Lecture 3 E1-Healing and Tissue Repair Flashcards
What 3 factors does the healing process depend on?
The type of tissue damaged
The extent of the injury
Underlying host factors
What is disease?
Deviation or interruption of normal structure and or function
What is healing and tissue repair?
Attempted to return to normal structure and function
what is parenchymal tissue
Parenchymal tissue refers to the functioning cells of a body part, such as a hepatocyte or nephron.
-usually think of these when you think of cells
-do organs primary function
What is stromal tissue?
Stromal tissue refers to the structural cells of a body part such as connective tissue or the ECM.
connective, supportive framework that promotes or helps enable the function of the parenchymal tissue
What are the 3 cell types?
Labile, Stable, and Permanent
what are labile cells
They are cells that continually reproduce/divide.
They are often found in epithelial tissue, such as the skin, oropharynx, bone marrow and GI/GU tract.
easier to replace themselves if damaged because they’re always making new
what are stable cells
Stable cells normally stop dividing once growth ceases, but can regenerate if given appropriate stimulus
Usually found as hepatocytes or smooth muscle cells, blood vessel walls, gut walls
They require a stromal framework for regeneration.
What are permananent (fixed) cells
Fixed cells that rarely regenerate or divide.
Examples include neurons, heart, skeletal muscle cells, and RBCs.
-when they’re gone, they’re gone,
- very specific structure and differentiate a lot
What 4 categories make up the ECM?
Fibrous Structural Proteins, Water-hydrated gels, Adhesive glycoproteins, and ground substance.
What are the fibrous structural proteins of the ECM?
Collagen and elastin
keep cells as close as they should be
What are the water-hydrated gels of the ECM?
Hyaluronan and proteoglycans
What are the adhesive glycoproteins of the ECM?
Fibronectin and laminin
help cells stick to the ECM
What is ground substance?
It refers to the ECM except for fibrous proteins.
What is a basement membrane?
It is the underlying epithelial, endothelial, and smooth muscle cells; separating the lining from the connective tissue.
must be present before re epithelializtion can occur (+ new cells grow)
What is the interstitial matrix?
It is the gel-like substance found between cells.
What are integrins and what are they used for?
They are integral/transmembrane proteins that allow for attachment to the ECM and communication between the intracellular and extracellular environment.
exchange things we do or do not need
What is granulation tissue?
It is the precursor to scar tissue. It develops when there is a wound that can’t be resolved with regeneration alone. It is a highly vascularized tissue that is typically reddish, moist, soft, bumpy, and granular in appearance. It is very fragile and bleeds easily.
difference between elastic ECM fiber sin 6 year old v 90 year old
6 year old- very stout, smooth, in good shape
90 year old- they have less elastic skin due to these elastins wearing down, look like shredding/ dying network
what is the precursor to scar tissue and when does it develop
granulation tissue
Develops when there is a wound that cannot be resolved with regeneration alone
temporary, helps give nutrients and fibroblasts to help lay down new tissue to become scar tissue
characteristics of granulation tissue
highly vascularized
typically reddish, moist, soft, bumpy or granular in appearance
fragile, bleeds easy
what 3 things make up granulation tissue
new capillaries (angiogenesis), proliferating fibroblasts, residual inflammatory cells
What is angiogenesis and what triggers it?
It is the generation of new blood vessels from existing blood vessels,
triggered by the release of VEGF (vascular endothelial growth factor) from hypoxic cells (deficient in O2).
What are the 4 steps of angiogenesis?
- Proteolytic (enzyme) degradation of parent vessel basement membrane by VEGF, leading to a sprout.
- Migration of endothelial cells from parent vessel towards an angiogenic stimulus.
- Proliferation of endothelial behind the leading edge of migrating cells.
- Maturation of endothelial cells and vessel walls.
What are examples of conditions that cause angiogenesis?
Damaged or disrupted tissue- infection or injury
Cancerous lesions- cancer hogs the blood supply and theres not enough for it plus the normal cells so sends out VEGF to make more vessels
Diabetic Retinopathy- if too many new vessels grow it can block normal light transduction to retina and impair vision
what does scar tissue build on
builds on granulation tissue framework of new vessels and loose ECM
What makes scar tissue?
Fibroblasts
What are the initial ECM components secreted by fibroblasts?
Fibronectin, collagen, hyaluronan, and proteoglycans
how are ECM components (secreted by fibroblasts) degraded into scar tissue
overtime by proteases and they are replaced by new components as granulation tissue transitions to scar tissue
What happens to scar tissue over time as it is constructed?
Increased collagen synthesis, diminished (slowed) fibroblast proliferation, and diminishing new blood vessels.
Involves loss of vascularization and becomes a dense collagen matrix.
usually pale due to loss of vascularization (pink when scar is new)
What mediators regulate the healing process and how do they do it?
ILs, IFNs, prostaglandins, and leukotrienes,
released from cells that participate in tissue regeneration and healing process
promote chemotaxis of leukocytes and fibroblasts, along with mediating the inflammatory response.
What are the 4 growth factors?
Vascular Endothelial Growth Factor (VEGF)(promote new blood vessels)
Platelet-Derived Growth Factor (PDGF)
Fibroblast Growth Factor (FGF)
Epithelial Growth Factor (EGF)
What are the effects of growth factors?
Mediate proliferation, differentiation, cell metabolism, and inflammatory response.
Promote chemotaxis of leukocytes and fibroblasts
Stimulate angiogenesis
Contribute to the generation of ECM
What are the stages of Tissue Repair?
Hemostasis: clotting and vascular response
Inflammation
Proliferation: Epithelial healing, contraction, and scar formation. (removal of debris and restoration of structural integrity)
Remodeling: Scar remodeling (restoration of functional integrity, remodeling of healed tissue)
need to rebuild kitchen STRUCTURE before you can cook gain which is its FUNCTION
What are the 3 types of wound intention?
Primary: small, incision-like wounds with well-approximated edges that can be sutured easily. (heal easiest, narrow)
Secondary: large, crater-like wounds with greater loss of tissue. (necrotic ares, pressure ulcers, MI, stroke)
Tertiary: large wounds that are intentionally left open to drain or are infected (to avoid abscess formation) and are then sutured at a later date.
what determines the length of each stage of healing
impacted on what intention a wound is healing by
Describe the process of hemostasis
- Initial blood vessel constriction at the site (transient vasoconstriction)
- Increased platelet aggregation and attraction
- Thrombus forms to promote hemostasis and prevent entry of foreign agents.
- Following the blockage of the vessel injury, dilation and increased capillary membrane permeability can then occur.
what two things are heavily involved in homeostasis
inflammatory mediators
Leukocytes neutralize foreign bodies and pathogens introduced into the tissue at the site of injury.
What removes debris?
Neutrophils and Macrophages
They remove foreign matter, extracellular debris, damaged fibrin, and cell fragments.
What additional things do macrophages do over neutrophils?
Macrophages also release growth factors to stimulate cell growth, attract fibroblasts, and help with angiogenesis.
(show up about 24 hours after wound, and are predominant after 48 horus)
When does proliferation(resotring structural integrity) in wound healing begin occurring?
Within 2 days. (unless theres a lot of pus or patient is septic, body isnt in a rush then)
what is primary aim in restoring structural integrity
building new tissue to fill the wound space
What is the early form of the ECM called during proliferation?
Provisional matrix
What is the purpose of provisional matrix?
Attracting and supporting fibroblasts, endothelial cells, and epidermal cells.
Provides the materials to start granulation tissue construction.
How soon can granulation tissue begin forming? what causes the new formation?
Within 24 hours.
fibroblasts and vascular endothelial cells proliferate at 24 hours
What begins forming granulation tissue?
Fibrolasts begin secreting collagen and other components, as well as releasing growth factors to encourage the healing process.
over time what happens to granulation tissue in restoration of structural integrity
granulation tissue regresses, leaving a framework for the final produc tof repair
what is re epithelialization
new epithelial barriers form between wound and external environment
(doesn’t mean it is fully healed but there is no open area that needs to be continually defended)
looks like gray/pink matter on outside of scar that is taking over
what is the primary aim in restoring functional integrity
restore the functional integrity of parenchymal tissues
What are the 3 healing outcomes?
Resolution, Regeneration, and Replacement
what is replacement healing outcome
production of scar tissue when regeneration isnt possible
seen with injuries to permanent cells, extensive or major injuries (MI, STROKE)
what is resolution healing outcome
very mild injury with minimal disruption
rapid healing, minimal to no scarring
(3 y/o bit and split tongue, will heal wuick with musus membrane)
What cell types are seen in regeneration?
Labile or stable cell types.
They can differentiate ( local cells mature and become specialized), proliferate (reproduce and grow), and do diapedesis ( local similar cells migrate to replace lost or damged cells).
How soon can remodeling begin in uncomplicated wounds? how long can it last?
3 weeks - 6 months
can continue for 6 months or more
What occurs during remodeling?
- Collagenase enzymes remove collagen
- Fibroblasts lay down new collagen
- Reorientation of scar architecture to surrounding tissue to maximize tensile strength of wound. (cleavage lines of skin)
How much strength does a sutured wound have? After suture is removed?
70% once closed (dur to tensile strength of suture, not skin)
10% once removed ( rapid increase in strength over next 4 weeks but very fragile to mechanical stress - may reopen at this time)
What is the most tensile strength wounds have after 3 ( to 6) months?
70-80% of unwounded skin
Why is secondary contraction(intention) common in large wounds?
Wounds often undergo contraction during proliferative and remodeling phases if they are in an area that constantly stretches, such as at the base of the neck.
common characteristics of secondary contraction in healed wounds
scar tissue is often smaller than original wound
can cause limited mobility and deformities
What are all the complications that can occur during wound healing?
Ulcerations, Dehiscence, Keloids, Hypertrophic Scars, Adhesions, and Proud Flesh
What is an ulceration and what makes it hard to heal?
It is an open, crater-like lesion of skin or mucous membranes. Common to have necrotic epithelium with subepithelial inflammation.
It is difficult to heal( long healing periods) because of poor perfusion (blood flow) to that area, the patient’s limited inflammatory or immune response, and frequent colonization by microbes.
What is a dehiscence and what are the early/late causes of its formation?
It is a deficient scar formation, usually caused by a wound bursting at the site of injury before scarring finishes (after sutures removed and only have 10% strength in area).
Early causes include mechanical stress
Later causes include deficient ECM or collagen formation (vitamin C deficiency), such as someone with Ehlers-Danlos Syndrome.
What is a keloid and its risk factors?what can help decrease size?
Excessive collagen production at the site of injury which often exceeds margins of wound
Risk factors include darker pigmented skin, age 10-30, and family history of keloids.
can try to decrease with corticosteroids or injections
What is a hypertrophic scar?
Excessive collagen production at site of injury that stays within the margins of the wound.
What are adhesions and where are they normally found?
Inappropriate fibrous connections between injury and nearby tissues. Commonly inhibits the movement of surrounding tissues.
Most commonly occurs in intra-abdominal surgeries.
can lead to pain and distortion of normal tissue structure (infertility if in pelvic region)
Why are adhesions difficult to treat?
Excision of an adhesion typically causes more scarring.
What is proud flesh and how is it treated?
It is the excess production of granulation tissue and extends beyond the anatomical edges of the wound. Prevents normal healing such as re-epithelialization (because granulation is in its way).
Treated with surgical removal and/or chemical cauterization.
like a keloid but with granulation tissue instead of scar tissue
What factors affect wound healing?
Malnutrition, blood flow/oxygenation, immune/inflammatory response, infection, foreign bodies, and age.
proteins (malnutrition)
needed for mediation of inflammatory phase, fibroblast proliferation, collagen synthesis, angiogenesis, and remodeling
carbohydrates ( malnutrition)
needed for energy for WBC and reduce use of proteins for energy
most produced and rapid source of energy
fats (malnutrition)
needed for synthesis of new cells
no lipids no phospholipid membrane, no new cells (all cells have phospholipid bilayer)
What does a deficiency in Vitamin C cause?
Collagen synthesis impairment.
- need C to make and maintain scar tissue
scar remodeling is an active process
scurvy- old wounds reopened (poor collagen formation) adn also bleeding gums
What does a deficiency in Vitamin A cause?
needed for epithelialization, capillary formation, and collagen synthesis
Can reduce the anti-inflammatory effects of corticosteroids. (important in body ability to heal and fight infections- wont make epithelial cells as well)
measles complication
What does a deficiency in zinc cause?
It is required for the enzyme used in cell proliferation. produces cell mediators
What does a protein deficiency cause for inflammation?
Needed for the mediation of the inflammatory phase, fibroblast proliferation, collagen synthesis, angiogenesis, and remodeling.
blood flow
supplies nutrients and ells to injury and removes waste products, toxins, pathogens
good blood flow doesn’t always mean they have good O2
Why is oxygen important in healing?
It is required for collagen synthesis and intracellular destruction of organisms by phagocytes (oxidation)
What is the purpose of hyperbaric oxygen?
Hyperbaric oxygen is high pressure oxygen that is thought to improve the partial pressure of oxygen in the blood and improve the healing process.
force more O2 into tissues
What conditions can impair inflammation/immune response?
Impaired perfusion to injury site
Impaired phagocytic function
Diabetes Mellitus
Corticosteroid Administration
What is the effect of diabetes mellitus on inflammation?
Diminishes chemotaxis and phagocytosis
Impairs perfusion due to microvascular disease (not great blood flow, limit WBC to phagocytes)
limit ability of WBC, fibroblasts to move to injured area
WBC don’t do their job as well, diabetes pt usually more immunocompromised
What is the effect of Corticosteroids on inflammation and the immune response?
Decreased immune mediator production (inhibit arachidonic pathway)
Decreased capillary permeability (limit vascular response)
Impaired phagocytosis
Inhibited fibroblast proliferation and function
How do foreign bodies inhibit the healing process?
They prolong the inflammatory phase
They impair granulation tissue formation
They inhibit the proliferation of fibroblasts and deposition of collagen fibers
Contribute to pathogen invasion via becoming a reservoir (infection in artificial joint, may need new one because infection hiding in it) and mechanical barrier to wound closure.
Why are children bad at healing?
They have a greater capacity for healing but greater metabolic demands. They also have an immature immune system and therefore a prolonged immune response (longer immune response allows pathogen to spread in body)
Why are old people bad at healing?
The elderly have decreased dermal thickness, collagen content in their skin, and elasticity of skin.
They produce less fibroblasts and less collagen.
They take longer to re-epithelialize their wounds and are more vulnerable to slower wound healing and chronic wounds.
What are the two most common causes for chronic inflammation?
Persistent injury/infection (Ulcerations, pathogens, and foreign bodies)
Autoimmune conditions (RA, MS, SLE)
What are the systemic manifestations of chronic inflammation?
Fever, malaise, fatigue/weakness, anemia, anorexia and weight loss
5 cardinal signs of chronic inflammation
redness, heat, swelling, pain , loss of function
What causes anemia in chronic inflammation?
IL-6 production, which goes to the liver and makes more hepcidin, which is an inhibitor for ferroportin.
Ferroportin is an iron exporter (leave gut go to bloodstream) , so reduced iron leads to reduced RBC formation.
what do IL-1, TNF, and IFN-gamma do in chronic inflammation causing anemia
inhibit erythropoetin release (kidneys - tell marrow to make more RBC) and augmenting RBC phagocytosis
promotoe breakdown/consumption of RBC (maybe by spleen)
What inhibits the release of erythropoietin?
Il-1, TNF-alpha, and IFN-gamma
Why do cancer cells proliferate?
They are classified as abnormal/damaged by the body and cause go into cellular distress. (tumor cells have abnormal markers that immune attacks and often outgrow local supply of nutrients leading to cell distress and ischemia)
They then release cytokines and cause angiogenesis and nutrients to come to them.
The release of more growth factors allow them to expand and proliferate.
what can enhance the ability of tumor cells to grow and spread
proteases and remodeling of ECM
What is granulamatous inflammation?
They are nodular inflammatory lesions that encase substances not easily destroyed by usual inflammatory and immune responses.
foreign bodies- splinters, sutures, silica, asbestos
pathogens- TB, syphilis, deep fungal infections
create a wall around infection if its cant destroy it to at least keep away from rest of body
giant cells and epithelioid cells
Giant cells are formed by macrophages and surround the insult.
Epithelioid cells then surround the offending agent and the giant cells.
Fibrous tissue is formed to encapsulate the area, which then becomes a bubble of necrotic remains.
non specific chronic inflammation
- diffuse accumulation of macrophages and lymphocytes at site of injury
-cytokines produced by underlying cause lead to persistent chemotaxis of leukocytes and fibroblasts - significant scar tissue formation- often replaces normal stromal and parenchymal tissues
-loss of normal structure and function of tissue
What commonly causes granulamatous inflammation?
Retained foreign bodies and certain bacterias, such as M. tub, syphilis, and fungal infections.
