10. Wound Healing II Flashcards
Growth Factors/Cytokines •Survival/Proliferation/Migration/Differentiation • Activate cell surface Receptors • \_\_\_\_ • Gene Expression – Promote \_\_\_\_ entry – Relieve \_\_\_\_ on cell cycle Progression – Prevent \_\_\_\_ – Growth control genes (\_\_\_\_)
Phosphorylated at tyrosine residues > activate downstream signaling pathways
GPCR > chemoattractants, leukotrienes > increased vascular permeability > resolution of inflammation (during inflammation)
[REWATCH ABOVE]
Cytokines > IL1, IL6, TNF > produced from inflammtory cells > targets: ____ cells; if IL1/IL6 produced from macro’s > activate receptors on surface of endothelial cells to increase expression of ____
Activated GPCR to bring in neutrophils, but for fibroblasts and EC you bring in GF
pleiotropic cell cycle block apoptosis proto-oncogenes endothelial cells ICAM-1
AUTOCRINE
____ Proliferation by cytokines
____hyperplasia
(____ Regeneration)
PARACRINE
Recruitment of ____ Cells
ENDOCRINE
GF/cytokines mechanisms
Autocrine > secretes particular protein > receptors on same cell; lymphocyte prolif by cytokines, and compensatory hyperplasia (inc cell growth; chops off part of liver, and replaced by new liver > damaged cell is producing ____, and working back on itself to promote regeneration)
Paracrine > cell secretes, and works on receptor that is present on different cell; recruitment of inflam cells
Endocrine > taken up by blood
Macrophages that produce cytokines, enter BS, activated liver > produces ____ that have effect on systemic inflammation
lymphocyte
compensatory
liver
inflammatory
GF
acute phase proteins
Initiation of the Healing response after clot formation:
Platelet-Derived Growth Factor (PDGF)
• Produced by \_\_\_\_, macrophages, endothelial cells and keratinocytes • \_\_\_\_ for: – neutrophils, monocytes and fibroblasts • Proliferation of: – \_\_\_\_ cells and \_\_\_\_. • Synthesis/remodeling of \_\_\_\_.
____ is used clinically for the treatment of diabetic ulcers.
____ > first cell to be activated at site of injury > PDGF is a GF produced from platelets, and from macro’s/EC/and keratinocytes
Fact that platelets is first activated at site of injury; important in ____ healing process
Most GF are ____; produced from multiple sources, and has an effect on multiple cell types
platelets chemoattractant endothelial macrophages ECM
recombinant PDGF (regranex)
platelet
initiating
pleiotropic
Re-Epithelialization:
Epidermal Growth Factor (EGF)
- Produced by ____, Macrophages, Keratinocytes etc…
- Proliferation and migration of ____
- Initiates ____
- Proliferation of ____
- ____formation
EGF > promotes re-epithelialization; promotes the ____ process (produced from the salivary gland, licking the wound)
salivary gland keratinocytes re-epithelialization fibroblast granulation tissue
healing
Angiogenesis/Granulation tissue
Vascular Endothelial Growth Factor (VEGF)
- Produced by ____ cells in response to PDGF, TGF-β and ____
- Promotes migration and proliferation of ____ cells
- Capillary sprouting in ____
- Promotes vasodilation and contributes to the formation of ____
- ____ in ischemic wound (MI).
- Saliva ; ____ homeostasis
- Cancer (____ against some cancers)
New BV > granulation tissue formation
PDGF > EC > ____
Hypoxia > ____ > VEGF
Target VEGF via antibody, or antagonists that bind to the VEGF receptor
endothelial hypoxia endothelial angiogenesis vascular lumen collaterals oral antibodies
VEGF
myocardial infarct
Extracellular Matrix (ECM)
• Basement membrane
– ____ required for regeneration
• Interstitial matrix: \_\_\_\_ to soft tissue Minerals; Hardness to bone Regulates proliferation/differentiation Reservoir for \_\_\_\_ Substrate for cell \_\_\_\_/migration
intact ECM (BM)
turgor
growth factors
adhesion
Basement membrane
- “Chicken wire” mesh beneath epithelial, Endothelial, Smooth muscle structures
- Type ____ collagen/____/____
- Synthesized by overlying ____ and underlying ____ cells
- Scaffolding for tissue renewal (____)
IV laminin proteoglycan epithelium mesenchymal labile/stable
Interstitial matrix
Reservoir for growth factors
Proliferation/Differentiation
migration
No ____ > lack of ____ strength; upon conversion of Type III to Type I > weakness, pathogenic
ECM protein provide reservoir for ____, contained, and they are not activating random ____
Impt for proliferation/differentiation
cross-linking
tensile
GF
ECM Deposition and Scar Formation:
Transforming Growth Factor-β (TGF-β)
Platelets/Mac/Endo/Ker
Chemoattractant for ____
Promotes collagen/ECM synthesis
Inhibits ____
Induces ____
Fibrosis (____) Chronic Inflammation
Anti-inflammatory: Inhibits ____ activity and ____ proliferation
macro's/fibroblasts collagen degradation TIMPs (tissue inhibitor of metalloproteinases) kidney/lung/liver leukocyte T cell
Transforming Growth Factor-β (TGF-β
TGF-beta: impt in ECM deposition and scar formation
In fetal wounds, it heals without forming a ____ > TGFb is produced in a sufficient to heal the wound, but then it disappears > no scar
____ > excessive production of TGFb > promoting fibroblasts to produce excess amounts of collagen
Produced by most cells
Balance between synthesis and degradation; promoting synthetic and decrease degrad > increase synthesis; TGFb promotes not only synthesis, but also inhibits ____
Do not need ____ cells at this stage of wound healing > wound is focused only on this part of the ____ process
scar liver cirrhosis degradation inflammatory healing
Remodeling of Connective Tissue (MMPs/TIMPs)
- Matrix Metalloproteinases (MMPs) degrade ECM components (collagen)
- Produced by ____ cells
• During scarring:
– MMPs ____ (modify) the deposited ECM
– MMP activity shut down by ____ (produced by fibroblasts)
– ECM deposition depends on the ____ between synthesis and degradation:
• ____
• ____
• ____
macro's/fibro's/epithelial remodel TIMPs balance TGF-beta MMPs TIMPs
Oral mucosa - regeneration. This is seen in all the ____ deficiencies. Oral mucosa gets damaged and can get ulceration when neutrophil number goes down. Especially in ____. When neutrophil mucosa goes back up, and the oral mucosa goes back to normal. And there’s no scarring here because we don’t damage the ____. And it ____.
fetal wound - regenerates cause ____ responsible for scar formation is only there transiently.
Liver - these contain ____ cells, and livers have regeneration, but if the ____ of the liver is damaged like in ECM, we can get ____ and fibrosis
Lung - same as ____
Kidney - has some capacity of regeneration in cortical ____, but not to same extent as liver. Only for mild injury. So if see disease process here, the injury must be pretty ____. If someone has kidney disease and we stain area with trichome, most of the blue staining would be on ____ and not on tubules (at least in early stages). The tubules may be involved later but for glomeruli, these would form scar tissue/fibrosis mostly.
Heart - would form ____ and fibrosis.
Nervous system - CNS form ____ and when astrocytes proliferate, they get ____, which would be like the scarring we see in other tissues. The peripheral nervous system’s axons and dendrites have capacity to ____. We will talk about that a lil later.
LAD/leukocytes
cyclic neutropenia
BM
regenerates
TGFbeta
labile
framework
scar
liver
tubules
severe
glomeruli
scar
scar
gliosis
regenerate
IF HAVE CHRONIC INFLAMMATION OF KIDNEY, IT WOULD FIRST BE ON ____ BECAUSE THIS HAS LEAST ABILITY TO REGENERATE.
glomeruli
Day 1: not very uniform, presence of ____
2-3 days: ____ invade to remove dead tissue
7-10 days: ____ invade to remove apoptotic and dead tissue
10-14 days: ____ > new BV formation, and the presence of blue areas
2-6 weeks: formation of a ____
inflammation neutrophils macrophages granulation tissue scar
Traumatic Neuroma
• Not a ____
• Reactive proliferation of ____ tissue after damage
of nerve bundles
• Encounter ____ tissue/cannot reestablish ____
• ____ mass develops at the site of injury.
• Trauma/extraction
• Common sites: ____, tongue, ____ lip.
• Painful
• ____ excision.
neoplasm neuronal scar innervation tumor-like mental foramen lower surgical
Bone Formation/Fracture Repair
• Intramembranous ossification (e.g.skull, maxilla, mandible)
– ____ differentiation of mesenchymal cells into Osteoblasts
– Collagen + organic ECM = (____)
– ____ -Mineralized bone matrix
– Osteoclasts- bone remodeling
– Long bone grows in ____
• Endochondral ossification (long bones)
– Mesenchymal cells into ____
– Replacement of hyaline cartilage template by ____ – Long bone grows in ____
direct
osteoid
osteoid + Ca++/phosphates
width
hyaline chondrocyte
bone
length
Bone
• 1. Hematoma – PMN/Macrophage – \_\_\_\_ – \_\_\_\_ to initiate healing • 2. Fibrocartilaginous callus – \_\_\_\_/\_\_\_\_ tissue – Chondrocytes/Collagen proteoglycans – \_\_\_\_ callus • 3. Bony callus – \_\_\_\_ ossification – (Hyaline cartilage to bone) – \_\_\_\_ bone replaces the soft callus • 4. Remodeling – \_\_\_\_ bone replaces woven bone – Heals without \_\_\_\_
Important to maintain blood supply > placement of a cast is important to align the ____
Similar to what happens to regeneration, but the mechanism is via ____
debridement
GF
angiogenesis granulation fibrocartilage-soft endochondral woven cortical scar
blood supply
cartilage
Cellular Dynamics During Extraction of Socket Healing
Early phase > blood clot/neutrophil (hemostatic/inflamm)
Macro’s > new ____
Fibroblasts > secrete new ____
Osteoblasts/osteocytes > bone formation + ____
BV
ECM
remodeling
Healing of a socket wound
First pic - we have extracted tooth with blood clot for cessation of hemorrhage. If blood clot doesn’t form, we have complications.
2nd - Blood clot also has ____ tissue formation. Exactly by same mechanism that we talked about.
3rd - Now we have connective tissue and ____ forming. The ____ is beginning to come back
20 - Can see epithelium now, and can see the inner part of bone is becoming to get filled in.
40 - CT, and epithelium is coming back. And beginning to be filled by ____ bone.
Last pic - With time, we have immature bone which will remodel to give us ____ bone.
granulation
osteoid
epithelium
immature
mature
DRY SOCKET (Alveolar Osteitis)
• 1-3% of extractions • Infection/Trauma • Pain/Foul \_\_\_\_ • Dissolution of the blood clot • Predisposing factors: – \_\_\_\_ – Site of \_\_\_\_ (mandible) – Trauma – \_\_\_\_
Mandibular extraction > 20-30% develop into dry socket
Excessive trauma, and if tooth is infected (mandibular third molar is removed chance of dry socket is greater with infection)
Trauma/infection > inflammation of BM space > plasminogen > ____ > lyses the fibrin clot and formation of kinin > clot is resorbed
Reason it’s called dry: expect to see the formation of a clot > but clot is resorbed and ____
smell
oral contraceptives
trauma
smoking
plasmin
necrotized
DRY SOCKET (Alveolar Osteitis) Treatment and prognosis: • Socket irrigation • Packed with \_\_\_\_ dressing • \_\_\_\_ in socket • Dressing changed every 24 h then 2/3 days until \_\_\_\_ covers exposed bone.
Prior to treatment of dry socket > ____
No teeth, okay, only facilitating regrowth of granulation tissue
Once gran tissue covers exposed bone, normal wound healing process takes over
obtundent/antiseptic
antibiotic
granulation tissue
x-ray
Infection/Inflammation
• INFECTION: – Prolongs \_\_\_\_ Infection/Inflammation – Delays \_\_\_\_ regeneration – Increases \_\_\_\_ tissue – Increased risk of \_\_\_\_ formation – Common causes of death in \_\_\_\_ injuries
inflammation epithelial granulation scar burn
“Proud Flesh”
____ nodule; ____-surface; may be ____
At high power > see lots of ____ and some macro’s and fibro’s, moreso than you would see in normal tissue (velvety, granular, etc.)
erythemetous
smooth
ulcerated
BV
Pyogenic Granuloma
____ or ____ mass, usually ____ but some are ____
Surface typically ____ (red/pink), easily ____
____: ~75% of all cases
Pyogenic granuloma on a histological slide would look identical to ____
Sometimes women manifest with ____: pregnancy-tumor, it will regress over time
smooth
lobulated
pedunculated
sessile
ulcerated
bleeds
gingiva
“proud flesh”
pregnancy
Keloid
This scar does not contract, but ____ instead. After shaving and leaving a scar, it doesn’t contract and close. Grows this monstrosity instead.
1st pic - person got small incision from shaving.
2nd - woman got ear pierces and this happened
3rd pic - just from some guy stepping on a thorn walking barefoot.
4th pic - person gave birth through ____.
SCAR that expands. This is actually ____ than surrounding tissue
expands
C-site
darker
Keloid Pathogenesis
- Increased fibroblast proliferation and collagen synthesis
- Overexpression of ____
- Type ____ collagen
- Reduced fibroblast ____?
• Genetics:
– Occurs more frequently ____
– ____ genes may be involved
– Genes not yet ____
TGFbeta
III
apoptosis
African/Asian
multiple
identified
Hypertrophic Scar
Does not continue to ____ like keloid does; the color is a little ____; not as ____ as keloid
expand
redder
dark
Hypertrophic Scar
Excessive ____, continue to deposit collagen, and they contract (that’s why they do not ____)
myofibroblasts
expand
Keloid vs. Hypertrophic Scar
Keloid Complexion: \_\_\_\_ Growth: \_\_\_\_ Treatment: \_\_\_\_ Common scar: \_\_\_\_
HTS Complexion: \_\_\_\_ Growth: \_\_\_\_ Treatment: \_\_\_\_ Common scar: \_\_\_\_
Keloid is ____ in color.
Treatment for keloid - can do cosmetic treatment to get rid of keloid, but its NO, because its gonna ____. This is genetic disposition, so it will happen again. Not a common scar (occurs in few individuals of ____ descent). HTS is more common.
dark
yes
yes/no
no
light
no
yes
yes
grow back
african/asian
Liver Cirrhosis
When we see liver cirrhosis, we also seeing ____.
Myofibroblasts - synthesis of collagen and contractioon. This liver, instead of being smooth surfaced, its ____ and ____ surface.
Normal liver cells, then we have one that is crazy surrounded by ____ (trichome pic)
myofibroblasts
nodular
rough
collagen
Ehlers-Danlos-Syndrome (EDS) Abnormal collagen synthesis or structure: • Deficiency of \_\_\_\_ – Decreased collagen \_\_\_\_ – Skin \_\_\_\_ – \_\_\_\_ hypermobile
• Deficient synthesis of type ____ collagen
– Blood vessel ____ wall
– Predisposed to ____
Mutations in different collagen genes > abnormal collagen synthesis/structure
LH > hydroxylation of ____ residues > important for cross-linking
lysyl hyrdroxylase
cross-linking
hyperextendible
joint
III
bowel
rupture
lysine
Ehlers-Danlos-Syndrome (EDS)
Wound healing defects:
Minor injuries produce ____ defects
Surgical repair abnormal (____ strength)
____
Ruptureof____ Ruptureof____
gaping
tensile
dehisence
colon
arteries
Local Factors in Wound Healing
• NECROTIC TISSUE IN WOUND
– Promotes ____ growth
– ____ barrier
– Delays ____
• FOREIGN MATERIAL IN WOUND
– Harbor ____
– Promote ____
bacterial
physical
healing
bacteria
inflammation
Inadequate Blood Supply Decubitis Ulcer (Bed sore, Pressure Ulcer)
DECUBITIS ULCER
– ____ induced Ischemia
TREATMENT: – \_\_\_\_ relief – \_\_\_\_ and \_\_\_\_debridement – Clean/Moist – \_\_\_\_?
pressure pressure enzymatic surgical PDGF
LOCAL FACTORS IN WOUND HEALING
• Necrotic Tissue
• Foreign
materials
• INADEQUATE BLOOD SUPPLY: – Decubitus ulcers – \_\_\_\_ – \_\_\_\_ – \_\_\_\_
• Others: – \_\_\_\_ – Direction and location of wound – Movement of \_\_\_\_ – Drying out – \_\_\_\_
For enderteritis oblisterans, there is inflammation of ____ and size of ____ is decreased, compromising blood supply.
-if bone that we wanna make sure there’s no ____, want healing area to be ____. And no trauma.
endarteritis obliterans
atherosclerosis
smoking
radiation
wound
trauma
BV
lumen
movement
moist
MALNUTRITION
• ____:
– Decreased collagen synthesis
• Reduced Carbohydrate & Fat intake:
– ____ is used as an energy source
• ____ Deficiency:
– Abnormal collagen synthesizes
• Vitamin A Deficiency:
– Defective ____
• Vitamin D Deficiency:
– Defective ____
• Zinc Deficiency:
– Decreased cell ____ and ____ tissue formation
hypoproteinemia protein vitamin C epithelization bone healing proliferation granulation
DIABETES MELLITUS
• \_\_\_\_ depresses leukocyte function • Peripheral \_\_\_\_ • Depressed \_\_\_\_ and \_\_\_\_ Blood Supply • Ischemia • Infection • Decreased \_\_\_\_
Treatment: • \_\_\_\_ • HBO (Hyperbaric Oxygen) • \_\_\_\_ • Antimicrobial • \_\_\_\_
hyperglycemina neuropathy arterial peripheral GF
PDGF
SDF (stromal cell-derived factor)
amputation
