Wound Healing (including problems and treatments) Flashcards
What is wound healing?
Regeneration so that it returns to original purity
Induced by keratinocytes and endothelia
Only reptiles and amphibians can technically do this
What is wound repair?
Scars form so there is compromised functionality
Fibroblasts are responsible for this
Technically what we are calling “wound healing” when we talk about mammals
- except liver and fetal tissue can truly heal
What are the 4 stages of wound healing?
1) hemostasis*
2) inflammation*
3) repair (proliferation/granulation phase)
4) remodeling and scar formation
- hemostasis and inflammation have typically been lumped together for ones that say there are 3 stages because they both happen very quickly
What is the first thing that comes to the wound when it first forms?
Platelets
“activate and aggregate”
form the platelet plug
What is present at the end of the hemostasis phase of wound healing?
The fibrin clot
What is the primary initial recruiter of neutrophils to a wound?
Other neutrophils
What is a basic overview of what happens during the hemostasis phase of wound repair?
Occurs immediately to within hours of injury
Coagulation occurs forming a clot/scaffold
Recruits inflammatory cells
What is a basic overview of what happens during the inflammation phase of wound repair?
Should take minutes to 72 hours in healthy tissue
Immune infiltration
Debris clearance
Pathogen killing
What is a basic overview of what happens during the proliferation stage of wound repair?
2-10 days after injury
Fibroblast proliferation
Scar formation
Collagen synthesis
Angiogenesis
What is a basic overview of what happens during the remodeling stage of wound repair?
Within days to months
Epithelialization
EMC remodeling
Scar maturation and contraction
Apoptosis
What do injured/damaged cells produce that cause vasoconstriction (to stop hemorrhage) and then vasodilation (to get cells there)?
Histamine, serotonin, catecholamines
What is the primary activator of platelets?
Collagen (von Willebrand’s factor mediates linking of collagen and platelet)
What happens when platelets are activated?
They change shape to dendritic form
Release their granules (dense and alpha)
Release VWFs and thromboxane A2 –> help platelets stick
What are platelet dense granules?
Released by platelets
Have serotonin, adenosine diphosphate (ADP), and ATP
To help vasoconstriction and have platelets stay there
What are alpha granules?
Released by platelets
have fibronogen, fibronectin, PDGF, and P-selectin
What is the role of platelet-derived growth factor (PDGF) in wound healing?
Platelet is 1° source
Released from α granules
Function:
- Attract neutrophils & macrophages
- Initiates chemotaxis of smooth muscle cells & fibroblasts
- Stimulates contraction (platelet and macrophage, not fibroblast)
- Induce myofibroblast phenotype of fibroblasts
What is the role of transforming growth factor β1 (TGF-β1) in wound healing?
Platelets = most important storage factor
Elicits rapid chemotaxis of neutrophils & monocytes
Perpetuate inflammatory cell response
Intracellular signaling pathways
Adhesion molecules, coagulation factors, cytokines, GFs
Stimulates fibroblast contraction
Stimulates myofibroblast differentiation
Stimulate fibroblasts to produce hyaluronan (HA) and RHAMM ( its receptor)
What are the intrinsic factors in the coagulation cascade?
“For intrinsic factors if it not $12, but $11.98”
Factor XII –> factor XI –> factor IX
What are the common factors in the coagulation cascade?
“small change”
Factor X and factor I
What does thrombin do?
aka factor IIa
activating platelets
activating factors V, VIII, and IX
What are the functions of the fibrin clot?
Hemostasis
Microorganism barrier
Matrix scaffold for cell attachment
Growth factor reservoir (PDGF and TGF)
What is involved in clot-lysis?
Limit platelet aggregation & clot formation
Plasminogen activator
- Initiates clot lysis
Anti-thrombin III (AT III)
Protein C
- Factors V and VIII
Prostacyclin C (PC)
- Limit platelet aggregation
What are the main roles of neutrophils in wound healing?
Debridement and phagocytize
- necrotic debris
- microbes
- foreign material
Produce critical cytokines to recruit macrophages, fibroblasts and keratinocytes
When done they undergo effete/apoptosis
- remove with eschar or phagocytized by macrophages
What are the chemoattractants involved in neutrophil chemotaxis during wound healing?
IL-8, Gro, Kallikrein, FDPs, Fibrinopeptides, bacterial proteins, platelet released cytokines
What is diapedesis?
Immune cell going from blood vessel to outside of it
Facilitated by CD11/CD18 integrins adhering to endothelial I-CAM
What is the role of macrophages in wound healing?
Within 24-48 hours, become predominant
* Transition between inflammation & repair
Phagocytosis, killing bateria, clean up debris
Removal of effete (inactive/useless) neuts
Release GF (growth factor) and recruit and activate fibroblasts
- PDGF, FGF (fibroblast growth factor), TGFB1
Then are removed via apoptosis
What are M1 macrophages?
Traditional ones that phagocytize
What are M2 macrophages?
Aid in immune suppression and tissue repair
What induces macrophages to be M1 macrophages?
IFN-y
LPS
TNF-a
What induces macrophages to be M2 macrophages?
IL-4
IL-13
IL-10
TGF-b
What cells play a role in the repair phase of wound healing?
Macrophages
Fibrocytes
Endothelial cells
Keratinocytes
Which mediators play a role in the repair phase of wound healing?
Integrins
Growth Factors
Enzymes
Serine proteases
MMP’s
What is granulation tissue?
Occurs 3-5 days post injury in healthy wound
Functions as rudimentary tissue (2nd provisional matrix)
Grows until wound bed is covered
Consists of: new blood vessels, fibroblasts, inflammatory cells, endothelial cells, myofibroblasts, new ECM components (fibronectin, hyaluronan)
Lots of GAGS so cells can slide over each other
What happens to a fibroblast that experiences mechanical stress and/or is exposed to TGF-b?
It becomes a proto-myofibroblast –> myofibroblast
- now they can contract
- increases production of cytokines, collagen, and HA
Which cells store the most TGF-b1?
Platelets
What type of collagen is present in granulation tissue?
Type III (very thick so can easily be packed on!)
become type I (thinner) over remodeling phase
What type of collagen is found in vessels and hypertrophic scars?
Type V
What happens in wound contraction?
Fibroblasts contact simultaneously and equally across wound
Centripetal/concentric decreases in size of open wound
Degree of contraction
- Full thickness will contract up to 40%
- Partial thickness will contract less (due to adnexa)
Peaks at 2 weeks
Inhibited by:
- Excessive tension
- Necrotic tissue
What happens in the angiogenesis/neovascularization process?
Initiated by endothelial cells near wound
Starts 2 days post-injury
Proteinases (MMPs) break down
- Mature blood vessels
- ECM –> release stored growth factors
Stimulated by macrophage-released cytokines, decreased O2, lactic acid & GFs
What does Vascular Endothelial GF (VEGF) do during wound healing?
Stimulates angiogenesis
Induces neovascularization
Induces synthesis of MMPs