Regeneration and Repair Part II Flashcards
Main functions of ECM
- mechanical support –> anchorage and migration
- storage/release of regulatory molecules –> cell proliferation and differentiation control
- maintenance of cell shape and stromal integrity
- establishment of tissue microenvionments –> basement membrane acts as a boundary between epithelium and underlying connective
what are the 3 main components of ECM
- fibrous structural proteins
- adhesive glycoprotiens
- proteoglycans and hyaluronan
fibrous structural proteins of ECM
collagens and elastins provide strength and recoil of tissue
adhesive glycoproteins of ECM
connect the matrix elements together
proteoglycans and hyaluronan of ECM
provide the matrix in which other proteins are organized
the main components of the ECM form
the interstitial matrix and basement membranes
—- is most abundant component in ECM
collagen
what is collagen composed of
3 alpha chains forming a triple helix (procollagen)
procollagen is cleaved by
proteases to allow complete triple helix formation = collagen moecule
what does collagen form
form fibrils
function of collagen
undergo cross-linking which stabilizes the array and provides tensile strength
what are the 2 main types of collagen
- fibrillar collagens (type I, II, III V)
2. basement membrane collagen (type IV)
what do fibrillar collagens make up
most of the interstitial matrix and connective tissue in scar
basement membranes form
sheets instead of fibrils and is highly organized
what is required for cross-linking of collagen fibrils
vitamin C
vit C deficiency (scurvey) results in
- impaired cross-linking
- skeletal deformity
- inadequate wound healing
purpose of tissue elasticity
- allows for expansion and recoil
- is a functional requirement of tissue (iel vessels, skin)
what are elastic fibers
elastin, surrounded by a peripheral network of fibrillin microfibrils
Marfan syndrome
- inherited defect in fibrillin
- results in weakness of vessel walls (aortic dissection) and skeletal system
what are Cell Adhesion Molecules (CAM)
-diverse group of cellular receptors that bind to adhesion proteins allowing cellular interaction with other cells, with the ECM and btwn ECM components
what are the 4 main families of CAMs
- integrins
- cadherins
- Selectins
- immunoglobulins
integrins bind to
- adhesion proteins:
- laminin (basement membrane component)
- fibronectin (fibrillar component of interstital matrix)
integrins allow for
cell-cell and cell-ECM adhesion maintaining cell shape
integrins stimulate
cellular motility, proliferation and differentiation
what is the most abundant glycoprotein in basement membrane
laminin
laminin forms tight networks with
collagen IV
what can laminin bind
to integrins and other cell surface receotirs
laminin mutations results in
forms of epidermolysis bullosa, (separation of basement membrane and epidermis)
fibronectin is made by
connective tissue cells
fibronectin interacts with
cell surface integrins
fibronectin has binding sites for
collagen and fibrin
when is fibronectin abundant
during embryonic development and wound healing
what are cadherins
- calcium-dependent adherence proteins
- family of adhesion receptors that connect the membrane of adjacent cells
what is the function of cadherins during would healing
facilitate formation of cellular junctions
what do cadherins mediate
cell-cell interactions; regulate cell motility, proliferation and differentiation
loss of E-caderin results in
metastasis by disrupting intercellular contacts in human carcinomas (breast and gastric)
function of proteoglycans and GAGs
confer the ability to resist compression
what are proteoglyans
are extracellular proteins covalently bound to a special class of long-chain polysaccharides called glycosaminoglycans (GAGs)
what do proteoglycans and GAGs form
huge aggregates that occupy large volumes and entrap water
healing of a mild injury occurs through
regeneration
healing of chronic/severe injury occurs through
repair (scar formation, replacement of injured cells with connective tissue)
a combination of repair and regeneration is dependent on
- the proliferative capacity of the cells/tissue
- the integrity of the extracellular matrix
- the resolution or chronicity of the injury and inflammation
what are the basic steps of tissue repair
- inflammation
- granulation tissue formation
- scar formation
- remodelling of connective tissue
function of inflammation
- serves to contain damage
- remove damaged cells, promote deposition of ECM components
- stimulate angiogenesis
granulation tissue formation
- proliferating fibroblasts
- newly-formed blood vessels in loose ECM
- inflammatory cells (macrophage)
scar formation
progressive maturation of granulation tissue into dense fibrous tissue and scar
how does inflammation begin
- through the activation of coagulation pathways
- a blood clot forms containing fibrin, fibronectin and complement components
once inflammation is activated what does it do
- stops the bleeding
- contains damage
- lays down framework for wound healing
within 24 hrs of inflammation what cells enter
neutrophils enter at the wound’s margins and release proteolytic enzymes that clean out debris and bacteria
what do neturophils release
cytokines and GF that stimulate angiogenesis and granulation tissue formation begins to form
describe how granulation tissue from
- FIBROBLAST and vascular ENDOTHELIAL CELLS proliferate forming new LEAKY vessels that allow passage of plasma proteins and fluid into the extravascular space –> EDEMA
- granulation tissue progressively invades the wound space, filling it by day 5-7
- concurrently, MACROPHAGES replace neutrophils and clear fibrin and extracellular debris at the site of repair
what is angiogenesis
a physiologic process involving growth of new blood vessel
in injury, new vessels form from
pre-existing ones
what are the growth factors involved in angiogenesis
Vascular Endothelial Growth Factor (VEGF)
Fibroblast Growth Factor (FGF)
Angiopoietins (Ang1 and Ang2)
growth factors of angiogenesis active what
signaling cascades leading to proliferation of endothelial cells and fibroblast migration to injured cells
describe the process of scar formation
- collagen fibers first laid down vertically to allow epithelial cell mobilization
- re-epithelialization occurs when a continuous epithelial layer closes the wound
- epithelial cell proliferation thickens the layer
epithelial cell proliferation stimulated by what
- fibroblast production of FGF-7 (keratinocyte growth factor)
- HGF
- EGF
what cell becomes abundant and bridges the incision forming a scar
collagen fibrils (predominantly type III)
what happens by week 2 of scar formation and wound contraction
-leukocytic infiltrate, edema and vascularity decreases secondary to continuous collagen deposition
what collagen types is most abundant in scar formation
collagen type 1
what is blanching
replacement of original granulation tissue by a pale, avascular scar
what type of cells are scars composed of
- spindle-shaped fibroblasts
- dense collagen
- fragments of elastic tissue
- other ECM components
how is connective tissue remodeling achieved
through concurrent synthesis and degradation of ECM
what are matrix metalloproteinases (MMPs)
a large family of proteinases that degrade ECM components
MMPs are produced by
- fibroblasts
- macrophages
- neutrophils
- synovial cells
- some epithelial cells
what inhibits MMPs
inhibitors of metalloproteinases (TIMPs)
following wound healing, strength is only –% to –% compared to normal skin
70%-80%
the recovery or tensile strength depends on
- a greater synthesis over degradation of collagen
- structural changes of collagen fibers (cross-linking, increased fiber size) after collagen synthesis ceases
primary intention of cutaneous wound healing
- clean, uninfected would with adjacent borders
- minimal tissue damage allows for epithelial regeneration and minimal scarring
primary intention wound healing commonly seen in
sutured surgical incision
secondary intention of wound healing
- large wound with inflammation/ infection/ischemia and distant borders
- extensive scarring and wound contraction (repair)
what local factors influence wound healing
- infections
- mechanical factors
- foreign bodies
- size, location, and type of wound
how does infection affect wound healing
- cause delay in healing
- increases tissue injury and inflammation
- S. aureus can colonize
how can mechanical factors affect wound healing
Increased pressure/tension makes wounds prone to dehiscence
how can foreign bodies affect wound healing
persistance of foreign body will prolong infection therefore want to remove foriegn body
how can size, location and type of wound affect wound healing
- Vascularized areas (face) heal faster compared to poorly vascularized (foot)
- Small incisions heal faster than large wounds caused by blunt trauma
what systemic factors affect wound healing
- nutrition
- metabolic status
- circulator status
- glycocorticoids
how does nutrition affect wound healing
vitamin C and copper deficiency inhibt collagen synthesis and cross-linking
how does metabolic status affect wound healing
microangiopathy associated with diabetes mellitus results in delayed healing
how does circulatory status affect wound healing
inadequate blood supply or venous drainage (arteriosclerosis or venous abnormalities)
how does glucocorticoids (steroids) affect wound healing
have anti-inflammatory effects and inhibit collagen synthesis
deficient scar formation may lead to
wound dehiscence or ulceration
excessive production of repair components can form
- hypertrophic scars
- keloids form secondary to excessive collagen
what are contractures
exaggerated wound especially in the palms, the soles can cause restricted range of motion
what is fibrosis
excessive deposition of collagen and ECM components (excessive scarring) following a prolonged or chronic injury
