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Tissue repair

Isma’eel
Mohammad
7/11/2010Matalqa
Abu
Lec#3
1525
Taleb
‫بسم الله الرحمن الرحيم‬
Patho lec #15

Today we are going to enclose our discussion concerning the


tissue repair , and we are going to talk about just two aspects of
the repair .

* Note: For this lecture refer to {Patho Slide #8 - Tissue repair #2


- slide 23}, and {Patho slide #9 - Tissue repair #3}.

{ Patho Slide #8 - Tissue repair #2 - slide 23}

As you can see there are two sorts of repair as we said previously
it can be either repaired by regeneration ; which means
replacing the injured tissue by the same type of the original
tissue cells , and also you remember that we have dividing cells
like the labile cells and the stable cells which have the ability
( the doctor was interrupted by some 1 who asked about the
exam the doctor said that he will discuss the exam @ the end of
the lecture ) , so we have the labile and stable cells which both
have the capability to regenerate some of them are continuously
dividing during the cycle, some of them upon activation they can
get back to the cycle and regenerate themselves , so in order to
have proper regeneration we have to have two tissue
components :

 The cellular proliferation ; the cell that we need to


regenerate and this should be regulated by growth factors
and growth inhibitors as we have seen already

 And an extra cellular matrix and a cell matrix interactions


that we discussed in the last two lectures .
so an intact basement membrane directs epithelial cell polarity
and is essential for its orderly regeneration, without extra cellular
matrix we can’t have proper regeneration.

{Patho slide #9 - Tissue repair #3}

{slide #1}

The other way of repair is repair by connective tissue, and in


cases with a severe injury with damage to the parenchymal cells
and stroma this will preclude the parenchymal regeneration and
the repair will occur by the connective tissue (CT) or by the
fibrous tissue and that’s why we call it repair by fibrosis or repair
by connective tissue .

The components of the repair by connective tissue includes :

 The neovascularization ( angiogenesis ) ; which is the


formation of new blood vessels .

 Proliferation of fibroblasts

 Deposition of the extracellular matrix (ECM)

 And then the remodeling all these components together to


reengineer the damaged organ to its native situation

{slide #2}

so this is granulation tissue which *broke down* after the


injury and here you see the granulation tissue is composed
of proliferation of blood vessels and mixed with acute &
chronic inflammatory processes which with time will
organize and form the fibrous scar or the fibrous tissue
eventually .

{slide #3}

So what is angiogenesis, angiogenesis simply is the


formation of new blood vessels either from endothelial
precursor cells or pre-existing vessels.

The vascular endothelial growth factor (VEGF) effects on the


endothelial cells has a pleotrophic effect; it has different
actions so the actions of (VEGF) includes :

 the migration of the appropriate endothelial cells

 and then increase in the proliferation of these cells

 and with good differentiation

 end then increase in the permeability of these endothelial


cells

# {The angioipoitiens 1 & 2 , and the platelet-derived growth


factor (PDGF) ,and the transforming growth factor beta (TGF-
beta )} stabilize the newly formed blood vessels.

{slide #4}

So this is how it happens we have angiogenesis from the


endothelial precursor cells, and these precursor cells are
usually synthesized or produced from a differentiation from the
stem cells in the bone marrow and then they will migrate to
the other blood vessels in the whole body in a manner that we
call Homing effect.

So upon stimulation these endothelial precursor cells will


proliferate, migrate, proliferate, and form these newly formed
capillary plexuses which eventually transform into a mature
network of blood vessels at the site of injury or inflammation.

{slide #5}

So angiogenesis from Endothelial Precursor Cells (EPCs) as we


said the hemangioblast which is a hematopoietic stem cells &
the angioplasty which is the (EPCs) , they are stored in the
bone marrow and then they usually express markers of
hematopoietic stem cells & and of endothelial cells , they play
a very important role in the neovascularization, replacement of
endothelial cells and re-endothelialization of vascular
implants .

{Slide #6}

So this is the role of the endothelial precursor cells , the other


way is the formation of new blood vessels from pre-existing
blood vessels , as you can see here they will create what we
call a capillary sprouting ; which is an outgrowth of the main
blood vessel and this will proliferate under the action of growth
factors (different growth factors) including: the endothelial
growth factors and (PDGF)and others , and then eventually
forming a mature network of small newly formed blood
vessels .

So this is the angiogenesis from pre-existing blood vessels and


the other one which is by the migration of the precursor cells

{Slide #7}

In angiogenesis from a pre-existing blood vessel , a parent


vessel sends out capillary sprouts to produce new vessels

# The steps involved in this process include the following :

 degradation of the parent vessel basal membrane

 migration of endothelial cells outside the parent blood


vessels to the outside environment

 and then the proliferation of these endothelial cells

 followed by maturation and organization into a capillary


tubes .

# Growth factors involved are:

 basic fibroblast growth factor (beta FGF)

 vascular endothelial growth factor (VEGF)

Which are the main growth factors involved in the process.

{slide #8}
and this is a summary of the degradation of the basement
membrane and then migration , proliferation , organization and
formation of these small blood vessels , and after such
maturation there will be increased permeability through the gabs
and transcytosis which also will facilitate reaching the blood ,
blood components and blood cells to the outside area .

{slide #9}

So Fibrosis on the other hand is emigration and proliferation of


fibroblasts.

# Growth factors that are involved in facilitating the fibrosis


process are :

{ Platelet-derived growth factor (PDGF) , fibroblast growth factor


(FGF) , epithelial growth factor (EGF) and the transforming growth
factor beta (TGF beta)}.

# And the ones which facilitate deposition of (ECM) are:

{ (PDGF), (FGF), (TGF beta) and cytokines (IL-1 &TNF) }.

{slide #10}

And after the process of angiogenesis and fibrosis and the


deposition of (ECM) , there will be the process of remodeling we
call it scar remodeling, so if there is an excessive fibrous tissue
being made at that area of tissue injury or damage this might
produce some sort of structural abnormality or functional
abnormality, so we need another process which will do such
remodeling and reengineering of these structures & these
components so it’s a shift and change of the composition of the
(ECM) of the scar as result of synthesis & degradation .

So there are some specific enzymes we call them


metalloproteinase’s; which are enzymes produced by many cells
capable of degrading different (ECM) constituents, these include:

 interstitial collagenases

 gelatinases

 stromelysins

Now the metalloproteinase’s are ( ZN dependant ) and are


activated by HOCl or proteases ( plasmin ) . and they are
inactivated by tissue inhibitor of metalloproteinase’s which we
call them (TIMP), they are tissue inhibitors of these enzymes , so
there is a balance there is an equilibrium between the action of
these proteases and metalloproteinase’s and on the other hand
some kinds of inhibitors for them to keep balance and to keep the
equilibrium

And steroids also can inhibit the action of these


metalloproteinase’s, that’s why people who are having surgery or
they are having some sort of major injuries if there are taking
some sort of steroids this will alter the healing process of the
tissue or that injury, so most of the time it’s not really advised to
take steroids unless there is a proper and specific indication to do
so.

{slide #11}

So this is how the matrix metalloproteinase’s are regulated so we


have some stimulation to the macrophages here which will lead
to the procollagenase & prostromelysins activation , and by the
activation of other plasma proteins like plasminogen and
plasminogen activators this will lead to the activation of the
collagenas’s & stromelysins , and this will lead to degradation of
the (ECM) , this is balanced and controlled by the inhibitors like
steroids and (TGF beta ) so these steroids will inhibit this process
& activation and on the other hand we have an endogenous sort
of control mechanism which are the tissue inhibitors of
metalloproteinase’s also which can control and inhibit the
excessive degradation of such (ECM) .

{slide #12}

In wound healing in general usually we have a fibrin clot


formation when you have any cut wound you will have pits and
there will be a deposition of the fibrin clot which will fill the gap in
such defect , and then such injury will lead to acute inflammatory
process by the initial injury , and you know by now that the initial
first line of inflammatory cells are the neutrophils in the first 24
hours and followed by the monocytes by the third day , and this
will lead to a parenchymal cell regeneration , and then migration
& proliferation of parenchymal & connective tissue cells &
granulation tissue formation , so this is the process of granulation
tissue formation and this will activate the (ECM) protein synthesis

And then undergoing the process of remodeling of the


parenchymal elements to restore the tissue function and the
tissue structure, remodeling of (CT) to achieve as we said also the
proper wound strength, so any defect in skin or the substantial
tissue with time you need this tissue to restore its length, so how
long it takes to have such healing or to restore such length.

{slide #13+14}

So we have two types of healing , the first type we call it healing


by first intention, and if there is only a focal or minor disruption
of the basement membrane and loss of only few of epithelial cells
like in surgical incisions which are done by surgeons by the knife
so there is minimum loss of the epithelial elements and the
basement membrane with approximation of the later sides by the
suturing material we call this healing by first intention this will
lead eventually to the polishing of this scab which is a deposition
of fibrin and other inflammatory cells and then will undergo a
granulation tissue formation and fibroblastic proliferation leading
to fibrous scar formation , so we call it healing by first intention .

On the other hand when there is a larger injury like infarction,


abscess, trauma, direct blunt trauma sometimes or irregular
trauma to the presence of larger defect in the basement
membrane or the skin for example and this will lead eventually to
a larger scar with a deposition of more fibrous tissue and larger
scar tissue and then contraction of the tissue as a result of this
excessive fibrous tissue scar.

{slide #15}

So the phases of wound healing starts by inflammation and then


followed by granulation tissue formation , and during that time
will start the wound contraction , and with the process of
remodeling ( collagen accumulation and remodeling ) this will
continue the healing and increase in the strength of the wound .

{slide #16}

So the wound strength usually sutured wounds have 70% of the


strength of the unwounded skin , and after sutures are removed
at one week the wound strength is only 10% of the unwounded
skin . It needs 3-4 months until the wound strength is about 80%
of the unwounded skin , so basically this healing needs time to
achieve at least 70 or 80 percent of its original strength , and
that’s why in surgical wounds sometimes they give a lot of
advices to the patient regarding their activity physical activity
regarding their mobility … etc , and even regarding having some
sort of manipulation in that area or any maneuvers , so they can
keep the wounded cells with its maximum strength , sometimes
some surgical wounds may undergo some sort of weakness and
this will lead to what we call surgical herniation, and sometimes
infections which will weaken the whole process of regeneration .

{slide #17}

And that here will summarize the factors which affect healing , as
you can see here there are systemic and local factors.

# The systemic ones includes :

 the nutritional ones, so protein deficiency or vitamin C


deficiency or zinc deficiency all of these will impair proper
healing and regeneration, and by now you should know why
because vitamin c is important in collagen synthesis, zinc as
we just discussed is important in the remodeling because
the metalloproteinase’s are ZN dependent like other
proteins or enzymes, so protein deficiency will prevent
proper healing and regeneration.

 Systemic diseases like diabetes or arteriosclerosis or renal


failure or infections (systemic infections) also will impair
regeneration.

 Corticosteroid treatment

 Age the increase in age

 Or the immune status in the patient is compromised.

So all these are systematic.


# Locally at the site of the injury or inflammation:

 There is an infection this will again weaken the process of


regeneration and fibrosis.

 Poor blood supply and you can know why is that.

 type of tissue ; there are some tissue types which are known
to have weak capability of regeneration than the others

 presence of foreign body material

 ionizing radiation , and that’s why if somebody is having a


major operation even for cancer they have to wait for certain
time to start radiation for that specific cancer , because
radiation can effect such wound even the surgical wound .

 and there are some mechanical factors including :

_ excessive movement

_ hematoma

_ in appropriate apposition

All of these can affect the proper healing .

{slide #18}

So pathological aspects of repair include aberration of growth ,


excessive growth may occur in exuberant granulation tissue
formation during the wound healing , and also we can get what
we call the keloid which is excessive accumulation of collagen
during wound healing resulting in a raised tumorous scar we call
it keloid {slide #19} and this is an example of this .

All excessive fibrosis and an example of these as a reaction for


inflammation or to injury includes: the cirrhosis , pulmonary
fibrosis , rheumatoid arthritis (RA)

Other than the aberration of growth we can have tissue damage


like collagen destruction by collagenases in (RA)

And this is the keloid {slides #19} which is composed of


excessive accumulation of fibrous or collagen tissue in the
subcutaneous tissue , {slide #20} and this is the histology as you
can see the excessive collagen.

{slide #21}

So in summary what are the repair out come after injury, if you
have any injury in the proper context and proper sittings we have
cellular and vascular response. This just summarizes the whole
process , and if the stimulus is removed in acute injury we can
have parenchyma cell death where intact tissue framework and
this will lead to superficial wounds and some inflammatory
response and this will lead to regeneration . if there is damage to
the (ECM) or framework and the wound were deep this will lead to
healing by scar formation or organization of exudates, and these
are some examples for this (referring to the slide), and if there
were a persistent tissue damage this will be repaired and healed
by fibrosis and tissue scar, and examples for that are like chronic
inflammatory diseases like cirrhosis, chronic pancreatitis and
pulmonary fibrosis.

And I think this will conclude our lecture regarding inflammation


and repair.

‫الحمد لله الذي بنعمته تتم الصالحات‬

Please forgive me 4 any mistakes, I


did my best “with no help except from
god “

Done by: mo7mad abu 6aleb (Abu


Gasem)

Good luck :D

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