Path Week 2: Wound Healing

Front 1

What are the two types of healing

Back 1

Scarring and regeneration

Front 2

Define Regeneration

Back 2

Replacement of injured cells by parenchymal cells of the same type as the lost.

Front 3

Define Scarring

Back 3

Deposition of fibrous tissue and EM where destroyed parenchymal cells do not regenerate or when the EM framework is destroyed. Can also be due to chronic inflammation

Front 4

When will one get scarring?

Back 4

1) If there is injury to the Extracellular Matrix (EM)
2) If the destruction is of parenchymal cells which do not regenerate (permanent cells)
3) During chronic inflamation leads to GF and cytokine production which leads to fibroblast prolif and collagen synth.

Front 5

Wat determines if regeneration will occur and what are the 2 main processes?

Back 5

Depends on the severity of dmg and the damaged cells ability to proliferate. Ability of a cell to proliferate is inversely related to to the degree of differentiation.
2 main processes are migration of surviving cells into the vacant space and the proliferation of surviving cells.

Front 6

What stimulates replication

Back 6

Replication is stimulated by signals from the EM components via integrins and growth factors. Growth factors promote cell survival, locomotion, contractility, differentiation, and angiogenisis. They act as ligands that bind specific receptors which deliver signals to target cells.

Front 7

Labile cells ability to regenerate and examples

Back 7

Continuous turnover. Regeneration is through adult stem cells with unlimited ability to proliferate.
Ex. Squamous epithelium (mouth, vagina, skin), ducts, columnar epithelium (GI uterus), transitional epithelium (UT), and hematopoetic bone marrow cells.

Front 8

Stable (quiescent) cells ability to regenerate and examples

Back 8

Normally have low level of replication but are capable of cell division following injury. Cells are in G0 but can be induced to enter G1 and divide if stimulated.
Ex. Parenchyme of solid glandular tissue (liver, kidney, pancreas), mesenchymal cells (bone, cartilage, endothelium, smooth muscle, fibroblasts), resting lymphocytes and other white blood cells.

Front 9

Permanent cells ability to regenerate and examples

Back 9

Extremely limited ability to regenerate. Few or no stem cells. Heal with scarring.
Ex. Striated muscle - Can increase mass via hypertrophy but only surrounding satellite cells can actually regenerate.
Neurons - brain tissue is usually replaced with things like glial cells.

Front 10

Why is the EM necessary for proper wound healing.

Back 10

Provides the framework for cell cell migration, maintains the correct polarity for the construction of multi-layered tissues, and participates in angiogenesis.

Front 11

Fibrous structural proteins in the EM

Back 11

Provide strength and recoil:
1) Collagen type 1 and 3 - Cross linking of adjacent molecules gives strength. Contribute to tensile strength of collagen. Requires vitamin C and is what deteriorates in scurvy.
2) Elastin - Can stretch, important in vessels, skin, uterus, lung.

Front 12

Hydrating gels in the EM

Back 12

Provide resilience, lubrication, resevoir for GFs., regulate structure and permiability, modulate cell growth/differentiation.
1) Proteoglycans - Formed by polysach. GAGs attached to a protein core. Can take up water giving tissue compressibility.
2) Hyaluronan - large GAG molecule which binds alot of water allowing connective tissue to resist compression. Found in tissues that need to be compressed.

Front 13

Cell adhesion molecules in the EM

Back 13

Connect matrix components to themselves and to cells. Mediate attachment, migration, and spread of cells.
Fibronectin - Binds to cellular integrins and extracellular collagen. In stromal connective tissue stabilizing wound.
Laminin - Most abundant protein in basement membrane, mediates attachment of cells to connective tissue.
Cell surface glycoproteins - Including Selectins, Integrins, and Cadherins.

Front 14

Selectins

Back 14

Cell surface glycoproteins found in EM. Mediate initial adhesion of leukocytes to endothelial cells during inflammation.

Front 15

Integrins

Back 15

Cell surface glycoproteins found in EM. Are cell matrix adhesion molecules found in EM which bind leukocytes, fibroblasts, and epithelial cells.
Transmit signals regulating ell survival, prolif. differentiation, and migration. Allow communication between cell cytoskeleton and EM.

Front 16

Cadherins

Back 16

Cell surface glycoproteins found in EM. Cell-cell adhesion molecules. Link cell surface to cytoskeleton via actin and intermediate filaments. Form desmosomes and zonula adherens.

Front 17

Interstitial Matrix

Back 17

One of 2 general organizations of EM.
Is a 3 dimensional amorphous gel between connective tissue cells and between epithelial, endothelial, and smooth muscle cells. Is made by fibroblasts and consists of Fibrillar (type 1 and 3) and nonfibrillar (type 4) collagen, elastin, fibronectin, proteoglycans, and glycoproteins.

Front 18

Basement Membrane

Back 18

One of two general organizations of EM.
Platelike mesh between cells and interstitial matrix found in epithelia, endothelial and smooth muscle surfaces. Separate endothelium/epithelium from stroma. Made by cells resting on it.
Made of Amorphous non fibrilar type 4 collagen, laminin, enactin, heparin, proteoplycans, and adhessive glycoproteins.

Front 19

EM roles in wound healing

Back 19

1) Stores and secretes GF
2) Mechanical support for cells and maintenance of polarity.
3) Scaffolding for tissue renewal.

Front 20

Fibrosis

Back 20

Repair by connective tissue, if regeneration cannot take place.

Front 21

What 2 cytokines control angiogenesis

Back 21

VEGF and FGF

Front 22

Sequence of Angiogenesis

Back 22

1) NO induced vsodialation and VEGF induced leakage of preexisting vessels
2) Proteolysis of preexisting vessel basement membrane allowing capillary sprouts to form.
3) Endothelial cells migrate from original capillary to angiogenic stimulus.
4) Endothelial cells proliferate
5) Endothelial cells mature and organize into capillary tubes.

Front 23

What is the main cytokine regulating migration and proliferation of fibroblasts into an injury site?

Back 23

TGF-B. Causes fibroblast migration, proliferation, synthesis of collagen, and decreased EM degradation.

Front 24

Granulation tissue

Back 24

Is a Hallmark of Healing.
Is pink, soft, granular tissue, forms post injury.
Combination of Angiogenesis and proliferation of fibroblasts (key), macs, and myofibroblasts and their products, collagen, elastin, and proteoglycans.

Front 25

Remodeling process of fibrous tissue and scar formation

Back 25

1) After repair, vessels are reabsorbed. Tissue becomes largely avascular.
2) Fibroblasts turn into a scar of inactive fibroblasts, dense type 1 collagen, and elastic tissue.
3) EM proteins are degraded by metalloproteinases like collagenase. Metalloproteinases are induced by PDGF, FGF, TNF, and inhibited by TGF-B and steroids.

Front 26

Ordered process of wound healing

Back 26

1) Hemostasis and Vasoconstriction
2) Inflammation
3) Parenchymal and connective tissue cells migrate, proliferate and regenerate
4) Granulation tissue forms
5) EM proteins are synthesized
6) Parenchymal elements are remodeled to restore tissue function
7) Connective tissue contracts, remodels, giving wound strength.

Front 27

Inflammation

Back 27

Contains damage, eliminates damaging stimulus, removes damaged and dead tissue, and initiates deposition of EM.
Neutrophils are replaced by macs by day 2-4. Macs are necessary to wound repair b/c they remove dead cells, foreign material, and clots. They also orchestrate formation of granulation tissue by releasing cytokines and chemoattractants.

Front 28

What type of wounds heal by first intention?

Back 28

Sutured wounds with small clot, no infection, minimal tissue loss, and close apposition of wound edges. Only focal disruption of epithelial basement membrane.

Front 29

Steps in primary intention healing

Back 29

1) Hemostasis. Incision fills with clotted blood containing fibrin, fibronectin, complement components, and blood cells. Forms scab
2) Fibronectin attracts macs and and fibroblasts. Is also cross linked to fibrin and collagen.
3) 24h - PMN at margin, migrate toward clot. Basal epithelium prolif. and meet beneath the skin.
4) 48 - Epithelium prolifs along dermis, makes BM, and meets under the scab.
5) D3 - PMN gone. Macs and granulation tissue invade incision, epithelium thickens.
6) D5 - Granulation tissue fills space, vessels leaky and wound is edematous, collagen fibrils bridge incision, epidermis recovers nromal thickness and starts keratin production.
7) Wk2 - Collagen accumulates and fibroblasts prolif. Regression of vascularization, less leuks, edema.
8) 1Mo - Cellular connective tissue devoid of inflammation covers epidermis.

Front 30

Tensile strength in a primary intention wound

Back 30

10% by 1 week. Scar never exceeds 80% strength.

Front 31

Dehiscence

Back 31

Splitting apart of a surgical wound.

Front 32

Myofibroblasts

Back 32

Modified fibroblasts with cytoplasmic contractile filaments and cause wound contraction.

Front 33

Distinction between primary and secondary intention healing

Back 33

1) Larger mass of granulation and connective tissue is needed to fill wound in secondary
2) There is more necrotic debris in secondary
3) There is more inflammation in secondary and greater chance for secondary inflammation mediated injury in secondary.
4) Have larger, weaker scar in secondary.
5) Have more wound contraction in secondary.

Front 34

Local factors influencing wound healing

Back 34

1) Infection
2) Blood supply
3) Foreign body
4) Mechanical Stress
5) Denervation

Front 35

Systemic factors influencing wound healing

Back 35

1) Circulation
2) Nutritional status
3) Anemia
4) Diseases (diabetes)

Front 36

How do infection and foreign bodies delay wound healing

Back 36

They prolong inflammation and increase local tissue injury.

Front 37

Why do people with scurvy not heal normally?

Back 37

Vit C is necessary for collagen formation by hydroxylation of proline residues.

Front 38

How do steroids slow wound healing?

Back 38

Inhibit normal collagen synthesis

Front 39

Hypertrophic Scar (Keloid)

Back 39

Caused by formation of excess collagen which rises above skin surface.
People can have a predisposition to keloid formation especially dark skinned people.

Front 40

Contracture

Back 40

Wounds undergo excessive contracture due to the myofibroblasts.
Occur at scars near joints, after burns, and wounds in gut. A gut contracture is called a stricture and causes obstruction.

Front 41

Proud flesh

Back 41

A wound where the excess of granulation tissue is too high for the epithelium to grow over it.

Front 42

What happens when there is inflammation in spaces (pleural space, pericardium ect)

Back 42

Granulation tissue grows followed by a fibrous scar which causes adhesion between the visceral and the parietal layers of these tissues.

Front 43

Stellate lesion

Back 43

Star shaped lesion. Cancer + fibrosis.