纖維化疾病的治療講座

1、Therapy for Fibrotic Diseases Nearing the Starting Line 目的目的目錄CONTENTSCOMMON FEATURES OF FIBROSIS ACROSS TISSUESSOURCES OF FIBROGENIC CELLSPATHWAYS DRIVING MYOFIBROBLAST GENERATION FROM RESIDENT MESENCHYMAL CELLSTISSUE-SPECIFIC FEATURES OF FIBROSIS FOR THERAPEUTIC TARGETINGOBSTACLES TO TRANSLATION O

2、F BASIC SCIENCE INTO CLINICAL PRACTICETHERAPIES FOR FIBROSIS123456代謝途徑的失調(diào)Epithelial injury andEpithelial injury and dysfunctiondysfunction細(xì)胞死亡整合素TGF-間相互作用EMT上皮間質(zhì)轉(zhuǎn)化兩種類型免疫應(yīng)答TGF-與整合素6機(jī)械結(jié)合LAP片段C端N端6細(xì)胞內(nèi)骨架蛋白相互作用，如肌動(dòng)蛋白前體形式潛在相關(guān)肽前體形式潛在相關(guān)肽完成細(xì)胞粘附作用將ECM信號(hào)傳導(dǎo)至胞核內(nèi)損傷的上皮損傷的上皮細(xì)胞高度表達(dá)細(xì)胞高度表達(dá)ImmuneresponsesExtracellularm

3、atrixInnate lymphoidcellsPro-fibroticcytokinesCell deathCell stressER stressPathologic EMTTGF activationROS間充質(zhì)細(xì)胞肌成纖維細(xì)胞功能、形態(tài)轉(zhuǎn)錄調(diào)節(jié)分泌大量、膠原及細(xì)胞外致纖維化的基質(zhì)蛋白Appearance of myofbroblastAppearance of myofbroblasts s前體細(xì)胞肌成纖維細(xì)胞PDGF、CTGFTGF-結(jié)合(a-SMA) (pericytes,resident fibroblasts, hepatic stellate cells, and rena

4、l mesangial cells)pathways of gene regulation:TGFb :Smads JunDclassical tyrosine kinase signalingAutophagic signaling0101取代并取代并破壞正破壞正常組織常組織結(jié)構(gòu)結(jié)構(gòu)0202改變固有改變固有細(xì)胞及肌細(xì)胞及肌成纖維細(xì)成纖維細(xì)胞的功能胞的功能0303調(diào)節(jié)細(xì)胞調(diào)節(jié)細(xì)胞因子和生因子和生長(zhǎng)因子的長(zhǎng)因子的失活及激失活及激活狀態(tài)活狀態(tài)0404組織硬度增組織硬度增加，改變正加，改變正常和病理性常和病理性細(xì)胞應(yīng)答細(xì)胞應(yīng)答Properties of the fibrotic ECMPropert

5、ies of the fibrotic ECM異常正常分布于內(nèi)皮與上皮之間，層粘連蛋白及型膠原及蛋白聚糖混合物組成 、膠原、纖連蛋白、骨橋蛋白、透明質(zhì)酸增多本身也是固有免疫應(yīng)答的感應(yīng)器Immune cell recruitmentImmune cell recruitment 固有免疫應(yīng)答對(duì)肌成纖維細(xì)胞的轉(zhuǎn)化及纖維化十分重要Myofibroblastschemokines cytokines oxygen radicals靶點(diǎn)01030204Monocyte-derived cellsMonocyte-derived cellsMonocyte-derived cells (macrophag

6、es and dendritic cells) has been contributed to fibrosis disease in animal models.M1, inflammatoryM2a-like profibroticMreg/M2c likeregulatory靶點(diǎn)IL-4、L-13、CCL17、CCL2 chemokinesmacrophage colony-stimulating factorMonocyte-derived cell populations can dynamically control the fibrotic process through bot

7、h direct effects on matrix remodeling and indirect effects 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

8、determine whether the injury response leads to productivereepithelialization and healing or to pathologic scarring.Resolution and regression of fibrosisu纖維化是對(duì)組織損傷的保護(hù)性反應(yīng)。纖維化是對(duì)組織損傷的保護(hù)性反應(yīng)。u正常情況下正常情況下 ECM ECM被降解，重建正常的結(jié)構(gòu)和功能被降解，重建正常的結(jié)構(gòu)和功能 ( (急性損傷、自限性疾病急性損傷、自限性疾病) )u纖維化疾病時(shí)纖維化疾病時(shí) ECM MMP ECM MMP及其抑制劑被誘導(dǎo)及其抑制

9、劑被誘導(dǎo) 損傷初期損傷初期 MMP-7 MMP-7加速炎癥加速炎癥 纖維化期纖維化期 降解降解 ECM ECM 肌成纖維細(xì)胞肌成纖維細(xì)胞吞噬細(xì)胞吞噬細(xì)胞uPARAPMfge8吞噬纖維化逆轉(zhuǎn)的探討1.乙型病毒性肝炎抗病乙型病毒性肝炎抗病毒治療毒治療2.丙型病毒性肝炎干擾丙型病毒性肝炎干擾素的治療素的治療單核細(xì)胞單核細(xì)胞治療治療纖維化疾?。豪w維化疾?。海╥）分化為調(diào)節(jié)性巨噬細(xì)胞）分化為調(diào)節(jié)性巨噬細(xì)胞，產(chǎn)生局部產(chǎn)生局部抑制性細(xì)胞因子，包括抑制性細(xì)胞因子，包括IL-10；（ii）產(chǎn)生基質(zhì)金屬蛋白酶，可以直接）產(chǎn)生基質(zhì)金屬蛋白酶，可以直接降低間質(zhì)膠原（降低間質(zhì)膠原（MMP-1，2，8，9，13）；）；（

10、iii）局部消除必需氨基酸，抑制）局部消除必需氨基酸，抑制T細(xì)細(xì)胞和肌纖維母細(xì)胞增生；胞和肌纖維母細(xì)胞增生；（iv）促進(jìn)肌纖）促進(jìn)肌纖成成維母細(xì)胞的凋亡；維母細(xì)胞的凋亡；（v）吞噬）吞噬ECM和能和能活化活化纖維化細(xì)胞碎纖維化細(xì)胞碎片。片。1.逆轉(zhuǎn)晚期肝纖維化是肝逆轉(zhuǎn)晚期肝纖維化是肝臟獨(dú)特的再生能力？臟獨(dú)特的再生能力？2.哪哪種細(xì)胞成分決定什么種細(xì)胞成分決定什么時(shí)候纖維化是不可逆的？時(shí)候纖維化是不可逆的？SOURCES OF FIBROGENIC CELLSSOURCES OF FIBROGENIC CELLS最主要的1.內(nèi)皮細(xì)胞可以表達(dá)a-SMA2.關(guān)于間充質(zhì)細(xì)胞命運(yùn)組學(xué)的研究證明它并不是一

11、個(gè)致纖維化的祖細(xì)胞。Endothelial cell1.損傷的上皮細(xì)胞通過EMT成為肌成纖維細(xì)胞2.反對(duì)意見： 一些細(xì)胞亞群的存在 只在培養(yǎng)基上表達(dá)Epithelial cells在肝臟、腎臟纖維化模型中，髓系細(xì)胞（M2a亞型類似的）可以產(chǎn)生一小部分的型膠原。Leukocytes1.間充質(zhì)細(xì)胞的功能2.各個(gè)器官特異的間充質(zhì)細(xì)胞3.組織損傷修復(fù)復(fù)制了生長(zhǎng)發(fā)育的過程，但并未形成正常結(jié)構(gòu)白白細(xì)細(xì)細(xì)細(xì)細(xì)細(xì)細(xì)細(xì)胞胞胞胞皮皮上上胞胞內(nèi)內(nèi)皮皮間間充充質(zhì)質(zhì)前前體體胞胞 In a new study,injury or stress to endoderm- or mesoderm-derived epithe

12、lium,or injury to mesoderm -derived endothelium or myocytes,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 f

13、rom resident mesenchymal cellsPATHWAPATHWAY Y 之前人們研究的重點(diǎn)在間充質(zhì)細(xì)胞是如何從一個(gè)靜止的細(xì)胞表型轉(zhuǎn)化為具有肌成纖維細(xì)胞性質(zhì)的激活形態(tài)。例如，損傷的上皮例如，損傷的上皮細(xì)胞可以產(chǎn)生細(xì)胞可以產(chǎn)生NGFNGF、 TGFbTGFb、PDGF-BPDGF-B、 VEGF-AVEGF-A、WntsWnts、 hedgehog hedgehog 配體這些配體這些因子，并傳送到鄰因子，并傳送到鄰近的間充質(zhì)細(xì)胞中近的間充質(zhì)細(xì)胞中。保守的the conserved, or core, pathways of fibrosis for therapy新穎的TISS

14、UE-SPECIFIC FEATURES OF FIBROSIS FOR THERAPEUTIC TARGETINGinhibit fibrosiscollateral 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 receptor heterodimer composed of the angiotensin II type I receptor and the cannabinoid CB1 receptoryet few have emerged.OBSTACLES OBSTACLES THERAPIES FOR FIBROSISTHERAPIES FOR FIBROSISTGF-通路及其抑制劑整合素6及其抑制劑LPA1受體及其抑制劑IL4和IL13及其抑制劑