纤维化疾病治疗讲座.ppt

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1、纤维化疾病治疗讲座Fibrotic Diseases Fibrotic Diseases Pulmonary fibrosis,renal fibrosis,and hepatic cirrhosis are among the more common fibrotic diseases,which in aggregate represent a huge unmet clinical mon fibrotic diseases,which in aggregate represent a huge unmet clinical need.how tissue injury and repa

2、ir lead to fibrosispresent promising new approaches of diagnosis present promising treatment of fibrotic diseases 目的目的目录CONTENTSCOMMON FEATURES OF FIBROSIS ACROSS TISSUESSOURCES OF FIBROGENIC CELLSPATHWAYS DRIVING MYOFIBROBLAST GENERATION FROM RESIDENT MESENCHYMAL CELLSTISSUE-SPECIFIC FEATURES OF FI

3、BROSIS FOR THERAPEUTIC TARGETINGOBSTACLES TO TRANSLATION OF BASIC SCIENCE INTO CLINICAL PRACTICETHERAPIES FOR FIBROSISResolution and Resolution and regression of regression of fibrosisfibrosisImmune cell Immune cell recruitmentrecruitmentProperties of Properties of the fibrotic the fibrotic ECMECMAp

4、pearance of Appearance of myofibroblastsmyofibroblastsEpithelial Epithelial injury and injury and dysfunctiondysfunction123456代谢途径的失调Epithelial injury and dysfunctionEpithelial injury and dysfunction细胞死亡整合素TGF-间相互作用EMT上皮间质转化两种类型免疫应答TGF-与整合素6机械结合LAP片段C端N端6细胞内骨架蛋白相互作用，如肌动蛋白前体形式潜在相关肽前体形式潜在相关肽完成细胞粘附作用将E

5、CM信号传导至胞核内损伤的上皮损伤的上皮细胞高度表达细胞高度表达ImmuneresponsesExtracellularmatrixInnate lymphoidcellsPro-fibroticcytokinesCell deathCell stressER stressPathologic EMTTGF activationROSADCB间充质细胞肌成纤维细胞功能、形态转录调节分泌大量、胶原及细胞外致纤维化的基质蛋白Appearance of myofbroblastsAppearance of myofbroblasts前体细胞肌成纤维细胞PDGF、CTGFTGF-结合(a-SMA)(p

6、ericytes,resident fibroblasts,hepatic stellate cells,and renal mesangial cells)pathways of gene regulation:TGFb:Smads JunDclassical tyrosine kinase signalingAutophagic signaling0101取代并取代并破坏正破坏正常组织常组织结构结构0202改变固有改变固有细胞及肌细胞及肌成纤维细成纤维细胞的功能胞的功能0303调节细胞调节细胞因子和生因子和生长因子的长因子的失活及激失活及激活状态活状态0404组织硬度增组织硬度增加，改变正

7、加，改变正常和病理性常和病理性细胞应答细胞应答Properties of the fibrotic ECMProperties of the fibrotic ECM异常正常分布于内皮与上皮之间，层粘连蛋白及型胶原及蛋白聚糖混合物组成 、胶原、纤连蛋白、骨桥蛋白、透明质酸增多本身也是固有免疫应答的感应器Immune cell recruitmentImmune cell recruitment这些免疫分子包括：TNFa、IL-1b、NALP3/ASC、IL-6 and IL-17A,and type 2 cytokines including IL-4 and IL-13 IL-4 and I

8、L-13 及其他相关细胞因子可能是治疗纤维化疾病的新靶点 固有免疫应答对肌成纤维细胞的转化及纤维化十分重要Myofibroblastschemokines cytokines oxygen radicals（-）靶点01030204Monocyte-derived cellsMonocyte-derived cellsMonocyte-derived cells(macrophages and dendritic cells)has been contributed to fibrosis disease in animal models.M1,inflammatoryM2a-like pro

9、fibroticMreg/M2c likeregulatoryfibrosisM2a-like macrophagesMonocytesTGFb1,PDGF,FGF2IGFBP 靶点IL-4、L-13、CCL17、CCL2 chemokinesmacrophage colony-stimulating factorMonocyte-derived cell populations can dynamically control the fibrotic process through both direct effects on matrix remodeling and indirect e

10、ffects on the regulation of activated myofibroblasts,their precursor populations and ECs.Monocyte-derived cellsMonocyte-derived cellsThe recruitment of distinct functional subsets of macrophages and their relative concentrations during injury can determine whether the injury response leads to produc

11、tivereepithelialization and healing or to pathologic scarring.Resolution and regression of fibrosisu纤维化是对组织损伤的保护性反应。纤维化是对组织损伤的保护性反应。u正常情况下正常情况下 ECM ECM被降解，重建正常的结构和功能被降解，重建正常的结构和功能u (急性损伤、自限性疾病急性损伤、自限性疾病)u纤维化疾病时纤维化疾病时 ECM MMP ECM MMP及其抑制剂被诱导及其抑制剂被诱导u 损伤初期损伤初期 MMP-7 MMP-7加速炎症加速炎症u 纤维化期纤维化期 降解降解 ECM EC

12、M u 肌成纤维细胞肌成纤维细胞吞噬细胞吞噬细胞uPARAPMfge8吞噬纤维化逆转的探讨1.乙型病毒性肝炎抗病乙型病毒性肝炎抗病毒治疗毒治疗2.丙型病毒性肝炎干扰丙型病毒性肝炎干扰素的治疗素的治疗单核细胞治疗纤维化疾病：单核细胞治疗纤维化疾病：（i）分化为调节性巨噬细胞，产生局部）分化为调节性巨噬细胞，产生局部抑制性细胞因子，包括抑制性细胞因子，包括IL-10；（ii）产生基质金属蛋白酶，可以直接）产生基质金属蛋白酶，可以直接降低间质胶原（降低间质胶原（MMP-1，2，8，9，13）；）；（iii）局部消除必需氨基酸，抑制）局部消除必需氨基酸，抑制T细细胞和肌纤维母细胞增生；胞和肌纤维母细胞

13、增生；（iv）促进肌纤成维母细胞的凋亡；）促进肌纤成维母细胞的凋亡；（v）吞噬）吞噬ECM和能活化纤维化细胞碎和能活化纤维化细胞碎片。片。1.逆转晚期肝纤维化是肝逆转晚期肝纤维化是肝脏独特的再生能力？脏独特的再生能力？2.哪种细胞成分决定什么哪种细胞成分决定什么时候纤维化是不可逆的？时候纤维化是不可逆的？SOURCES OF FIBROGENIC CELLSSOURCES OF FIBROGENIC CELLS最主要的1.内皮细胞可以表达a-SMA2.关于间充质细胞命运组学的研究证明它并不是一个致纤维化的祖细胞。Endothelial cell1.损伤的上皮细胞通过EMT成为肌成纤维细胞2.反

14、对意见：一些细胞亚群的存在 只在培养基上表达Epithelial cells在肝脏、肾脏纤维化模型中，髓系细胞（M2a亚型类似的）可以产生一小部分的型胶原。Leukocytes1.间充质细胞的功能2.各个器官特异的间充质细胞3.组织损伤修复复制了生长发育的过程，但并未形成正常结构白白细细细细细细细细胞胞胞胞皮皮上上胞胞内内皮皮间间充充质质前前体体胞胞 In a new study,injury or stress to endoderm-or mesoderm-derived epithelium,or injury to mesoderm-derived endothelium or myo

15、cytes,can lead to increased fibrosis,or fibrogenesis,independent of injury to or recruitment of other cells such as leuko-cytes.these cells signal via paracellular mechanism to neighboring mesenchymal cells.driving myofibroblast genenration from resident mesenchymal cellsPATHWAY 之前人们研究的重点在间充质细胞是如何从一

16、个静止的细胞表型转化为具有肌成纤维细胞性质的激活形态。例如，损伤的上皮细例如，损伤的上皮细胞可以产生胞可以产生NGFNGF、TGFbTGFb、PDGF-BPDGF-B、VEGF-AVEGF-A、WntsWnts、hedgehog hedgehog 配体这些配体这些因子，并传送到邻近因子，并传送到邻近的间充质细胞中。的间充质细胞中。保守的the conserved,or core,pathways of fibrosis for therapy新颖的TISSUE-SPECIFIC FEATURES OF FIBROSIS FOR THERAPEUTIC TARGETINGinhibit fibr

17、osiscollateral effects impair tumor suppression cause chronic inflammation.specific cell surface moleculesunique intracellular targetsTISSUE-SPECIFIC FEATURES OF FIBROSIS FOR THERAPEUTIC TARGETINGpinpoint targets that are unique to diseased tissue or are only expressed in a specific organ.eg:a recep

18、tor heterodimer composed of the angiotensin II type I receptor and the cannabinoid CB1 receptoryet few have emerged.OBSTACLES THERAPIES FOR FIBROSISTHERAPIES FOR FIBROSISTGF-通路及其抑制剂整合素6及其抑制剂LPA1受体及其抑制剂IL4和IL13及其抑制剂Pentraxin-2及其抑制剂拮抗纤维交联 困难困难01纤维化仍在进展纤维化仍在进展02加重原发疾病加重原发疾病03临床试验的指标未临床试验的指标未出现统计学意义出现统计学意义04生物标记物检测不到生物标记物检测不到 Although success in treating fibrosis has been limitedfuture clinical trials are likely to provide more promising results.谢谢大家！结结 语语