9. Wound Healing I Flashcards by J L

WOUND HEALING

Regeneration
Replacement; same type. • Normal function.

• Scar formation:
• Replacement with connective
tissue (collagen, scar); ____

• Extensive deposition of collagen
• Chronic inflammation (Fibrosis)
• Loss of function;
____

Healing

Chronic Inflammation

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Mechanisms of Fibrosis

Persistent chronic injury leads to ____ (loss of tissue architecture)
Cytokines produced mainly by ____ leads to migration of fibroblasts/myofibroblasts
Deposition of collagen and other ECM proteins
Fibrosis

Severe injury > inflammation > macrophages + T lymphocytes > TGFbeta, and other GF > activating ____

Myofibroblasts and the result of fibrosis

chronic inflammation
macrophages
fibroblasts

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Cell types

Labile: tissue is damaged, the tissue will ____
Stable: tissue is damaged, it can either ____ or form a ____
Permanent: tissue is damaged, cannot regenerate, but will form a ____ and will result in a collagenous scar

regenerate
regenerate
scar
scar

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Labile Cells

Tissue that contains 1.5-2% of labile cells > considered to contain labile cells

Cells are continuously ____, so if all were labile that would result in the formation of ____

Only a small ____; exist to replace damaged cells

dividing
cancer
proportion

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Labile Cells

Most surface epithelia:
____ surfaces:
Skin, Oral Cavity, Vagina and cervix
____ of ducts of exocrine organs: • Salivary glands, pancreas, biliary duct
____ epithelia:
GI, uterus and fallopian tube
____ epithelium:
Urinary tract
____ in the bone marrow

stratified squamous
cuboidal epithelia
columnar
transitional
hematopoietic cells

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Injury to cells? Do they always regenerate? Depends on extent of injury

When labile cells divide, it gives two daughters, one remains as a ____ and the other cell differentiates into an ____ cell

If injury is persistent, you won’t see injury

If damages the BM (where ____ cells reside) > no regeneration, will get ____ formation

____ > scratching, damaging BM > scar formation

SC
epithelial

labile cells
scar

chicken pox

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Regeneration and Scar Formation

[NOTES]

Fracture of bone > high capacity to ____

But if BM infection > chronic inflammation > foci of inflammatory cells > ____ > lymphocytes + macrophages > ____ formation (no regeneration of bone)

regenerate
round-cells
scar

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Stable Cells

Cells that are in the ____ phase (exited CC)
Not continuously ____; but do have the potential to divide if they are ____ to do so (in response to GF)

Important example: ____

Go
dividing
stimulated
liver

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Stable Cells

Parenchymal cells of virtually all ____ organs of the body:
– ____
– Kidney
– ____

• Connective tissue and mesenchymal cells:
– ____
– smooth muscle cells
– ____ cells

glandular
liver
pancreas
fibroblasts
endothelial

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Injury to cell matrix > chronic ____ > scar formation > liver has undergone ____

alcoholism

fibrosis

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Human Liver has remarkable capacity to regenerate; 2 mechanisms

Resection of up to 90% of liver can be corrected by the proliferation of ____

In chronic injury or inflammation ____ in the liver contribute to regeneration

residual hepatocytes

progenitor cells

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Kidney Regeneration

Right: kidney undergone chronic inflammation and stain with trichrome > ____ formation, it would look blue (glomeruli, not much in tubules, bc the ____ have a greater capacity to regnerate than the ____ (glomeruli undergoes fibrosis))

Acute inflammation: tender, ____ because of fluid, ____

scar
tubules
glomeruli
larger
pallor

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Lung Regeneration

• left: normal lung
• 2nd left: ____ inflammation. alveolar septa filled w/ fluid/cells
◦ if it does not affect Fx of lung then it’s healing.

• 3rd: what happens if someone is exposed to ____ particle for a long period of time? as a result the lung
undergoes ____. H&E stain showing a lot of pink. ◦ ____ inflammation/____

• 4th: trichrome shows collagen.

acute
silica
fibrosis
chronic
LOF

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Permanent Cells

Cannot replicate after ____ .
____ , ____ muscle, ____ muscle.
Once destroyed, they are lost ____ .

if you have a MI, then no attempt to regenerate cells b.c myocardial cells are ____ . If a tissue is made up of permanent cells then it is most likely to undergo ____ . there are some cells that can regenerate, but w/e cells there are they aren’t significant in # to promote healing. You can predict how tissue will heal based upon their ____ (____ has greatest capacity).

birth
neurons
skeletal
cardiac
for ever

permanent cells
fibrosis
composition
liver

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Organized exudate > fibrosis forms on top of it > scarring (____, and if purulent originally: ____)

Acute inflammation, and etiology is not destroyed > \_\_\_\_:
\_\_\_\_ cells (myocard) > scarring

Labile or stable cells > framework intact > resolution of normal ____ (____ pneumonia); if framework destroyed > ____

pericarditis
fibropurulent

necrosis
permanent

normal structure
lobar
scarring/fibrosis

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Regenerative Medicine

Induced Pluripotent Stem cells (iPS)

Introduce SC genes into patient’s cells and grow in culture > making induced pluripotent stem cells (iPS) > can differentiate in ____ to whatever ____ you desire > myocytes

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vitro

cell type

5 Major Events in Wound Healing

• Early
◦ ____ + ____ components involving these cells listed (platelets, neutrophils, macrophages)

Intermediate phase made up mostly of ____ cells (fibroblasts, mast cells, endothelial cells) > in order to replace new tissue > ____ (different from the vascular response see in acute inflammation) > formation of new BV (not vasodilation) > influx of ____ (important for next phase); the epithelium is also undergoing ____

Late phase; once epithelium is replaced, and following formation of new BV; ____ enter > ____ synthesis (wound can contract) and then there is

REMODELING (initially one type of ____ that is produced to fill in the gap, and done quickly, and with time its replace with a more mature type of ____)

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hemostatic
inflammatory

resident
angiogenesis
nutrients
re-epithelialization

fibroblasts
collagen

collagen
collagen

Early (hemostatic/inflam) > ____ after injury
Int > overlaps with the ____ phase
____ phase follows
____ (remodeling) > lasts for a long time

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instantenous
early
late
terminal

WOUND HEALING

• FIRST INTENTION:
– ____ tissue loss
– Wound edges are ____
– No ____ and little ____

• SECOND INTENTION:
– ____ tissue loss – ____ wounds
– Extensive ____

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minimal
close together
infection
scarring

extensive
ulcer/large
scarring

Healing by First Intention

HEMOSTASIS

\_\_\_\_ 
\_\_\_\_ (Clot) 
-Cements cut \_\_\_\_
-Chemotactic factors
-Forms \_\_\_\_

Hemostatic phase > ____ important > aggregate once find damaged epithelial cells > generate ____ and ____ (Tx is a ____ and promotes further aggregation); ____ converts soluble fibrin into insoluble fibrinogen

Platelets release ____ factors > brings in the new group of cells into the wounded area

Forms a ____ > neutrophils require a scaffold > provides a road-network

No platelets > clot delay > ____ delay

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5HT/TxA2
fibrin/fibrinogen
margin
scaffolds

platelets
5HT
TxA2
vasconstrictor

chemotactic

scaffold

wound-healing

Healing by First Intention

INFLAMMATION
(Neutrophils)

Important in ____ wound
Phagocytose ____
Digest ____
Also, cause ____ damage

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infected
bacteria
ECM
tissue

Wound Healing Defect: LAD-I

LAD1 > neutrophils cannot release the stump of ____ because cannot diapedese > leading to infection

Wound is still red and inflamed > defects is only in recruitment of neutrophils, no defect in the ____ phase > tries to wall off and prevent spreading

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umbilical cord

vascular

Classical and Alternate macrophage activation

• Classical macrophage activation:
– Induced by ____ products and ____
- ____ activity
– Cytokines/____

• Alternative macrophage activation: 
– Induced by cytokines other than \_\_\_\_
– No \_\_\_\_ activity
– \_\_\_\_ healing
– \_\_\_\_

If neutrophils cannot be recruited/activated > macrophages become the primary cell

Classically-activated macrophages:
Can be activated by IFNgamma (from ____) which comes from T cells; or microbial ligands can also activated

Release ____ and ____ enzymes, Action of mediators is to phagocytose microbes; ROS produced predominantly by neutrophils, but to a lesser extent by macrophages; also produce chemokines, which results in inflammation

Alternatively-activated macrophages:
Induced by cytokines other than IFNgamma; have no anti-microbial activity, promote healing by producing cytokines that are anti-inflammatory and ____

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microbial
IFNgamma
phagocytosis/antimicrobicidal
inflammation

IFNgamma
antimicrobicidal
wound
anti-inflammatory

monocytes

ROS
lysosomal

pro-healing

INFLAMMATION/Healing
(Macrophages)

____ disposal (____)
Digest ____
____ chemotaxis
____
____

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waste
debridement
ECM
fibroblast
cytokines
angiogenesis

RE-EPITHELIALIZATION * Basal ____ migrate under the clot * Phagocytic activity & digestion through clot * Mitotic activity ____ cells back from leading edge BM is slightly damaged On the right: one cell is undergoing mitosis; have phagocytic activity and can digest through clot; mitotic activity 4-5 cells back from leading edge > end result: filling the gap with ____ cells, not a ____

``` epidermal keratinocytes 4-5 epithelial scar ```

RE-EPITHELIALIZATION • eventually ____ is removed + cells will migrate towards one another and when they contact, they stop ____. forming epithelium • (cole's synposis: kind of hard to tell from pics but basically what's happening is the clot is formed and the epidermal keratinocytes from the basement membrane are chewing through the clot, while the cells behind them ____ to fill the gaps and seal off the bottom.)

clot migrating proliferate

Angiogenesis/Granulation Tissue BV is severed > sprouts onto the clot (immature vessels) > would look ____ (the new vessels are very ____) Upon removal of clot, more ____ and more BV are entering

wet leaky fibroblasts

1. Proteolysis of ____ 2. ____ and Chemotaxis 3. ____ 4. ____ formation, maturation 5. Increased ____ BV that has been injured > endothelial cells release collagenases and proteases > proteolyze ____ Endothelial cells will migrate laterally bc of ____; at (3) > cells are undergoing proliferation Lumen is then formed, maturation, and increased ____ bc the endothelail cells are not in proper contact with one another One BV becomes many small BV > ____ tissue > contains some fibroblasts, some macrophages (cytokines inducing this process come from macrophages), highly unlikely you see any ____, may see some mast cells

``` ECM migration proliferation lumen permeability ``` ECM cytokines/GF vascular permeability granulation neutrophiles

Granulation tissue > lots of ____, and if you were to feel it would still be ____; removed epithelium > it would bleed very easily > provides ____ for the next phase (____ of fibroblasts) Blue dots (arrows) > macrophages (cannnot see mast in H/E) and some fibroblasts [no ____!]

``` BV soft nutrients activation neutrophils ```

``` Granulation Tissue Fibrosis (Scar Formation) • Proliferation of ____ • Deposition of ____ • Increased ____ synthesis ``` Arrow indicates that there is some scar tissue, but mostly the presence of BV Transition to fibrosis > landscape change: in fibrosis you mostly have ____ tissue > fibroblast migrate and proliferate following ____ availability

``` fibroblasts ECM collagen scar nutrient ```

Late Phase: Wound Contraction * Fibroblast ____ * Wound edges move ____ together * Myofibroblast (____ Intention) When fibroblasts form function of laying down collagen > undergo apoptosis > wound edges move closer together B: granulation tissue; once BV deliver nutrients, they disappear C: collagen deposition > upon fibroblasts form function they disappear D: wound of second intent > much bigger gap > myofibroblast > dual function cell, have ____ and ____ [act as ____, can contract], but they also secrete ____

apoptosis close second actin myosin SM collagen

TERMINAL PHASE ``` •Maturation/ increased ____ strength Remodeling • Continual turnover of ____ • Increased ____ • Resistance to rupture ____ weeks after: – ____% of original ``` ``` – Type I: • ____, bone, and ____ scars – Type II: • ____ – Type III: • ____ tissue, • First ____ deposited in wound healing – Type IV: • does not form ____, • associates with ____, • exclusively found in ____ ``` ____ > collagen will not be strong, if you apply pressure then the wound may rupture During remodeling, Type III is replaced by ____ (increased cross-linking, resulting in increased tensile strength) Not completely back to normal because you have replaced some dermal tissue with scar

``` tensile collagen cross-links 6 80 ``` ``` skin mature cartilage embryonic collagen fibers laminin basement membrane ``` Type III Type I

Healing by Second Intention • SECOND INTENTION: – Extensive ____ loss – ____ wounds – Extensive ____/____

tissue ulcer/large scarring myofibroblasts

Healing by Second Intention Left: fibroblasts have ____ > when recruited/proliferate > undergo mechanical stress > ____ (there is CCA and there is also fibronectin) > increased ____ stress, ____, and ____ > become differentiated myofibroblasts (____ smooth muscle actin; the proto doesn't have any…?) > once it performs function, you want it to return to original ____, or else some pathology may occur Right: as a result of cytokines, fibroblasts migrate into wound > becomes a ____ > lots of dfferentiated ____ > produce ____ and ____wound simultaneously; following contract > you want myofibroblasts to return back to fibroblasts and then remove those (____) If you do not removed myofibroblasts > more collage is produced > more contraction > complication of ____ scar

``` cortical cytoplasmic actin proto-myofibroblasts mechanical TGFbeta fibronectin alpha fibroblasts ``` ``` proto-myofibroblast myofibroblast collagen contract apoptosis ``` hypertrophic

Healing by Second Intention Left: initially clot, ____ enter (initial phase); later epithelium has returned (the cells will remove under clot) > epithelium is back > ____ tissue is formed (macro's/fibro's) > new capillary ____ > ____ regress > fibroblasts enter and synthesize collagen > form ____ tissue (and the fibroblasts will eventually ____) Healing by second intention: sequence of events is the same; the only difference is that there are more cells and more BV > bc of a greater need to heal the bigger wound > greater contraction (***____ enter***) Illustrates both regeneration and scar formation; occur ____

``` neutrophils granulation angiogenesis BV scar apoptose ``` myofibroblasts simultaneously

Healing by Second Intent - Skin ulcer - Re-epithelialization and granulation tissue - Continuing re-epithelialization and wound contraction healing by 2nd intent: lots of ____, no ____, continued ____, eventual ____

BV neutrophils re-epithelialization contraction

Healing by Second Intent Skin graft > wait a little bit so ____ process facilitates > myofibroblasts recruited and help contract wound > because of size of wound the natural process will not be enough to fill the graft > once it cannot go any further > you undergo the ____

natural | skin graft

9. Wound Healing I Flashcards

(37 cards)