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Mechanism of tissue repair
Dr Walidad
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General concept
Damage to parenchymal cell, non dividingcells or stromal network repair occurs by
fibrosis.
Begins in 24 hours of injury by emigration offibroblasts and induction of endothelial cells.
In 3 to 5 days granulation tissue is formed
which is soft, pink and granular in appearance.
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It contains fibrobroblasts and capillaries in
loose extracellular matrix(ECM).
Granulation tissue then accumulates
connective tissue matrix and results in scar
formation.
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Processes
Repair by connective tissue deposition
consists of four processes:
1. Angiogenesis
2. Migration and proliferation of fibroblasts.
3. Deposition of ECM(scar formation)
4. Remodeling
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Angiogenesis
Blood vessels are produced in two ways:
1. Vasculogenesis, in which primitive vascular
network is assembled from angioblasts
(endothelial cell precursors).
Endothelial precursor cells(EPC) present in
bone marrow may contribute in angiogenesis
by moving towards the injured tissue.
They may replace the lost endothelial cells.
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2. Neovascularization, in which pre-existing
vessels send out capillary sprouts to produce
new vessels. It occurs in 5 steps:
1. Vasodilation due to nitric oxide and increased
capillary permeability of pre-existing vesselsinduced by vascular endothelial growth
factor(VEGF)
2. Migration of endothelial cells toward area oftissue injury.
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3. Proliferation of endothelial cells just behindthe leading front of migrating cells.
4. Inhibition of endothelial cell proliferation andremodelling into capillary tubes.
5. Recruitment of periendothelial cells(pericytesor smooth muscle cells) to form mature
vessels.
New vessels are leaky due to incompletelyformed interendothelial junctions and
increased transcytosis. For this reason granulation tissue is
edematous.
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Growth factors in angiogenesis:
Several factors induce angiogenesis, but mostimportant are:
1. Vascular endothelial growth factor(VEGF)
2. Basic fibroblast growth factor(FGF).
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VEGFs are expressed in low levels in tissue
can be induced by various factors like PDGF,TGF-, TGF- and hypoxia.
Stimulate proliferation and motility ofendothelial cells resulting in capillarysprouting.
FGFs consists of 20 members including FGF-1and FGF-2.
FGF-2 stimulates proliferation of endothelial
cells. Also promotes migration of macrophages and
fibroblasts to damaged area
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Newly formed vessels need stabilization.
Angiopoietins 1 and 2 initiate stabilization
process by recruiting pericytes
PGDF recruits smooth muscle cells.
TGF- enhances production of ECM proteins
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Migration of fibroblasts and ECM
deposition(scar formation)
Scar formation builds on granulation tissueframework.
Occurs in 2 steps:
1. Migration and proliferation of fibroblasts intothe site of injury.
2. Deposition of ECM by these cells.
The recruitment and proliferation offibroblasts is driven by many growth factorslike PDGF, FGF-2, and TGF-.
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These factors are derived from activated
endothelium and inflammatory cells especially
macrophages.
Mast cells and lymphocytes may also
contribute in fibroblast proliferation.
Later, number of proliferating fibroblasts andnew vessels decreases and ECM deposition is
increased.
Collagen is synthesized by fibroblasts. Same growth factors stimulate ECM synthesis.
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Ultimately scar is evolved in the granulation
tissue.
Scar consists of inactive fibroblasts, dense
collagen, fragments of elastic tissue and other
ECM components.
As scar matures, vascular regression occurs in
scar which becomes pale and largely
avascular.
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Growth factors involved in scar
formation
Factors involved in scar formation include TGF-
, PDGF, FGF and cytokines.
TGF- is a polypeptide and a potent
fibrogenic agent.
It stimulates production of collagen,
fibronectin, and proteoglycans.
Inhibits collagen degradation by decreasing
proteinase activity.
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It also inhibits lymphocyte proliferation and
can have strong anti-inflammatory effect.
PDGF is stored in platelets and released onplatelet activation.
Produced by endothelial cells, activated
macrophages and smooth muscle cells. It causes migration and proliferation of
fibroblasts, smooth muscle cells and
macrophages.
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Cytokines like IL-1 and TNF- may also
function as growth factors and participate in
scar formation.
They induce fibroblast proliferation and can
have fibrogenic effect.
They stimulate synthesis of collagen as well.
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ECM and tissue Remodeling
Scar ECM continues to be modified and
remodeled even after deposition.
The outcome of repair process is a balance
between ECM synthesis and degradation.
The degradation of collagens and other ECM
components is done by matrix
metalloproteinases(MMPs).
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MMPs include:
1. Interstitial collagenases, which cleave fibrillar
collagen.2. Gelatinases which degrade amorphous
collagen and fibronectin.
3. Stromelysins which degrade ECMconstituents like proteoglycans, laminin,
fibronectin and amorphous collagen.
MMPs are produced by various cells likefibroblasts, macrophages, neutrophils and
epithelial cells.
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Their synthesis is regulated by growth factors,
cytokines and some other factors.
TGF- inhibits MMPs synthesis. The activity of MMPs is tightly controlled due
to their potential to produce havoc in tissues.
They are activated only at site of tissue injury.
Activated collagenases can be rapidly inhibited
by tissue inhibitors of metalloproteinases
(TIMPs), produced by mesenchymal cells.
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Thank you