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1、Therapy for Fibrotic Diseases,Nearing the Starting Line,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
2、 injury and repair lead to fibrosis,present promising new approaches of diagnosis,present promising treatment of fibrotic diseases,目的,COMMON FEATURES OF FIBROSIS ACROSS TISSUES,SOURCES OF FIBROGENIC CELLS,PATHWAYS DRIVING MYOFIBROBLAST GENERATION FROM RESIDENT MESENCHYMAL CELLS,TISSUE-SPECIFIC FEATU
3、RES OF FIBROSIS FOR THERAPEUTIC TARGETING,OBSTACLES TO TRANSLATION OF BASIC SCIENCE INTO CLINICAL PRACTICE,THERAPIES FOR FIBROSIS,组织间纤维化的共同特点,1,2,3,4,5,6,代谢途径的失调,Epithelial 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,完成细胞粘附作用,将E
4、CM信号传导至胞核内,损伤的上皮细胞高度表达,Immuneresponses,Extracellularmatrix,Innate lymphoidcells,Pro-fibroticcytokines,Cell death,Cell stress,ER stress,Pathologic EMT,TGF activation,ROS,分泌大量、胶原及细胞外致纤维化的基质蛋白,Appearance of myofbroblasts,(a-SMA),(pericytes,resident fibroblasts, hepatic stellate cells, and renal mesangi
5、al cells),pathways of gene regulation:TGFb :Smads JunDclassical tyrosine kinase signalingAutophagic signaling,01,取代并破坏正常组织结构,02,改变固有细胞及肌成纤维细胞的功能,03,调节细胞因子和生长因子的失活及激活状态,04,组织硬度增加，改变正常和病理性细胞应答,Properties of the fibrotic ECM,、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 recruitment,固有免疫应答对肌成纤维细胞的转化及纤
6、维化十分重要,Myofibroblastschemokines cytokines oxygen radicals,（-）,靶点,01,03,02,04,Monocyte-derived cells,Monocyte-derived cells (macrophages and dendritic cells) has been contributed to fibrosis disease in animal models.,M1, inflammatoryM2a-like profibroticMreg/M2c likeregulatory,靶点,IL-4、L-13、CCL17、CCL2
7、chemokinesmacrophage colony-stimulating factor,Monocyte-derived cells,Resolution and regression of fibrosis,纤维化是对组织损伤的保护性反应。正常情况下 ECM被降解，重建正常的结构和功能 (急性损伤、自限性疾病)纤维化疾病时 ECM MMP及其抑制剂被诱导 损伤初期 MMP-7加速炎症 纤维化期 降解 ECM,肌成纤维细胞,吞噬细胞,uPARAP,Mfge8,吞噬,1.乙型病毒性肝炎抗病毒治疗2.丙型病毒性肝炎干扰素的治疗,单核细胞治疗纤维化疾病：（i）分化为调节性巨噬细胞，产生局部抑制
8、性细胞因子，包括IL-10；（ii）产生基质金属蛋白酶，可以直接降低间质胶原（MMP-1，2，8，9，13）；（iii）局部消除必需氨基酸，抑制T细胞和肌纤维母细胞增生；（iv）促进肌纤成维母细胞的凋亡；（v）吞噬ECM和能活化纤维化细胞碎片。,1.逆转晚期肝纤维化是肝脏独特的再生能力？2.哪种细胞成分决定什么时候纤维化是不可逆的？,SOURCES 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 cell,1.损伤的上皮细胞通过EMT成为肌成纤维细胞2.反对意见： 一些细
9、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。,Leukocytes,1.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,细,细,细,细,胞,胞,皮,上,胞,内,皮,间,充,质,前,体,胞,In a new study,injury or stress to endoderm- or mesoderm-derived epithelium,or injury to mesoderm -derived endothelium or myoc
10、ytes,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 cells,PATHWAY,之前人们研究的重点在间充质细胞
11、是如何从一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，损伤的上皮细胞可以产生NGF、 TGFb、PDGF-B、 VEGF-A、Wnts、 hedgehog 配体这些因子，并传送到邻近的间充质细胞中。,保守的,the conserved, or core, pathways of fibrosis for therapy,新颖的,inhibit fibrosiscollateral effects,impair tumor suppression cause chronic inflammation.,specific cell surface molecules,unique
12、 intracellular targets,pinpoint 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 receptor,yet few have emerged.,THERAPIES FOR FIBROSIS,TGF-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,01,纤维化仍在进展,02,加重原发疾病,03,临床试验的指标未出现统计学意义,04,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.,谢谢聆听,
