9. Wound Healing I Flashcards
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
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
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
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
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
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
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
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
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
Injury to cell matrix > chronic ____ > scar formation > liver has undergone ____
alcoholism
fibrosis
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
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
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
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
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
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
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 ____)
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
instantenous
early
late
terminal
WOUND HEALING
• FIRST INTENTION:
– ____ tissue loss
– Wound edges are ____
– No ____ and little ____
• SECOND INTENTION:
– ____ tissue loss – ____ wounds
– Extensive ____
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
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
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
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 ____
microbial
IFNgamma
phagocytosis/antimicrobicidal
inflammation
IFNgamma
antimicrobicidal
wound
anti-inflammatory
monocytes
ROS
lysosomal
pro-healing
INFLAMMATION/Healing
(Macrophages)
- ____ disposal (____)
- Digest ____
- ____ chemotaxis
- ____
- ____
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
- Proteolysis of ____
- ____ and Chemotaxis
- ____
- ____ formation, maturation
- 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
