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Wound Healing

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nick thiessen

on 24 July 2014

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Transcript of Wound Healing

MACROPHAGES
Induce apoptosis of PMNs
24-48hrs
LPS - free radicals and cytokines - IL-2 furthers this process
free radicals causes more bacterial debris-> cycles
cell membranes are broken down -> Thrombaxane A2 and leukotriene B4 - potent chemotaxin

NO - antimicrobial, vasodilation

MMPs (1,2,3,9) - degrade ECM, promotes cell movement, foreign material removal (blocked by NSAIDS/steroids)
Collagen
ECM degradation
Matrix proteolysis helps cells migrate:
clears a path through the matrix
exposes binding sites
facilitates cell detachment ->movement
signaling to promote cell migration
Infection - 10^5 bacterial count or any beta-hemolytic strep

Hypoxia- atherosclerosis, Cardiac failure, wound tension
stimulates angiogenesis - collagen assembly effected
Tobacco - vasoconstriction and elevated CO levels
Diabetes - microvascular. VEGF impaired. repeated trauma->increase glucose causes glycosylation of collagen->brittle, poor adhesion
New Horizons
GOAL!
Wound Healing 30min
Nicholas Thiessen M.D.
7/24/14

Inflammatory Phase
Hemostasis and inflammation
Increased Vascular Permeability
Platelets bind to exposed collagen (IV,V)
Leads to aggregation
Requires vWF/VIII
Adhesion is mediated GPIIb/IIIa
Alpha granules - PDGF, TGF-B, IGF-1, fibronectin, fibrinogen, thrombospondin, vWF

Dense bodies - vasoactive amines, serotonin-vasodilation and increase vascular permeability

Mast cells release histamine and serotonin - massive leakage of plasma from intravascular space - extravascular space
Thromboxane A2 and prostaglandin F2a - formed from the degradation of cell membranes in the arachidonic acid cascade -->

increase platelet aggregation and vasoconstriction
Chemokines
CXC, CC, C - ligand families bind to G-proteins

Macrophage, monocytes, T cells, mast cells, PMNS, Interleukins, MMPs
PMNs
Histamine and serotonin - Increase vasc. perm
C5a and leukotriene B4 - promote neutrophil adhe and cxc

Monocytes and endothelial cells - IL1 and TNF-a
further promote endo/neutrophil adhesion
Intense vasodilation and permeability
Rubor
Dolor
Calor
Tumor
Superoxide dismutase
Hydroxyl free radicals - bactericidal
If PMNs persist in wounds = cont.
contamination/infection = chronic wounds, tissue necrosis, abscess
low levels fetal wounds
Macrophages also important in proliferative phase
Lymphocytes
T-lymphocytes peak ~7th day
Macrophages antigen presenting cell to lymphocytes
stims to release more cytokines
IFN-g - decreases prostaglandins ->enhance inflam
- suppresses collagen syn
- inhibits macrophages from leaving injury
Involved in chronic non-healing wounds (T-cells)
Proliferative Phase!
Angiogenesis, fibroplasia, epithelialization

Granulation tissue -> capillary bed, fibroblasts, macrophages, collagen, fibronectin, hyaluronic acid


Fibroplasia
Fibroblasts - differentiate from resting mesenchymal cells in connective tissue

normally quiescent - cxc ->ECM

G0 phase - PDGF - FGF-2 -> require growth factors for proliferation

Collagen synthesis - 3-5 days -> declines after 4weeks ---> maturation phase cont. months/years (MMP-1 - collagenase)
Epithelialization
Prevent fluid loss and bacterial invasion

Hemidesmosomes

Begins within hours


Keratinocytes -> detachment, migration, proliferation, differentiation, stratification
ECM - scaffold
GAGs - covalently linked to protein -> proteoglycans
collagen, elastin, fibronectin, laminin
Fibrin sealant can delay wound healing
TGF-B - increase tensile strength
GAGs and Proteoglycans
Wound healing
Abnormal wound healing
Keloids - scar grows beyond the border of original wound
Hypertrophic scars - within confines of original wound -regress over time

Stretched collagen bundles aligned in the same plane as the epidermis

Scars perpendicular to muscle fibers
25% of protein mass
Proline-glycine rich

Type I - most common Skin and Bone
Skin 80% I and 20% III
Newborns III

Early wound healing Type III
Hydroxylation of proline and lysine
Ascorbic acid deficiency - proline hydox. prevented
unstable 3 helices - defect in pro-a chains
ECM - cleaved by proteases
Covalent cross linking of the lysine = tensile strength

Osteogenesis imperfecta - deletion of one procollgen a1 allele
Elastic Fibers
Elastin - produced early in life, stabilizes, does not undergo further synthesis or degradation - turnover approaches a life span

Age related modification - frayed, porous

Mutations in fibrillin = Marfan syndrome
Hyaluronan
Chondroitin
Heparin sulfate
Keratin sulfate
High neg. charge attracts osm + cations, Na

= large amounts of water into the matrix

responsible for turgor that enables the matrix to withstand compressive forces

Hyaluronan - present in fetal tissues
expands the ECM, allows cells space to migrate
Proteoglycans
Immobilize the protein, restrict range of action
Reservoir of the protein for delayed release
Alters protein=more effective presentation to cell surface receptors
Prolongs action by protecting protein from degradation
Blocks activity of protein
Basal Lamina
molecular filter, selective barrier
scaffold for regenerative cells
Type IV collagen - perlecan
Proteolysis is tightly regulated
Maturation
Wound contraction - centripetal movement of the whole thickness of surrounding skin

Wound contracture - physical constriction/limitation of function as a result of contraction

Contractures occur when excessive scar exceeds normal wound contraction

Fibroblasts -> myofibroblasts
Radiation
Aging
Malnutrition - albumin <2g/dl
vit and min deficiency
Full transcript