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1、脓脓毒毒症症发发病病机机制制及及其其防防治治研研究究新新进进展展病例摘要男，男，男，男，6868岁，直肠癌根除术后半年、腹胀不适一天急诊入院。既岁，直肠癌根除术后半年、腹胀不适一天急诊入院。既岁，直肠癌根除术后半年、腹胀不适一天急诊入院。既岁，直肠癌根除术后半年、腹胀不适一天急诊入院。既往无高血压、心脏病、糖尿病、肾病等病史。往无高血压、心脏病、糖尿病、肾病等病史。往无高血压、心脏病、糖尿病、肾病等病史。往无高血压、心脏病、糖尿病、肾病等病史。入院体格检查：神志清，精神差，体温（入院体格检查：神志清，精神差，体温（入院体格检查：神志清，精神差，体温（入院体格检查：神志清，精神差，体温（T T）
2、38.538.5，心率，心率，心率，心率（HRHR）108108次次次次/min/min，呼吸频率（，呼吸频率（，呼吸频率（，呼吸频率（R R）3030次次次次/min/min，血压，血压，血压，血压（BPBP）130/88mmHg130/88mmHg，腹部膨隆，移动性浊音（，腹部膨隆，移动性浊音（，腹部膨隆，移动性浊音（，腹部膨隆，移动性浊音（+ +），叩诊鼓音，），叩诊鼓音，），叩诊鼓音，），叩诊鼓音，肝脾肋下未及，双下肢无水肿，神经系统检查阴性。腹部可见约肝脾肋下未及，双下肢无水肿，神经系统检查阴性。腹部可见约肝脾肋下未及，双下肢无水肿，神经系统检查阴性。腹部可见约肝脾肋下未及，双下肢无
3、水肿，神经系统检查阴性。腹部可见约10cm10cm陈旧疤痕。肛门指诊距肛陈旧疤痕。肛门指诊距肛陈旧疤痕。肛门指诊距肛陈旧疤痕。肛门指诊距肛5cm5cm可触及肿块，质硬，食指未能可触及肿块，质硬，食指未能可触及肿块，质硬，食指未能可触及肿块，质硬，食指未能通过。通过。通过。通过。血常规检查：白细胞计数血常规检查：白细胞计数血常规检查：白细胞计数血常规检查：白细胞计数18.41018.4109 9/L/L，中性粒细胞，中性粒细胞，中性粒细胞，中性粒细胞84.6%84.6%，血红，血红，血红，血红蛋白蛋白蛋白蛋白70 g/L 70 g/L ，血小板计数，血小板计数，血小板计数，血小板计数203102
4、03109 9/L/L。胸片：双肺呈弥漫性、渗出性改变，肺部阴影有大片状融合。胸片：双肺呈弥漫性、渗出性改变，肺部阴影有大片状融合。胸片：双肺呈弥漫性、渗出性改变，肺部阴影有大片状融合。胸片：双肺呈弥漫性、渗出性改变，肺部阴影有大片状融合。 诊断：直肠癌术后复发；诊断：直肠癌术后复发；诊断：直肠癌术后复发；诊断：直肠癌术后复发； 吻合口梗阻吻合口梗阻吻合口梗阻吻合口梗阻; ; ALI/ARDS? ALI/ARDS?次次次次日日日日因因因因神神神神志志志志不不不不清清清清、休休休休克克克克，急急急急诊诊诊诊静静静静脉脉脉脉快快快快诱诱诱诱导导导导气气气气管管管管插插插插管管管管全全全全麻麻麻麻下
5、下下下行行行行剖剖剖剖腹腹腹腹探探探探查查查查+ +肠肠肠肠粘粘粘粘连连连连松松松松解解解解+ +小小小小肠肠肠肠肠肠肠肠段段段段切切切切除除除除+ +小小小小肠肠肠肠造造造造瘘瘘瘘瘘术术术术。手手手手术术术术操操操操作作作作顺顺顺顺利利利利，术术术术中中中中出出出出血血血血少少少少，术术术术中中中中患患患患者者者者循循循循环环环环不不不不稳稳稳稳BP78/40mmHgBP78/40mmHg，采采采采用用用用乳乳乳乳酸酸酸酸林林林林格格格格液液液液3000ml3000ml、5%5%人人人人血白蛋白血白蛋白血白蛋白血白蛋白200ml200ml积极扩容，并输血浓缩积极扩容，并输血浓缩积极扩容，并输
6、血浓缩积极扩容，并输血浓缩RBC2URBC2U。术术术术后后后后PACUPACU复复复复苏苏苏苏拔拔拔拔管管管管送送送送外外外外科科科科普普普普通通通通病病病病房房房房，3h3h后后后后再再再再次次次次出出出出现现现现神神神神志志志志不不不不清清清清，血血血血气气气气分分分分析析析析显显显显示示示示COCO2 2蓄蓄蓄蓄积积积积（101mmHg101mmHg），紧紧紧紧急急急急气气气气管管管管插插插插管管管管+PCV+PCV转转转转ICUICU，去去去去甲甲甲甲肾肾肾肾上上上上腺腺腺腺素素素素和和和和肾肾肾肾上上上上腺腺腺腺素素素素0.01ug/kg/min0.01ug/kg/min维持血压。
7、维持血压。维持血压。维持血压。术后第一天 2002年巴塞罗那宣言年巴塞罗那宣言 全全社社会会要要像像当当年年重重视视“ “中中风风” ”和和“ “急急性性心心梗梗” ”一一样样，重重视视对对脓脓毒毒症症的的研研究究和和治治疗疗，争争取取把把脓脓毒毒症症的的发发生生率率和和死死亡亡率率降降低低到到可可接接受受的的水水平平（五五年时间病死率降低年时间病死率降低25%25%）。）。 全世界脓毒症死亡人数超过全世界脓毒症死亡人数超过1.41.4万万/ /天；天； 发病人数正以年发病人数正以年1.58.0%1.58.0%的比例增长；的比例增长； 过去过去1010年间增加病例年间增加病例139%139%，
8、且有继续增加的趋势。，且有继续增加的趋势。2121世纪对人类健康和经济发展的重大挑战世纪对人类健康和经济发展的重大挑战 全球每年超过全球每年超过1800 万人万人罹患脓毒症罹患脓毒症 死亡率高达死亡率高达30-70% 患者直接医疗花费约患者直接医疗花费约120,000元元/ /例例脓毒症脓毒症高发生率、高死亡率、高医疗负担高发生率、高死亡率、高医疗负担New Eng J Med, 2003; Crit Care Med, 2007New Eng J Med, 2003; Crit Care Med, 2007TLRsTLRsNLRsNLRs免疫细胞免疫细胞免疫细胞免疫细胞病原相关病原相关病原相
9、关病原相关分子模式分子模式分子模式分子模式PAMPsPAMPs内源性危险内源性危险内源性危险内源性危险分子分子分子分子DAMPsDAMPs免疫稳态失衡免疫稳态失衡免疫稳态失衡免疫稳态失衡病原微生物病原微生物病原微生物病原微生物清除障碍清除障碍清除障碍清除障碍重要脏器功重要脏器功重要脏器功重要脏器功能损伤能损伤能损伤能损伤/ /衰竭衰竭衰竭衰竭促炎促炎促炎促炎/ / / /抗炎介质瀑布样释放抗炎介质瀑布样释放抗炎介质瀑布样释放抗炎介质瀑布样释放警报素：募集、活化免疫效应细胞警报素：募集、活化免疫效应细胞HNPHNP、 、 、 、EDNEDNLL-37LL-37、 、 、 、NPMNPMBlood
10、 vesselBlood vessel警报素警报素警报素警报素EDNEDN、NPMNPM、HMGB1HMGB1上调免疫效应细胞产生上调免疫效应细胞产生上调免疫效应细胞产生上调免疫效应细胞产生炎性介质、介导组织脏器损伤炎性介质、介导组织脏器损伤炎性介质、介导组织脏器损伤炎性介质、介导组织脏器损伤 J Leukoc Biol, 2009J Leukoc Biol, 2009NPMNPM诱导鼠巨噬细胞促诱导鼠巨噬细胞促诱导鼠巨噬细胞促诱导鼠巨噬细胞促纤维化因子纤维化因子纤维化因子纤维化因子MCP-1MCP-1释放释放释放释放J Exp Med, 2008J Exp Med, 2008EDNEDN上调
11、上调上调上调DCDC细胞细胞细胞细胞TNF-a TNF-a 等细胞因子产生等细胞因子产生等细胞因子产生等细胞因子产生HMGB-1HMGB-1诱导鼠心脏诱导鼠心脏诱导鼠心脏诱导鼠心脏缺血再灌注损伤缺血再灌注损伤缺血再灌注损伤缺血再灌注损伤Circulation, Circulation, 20082008HNPHNP和和和和HBDHBD不仅直接作用于病原微生物的胞膜，且介不仅直接作用于病原微生物的胞膜，且介不仅直接作用于病原微生物的胞膜，且介不仅直接作用于病原微生物的胞膜，且介导免疫应答，是一类很有前景的新一代抗感染药物！导免疫应答，是一类很有前景的新一代抗感染药物！导免疫应答，是一类很有前景的
12、新一代抗感染药物！导免疫应答，是一类很有前景的新一代抗感染药物！20072007年：年：年：年：HNPHNP和和和和HBDHBD： 从从从从“ “防御防御防御防御” ”到到到到 进攻？进攻？进攻？进攻？阳离子抗菌肽：阳离子抗菌肽：阳离子抗菌肽：阳离子抗菌肽：HNPHNPHNPHNP等等等等警报素警报素HNP1-3在脓毒症中是在脓毒症中是双刃剑？双刃剑？20092009年：目前认为抗菌肽是把年：目前认为抗菌肽是把年：目前认为抗菌肽是把年：目前认为抗菌肽是把“ “双刃剑双刃剑双刃剑双刃剑” ”抗菌肽抗菌肽抗菌肽抗菌肽LL-37LL-37、HNPHNP、HBDHBD可能可能可能可能通通通通过异常过异
13、常过异常过异常“ “alarming”alarming”机体细胞，触机体细胞，触机体细胞，触机体细胞，触发炎症反应、破坏自身免疫稳态，发炎症反应、破坏自身免疫稳态，发炎症反应、破坏自身免疫稳态，发炎症反应、破坏自身免疫稳态，诱发人类自身免疫性疾病银屑病等诱发人类自身免疫性疾病银屑病等诱发人类自身免疫性疾病银屑病等诱发人类自身免疫性疾病银屑病等警报素警报素警报素警报素HNP1-3HNP1-3基因高拷贝数是脓毒症致脏器损伤的基因高拷贝数是脓毒症致脏器损伤的基因高拷贝数是脓毒症致脏器损伤的基因高拷贝数是脓毒症致脏器损伤的独立危险因素独立危险因素独立危险因素独立危险因素脓毒症临床研究脓毒症临床研究CN
14、PCNP 8 8CNPCNP8 8P P =1.1310=1.1310-9-9Area=0.77Area=0.77其卓越性能推动麻醉学发展并对医学和消费者媒体具有潜在其卓越性能推动麻醉学发展并对医学和消费者媒体具有潜在其卓越性能推动麻醉学发展并对医学和消费者媒体具有潜在其卓越性能推动麻醉学发展并对医学和消费者媒体具有潜在吸引力，使医务人员和病人了解临床研究和治疗的最新进展吸引力，使医务人员和病人了解临床研究和治疗的最新进展吸引力，使医务人员和病人了解临床研究和治疗的最新进展吸引力，使医务人员和病人了解临床研究和治疗的最新进展中性粒细胞是脓毒症时机体免疫应答的首要防御体系，而中性粒细胞是脓毒症时
15、机体免疫应答的首要防御体系，而中性粒细胞是脓毒症时机体免疫应答的首要防御体系，而中性粒细胞是脓毒症时机体免疫应答的首要防御体系，而HNP1-3HNP1-3HNP1-3HNP1-3是中性粒细胞最先释放的、含量最多的警报素分子是中性粒细胞最先释放的、含量最多的警报素分子是中性粒细胞最先释放的、含量最多的警报素分子是中性粒细胞最先释放的、含量最多的警报素分子科学问题的提出科学问题的提出始动脓毒症脏器功能损伤始动脓毒症脏器功能损伤始动脓毒症脏器功能损伤始动脓毒症脏器功能损伤？始动脓毒症脏器功能损伤的分子机制始动脓毒症脏器功能损伤的分子机制始动脓毒症脏器功能损伤的分子机制始动脓毒症脏器功能损伤的分子机制
16、？作为脓毒症治疗的分子靶标作为脓毒症治疗的分子靶标作为脓毒症治疗的分子靶标作为脓毒症治疗的分子靶标？p 研究目的研究目的 针对前面提出的科前面提出的科学学问题，进行行阐述述 一般分一般分为2-3部分，先部分，先从从临床或床或实验动物物来来明确明确某某种种作用，再在作用，再在细胞水平胞水平来来探探讨机理机理 要重点突出，切忌面面俱到要重点突出，切忌面面俱到例：例：题题题题为为为为“ “警警警警报报报报素素素素 HNP1-3HNP1-3在在在在始始始始动动动动脓脓脓脓毒毒毒毒症症症症致致致致多多多多脏脏脏脏器器器器损损损损伤伤伤伤中中中中的作用、机制及其干预治疗的研究的作用、机制及其干预治疗的研究
17、的作用、机制及其干预治疗的研究的作用、机制及其干预治疗的研究” ”的研究目的：的研究目的：的研究目的：的研究目的：一一一一、证证证证明明明明警警警警报报报报素素素素HNP1-3HNP1-3在在在在脓脓脓脓毒毒毒毒症症症症致致致致多多多多脏脏脏脏器器器器损损损损伤伤伤伤中中中中的的的的始动作用始动作用始动作用始动作用二二二二、明明明明确确确确警警警警报报报报素素素素HNP1-3HNP1-3始始始始动动动动脓脓脓脓毒毒毒毒症症症症致致致致多多多多脏脏脏脏器器器器损损损损伤伤伤伤的的的的分子机制分子机制分子机制分子机制（1 1）HNP1-3HNP1-3能够结合巨噬细胞表能够结合巨噬细胞表能够结合巨噬
18、细胞表能够结合巨噬细胞表面面面面P2X7P2X7受体受体受体受体（2 2）HNP1-3HNP1-3活化活化活化活化NLRP3NLRP3导致巨噬导致巨噬导致巨噬导致巨噬细胞细胞细胞细胞 pyroptosispyroptosis（3 3）HNP1-3HNP1-3通过非通过非通过非通过非NLRP3NLRP3途径促途径促途径促途径促进巨噬细胞进巨噬细胞进巨噬细胞进巨噬细胞IL-1IL-1 活化释放活化释放活化释放活化释放阳阳阳阳离子抗菌离子抗菌离子抗菌离子抗菌肽肽HNP1-3HNP1-3在脓毒症发生发展中的作用机制在脓毒症发生发展中的作用机制在脓毒症发生发展中的作用机制在脓毒症发生发展中的作用机制In
19、nate Immunity, 2013Innate Immunity, 2013Sphingosine Sphingosine 1-phosphate 1-phosphate receptor receptor 2 2 (S1PR2) (S1PR2) signaling signaling suppresses suppresses macrophage phagocytosis and impairs host defense against sepsismacrophage phagocytosis and impairs host defense against sepsis丝丝氨氨酸棕
20、酸棕榈酰榈酰CoACoA神神经酰经酰胺胺鞘磷脂鞘磷脂SPTSPT鞘磷脂酶鞘磷脂酶神神经经鞘鞘氨氨醇醇神神经酰经酰胺胺酶酶S1PS1P磷酸乙醇磷酸乙醇胺胺软软脂脂醛醛CoACoASPHKSPHK神神经经鞘鞘氨氨醇磷酸酶醇磷酸酶S1PS1P裂解酶裂解酶AbstractAnimalAnimalPhenotypePhenotypeFunctionFunctionClinical significanceClinical significanceCellCellMolecularMolecularPatientsPatientsMechanismsMechanisms The relationship
21、between S1PR2 and the outcome The relationship between S1PR2 and the outcome of sepsisof sepsisImpact of S1PR2 on the regulation of macrophage Impact of S1PR2 on the regulation of macrophage phagocytosis phagocytosis The molecular mechanisms of S1PR2 in inhibiting The molecular mechanisms of S1PR2 i
22、n inhibiting macrophage phagocytosis macrophage phagocytosis The relationship between S1PR2 expression in The relationship between S1PR2 expression in monocytes and the outcome of septic patientsmonocytes and the outcome of septic patientsContentsThe relationship between S1PR2 and the outcome of sep
23、sisImpact of S1PR2 on the regulation of macrophage phagocytosis The molecular mechanisms of S1PR2 in inhibiting macrophage phagocytosis The relationship between S1PR2 expression in monocytes and the outcome of septic patientsPart 1. The relationship betweenS1PR2 lung injury S1pr2S1pr2+/+/+ & & S1pr2
24、S1pr2-/- -/- micemiceuuAbdominal infection modelAbdominal infection model：Cecal ligation Cecal ligation and and puncture(Mediupuncture(Medium)m)uuPneumonia modelPneumonia model：S1pr2S1pr2+/+/+ & & S1pr2S1pr2+/- +/- & & S1pr2S1pr2-/-/- micemice intratracheal intratracheal instillation of instillation
25、 of E. E. coli coli （2102106 6, 50 , 50 ll）Survival Survival Bacterial burdenBacterial burdenHistomorphologyHistomorphologyPart 1. The relationship betweenS1PR2 and sepsis induced lung injury S1PR2 signaling negatively regulates host response to cecal ligation and S1PR2 signaling negatively regulate
26、s host response to cecal ligation and puncture (CLP) sepsis. puncture (CLP) sepsis. Part 1. The relationship betweenS1PR2 and sepsis induced lung injury S1PR2 S1PR2 signaling signaling negatively negatively regulates regulates host host response response to to bacterial bacterial infection caused by
27、 intratracheal inoculation with infection caused by intratracheal inoculation with E. coliE. coli. . Part 1. ConclusionS1PR2 signaling S1PR2 signaling negatively regulates negatively regulates pulmonary antimicrobial pulmonary antimicrobial immune defenseimmune defenseCecal ligation Cecal ligation a
28、nd punctureand puncture(Medium)(Medium)S1pr2S1pr2-/-/-survival survival S1pr2S1pr2-/- -/- Bacterial Bacterial burdenburdenS1pr2S1pr2-/-/-lung lung injuryinjuryWT WT Bacterial Bacterial burdenburdenWTWT lung lung injuryinjuryIntratracheal Intratracheal instillation of instillation of E. E. colicoliWT
29、 WT survival survival ContentsThe relationship between S1PR2 and the outcome The relationship between S1PR2 and the outcome of sepsisof sepsisImpact of S1PR2 on the regulation of macrophage Impact of S1PR2 on the regulation of macrophage phagocytosis phagocytosis The molecular mechanisms of S1PR2 in
30、 inhibiting The molecular mechanisms of S1PR2 in inhibiting macrophage phagocytosis macrophage phagocytosis The relationship between S1PR2 expression in The relationship between S1PR2 expression in monocytes and the outcome of septic patientsmonocytes and the outcome of septic patientsPart 2. Backgr
31、ound肺肺损伤损伤机制（机制（内内皮，免疫皮，免疫细细胞）胞）2012 Nature Review2012 Nature ReviewPart 2. Impact of S1PR2 on the regulation of macrophage phagocytosis uubone marrow chimeras bone marrow chimeras ：CD45.1 WT & CD45.2 CD45.1 WT & CD45.2 S1pr2S1pr2-/- -/- micemiceX ray 8 X ray 8 GyGyS1pr2S1pr2+/+/+ & & S1pr2S1pr2-/-
32、-/- micemiceIntratracheal Intratracheal instillation of instillation of clodronate liposomes clodronate liposomes or control liposomesor control liposomesuuAlveolar macrophage (AMs) deletion Alveolar macrophage (AMs) deletion ：Survival Survival Bacterial burdenBacterial burden Intratracheal instilla
33、tion of Intratracheal instillation of E. E. colicoliReplacement cell type: Replacement cell type: macrophage, neutrophil, macrophage, neutrophil, lymphocyte, lymphocyte, et alet al. .Non-replacement cell type: Non-replacement cell type: endothelia, epithelia, endothelia, epithelia, et alet al. .Dele
34、tion of S1PR2 in macrophage is responsible for its protective function Deletion of S1PR2 in macrophage is responsible for its protective function against bacterial infectionagainst bacterial infectionPart 2. Impact of S1PR2 on the regulation of macrophage phagocytosis S1PR2 signaling suppresses phag
35、ocytic function of alveolar macrophages (AMs). S1PR2 signaling suppresses phagocytic function of alveolar macrophages (AMs). Part 2. Impact of S1PR2 on the regulation of macrophage phagocytosis Part 2. ConclusionBone Bone marrow marrow chimeraschimerasAlveolar Alveolar macrophage macrophage deletion
36、deletionPhagocytosis Phagocytosis and and bactericidal bactericidal assayassay Deletion of S1PR2 in Deletion of S1PR2 in the the BM-derived cellsBM-derived cells leads to increased leads to increased bacterial clearance bacterial clearance activity in the lung.activity in the lung. Deletion of S1PR2
37、 in Deletion of S1PR2 in AMsAMs improves improves pulmonary bacterial pulmonary bacterial clearance.clearance. S1PR2 deficiency S1PR2 deficiency enhances AMs enhances AMs phagocytic functionphagocytic function. .in vivoin vivoin vivoin vivoex vivoex vivoContentsThe relationship between S1PR2 and the
38、 outcome The relationship between S1PR2 and the outcome of spsisof spsisImpact of S1PR2 on the regulation of macrophage Impact of S1PR2 on the regulation of macrophage phagocytosis phagocytosis The molecular mechanisms of S1PR2 in inhibiting The molecular mechanisms of S1PR2 in inhibiting macrophage
39、 phagocytosis macrophage phagocytosis The relationship between S1PR2 expression in The relationship between S1PR2 expression in monocytes and the outcome of septic patientsmonocytes and the outcome of septic patientsGTPase cascades involved in cytoskeleton organizationGTPase cascades involved in cyt
40、oskeleton organizationPart 3. BackgroundRonald S. Flannagan, Ronald S. Flannagan, et alet al. Annu Rev Pathol. 2012. Annu Rev Pathol. 2012.Giovanna Chimini, Giovanna Chimini, et alet al. Nature cell biology. 2000. Nature cell biology. 2000.Sandrine Etienne-Manneville, Sandrine Etienne-Manneville, et
41、 alet al. Nature. 2002. Nature. 2002.uuActin polymerization is the key step of Actin polymerization is the key step of phagocytosisphagocytosisuuRho GTPase cascades involved in actin Rho GTPase cascades involved in actin polymerizationpolymerizationIn vivoIn vivo, S1P concentration increased from 0
42、h to 18 h after lung infection., S1P concentration increased from 0 h to 18 h after lung infection.Exogenous S1P (from 100 nM to 5 Exogenous S1P (from 100 nM to 5 M) reduced phagocytosis by 40% in WT M) reduced phagocytosis by 40% in WT BMDMs, but not in BMDMs, but not in S1pr2S1pr2-/-/- BMDMs. BMDM
43、s.Part 3. The molecular mechanisms of S1PR2 in inhibiting macrophage phagocytosis A AB BPart 3. The molecular mechanisms of S1PR2 in inhibiting macrophage phagocytosis uuLow S1P concentrationLow S1P concentrationuuHigh S1P concentration:High S1P concentration:S1pr2S1pr2+/+/+ & & S1pr2S1pr2-/- -/- BM
44、DMBMDME. coli E. coli (30 min(30 min or or 60 min)60 min)Confocal microscopyConfocal microscopy：F-actin, F-actin, IQGAP1 distributionIQGAP1 distribution；Pull DownPull Down：RAC1-GTPRAC1-GTP；Western blotWestern blot：F-actinF-actin；Co-ImmunoprecipitationCo-Immunoprecipitation：IQGAP1-RAC1IQGAP1-RAC1 bin
45、dingbinding；Small interfering RNASmall interfering RNA: : IQGAP1IQGAP1S1pr2S1pr2+/+/+ & & S1pr2S1pr2-/- -/- BMDMBMDMS1P 100nM +S1P 100nM +E. coli E. coli (30 min)(30 min)Confocal microscopyConfocal microscopy：F-F-actin and RAC1distributionactin and RAC1distribution；Pull DownPull Down：RhoA-GTPRhoA-GT
46、PPart 3. The molecular mechanisms of S1PR2 in inhibiting macrophage phagocytosis At At early early stages stages of of E. E. coli coli intratracheal intratracheal infection infection (low (low S1P S1P concentration), concentration), IQGAP1-Rac1 is required for enhanced phagocytosis in IQGAP1-Rac1 is
47、 required for enhanced phagocytosis in S1pr2S1pr2-/-/- macrophages. macrophages.Part 3. The molecular mechanisms of S1PR2 in inhibiting macrophage phagocytosis A AB BAt At later later stages stages of of E. E. coli coli intratracheal intratracheal infection infection (high (high S1P S1P concentratio
48、n),concentration), S1PR2 S1PR2 actived actived RhoA-GTP RhoA-GTP and and promoted promoted the the WT WT cells cells adopt adopt a a contracted contracted round round morphology.morphology.Part 3. ConclusionContentsThe relationship between S1PR2 and the outcome The relationship between S1PR2 and the
49、 outcome of sepsisof sepsisImpact of S1PR2 on the regulation of macrophage Impact of S1PR2 on the regulation of macrophage phagocytosis phagocytosis The molecular mechanisms of S1PR2 in inhibiting The molecular mechanisms of S1PR2 in inhibiting macrophage phagocytosis macrophage phagocytosis The rel
50、ationship between S1PR2 expression in The relationship between S1PR2 expression in monocytes and the outcome of septic patientsmonocytes and the outcome of septic patientsPart 4. The relationship between S1PR2 expression in monocytes and the outcome of septic patientsuuPeripheral blood mononuclear c
51、ells were isolated by density gradient Peripheral blood mononuclear cells were isolated by density gradient centrifugationcentrifugationSeptic patients or Septic patients or controlcontrolS1PR2 expression on S1PR2 expression on monocytes;monocytes;Monocytes phagocytosis assayMonocytes phagocytosis a
52、ssayRPMI 1640RPMI 1640Exclusion criteria: Exclusion criteria: Age younger than 18 yr;Age younger than 18 yr; With human With human immunodeficiency virus immunodeficiency virus Infection;Infection; Treatment with Treatment with corticosteroids or corticosteroids or chemotherapy within 4 chemotherapy
53、 within 4 weeks;weeks; Inability to provide Inability to provide informed consent.informed consent.Layers before centrifugationLayers before centrifugationLayers after centrifugationLayers after centrifugationPart 4. The relationship between S1PR2 expression in monocytes and the outcome of septic pa
54、tientA AB BS1PR2 S1PR2 mRNA mRNA levels levels were were significantly significantly higher higher in in septic septic patients patients compared compared to to those in non-septic controls.those in non-septic controls.Increased Increased S1PR2 S1PR2 expression expression was was positively positive
55、ly correlated correlated to to the the severity severity of of sepsis, sepsis, evaluated evaluated by by Acute Acute Physiologic Physiologic and and Chronic Chronic Health Health Evaluation Evaluation II II (APACHE (APACHE II) II) scores.scores.Part 4. The relationship between S1PR2 expression in mo
56、nocytes and the outcome of septic patientPBMCs with higher expression levels of S1PR2 showed lower phagocytic abilityPBMCs with higher expression levels of S1PR2 showed lower phagocytic abilityPart 4. ConclusionExpression level of S1PR2 Expression level of S1PR2 was evaluatedwas evaluatedElevated S1
57、PR2 levels were Elevated S1PR2 levels were positively correlated with the positively correlated with the severity of sepsisseverity of sepsisS1PR2 is a potential biomarker or S1PR2 is a potential biomarker or molecular target for infectious diseasemolecular target for infectious disease PBMCs with h
58、igher PBMCs with higher expression levels of S1PR2 expression levels of S1PR2 showed lower phagocytic showed lower phagocytic abilityabilityImmune-inflammatory responseImmune-inflammatory responseCell Cell Membrane Membrane TLRsTLRsMembrane-associated Non-TLRs: Membrane-associated Non-TLRs: TREMs, S
59、1PRs, etc.TREMs, S1PRs, etc.PAMPs and DAMPsPAMPs and DAMPsCytosolic Non-TLRs: Cytosolic Non-TLRs: NLRs, etc.NLRs, etc.Nuclear Non-TLRs: Nuclear Non-TLRs: NR4A1, PPAR, etc.NR4A1, PPAR, etc.Endosome Endosome or or PhagosomePhagosomeCytoplasmaCytoplasmaTLRsTLRsGene TranscriptionGene TranscriptionNucleusNucleusSepsisSepsis规范的住院医师、专科医师培养规范的住院医师、专科医师培养( (共识指南、共识指南、虚拟仿真虚拟仿真) )术前快速前快速评估和准估和准备 术中麻醉管理中麻醉管理 术后后复复苏和器官功能支持和器官功能支持谢谢大家！谢谢大家！
