Tissue Repair Lecture Oct 3 Flashcards
What is the difference between regeneration and repair?
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)
What determines the relative contribution of regeneration and fibrosis following injury?
It depends on the ability of the tissue to regenerate
the extent of the injury
What tissues are capable of regeneration without fibrosis?
Anything that actually has stem cells - these are the renewing tissues:
epidermis, GI tract, Epithelium, hematopoietic system
What type of healing occurs in chronic inflammation?
fibrosis
What three things determine the size of a cell poplation in adult tissue?
- rates of cell proliferation
- rates of terminal differentiation
- rates of apotposis
How are the tissues of the body classified based on proliferative activity? Aka. what are the categories?
- Continously dividing = labile
(skin, vagina, cervix, oral cavity, GI tract, endometrium, urinary epithelium, bone marrow) - 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) - Nondividin = permanent tissues
(neurons, skeletal muscle, cardiac muscle)
What do epidermal growth factor (EGF) and Transforming Growth Factor alpha (TGT-alpha) have in commong?
They share a receptor - EGFR
Mutaitons in this receptor have been detected in a variety of cancers - both in EGFR1 and in Her2/Neu
Which growth factor is involved primarily in angiogensis?
Vascular Epithelial Growth Factor (VEGF)
THey activate both vasculogenesis in embryos and angiogenesis in adults
also lymphangiogenesis
Which growth factor contributes largely to wound repair?
Fibroblast growth Factor (FGF)
they contribute to wound repair by promoting repeithelialization of skin wounds and angiogenesis
Which growth factor is responsible for causing fibrosis?
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
Which two cytokines largely play a role in wound healing?
tumor necrosis factor and IL2
What kind of receptor do most growth factors utilize?
tyrosine kinase receptors
What is the liver’s response to a partial dissection?
It triggers compensatory hyperplasia
it’s not exactly regeneration because it doesn’t preserve the original architecture of the liver
What function does the ECM have in tissue repair?
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
What three groups of macromolecules compose the ECM?
fibrous structural proteins (collagen, elastin)
Adhesive glycoprotines
proeoglycans/hyaluronan
What are the two basic forms of ECM and where are they located?
Interstitial matrix: found in spaces between epithelial, endothelial, smooth muscle cells, and CT
Basement membrnaes: assoiated with cell surfaces
What CT disorder leads to greater risk of aortic disection?
Marfan Syndrome
An inherited disorder of fibrillin, resultin in abnormal elastic fibers and changes in the CV system and skselton
What is the most abundant glycoprotein in the basement membrane?
laminin
Which cell adhesion protein plays an importnat role in the stabilization of blood clots in wounds?
fibronectin - it binds to collagen, fibrin, proteoglycans and cell surface receptors
What is hyaluronan and what does it do for a tissue?
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
Repair thorugh the deposition of connective tissue involves these 5 things:
inflammation
angiogenesis
migration and proliferation of fibroblasts
fibrosis (scar formation)
connective tissue remodeling
What are the 2 ways angiogenesis can occur?
- sprouting off of pre-existing vessels
- mobilization of endothelial precursor cells from the bone marrow
If angiogenesis is occuring off a pre-existing vessel, what are the steps?
- vasodilation
- proteolytic degradation of the basement membrane of the parent bessel
- Migration of endotherlial cells toward the angiogenic stimulus
- proliferation of endothelial cells
- maturation of endotherlial cells
- recruitment of periendotherlial cells to form mature vessel (pericytes and smooth muscle)
Which signalling pathway seems to be involved in angiogenesis?
THe Notch signalling pathway
(and VEGF)
What are the three phases of cutaneous wound healing?
- inflammation
- proliferation
- maturation
What kind of healing process is used for thin wounds?
What process is used for excisional wounds?
thin wounds = healing by primary union or first intention
excision wounds = healing by secondary union or second intention
How do primary union and secondary union healing differ?
secondary union has more inflammation, more granulation tissue and greater fibrosis
What are the actual steps in cutaneous wound healing?
- formation of a blood clot (stops bleading and acts as a scaffolding for migrating cells)
- 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)
- 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)
- Wound contraction (mediated by myofibroglasts at the edges of the wound with smooth muscle alpha actin and vimentin)
- Connective tissue remodelling (replacement of granulation tissue by fibrous tissue, remodeling th eEDM by balancing synthesis and degradation)
- Recovery of tensile strength (resulting from collagen deposition and modification of that collagen–takes a while though)
What are some systemic factors that influence wound healing?
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
What are some local factors that influence wound healing? What’s the really big one?
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
What is dehiscence? Where does it often occur?
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
What might cause a wound fo ulcer?
Why are diabetics particulalry prone to ulceration?
Wounds can ulcerate in areas of inadequate vascularization (impaired microvasculature) and in areas devoid of sensation (as in neuropathy)
What is the reuslt if there is excessive formation of the components of the repair process?
hpertrophic scars and keloids
What should we be concerned about for patients with severe burns when it comes to scar tissue formation?
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
What is the accuracy of a test?
WHat is the precision of a test?
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
How are reference intervals established and why is this a good thing to keep in mind when interpreting test results?
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
What is the sensitivity of a test? How is it calculated?
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.
What is the specificity of a test and how is it calculated?
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
What kind of test do you want to use for screening?
What kind of test do you want to use to rule out?
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)
What is the positive predictive value of a test?
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
What is the negative predictive value of a test?
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
What are the PPV and NPV affected by that sensitivity and specificity aren’t?
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.
