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Mechanisms of Fibrogenesis

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Title: 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
  • ???????????,??????????????????????????????????????
    ????,??????????????????
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