Title: Mechanisms of Fibrogenesis
1Mechanisms of Fibrogenesis
2- ??????????????????????????????,??????????????
- ?????????,?????????????????????????(ECM)??????????
???
3??????
???TGF-ß1
??????
?/?????????
?????(ROS)???
??????
??????????
????
??????,?????
4Damage to Epithelial/Endothelial Barrier
- ??????,????????????????TGF- ß1?????????????????NO,
????????? - ??????????????
- ??
- ???
5Vascular Damage and Vasculogenesis
- ??????(EC)???,??????????????,?????????????????,???
???EC????? - ???????,???????????????????????????
6- ??????,EC????????????????????????????
- Vasculogenesis??????????????????
- ????????????????? angiopoietins?transforming
growth factor (TGF-ß1)?platelet-derived growth
factor (PDGF)?tumor necrosis factor-alpha
(TNF-a)? interleukins??fibroblast growth factor
family (FGF)
7- ?EC,????????????????????sphingosine 1-phosphate
(S1P)??? - ??????????????,CXCL18????CXCR2?CXCR3???????????
8Apoptosis of Epithelial Cells
- ????EC,????????????????????
- ?????????,????????
- ??????????(Fas-FasL?????)
- ?????????
- ?????????
9- ??????????????????????
- ????????,???????????????
- ??????????????????????????????TGF-
ß1,??????????????
10- ????????????????TGF- ß1??????????(ROS),???????????
????? - endothelial/epithelial barrier????????????????,???
Toll-like receptor(TLR)????????????????????
11Release of TGF- ß1
- Transforming growth factor- ß1 (TGF-ß1)??????,????
??????? - ???????????,?????TGF-ß1???????????,???TGF-ß1??????
???????
12??????
?????
1.?????? 2.Kupffer cells
1.monocyte 2.Eosinophils 3.Myofibroblasts 4.fibrob
lasts
??TGF-ß1
13- TGF-ß1????thrombospondin 1(TSP-1)?a?ß6????????????
???? - ????TGF-ß1,???????TGF-ß1??TßR?????????
- TGF-ß1???,??Smad?Mad??????????,??????????
- ????Smads(R-Smads)
- ????(co-Smads)
- ?????Smads
14Smad3 ???????????????
Smad2 ??Smad3,???????????
Smad4 ?Smad2/3?????????,?????????TGF-ß1??????
Smad7 TGF-ß1????,????TGF-ß1?????,Ski?SnoN?Bambi??????TGF-ß1???
15- Connective tissue growth factor
(CTGF)????????????,??????????CTGF?TGF-ß1???? - CTGF??????TGF-ß1???
- CTGF??TGF-ß1?????????
16(No Transcript)
17- Hepatocyte growth factor(HGF)?????????????????????
????? - HGF????????????????????????????????
- TGF-ß1?HGF?????,????TGF-ß1??????HGF???,??HGF?????
????????????
18Inflammation
Neutrophils
? ?
? ?
???????????????
????
Neutrophils macrophages
???????
????????????????
19??? ????????,???fibroblasts fibrocyte????????????
??? ??????????TGF-ß1,??????????
? ???Angiotensin II (Ang II)?????????
20- ???,??????TLRs??????????????
- ???????,????????????????,???????????????????
21Oxidative Stress
- ??ROS??????????,?????????????,??????????????,?????
???
? ??????????Kupffer cells????HSCs?neutrophils??ROS???HSC???
? Neutrophils?eosinophils??????????????????ROS???
? ???????????????????????????????????ROS??????????
22Activation of Collagen-Producing Cells
- ???????????,?????????????????????????
- ????????????,???????????????????????????
23- ???????????????, ?TGF-ß1???????????????(fibronecti
n?Type I collagen),????myofibroblast??? - ?????????????fibroblasts/myofibroblasts???????????
??
24Epithelial-to-Mesenchymal Transition (EMT)
- ???????????,????????EMT???????,?????
- EMT???????????????,?????????( fibroblasts?myofibro
blasts )???
25- EMT????????????????,??????????,?????????EMT
- EMT???????????????TGF-ß1
- ?????, epithelial growth factor (EGF)? basic
fibroblasts growth factor (bFGF)?
interleukin-1(IL-1)????EMT
26??????????
?????????
??????????????????????????
??????????????a-SMA
27? ???1/3????????????????????EMT????
? ???????????(ATIATII),ATII?????????????????,?????EMT
? ??????????????????????EMT???,??????????????????,EMT??????????????
28- TGF-ß1?EMT??????,????????Smad3-dependent?Smad3-ind
ependent???,?????EMT - ???????????EMT???
- ????EMT,?TGF-ß1?????????
- ??????myofibroblasts???,???fibroblast-specific
protein 1 (FSP1)
29- ?????????endothelial-to-mesenchymal transition
(EndMT)?????? - ??EMT?EndMT????????????????,??????????????????????
?????????????????myofibroblast??????ECM???,???????
???myofibroblast????
30Fibrocytes
- ???????????????????
- ?????????????????????,????????CD45??
- ????,?????BM??????(lt1)??????,????????????????????
?
31- ?????,?????????????????,???????????????
- ???????,???????,?????????lymphoid markers?myeloid
markers?adhesion molecules??fibroblastic
markers,?????????????ECM????????????
32- ?????????????????????????,????????????????????????
? - ??????CCR2.3.5.7?CXCR4??????,???????????????
- ?????????????????????,????????????????
33BM-Derived Fibroblasts
- ????????,?????????????,???BM-derived?fibroblasts
- ?????????? a-SMA?myofibroblast??????,????????????
??????
34Matrix-Induced Activation of Myofibroblasts
- ??TGF-ß1??????????,??????????????,????????????????
??????? - ??????,???ECM???????(fibronectin?collagen
I.III)????????,??????????????
35- HSCs??????????,?????????????????????????
- ???????????????????????????,????????????,???????
36Concluding Remarks
- ???????????,??????????????????????????????????????
????,??????????????????