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1、,脓毒症发病机制及其防治研究新进展,病例摘要,男，68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。 入院体格检查：神志清，精神差，体温（T）38.5，心率（HR）108次/min，呼吸频率（R）30次/min，血压（BP）130/88mmHg，腹部膨隆，移动性浊音（+），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10cm陈旧疤痕。肛门指诊距肛5cm可触及肿块，质硬，食指未能通过。 血常规检查：白细胞计数18.4109/L，中性粒细胞84.6%，血红蛋白70 g/L ，血小板计数203109/L。 胸片：双肺呈弥漫性、渗出性改变
2、，肺部阴影有大片状融合。 诊断：直肠癌术后复发； 吻合口梗阻; ALI/ARDS?,次日因神志不清、休克，急诊静脉快诱导气管插管全麻下行剖腹探查+肠粘连松解+小肠肠段切除+小肠造瘘术。手术操作顺利，术中出血少，术中患者循环不稳BP78/40mmHg，采用乳酸林格液3000ml、5%人血白蛋白200ml积极扩容，并输血浓缩RBC2U。 术后PACU复苏拔管送外科普通病房，3h后再次出现神志不清，血气分析显示CO2蓄积（101mmHg），紧急气管插管+PCV转ICU，去甲肾上腺素和肾上腺素0.01ug/kg/min维持血压。,术后第一天,2002年巴塞罗那宣言,全社会要像当年重视“中风”和“急性心
3、梗”一样，重视对脓毒症的研究和治疗，争取把脓毒症的发生率和死亡率降低到可接受的水平（五年时间病死率降低25%）。,全世界脓毒症死亡人数超过1.4万/天； 发病人数正以年1.58.0%的比例增长； 过去10年间增加病例139%，且有继续增加的趋势。,21世纪对人类健康和经济发展的重大挑战,全球每年超过1800 万人罹患脓毒症 死亡率高达30-70% 患者直接医疗花费约120,000元/例,脓毒症高发生率、高死亡率、高医疗负担,New Eng J Med, 2003; Crit Care Med, 2007,病原相关分子模式PAMPs,免疫稳态失衡,病原微生物清除障碍,重要脏器功能损伤/衰竭,脓毒
4、症 发病机制,促炎/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EDN、NPM、HMGB1上调免疫效应细胞产生炎性介质、介导组织脏器损伤,HNP和HBD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！,2007年：HNP和HBD： 从“防御”到 进攻？,阳离子抗菌肽：HNP等,警报素HNP1-3在脓毒症中是双刃剑？,2009年：目前认为抗菌肽是把“双刃剑”,抗菌肽LL-37、HNP、HBD可能通过异常“alarming”机体细胞，触发炎症反应、破坏自身免疫稳态，诱发人类自身免疫性疾病银屑病等,警报素HNP1-3基因高拷贝数是脓毒症致脏器损伤的独立
5、危险因素,脓毒症临床研究,中性粒细胞是脓毒症时机体免疫应答的首要防御体系，而HNP1-3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,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？ 作为脓毒症治疗的分子靶标？,HNP1-3,研究目的,针对前面提出的科学问题，进行阐述 一般分为2-3部分，先从临床或实验动物来明确某种作用，再在细胞水平来探讨机理 要重点突出，切忌面面俱到,例：,题为“警报素 HNP1-3在始动脓毒症致多脏器损伤中的作用、机制及其干预治疗的研究”的研究目的： 一、证明警报素HNP1-3在脓毒症致多脏器损伤中的始动作用 二、明确警报素HNP1-3始动脓毒
6、症致多脏器损伤的分子机制,（1）HNP1-3能够结合巨噬细胞表面P2X7受体 （2）HNP1-3活化NLRP3导致巨噬细胞 pyroptosis （3）HNP1-3通过非NLRP3途径促进巨噬细胞IL-1活化释放,阳离子抗菌肽HNP1-3在脓毒症发生发展中的作用机制,Innate Immunity, 2013,Sphingosine 1-phosphate receptor 2 (S1PR2) signaling suppresses macrophage phagocytosis and impairs host defense against sepsis,Abstract,Animal,
7、Phenotype,Function,Clinical significance,Cell,Molecular,Patients,Mechanisms,The relationship between S1PR2 and the outcome of sepsis,Impact of S1PR2 on the regulation of macrophage phagocytosis,The molecular mechanisms of S1PR2 in inhibiting macrophage phagocytosis,The relationship between S1PR2 exp
8、ression in monocytes and the outcome of septic patients,Contents,The relationship between S1PR2 and the outcome of sepsis,Impact of S1PR2 on the regulation of macrophage phagocytosis,The molecular mechanisms of S1PR2 in inhibiting macrophage phagocytosis,The relationship between S1PR2 expression in
9、monocytes and the outcome of septic patients,Part 1. The relationship betweenS1PR2 lung injury,Part 1. The relationship betweenS1PR2 and sepsis induced lung injury,S1PR2 signaling negatively regulates host response to cecal ligation and puncture (CLP) sepsis.,Part 1. The relationship betweenS1PR2 an
10、d sepsis induced lung injury,S1PR2 signaling negatively regulates host response to bacterial infection caused by intratracheal inoculation with E. coli.,Part 1. Conclusion,S1PR2 signaling negatively regulates pulmonary antimicrobial immune defense,Cecal ligation and puncture (Medium),S1pr2-/-surviva
11、l,S1pr2-/- Bacterial burden,S1pr2-/-lung injury,WT Bacterial burden,WT lung injury,Intratracheal instillation of E. coli,WT survival,Contents,The relationship between S1PR2 and the outcome of sepsis,Impact of S1PR2 on the regulation of macrophage phagocytosis,The molecular mechanisms of S1PR2 in inh
12、ibiting macrophage phagocytosis,The relationship between S1PR2 expression in monocytes and the outcome of septic patients,Part 2. Background,肺损伤机制（内皮，免疫细胞）,2012 Nature Review,Part 2. Impact of S1PR2 on the regulation of macrophage phagocytosis,bone marrow chimeras ：,CD45.1 WT & CD45.2 S1pr2-/- mice,
13、X ray 8 Gy,Intratracheal instillation of clodronate liposomes or control liposomes,Alveolar macrophage (AMs) deletion ：,Intratracheal instillation of E. coli,Replacement cell type: macrophage, neutrophil, lymphocyte, et al. Non-replacement cell type: endothelia, epithelia, et al.,Deletion of S1PR2 i
14、n macrophage is responsible for its protective function against bacterial infection,Part 2. Impact of S1PR2 on the regulation of macrophage phagocytosis,S1PR2 signaling suppresses phagocytic function of alveolar macrophages (AMs).,Part 2. Impact of S1PR2 on the regulation of macrophage phagocytosis,
15、Part 2. Conclusion,Bone marrow chimeras,Alveolar macrophage deletion,Phagocytosis and bactericidal assay,Deletion of S1PR2 in the BM-derived cells leads to increased bacterial clearance activity in the lung.,Deletion of S1PR2 in AMs improves pulmonary bacterial clearance.,S1PR2 deficiency enhances A
16、Ms phagocytic function.,in vivo,in vivo,ex vivo,Contents,The relationship between S1PR2 and the outcome of spsis,Impact of S1PR2 on the regulation of macrophage phagocytosis,The molecular mechanisms of S1PR2 in inhibiting macrophage phagocytosis,The relationship between S1PR2 expression in monocytes
17、 and the outcome of septic patients,GTPase cascades involved in cytoskeleton organization,Part 3. Background,Ronald S. Flannagan, et al. Annu Rev Pathol. 2012. Giovanna Chimini, et al. Nature cell biology. 2000. Sandrine Etienne-Manneville, et al. Nature. 2002.,Actin polymerization is the key step o
18、f phagocytosis,Rho GTPase cascades involved in actin polymerization,In vivo, S1P concentration increased from 0 h to 18 h after lung infection. Exogenous S1P (from 100 nM to 5 M) reduced phagocytosis by 40% in WT BMDMs, but not in S1pr2-/- BMDMs.,Part 3. The molecular mechanisms of S1PR2 in inhibiti
19、ng macrophage phagocytosis,A,B,Part 3. The molecular mechanisms of S1PR2 in inhibiting macrophage phagocytosis,Low S1P concentration,High S1P concentration:,E. coli (30 min or 60 min),S1P 100nM + E. coli (30 min),Part 3. The molecular mechanisms of S1PR2 in inhibiting macrophage phagocytosis,At earl
20、y stages of E. coli intratracheal infection (low S1P concentration), IQGAP1-Rac1 is required for enhanced phagocytosis in S1pr2-/- macrophages.,Part 3. The molecular mechanisms of S1PR2 in inhibiting macrophage phagocytosis,A,B,At later stages of E. coli intratracheal infection (high S1P concentrati
21、on), S1PR2 actived RhoA-GTP and promoted the WT cells adopt a contracted round morphology.,Part 3. Conclusion,Contents,The relationship between S1PR2 and the outcome of sepsis,Impact of S1PR2 on the regulation of macrophage phagocytosis,The molecular mechanisms of S1PR2 in inhibiting macrophage phag
22、ocytosis,The relationship between S1PR2 expression in monocytes and the outcome of septic patients,Part 4. The relationship between S1PR2 expression in monocytes and the outcome of septic patients,Peripheral blood mononuclear cells were isolated by density gradient centrifugation,RPMI 1640,Exclusion
23、 criteria: Age younger than 18 yr; With human immunodeficiency virus Infection; Treatment with corticosteroids or chemotherapy within 4 weeks; Inability to provide informed consent.,Layers before centrifugation,Layers after centrifugation,Part 4. The relationship between S1PR2 expression in monocyte
24、s and the outcome of septic patient,A,B,S1PR2 mRNA levels were significantly higher in septic patients compared to those in non-septic controls. Increased S1PR2 expression was positively correlated to the severity of sepsis, evaluated by Acute Physiologic and Chronic Health Evaluation II (APACHE II)
25、 scores.,Part 4. The relationship between S1PR2 expression in monocytes and the outcome of septic patient,PBMCs with higher expression levels of S1PR2 showed lower phagocytic ability,Part 4. Conclusion,Elevated S1PR2 levels were positively correlated with the severity of sepsis,PBMCs with higher expression levels of S1PR2 showed lower phagocytic ability,Sepsis,规范的住院医师、专科医师培养(共识指南、虚拟仿真),谢谢大家！,