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41 Cards in this Set
- Front
- Back
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fibrosis
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the PERSISTANT production of ECM (in particular fibrillar collagens) in tissue in response to injury, infection, inflammation such that MATRIX DEPOSITION OBSTRUCTS and INTERFERES with normal tissue/organ function
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kidney fibrosis costs
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2bn GBP to NHS
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kindey fibrosis risk factors
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diabetes
immune mediated inflammation urinary tract infection |
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fibrosis leads to _______ in arteries
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restenosis
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in kidneys
interstital fibrosis + ________ ________ ----> vascular occlusion ---> _________ ______ |
glomerular sclerosis
vascular occlusion |
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transient TGFbeta expression
(e.g from platelet release in wound healing) |
Repair
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persistant TGFbeta expression
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FIBROSIS
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Profibrotic GFs
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TGFbeta 1,2,3
IL-1beta Connective Tissue GF (downstream from TGFbeta1) |
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TGFbeta3
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predominant in foetus
foetuses DOES NOT SCAR |
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TGFbeta family
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TGFbeta
Activin BMP-2,4,7 |
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TGFbeta receptor
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S/T kinase
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R-Smads
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1
2 |
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coSMAD
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4
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inhibitory smad
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6
7 |
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TGF beta overexpression in kidney
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GLOMERULOSCLEROSIS
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TGF beta underexpression
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death at 3 weeks
-> SYSTEMIC NECROSING VASCULITIS in vital organs (immune activation, auto-Abs) ~ to systemic lupus erythematous |
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TGF beta production
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EC
SMC epithelial cells fibroblasts lymphocytes monocytes/macrophages |
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TGFbeta acts mainly on
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fibroblasts
-->myofibroblasts |
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TGF beta is secreted as ______ _______ _______
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biologically inactive complex
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HGF secreted as
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proform
needs enzymatic activation |
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TGFbeta is _______________
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immunosuppresent
V.POTENT |
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TGFbeta function
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accumulation of ECM
increase ECM components (TIMPs, PAI, Fibronectin, Collagen I, III, IV, V PGs) decreases ECM degredation (collagenase, MMPs, plasminogen activator) |
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TGFbeta expression
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trx activated in response to hypoxia, inflammation
+ve feedback via AP-1 sites |
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TGFbeta1 SNP
-800A |
destroys AP-1 tc site in promotor
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-800GG
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2X more TGFbeta protein then GA (via increased trx)
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-800GA
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PROTECTION from renal scarring in patients with SLE nephritis
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precursor TGFbeta protein
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signal peptide + LAP + active TGFbeta
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LTBP
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>4
different protein binding properties can bind matrix |
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Thrombospondin
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activates TGFbeta
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Fibrillin
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inhibits TGFbeta
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General mechanisms of TGFbeta activation from slc/llc
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ECM proteins
Proteases (plasmin, thrombin, chymase) cell surface receptors (integrin) Others (free radicals, radiation) |
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TGFbeta induces __ ____ _______
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it's own production
*unique |
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TGFbeta receptors
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HETERODIMERISES
RI RII |
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TGFbeta can also activate
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Ras signalling
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At cellular level TGFbeta causes
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epithelial -> mesenchymal cell transition
stabilise newly formed matrix promote myofibroblast differentiation |
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demethylating agent
5’-azacytidine |
removes DNA methylation
increases trx ---> quiescent fibroblasts |
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persistant TGFbeta exposure
(> 5 days) |
consititutively active fibroblast
due to hypermethylation of RASAL1 promoter via methyltransferase Dnmt1 |
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RASAL1
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natural inhibitor of Ras pathway
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hypermethylation of RASAL1
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increased Ras signalling
--> Fibroblast activation and proliferation |
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Tissue transglutaminase
tTG2 |
cross-linker (glutamyl-lysine)
STABILISED COLLAGEN, preventing degredation |
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KO tTG2
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impaired wound healing
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