Mechanisms of Fibrogenesis

1
Mechanisms of Fibrogenesis

• ??????

2

• ??????????????????????????????,??????????????
• ?????????,?????????????????????????(ECM)??????????
  ???

3
??????
???TGF-ß1
??????
?/?????????
?????(ROS)???
??????
??????????
????
??????,?????
4
Damage to Epithelial/Endothelial Barrier

• ??????,????????????????TGF- ß1?????????????????NO,
  ?????????
• ??????????????
• ??
• ???

5
Vascular 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???????????

8
Apoptosis of Epithelial Cells

• ????EC,????????????????????
• ?????????,????????
• ??????????(Fas-FasL?????)
• ?????????
• ?????????

9

• ??????????????????????
• ????????,???????????????
• ??????????????????????????????TGF-
  ß1,??????????????

10

• ????????????????TGF- ß1??????????(ROS),???????????
  ?????
• endothelial/epithelial barrier????????????????,???
  Toll-like receptor(TLR)????????????????????

11
Release 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

14
Smad3 ???????????????
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?????
  ????????????

18
Inflammation
Neutrophils
? ?
? ?
???????????????
????
Neutrophils macrophages
???????
????????????????
19
??? ????????,???fibroblasts fibrocyte????????????
??? ??????????TGF-ß1,??????????
? ???Angiotensin II (Ang II)?????????
20

• ???,??????TLRs??????????????
• ???????,????????????????,???????????????????

21
Oxidative Stress

• ??ROS??????????,?????????????,??????????????,?????
  ???

? ??????????Kupffer cells????HSCs?neutrophils??ROS???HSC???
? Neutrophils?eosinophils??????????????????ROS???
? ???????????????????????????????????ROS??????????
22
Activation of Collagen-Producing Cells

• ???????????,?????????????????????????
• ????????????,???????????????????????????

23

• ???????????????, ?TGF-ß1???????????????(fibronecti
  n?Type I collagen),????myofibroblast???
• ?????????????fibroblasts/myofibroblasts???????????
  ??

24
Epithelial-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????

30
Fibrocytes

• ???????????????????
• ?????????????????????,????????CD45??
• ????,?????BM??????(lt1)??????,????????????????????
  ?

31

• ?????,?????????????????,???????????????
• ???????,???????,?????????lymphoid markers?myeloid
  markers?adhesion molecules??fibroblastic
  markers,?????????????ECM????????????

32

• ?????????????????????????,????????????????????????
  ?
• ??????CCR2.3.5.7?CXCR4??????,???????????????
• ?????????????????????,????????????????

33
BM-Derived Fibroblasts

• ????????,?????????????,???BM-derived?fibroblasts
• ?????????? a-SMA?myofibroblast??????,????????????
  ??????

34
Matrix-Induced Activation of Myofibroblasts

• ??TGF-ß1??????????,??????????????,????????????????
  ???????
• ??????,???ECM???????(fibronectin?collagen
  I.III)????????,??????????????

35

• HSCs??????????,?????????????????????????
• ???????????????????????????,????????????,???????

36
Concluding Remarks

• ???????????,??????????????????????????????????????
  ????,??????????????????