药物性肝损伤,炎症治疗的最新进展课件.pptx

1、 报告人：张靖垚 导师：刘昌教授药物性肝损伤，炎症治疗的最新进展药物性肝损伤，炎症治疗的最新进展n2n3Benzyl alcohol：苯甲醇，1. 苯甲醇是最简单的芳香醇之一2. 健康危害：具有麻醉作用，对眼、上呼吸道、皮肤有刺激作用。摄入引起头痛、恶心、呕吐、胃肠道刺激、惊厥、昏迷。3. 有抑菌、止痒作用n4BA (270 ug/g, IP).n5 3 of 3 mice diedBA (270 ug/g, IP). 6 hours用BA的时间6 hoursn6High-mobility group box 1： important mediator of injury inboth ste

2、rile and nonsterile liver injury, including APAP toxicity. BA treatment reduced APAP-induced inflammation. n7APAP-induced liver injury is dependent, in part, on TLR9, RAGE, HMGB-1, and IL-6 expression. 6-hourPrecognition receptors (PRRs) TLR2, TLR4, TLR9 or RAGESeveral studies have highlighted the r

3、ole of different PRRs and inflammasome activation on APAP-induced liver injury. n8Glycyrrhizin（甘草酸）, which poses anti-HMGB-1 propertiesMice deficient in hepatocyte-specificexpression of HMGB-1n9n10Together, these data suggest a pathway of TLR9- or RAGE-mediated injury that signals, or is amplified b

4、y, hepatocyte parenchymal HMGB1 release and subsequent increases in serum IL-6.n11 BA protects through TLR4 receptor expression. BA failed to protect against liver injury in mice deficient in TLR4 expression, suggesting that BA signaled, at least in part, through this receptor. CD14 has been shownto

5、 be a coreceptor of TLR4Hepatocyte-specific KO DC-specific KO myeloid cellspecific KOGlobal knockout adipose-specific KOn12n13 mitochondrial injury plasma levels of mtDNAn14体外实验 APAP (5 mM) on primary mouse (C57BL/6) hepatocytesn151.APAP-induced injury is partially mediated by activation of the Nalp

6、3 inflammasome.2. activation of Nalp3 can be be downstream of TLR9.3. Critical to Nalp3 inflammasome signaling is cleavage and activation of caspase-1，which, in turn, cleaves the pro-forms of IL-1b and IL-18.n16BAs inhibition in hepatic inflammasome signaling was TLR4 dependent. n理论基础17BA can inhibi

7、t mitochondrial electron transport at several points along the respiratory chainChazotte B, Vanderkooi G. Multiple sites of inhibition of mitochon-drial electron transport by local anesthetics. Biochim Biophys Acta1981;636:153-161.n18n19n20First, as the authors discussed themselves, BA can inhibit m

8、itochondrial respiration and is toxic at higher doses.Second, BA was most effective when given during a narrow window around the time of APAP treatment, BA only protects when present during the metabolism phase of APAP.the established clinical antidote N-acetylcysteinen（乙酰半胱氨酸）is most effective duri

9、ng the metabolism phase and beyond with lower risk. Third, Most importantly, all agree that only a few pg/ml IL-1 are actually produced during APAP hepatotoxicity.n21n22低温，紫外线照射，缺氧n23240 min after hemorrhage Shock RatHemorrhageShock modelshockn24 Recombinant CIRP+RAW 264.7 cells 4 h 100 ng ml1Polymy

10、xin B, PMB, an LPS-binding antibioticn25Blockade of CIRP reduces TNF- and IL-6 production, hepatic injury and mortality after hemorrhage. n26n27n28rat peritoneal macrophages细胞裂解物conditioned medium from rat peritoneal macrophages conditioned medium of RAW 264.7 cellsSepsis modeln29 rmCIRP+peritoneal

11、macrophagesn30n31小鼠盲肠n32生物膜，防粘连膜Activated protein C ： 1.anticoagulant and antiinflammatory protease2. potent antiinflammatory, cytoprotective, and profibrinolytic propertiesn33Nair et al Leach et alsscalen34 peritoneal fluid炎症因子水平n35peritoneal tissues炎症因子转录水平n36一般的APC has the signaling function has

12、normal anticoagulant but defective PAR1 signaling function无活性的APCn37n38n39n40 thrombin-antithrombin (TAT) complex肝素.To further determine whether the inhibition of coagulation cascade makes any contribution to post-surgical adhesion band formation Analysis of coagulation and fibrinolytic markersn41影响腹膜液中的凝固与纤溶系统n42HighlightsThe long noncoding RNA lncTCF7 is highly expressed in liver cancer tissues and CSCsLncTCF7 is important for self-renewal of liver CSCsLncTCF7 activates the Wnt signaling pathway through TCF7 expressionLncTCF7 recruits the SWI/SNF complex to activate the TCF7 promotern43谢谢