03 - Repair

Question 1

Entry and progression of cells through the cell cycle are controlled by what proteins?

Answer 1

a. The most important regulatory controls of cell growth are mediated through growth factors that recruit resting cell (G0) cells into the cell cycle.
b. Entry and progression of cells through the cell cycle are controlled by the cyclin family of proteins. Cyclins function by interacting with cyclin-dependent kinases (CDKs).

Question 2

Labile tissues

Answer 2

Continuously Dividing Tissues

a. These cells continue to multiply throughout life to replace those shed or destroyed by normal physiologic processes.
b. This ability to repeatedly multiply is based on a large population of stem cells.

c. Examples:
1) Cells of surface epithelium, such as in the skin, mucosa, GI tract and urinary tract
2) Some types of ductal epithelium of exocrine glands (cuboidal cells)
3) Stem cells of hematopoietic system (in bone marrow and lymphoid organs)

Question 3

Stable Tissues

Answer 3

Quiescent Tissues
a. These cells retain the latent capacity to regenerate, but under normal circumstances do not actively replicate.

b. These cells have a long but limited survival time (years or even life-time of the organism) and so they only regenerate under certain conditions.

c. Examples:
1) Parenchymal cells of most solid glandular organs, such as liver, pancreas, kidney, parotid, etc.
2) Mesenchymal cells, such as fibroblasts, endothelial cells and smooth muscle cells

Question 4

Permanent tissues

Answer 4

Non-dividing Tissues

a. These terminally differentiated cells have essentially no regenerative capacity once growth to adulthood is complete.

b. Examples:
1) Most neurons and cardiac muscle cells
2) Skeletal muscle cells

Question 5

Epidermal Growth Factor (EGF)

Answer 5

1) EGF is mitogenic for keratinocytes and fibroblasts.
2) Stimulates keratinocyte migration and granulation tissue formation.
3) Sources: Macrophages, salivary gland, keratinocytes, other cells.

Question 6

Transforming Growth Factor α (TGF-α)

Answer 6

1) Similar to EGF. Stimulates replication of many types of epithelial cells and hepatocytes.
2) Sources: Macrophages, T lymphocytes, keratinocytes, many other cells.

Question 7

c. Vascular Endothelial Growth Factor (VEGF)

Answer 7

1) Stimulates proliferation and motility of endothelial cells, which is important in angiogenesis.
2) In wound healing and chronic inflammation it also produces marked increased vascular permeability. This allows exudation of plasma proteins which serve as the matrix for fibroblast and endothelial ingrowth.
3) Sources: Most cells.

Question 8

d. Platelet-derived Growth Factor (PDGF)

Answer 8

1) Chemotactic for PMNs, macrophages, fibroblasts and smooth muscle cells.
2) Activates PMNs, macrophages and fibroblasts.
3) Mitogenic for fibroblasts, endothelial cell and smooth muscle cells.
4) Stimulates angiogenesis and wound remodeling.
5) Stimulates production of some ECM – MMPs, fibronectin and hyaluronic acid.
6) Regulates integrin expression.

Question 9

Fibroblast Growth Factors (FGF)

Answer 9

1) FGF-1 is acidic, whereas FGF-2 is basic.
2) Actions of FGF family (especially FGF-2)
a) Chemotactic for fibroblasts
b) Mitogenic for fibroblasts, and keratinocytes
c) Stimulates keratinocyte migration, angiogenesis, wound contraction, and matrix deposition.
3) FGF-7 is also known as keratinocyte growth factor (KGF). It stimulates keratinocyte proliferation, migration and differentiation. It is derived from fibroblasts.

Question 10

Transforming Growth Factor β (TGF-β)

Answer 10

1) TGF-β has many actions, and can have opposite effects depending on local factors.
2) In the context of inflammation and repair, major actions of TGF-β are:
a) Stimulates fibrogenesis – stimulates production of collagen and other ECMs, inhibits degradation of collagen.
b) Inhibits lymphocyte proliferation and has strong anti-inflammatory effects.
3) Sources: Platelets, endothelial cells, T lymphocytes, macrophages, keratinocytes, smooth muscle cells, fibroblasts.

Question 11

Cytokines (TNF, Il-1)

Answer 11

1) TNF induces migration of fibroblasts (chemotactic) and fibroblast proliferation. TNF also stimulates production of collagenase.
2) Il-1 mediates migration of fibroblasts and induces collagen synthesis

Question 12

What are the components of repair by connective tissue?

Answer 12

1. Formation of new blood vessels (angiogenesis)
2. Migration and proliferation of fibroblasts
3. Deposition of extracellular matrix – especially collagen
4. Maturation and reorganization of the fibrous tissue, also known as remodeling

Question 13

Angiogenesis (steps, regulation)

Answer 13

Steps of Angiogenesis

a. Proteolytic degradation of the parent vessel basement membrane and formation of the capillary sprout.
b. Migration of endothelial cells toward the angiogenic stimulus
c. Proliferation of endothelial cells behind the migrating front
d. Maturation of endothelium with formation of capillary tubes

Regulation of Angiogenesis

a. Growth factors that induce angiogenesis include PDGF and VEGF and FGF-2.
b. Extracellular matrix proteins regulate sprouting, cell migration and remodeling.

Question 14

Collagen – fibrillar and non-fibrillar

Answer 14

1) Fibrous structural protein which confers tensile strength

2) Fibrillar collagen forms a major portion of the scar tissue patch in wound healing

Question 15

Elastin

Answer 15

1) Protein core with surrounding glycoprotein meshwork

2) Provides recoil and return to baseline structure

Question 16

Proteoglycans and Hyaluronan

Answer 16

1) Polysaccharides which form hydrated compressible gels that confer tissue resiliency and lubrication (joint spaces, etc.)
2) Serve as reservoirs of growth factors

Question 17

Adhesive Glycoproteins and Integrins – includes cadherins, selectins, and integrins

Answer 17

1) Fibronectin
a) Associated with cell surfaces
b) Play a role in cell adhesion
2) Laminin
a) Glycoprotein in basement membrane
b) Connects cells to extracellular matrix (type IV collagen, especially)
c) Modulates cell survival, proliferation, differentiation and motility

Question 18

Scar Formation – Migration of Fibroblasts and ECM Deposition (steps, regulation)

Answer 18

Fibrosis occurs on the granulation tissue framework of new vessels and loose extracellular matrix.

Steps
a. Migration and proliferation of fibroblasts into the site of injury
b. Deposition of ECM by fibroblasts
Regulation of Fibrosis
a. Growth factors which recruit and stimulate fibroblasts include PDGF, FGF and TGF-β.
b. Collagen synthesis is induced by TGF-β, PDGF, and FGF, as well as Il-1 and TNF.
c. Net collagen accumulation depends on both increased synthesis and reduced collagen degradation.

Question 19

Extracellular Matrix and Tissue Remodeling

Answer 19

1. Collagens and ECM components are degraded by matrix metalloproteinases (MMPs) which are zinc dependent.
   a. Interstitial collagenases – cleave fibrillar collagen types I, II, and III
   b. Gelatinases (type IV collagenase) – degrades amorphous collagen and fibronectin
   c. Stomelysins – catabolize proteoglycans, laminin, fibronectin, and amorphous collagen
2. Activity of metalloproteinases is tightly controlled.
   a. Must be activated from a preformed precursor. Activators include plasmin and other mediators from the injury site.
   b. Rapidly inactivated by specific tissue inhibitors of metalloproteinases (TIMPs) produced by mesenchymal cells.

Question 20

Healing by first intention (primary union)

Answer 20

24 hours
24-48
Day 3
Day 5
Second week
End of 1st month
Pg 47

Question 21

Healing by second intention (secondary union)

Answer 21

1
2
3
4
5
6
7
8
pg 48

Question 22

Factors that complicate healing (extrinsic)

Answer 22

a. Infection – single most important cause of delayed wound healing
b. Nutrition – especially deficiencies of protein and Vitamin C
c. Glucocorticoids – retard healing by inhibiting collagen synthesis
d. Mechanical factors leading to wound dehiscence – new wounds
e. Poor perfusion (inadequate blood supply) – necrosis
f. Foreign bodies –

Question 23

Factors that complicate healing (intrinsic)

Answer 23

a. The type and volume of tissue injured
1) The larger the volume of injured tissue, the larger the resulting scar will be.
2) Injuries is permanent tissues have no option for repair except scarring.
b. The location of the injury near a body cavity promotes more exudation – the exudate is more likely to become organized, producing scar tissue.

Question 24

Keloid formation

Answer 24

a. Excessive amounts of collagen give rise to a protruding scar.
b. Caused by inadequate rate of lysis of fibrous proteins

Question 25

Exuberant Granulation = “Proud Flesh”

Answer 25

a. Excessive amounts of granulation tissue protrude above the level of the surrounding skin and block reepithelialization.
b. Must be surgically removed so healing can proceed normally.