的急诊处理(附72例报告)[A];第十七届全国泌尿外科学术会议论文汇编[C];2010年
6 蒋丽;;核因子-κB活化在大鼠脓毒血症胃肠黏膜屏障中的作用[A];中华医学会急诊分会第五届全国危重病学术交流会论文汇编[C];2004年
7 马中富;翟诚顺;梁艳冰;詹红;唐皓;叶海宁;;脓毒血症大鼠心肌细胞凋亡及其机制研究[A];2005年全国危重病急救医学学术会议学术论文集[C];2005年
8 胡静;陆国平;陆铸今;卢亚芳;贺骏;张灵恩;;新生儿脓毒血症血液净化的护理[A];中华医学会第十四次全国儿科学术会议论文汇编[C];2006年
9 胡静;陆国平;陆铸今;卢亚芳;贺骏;张灵恩;;新生儿脓毒血症血液净化的护理[A];2006(第三届)江浙沪儿科学术会议暨浙江省儿科学术年会论文汇编[C];2006年
10 高巨;;中西医结合对脓毒血症发病机制和治疗的进展[A];中国中西医结合学会围手术期专业委员会成立大会暨第二届全国中西医结合围手术期医学专题研讨会论文集[C];2007年
相关重要报纸文章 前10条
1 本报记者 东辰;礼来脓毒血症新药获准欧洲上市[N];中国高新技术产业导报;2002年
2 力信 小涛;生物工程点石成金 人体蛋白也成良药[N];医药经济报;2002年
3 本报记者 孙晨 中国金药网联合报道;“第一”——礼来追求的竞争高标[N];中国高新技术产业导报;2002年
4 陶振峰 李晓明;咽源性纵隔脓肿的诊治[N];中国中医药报;2004年
5 杨冉;痔疮的危害[N];医药经济报;2003年
6 ;感染性疾病检测酝酿革命[N];中国医药报;2002年
7 骆景铭;秋疖的防治[N];中国中医药报;2001年
8 北京协和医院老年示范病房 曲璇 朱鸣雷 刘晓红;生命终点,选择尊严[N];健康报;2011年
9 王晓丽;年轻女性患阑尾炎治疗要彻底[N];农村医药报(汉);2009年
10 杜长明;少女阑尾炎应尽早切除[N];大众卫生报;2002年
相关博士学位论文 前10条
1 高蓉;Sirt1在脓毒血症继发的急性肺和肾损伤中的保护作用[D];吉林大学;2014年
2 谢俊然;羟乙基淀粉130/0.4对脓毒血症大鼠全身抗炎作用及相关机制研究[D];浙江大学;2010年
3 唐e
本文编号:2196904
本文链接:https://www.wllwen.com/yixuelunwen/jjyx/2196904.html