Lecture 3 Flashcards
What 3 factors does the healing process depend on?
The type of tissue damaged
The extent of the injury
Underlying host factors
Disease
Deviation or interruption of normal structure and/or function
Healing and Tissue Repair
Attempt to return to normal structure and function
Parenchymal vs Stromal
Parenchymal tissue refers to the functioning cells of a body part, such as a hepatocyte or nephron.
Stromal tissue refers to the structural cells of a body part such as connective tissue or the ECM.
What are the 3 cell types?
Labile, Stable, and Permanent
Where do I find 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.
Where do I find stable cells?
Stable cells normally stop dividing once growth ceases, but can regenerate.
Usually found as hepatocytes or smooth muscle cells.
They require a stromal framework for regeneration.
Where do I find permanent cells?
Fixed cells that rarely regenerate or divide.
Examples include ocular, neurons, heart, skeletal muscle cells, and RBCs.
What 4 categories make up the ECM?
Fibrous Structural Proteins, Water-hydrated gels, Adhesive glycoproteins, and ground substance.
What is another name for ECM?
interstitial matrix
What are the fibrous structural proteins of the ECM?
Collagen and elastin
What are the water-hydrated gels of the ECM?
Hyaluronan and proteoglycans
What are the adhesive glycoproteins of the ECM?
Fibronectin and laminin
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.
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.
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.
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 from hypoxic cells.
What are the 4 steps of angiogenesis?
- Proteolytic 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
Cancerous lesions
Diabetic Retinopathy
What makes scar tissue?
Fibroblasts
What are the initial ECM components secreted by fibroblasts?
Fibronectin, collagen, hyaluronan, and proteoglycans
What happens to scar tissue over time as it is constructed?
Increased collagen synthesis, diminished fibroblast proliferation, and diminishing new blood vessels.
Involves loss of vascularization and becomes a dense collagen matrix.
What mediators regulate the healing process?
ILs, IFNs, prostaglandins, and leukotrienes, which promote chemotaxis and leukocytes and fibroblasts, along with mediating the inflammatory response.
What are the 4 growth factors?
Vascular Endothelial Growth Factor (VEGF)
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.
Remodeling: Scar remodeling
What are the 3 types of wound intention?
Primary: small, incision-like wounds with well-approximated edges that can be sutured easily.
Secondary: large, crater-like wounds with greater loss of tissue.
Tertiary: large wounds that are intentionally left open to drain or are infected and are then sutured at a later date.
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.
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.
When does proliferation in wound healing begin occurring?
Within 2 days.
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?
Within 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.
Reepithelialization
new epithelial barriers between wound and external environment
What are the 3 healing outcomes?
Resolution, Regeneration, and Replacement
Resolution injury
very mild injury with minimal disruption: rapid healing, minimal to no scarring
primary aim of restoring functional integrity
restore parenchymal tissues
What cell types are seen in regeneration?
Labile or stable cell types. They can differentiate, proliferate, and do diapedesis.
Diapedesis
local similar cells migrate to replace lost or damaged cells
Replacement
production of scar tissue when regeneration is not possible (injury to permanent cells or major injuries)
How soon can remodeling begin in uncomplicated wounds?
3 weeks - 6 months
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.
How much strength does a sutured wound have? After its removed?
70% once closed, 10% once removed.
What is the most tensile strength wounds have after 3-6 months?
70-80%
Why is secondary contraction common in large wounds?
Wounds often undergo contraction if they are in an area that constantly stretches, such as at the base of the neck.
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 because of poor perfusion 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.
Early causes include mechanical stress
Later causes include deficient ECM or collagen formation, such as someone with Ehlers-Danlos Syndrome.
What is a keloid and its risk factors?
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.
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.
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.
Treated with surgical removal and/or chemical cauterization.
What factors affect wound healing?
Malnutrition, blood flow/oxygenation, immune/inflammatory response, infection, foreign bodies, and age.
What does a deficiency in Vitamin C cause?
Collagen synthesis impairment.
What does a deficiency in Vitamin A cause?
Epithelialization, capillary formation, and collagen synthesis impairment.
Can reduce the anti-inflammatory effects of corticosteroids.
What does a deficiency in zinc cause?
It is required for the enzyme used in cell proliferation.
What does a protein deficiency cause for inflammation?
Needed for the mediation of the inflammatory phase, fibroblast proliferation, collagen synthesis, angiogenesis, and remodeling.
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.
What conditions can impair inflammation/immune response?
Impaired perfusion to injury site
Impaired phagocytic function
Diabetes Mellitus
Corticosteroid Administration
What is the effect of DM on inflammation?
Diminishes chemotaxis and phagocytosis
Impairs perfusion due to microvascular disease
What is the effect of Corticosteroids on inflammation and the immune response?
Decreased immune mediator production
Decreased capillary permeability
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 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.
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
Redness, heat, swelling, pain, loss of function
What causes anemia in chronic inflammation?
Prolonged inflammation: IL-6 production, which goes to the liver and makes more hepcidin, which is an inhibitor for ferroportin.
Ferroportin is an iron exporter, so reduced iron leads to reduced RBC formation.
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. 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 due to inflammatory response.
How does nonspecific chronic inflammation lead to loss of normal structure and function of tissue?
Accumulates macrophages and lymphocytes at site of injury.
Cytokines produced by underlying cause lead to persistent chemotaxis of leukocytes and fibroblasts.
Significant scar tissue formation replacing normal stromal and parenchymal tissues.
What is granulamatous inflammation?
They are nodular inflammatory lesions that encase substances not easily destroyed by usual inflammatory and immune responses.
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.
What commonly causes granulamatous inflammation?
Retained foreign bodies and certain bacterias, such as M. tub, syphilis, and fungal infections.
