纖維化疾病治療講座

1、纖維化疾病治療講座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 repair lead to fib

2、rosispresent promising new approaches of diagnosis present promising treatment of fibrotic diseases 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 THERA

3、PEUTIC TARGETINGOBSTACLES TO TRANSLATION OF BASIC SCIENCE INTO CLINICAL PRACTICETHERAPIES FOR FIBROSIS組織間纖維化的共同特點Resolution and regression of fibrosisImmune cell recruitmentProperties of the fibrotic ECMAppearance of myofibroblastsEpithelial injury and dysfunction123456代謝途徑的失調Epithelial injury and d

4、ysfunction細胞死亡整合素TGF-間相互作用EMT上皮間質轉化兩種類型免疫應答TGF-與整合素6機械結合LAP片段C端N端6細胞內骨架蛋白相互作用，如肌動蛋白前體形式潛在相關肽完成細胞粘附作用將ECM信號傳導至胞核內損傷的上皮細胞高度表達ImmuneresponsesExtracellularmatrixInnate lymphoidcellsPro-fibroticcytokinesCell deathCell stressER stressPathologic EMTTGF activationROSADCB間充質細胞肌成纖維細胞功能、形態(tài)轉錄調節(jié)分泌大量、膠原及細胞外致纖維化的基

5、質蛋白Appearance of myofbroblasts前體細胞肌成纖維細胞PDGF、CTGFTGF-結合(a-SMA) (pericytes,resident fibroblasts, hepatic stellate cells, and renal mesangial cells)pathways of gene regulation:TGFb :Smads JunDclassical tyrosine kinase signalingAutophagic signaling01取代并破壞正常組織結構02改變固有細胞及肌成纖維細胞的功能03調節(jié)細胞因子和生長因子的失活及激活狀態(tài)04組

6、織硬度增加，改變正常和病理性細胞應答Properties of the fibrotic ECM異常正常分布于內皮與上皮之間，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、透明質酸增多本身也是固有免疫應答的感應器Immune cell recruitment這些免疫分子包括：TNFa、IL-1b、NALP3/ASC、IL-6 and IL-17A, and type 2 cytokines including IL-4 and IL-13 IL-4 and IL-13 及其他相關細胞因子可能是治療纖維化疾病的新靶點 固有免疫應答對肌成纖維細胞的轉化及纖維化十分重要Myof

7、ibroblastschemokines cytokines oxygen radicals（-）靶點01030204Monocyte-derived cellsMonocyte-derived cells (macrophages and dendritic cells) has been contributed to fibrosis disease in animal models.M1, inflammatoryM2a-like profibroticMreg/M2c likeregulatoryfibrosisM2a-like macrophagesMonocytesTGFb1, P

8、DGF, FGF2IGFBP 靶點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 effects on the regulation of activated myofibroblasts, their precursor popu

9、lations and ECs.Monocyte-derived cellsThe recruitment of distinct functional subsets of macrophages and their relative concentrations during injury can determine whether the injury response leads to productivereepithelialization and healing or to pathologic scarring.Resolution and regression of fibr

10、osis纖維化是對組織損傷的保護性反應。正常情況下 ECM被降解，重建正常的結構和功能 (急性損傷、自限性疾病)纖維化疾病時 ECM MMP及其抑制劑被誘導 損傷初期 MMP-7加速炎癥 纖維化期 降解 ECM 肌成纖維細胞吞噬細胞uPARAPMfge8吞噬纖維化逆轉的探討1.乙型病毒性肝炎抗病毒治療2.丙型病毒性肝炎干擾素的治療單核細胞治療纖維化疾?。海╥）分化為調節(jié)性巨噬細胞，產(chǎn)生局部抑制性細胞因子，包括IL-10；（ii）產(chǎn)生基質金屬蛋白酶，可以直接降低間質膠原（MMP-1，2，8，9，13）；（iii）局部消除必需氨基酸，抑制T細胞和肌纖維母細胞增生；（iv）促進肌纖成維母細胞的凋亡；

11、（v）吞噬ECM和能活化纖維化細胞碎片。1.逆轉晚期肝纖維化是肝臟獨特的再生能力？2.哪種細胞成分決定什么時候纖維化是不可逆的？SOURCES OF FIBROGENIC CELLS最主要的1.內皮細胞可以表達a-SMA2.關于間充質細胞命運組學的研究證明它并不是一個致纖維化的祖細胞。Endothelial cell1.損傷的上皮細胞通過EMT成為肌成纖維細胞2.反對意見： 一些細胞亞群的存在 只在培養(yǎng)基上表達Epithelial cells在肝臟、腎臟纖維化模型中，髓系細胞（M2a亞型類似的）可以產(chǎn)生一小部分的型膠原。Leukocytes1.間充質細胞的功能2.各個器官特異的間充質細胞3.組

12、織損傷修復復制了生長發(fā)育的過程，但并未形成正常結構白細細細細胞胞皮上胞內皮間充質前體胞 In a new study,injury or stress to endoderm- or mesoderm-derived epithelium,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.

13、these cells signal via paracellular mechanism to neighboring mesenchymal cells .driving myofibroblast genenration from resident mesenchymal cellsPATHWAY 之前人們研究的重點在間充質細胞是如何從一個靜止的細胞表型轉化為具有肌成纖維細胞性質的激活形態(tài)。例如，損傷的上皮細胞可以產(chǎn)生NGF、 TGFb、PDGF-B、 VEGF-A、Wnts、 hedgehog 配體這些因子，并傳送到鄰近的間充質細胞中。保守的the conserved, or core

14、, pathways of fibrosis for therapy新穎的TISSUE-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 THERAPIES FOR FIBROSISTGF-通路及其抑制劑