Tissue Repair Lecture Oct 3

Question 1

What is the difference between regeneration and repair?

Answer 1

Regeneration is the proliferation of cells and tissues following injury which REPLACES LOST STRUCTURES. (this occurs when there is no damage to the ECM - only cells)

Repair consists of a combination of regeneration and fibrosis which is the typical response following injury. This does NOT always replace lost structure with the same architecture as before

(this is when there is damage to the cells and ECM)

Question 2

What determines the relative contribution of regeneration and fibrosis following injury?

Answer 2

It depends on the ability of the tissue to regenerate

the extent of the injury

Question 3

What tissues are capable of regeneration without fibrosis?

Answer 3

Anything that actually has stem cells - these are the renewing tissues:

epidermis, GI tract, Epithelium, hematopoietic system

Question 4

What type of healing occurs in chronic inflammation?

Answer 4

fibrosis

Question 5

What three things determine the size of a cell poplation in adult tissue?

Answer 5

• rates of cell proliferation
• rates of terminal differentiation
• rates of apotposis

Question 6

How are the tissues of the body classified based on proliferative activity? Aka. what are the categories?

Answer 6

1. Continously dividing = labile
   (skin, vagina, cervix, oral cavity, GI tract, endometrium, urinary epithelium, bone marrow)
2. Quiescent = stable tissues
   (low level or replication but can undergo rapid division in the repsonse to stimuli - liver, kidney, pancreas, smooth muscle, fibroblasts, vascular endothelial cells, osteocytes)
3. Nondividin = permanent tissues
   (neurons, skeletal muscle, cardiac muscle)

Question 7

What do epidermal growth factor (EGF) and Transforming Growth Factor alpha (TGT-alpha) have in commong?

Answer 7

They share a receptor - EGFR

Mutaitons in this receptor have been detected in a variety of cancers - both in EGFR1 and in Her2/Neu

Question 8

Which growth factor is involved primarily in angiogensis?

Answer 8

Vascular Epithelial Growth Factor (VEGF)

THey activate both vasculogenesis in embryos and angiogenesis in adults

also lymphangiogenesis

Question 9

Which growth factor contributes largely to wound repair?

Answer 9

Fibroblast growth Factor (FGF)

they contribute to wound repair by promoting repeithelialization of skin wounds and angiogenesis

Question 10

Which growth factor is responsible for causing fibrosis?

Answer 10

Transforming Growth Factor Beta (TGT-Beta)

It inhibits growth of most epithelial cells and acts as a potent fibrogenic agent.

It also have a strong anti-inflammatory effect, but can enhance some ummune rungionts.

It is implicated in the development of fibroisis in a variety of chronic inflammatory conditions

Question 11

Which two cytokines largely play a role in wound healing?

Answer 11

tumor necrosis factor and IL2

Question 12

What kind of receptor do most growth factors utilize?

Answer 12

tyrosine kinase receptors

Question 13

What is the liver’s response to a partial dissection?

Answer 13

It triggers compensatory hyperplasia

it’s not exactly regeneration because it doesn’t preserve the original architecture of the liver

Question 14

What function does the ECM have in tissue repair?

Answer 14

the ECM (in tandem with growth factors and cytokines) regulate growth, proliferation, movement and differentiation of the cells that live within it

It controls cell growth

it maintains cell differentiation

It acts as scaffolding for tissue regeneration - if the ECM is damaged, collagen deposition will occur resultin gin fibrosis

Question 15

What three groups of macromolecules compose the ECM?

Answer 15

fibrous structural proteins (collagen, elastin)

Adhesive glycoprotines

proeoglycans/hyaluronan

Question 16

What are the two basic forms of ECM and where are they located?

Answer 16

Interstitial matrix: found in spaces between epithelial, endothelial, smooth muscle cells, and CT

Basement membrnaes: assoiated with cell surfaces

Question 17

What CT disorder leads to greater risk of aortic disection?

Answer 17

Marfan Syndrome

An inherited disorder of fibrillin, resultin in abnormal elastic fibers and changes in the CV system and skselton

Question 18

What is the most abundant glycoprotein in the basement membrane?

Answer 18

laminin

Question 19

Which cell adhesion protein plays an importnat role in the stabilization of blood clots in wounds?

Answer 19

fibronectin - it binds to collagen, fibrin, proteoglycans and cell surface receptors

Question 20

What is hyaluronan and what does it do for a tissue?

Answer 20

It’s a polysacchardie found in the ECM of many tissues. It binds water and helps provide resilience and lubrication to connective tissue in particular

Question 21

Repair thorugh the deposition of connective tissue involves these 5 things:

Answer 21

inflammation

angiogenesis

migration and proliferation of fibroblasts

fibrosis (scar formation)

connective tissue remodeling

Question 22

What are the 2 ways angiogenesis can occur?

Answer 22

1. sprouting off of pre-existing vessels
2. mobilization of endothelial precursor cells from the bone marrow

Question 23

If angiogenesis is occuring off a pre-existing vessel, what are the steps?

Answer 23

1. vasodilation
2. proteolytic degradation of the basement membrane of the parent bessel
3. Migration of endotherlial cells toward the angiogenic stimulus
4. proliferation of endothelial cells
5. maturation of endotherlial cells
6. recruitment of periendotherlial cells to form mature vessel (pericytes and smooth muscle)

Question 24

Which signalling pathway seems to be involved in angiogenesis?

Answer 24

THe Notch signalling pathway

(and VEGF)

Question 25

What are the three phases of cutaneous wound healing?

Answer 25

1. inflammation 2. proliferation 3. maturation

Question 26

What kind of healing process is used for thin wounds? What process is used for excisional wounds?

Answer 26

thin wounds = healing by primary union or first intention excision wounds = healing by secondary union or second intention

Question 27

How do primary union and secondary union healing differ?

Answer 27

secondary union has more inflammation, more granulation tissue and greater fibrosis

Question 28

What are the actual steps in cutaneous wound healing?

Answer 28

1. formation of a blood clot (stops bleading and acts as a scaffolding for migrating cells) 2. Formation of granulation tissue (fibroblasts and endothelial cells proliferate to form mesenchymal tissue containing proliferatin fibroblasts and new small blood veessels - which are leaky causing edema) 3. Cell proliferation and collagen deposition (macrophages replace neutrophils and clean things out, while secreting chemokines and growth factors for the healing process. Collagen fibrils become mroe abundant - TFG-beta's doing) 5. Wound contraction (mediated by myofibroglasts at the edges of the wound with smooth muscle alpha actin and vimentin) 6. Connective tissue remodelling (replacement of granulation tissue by fibrous tissue, remodeling th eEDM by balancing synthesis and degradation) 7. Recovery of tensile strength (resulting from collagen deposition and modification of that collagen--takes a while though)

Question 29

What are some systemic factors that influence wound healing?

Answer 29

nutririon (protein or vitamin C deficiency) metabolic status (diabetes - microangiopathy) Circulatory status (arteriosclerosis or venous abnormalities) Hormones like glucocorticoids have anti-inflammatory effects that would inhibit collagen synthesis

Question 30

What are some local factors that influence wound healing? What's the really big one?

Answer 30

INFECTION!!!!! is the most important - it will delay healing Mechanical factors - ripping the wound back open Foriegn bodies (sutures) Size, location and type of wound vascularization will heal faster small incisional wounds will heal faster

Question 31

What is dehiscence? Where does it often occur?

Answer 31

Dehiscence is rupture of a wound due to inadequate formation of granulation tissue or assembly of the scar. This is most common following abdominal surgery

Question 32

What might cause a wound fo ulcer? Why are diabetics particulalry prone to ulceration?

Answer 32

Wounds can ulcerate in areas of inadequate vascularization (impaired microvasculature) and in areas devoid of sensation (as in neuropathy)

Question 33

What is the reuslt if there is excessive formation of the components of the repair process?

Answer 33

hpertrophic scars and keloids

Question 34

What should we be concerned about for patients with severe burns when it comes to scar tissue formation?

Answer 34

WIth severe burns, the healing process will often result in contracture of the tissue, which can be debilitating if it occurs with the limbs - think the fingers

Question 35

What is the accuracy of a test? WHat is the precision of a test?

Answer 35

Accuracy is the ability of the test to actually measure what it claimto measure correctly Presicision is the ability of the test to reproduce the same result when repeated

Question 36

How are reference intervals established and why is this a good thing to keep in mind when interpreting test results?

Answer 36

They are the values obtained in a defined population of health indviiduals that are free of disease and the reference limits are the values that encompass 95% of the values obtained in the reference population This means 5% of health individuals iwll have lab values outside the normal range

Question 37

What is the sensitivity of a test? How is it calculated?

Answer 37

Sensitivity is the probability that an individual with the disease will test positive sensitivity - TP / (TP +FN) So the proprtion people with the disease who test positive.

Question 38

What is the specificity of a test and how is it calculated?

Answer 38

Specificity is the probability that an individual without the disease will test negative. Specificity = TN / (TN + FP) THe proportion of people with the disease wo test negative

Question 39

What kind of test do you want to use for screening? What kind of test do you want to use to rule out?

Answer 39

Use a sensitive test to screen (becuase you don't want to miss anyone) Use a specific test to rule out (because if someone doesn't have the disease you need to know that)

Question 40

What is the positive predictive value of a test?

Answer 40

It's the probability that a positive test is actually supposed to be positive PPV = (TP) / (TP + FP) The proportion of people who tested positive that actually have the disease

Question 41

What is the negative predictive value of a test?

Answer 41

It's the probability that a negative test accurately indicates the person doesn't have the disease NPV = TN / (TN + FN) The proportion of negatives that are actually true negatives

Question 42

What are the PPV and NPV affected by that sensitivity and specificity aren't?

Answer 42

The actual prevalence of a disease within the population being tested if the prevalence is extremely low, then a positive test result is much more likely to be a false positive than a true positive, so the PPV goes way down.