Chronic Inflammation and Healing and Tissue Repair Flashcards
Define disease
A deviation or interruption of normal structure and/or function
What is healing and tissue repair?
An attempt to return to normal structure and function
What does the healing process vary on?
The type of tissue damaged, the extent of injury, and the underlying host factors
What is parenchymal tissue?
Functioning cells of a body part
What is stromal tissue?
Connective, supportive framework that promotes or helps to enable the function of parenchymal tissue
What are labile cells?
Cells that continually divide and replicate
What is an example of labile cell
Bone marrow, epithelial cells
What are stable cells?
Cells that normally stop dividing when growth stops, but can regenerate when stimulated
What is required for stable cells to regenerate properly?
A stromal framework
What are permanent cells?
Cells that rarely or never regenerate or divide
What is extracellular matrix?
Material secreted by local cells through the body that surrounds and supports the cells. Made up of fibrous structural proteins, water-hydrated gels, adhesive glycoproteins, and ground substance
What are the 2 types of fibrous structural protein?
Collagen, elastin
What are types of water-hydrated gels?
hyaluronan, proteoglycans
What are 2 examples of adhesive glycoproteins?
fibronectin, laminin
What does ground substance refer to?
all extracellular matrix except the fibrous proteins
What is a basement membrane?
A membrane underneath epithelial, endothelial, and smooth muscle cells. Separates lining from connective tissue
What must be present before re-epithelization can occur?
Basement membrane
What is interstitial matrix?
Gel-like substance between body cells
What are integrins?
Transmembrane proteins in cells that allow for attachment to extracellular matrix and communication between extracellular and intracellular
When does granulation tissue develop?
When there is a wound that cannot be resolved just by regeneration as a precursor to scar tissue
What does granulation tissue look like?
Reddish, moist, soft, and “bumpy” or granular. It is fragile and bleeds easily
What is the production of new capillaries called?
Angiogenesis
What is in granulation tissue?
New capillaries, proliferating fibroblasts, and residual inflammatory cells
What is the generation of new blood vessels from existing blood vessels?
Angiogenesis
What is a chemical signaling molecule for angiogenesis and what cells produce it
vascular endothelial growth factor, cells deficient in oxygen
What are the 4 steps in angiogenesis?
1) Degradation of parent vessel basement membrane, 2) Migration of endothelial cells from parent vessel toward angiogenic stimulus, 3) Proliferation of endothelial cells behind leading edge of migrating cells, 4) Maturation of endothelial cells and vessel walls
What tissue does scar tissue build on?
Granulation tissue framework of new vessels and loose ECM
What do fibroblasts do for scar tissue formation?
Fibroblasts move to area of injury and proliferate. They secrete ECM components (fibronectin, hyaluronan, proteoglycans, collage). These components are degraded over time by proteases and replaced
What happens after fibroblasts proliferate and secrete ECM in scar tissue formation?
Increased collagen synthesis and decreased fibroblast proliferation. Decreased new blood cells. Granulation tissue transitions to dense collagen fiber matrix. Loss of vascularization
What are the chemical mediators involved in the healing process?
Interleukins, interferons, prostaglandins, and leukotrienes
What do chemical mediators do for regulation of the healing process?
They promote chemotaxis of leukocytes and fibroblasts and mediate inflammatory response
What are the growth factors to know for regulation of the healing process?
Vascular endothelial growth factor, platelet-derived growth factor, fibroblast growth factor, epithelial growth factor
What are the functions of growth factors in the healing process?
-proliferation, differentiation, and cell metabolism
-mediate inflammatory response
-promote chemotaxis of leukocytes and fibroblasts
-stimulate angiogenesis
-contribute to generation of ECM
What are the 4 stages of healing and tissue repair?
Hemostasis. inflammation, proliferation, and remodeling
What are the three stages of wound intention?
primary intention, secondary intention, and tertiary intention
What is primary intention?
small incision-like wounds with well-approximated edges
What is secondary intention?
large, crater-like wounds with greater loss of tissue
What is tertiary intention?
large wound that is intentionally left open and then closed at a later date. Usually done when there is drainage or an infection
What occurs in hemostasis?
Blood vessels initially constrict. There is increased platelet attraction and aggregation. Then, thrombus forms to promote hemostasis and prevent entry of foreign agents. After the vessel injury, the capillary dilates and increases permeability
What do leukocytes do in inflammation?
Neutralize foreign bodies and pathogens introduced into the tissue
What do neutrophils and macrophages do?
Remove foreign matter and invading organisms, extracellular debris, damaged fibrin, and cell fragments
What do macrophages release to stimulate cell growth, fibroblast attraction, and angiogenesis
growth factors
When does the building of new tissue to fill wound space begin?
within 2 days depending on injury
What is produced early in the healing process in the area of the injury? (form of ECM)
provisional matrix
What is the function of the provisional matrix?
Attract and support fibroblasts, endothelial cells.
What is the provisional matrix turned into by macrophages and fibroblasts?
Granulation tissue
How soon after an injury can fibroblasts and vascular endothelial cells begin forming granulation tissue?
24 hours
What do fibroblasts secrete?
Collagen
What is re-epithelialization?
The forming of new epithelial barriers between wound and external environment
What are the 3 possible outcomes of restoring function integrity?
Resolution, regeneration, or replacement
What is resolution?
Very mild injury with minimal disruption, rapid healing, little to no scarring
What is regeneration?
Seen with labile or stable cell types. Cells proliferate (reproduce and grow), diffentiate (local cells mature and specialize), or diapedesis may occur (local similar cells migrate to replace lost or damaged)
What is replacement?
Scar tissue is produced when regeneration isn’t possible
When does remodeling begin?
about 3 weeks in uncomplicated wounds and can continue for 6 months or more
How is scar tissue remodeled?
Colleganse enzymes remove collage, fibroblasts lay down new collagen, and scar architecture is reoriented to surrounding tissue to maximize tensile strength
What percent of prior strength do sutured wounds hav?
70%
What percent of tensile strength do wounds have after suture removal?
10%
What percent of tensile strength do wounds have 3 months after injury?
70-80% of unwounded skin, this is the maximal strenght
What is secondary intention?
Wounds undergo contraction during proliferative and remodeling phases that can cause limited mobility and defomity
What are the 5 common complications of healing?
Ulceration, dehicence, keloids, hypertrophic scars, and adhesions
What is an ulceration?
A craterlike lesion of skin or mucous membrane that is often associated with poor perfusion.
What are some complications of ulcerations?
They have poor perfusion so they have limited inflammatory and immune response. They are frequently colonized by microorganisms and have very long healing periods
What is a dehiscence?
A deficient scar formation that breaks open
What is the cause of dehiscence early after injury?
Mechanical stress
What is the cause of dehiscence late after injury?
Deficient ECM or collagen formation
Why would dehiscence occur years after an injury?
The scar is constantly being rebuilt. They may have nutritional deficiency or autoimmune condition
What is a keloid?
A excess of collagen production at site of injury that often exceeds the margins of a wound
What are some risk factors for keloids?
Darker pigmented skin, age 10-30 and family history
What is a hypertrophic scar?
Excessive collagen production at the site of injury that is less severe than keloids and stays within wound margins
What is an adhesion?
An innapropriate fibrous connection between injury and nearby tissues that can inhibit movement of surrounding tissues. This is common in intra-abdominal surgeries
What is proud flesh?
Excess production of granulation tissue that extends beyond anatomical edges of wound. This can impair reepithelialization from taking place and can be treated by surgical removal or chemical cauterization.
What are some factors that affect wound healing? (6)
malnutrition, blood flow/oxygenation, immune and inflammatory response, infection, foreign bodies, and age
Why are proteins needed for wound healing?
They mediate the inflammatory phase, are involved in fibroblast proliferation, collagen synthesis, angiogenesis. and remodeling
Why are carbohydrates needed for wound healing?
They provide energy for WBCs and reduce the use of proteins for energy
Why are fats needed for wound healing?
They are needed for synthesis of phospholipid membranes of new cells
What is vitamin C used for in wound healing?
Collagen synthesis
What is vitamin A used for in wound healing?
Epithelialization, capillary formation, collagen synthesis, and can reduce anti-inflammatory effects of corticosteroids. It is fat soluble so can be stored
Why is zinc necessary for wound healing?
needed for enzymes responsible for cell proliferation
What can cause an increased risk for severe malnutrition?
Dementia, alcoholism, unhoused, anorexia
What does blood flow do for healing?
Supplies nutrients and cells to injury and removes waste products, toxins, and pathogens
What does oxygen do for healing?
Necessary for collagen synthesis and intracellular destruction of organisms by phagocytes
Why would someone use hyperbaric oxygen to promote wound healing?
It is thought to increase partial pressure of oxygen in plasma to improve collagen synthesis and intracellular destruction of organisms by phagocytes
What could limit the immune/inflammatory response?
Lack of perfusion to injury site, impaired phagocytic function, diabetes mellitus, or corticosteroid administration
Why does diabetes mellitus impair the immune response?
diminished chemotaxis and phagocytosis because of all of the sugar in blood, impaired perfusion due to microvascular disease
Why does corticosteroid administration limit the immune response?
decreased immune mediator production, decreased capillary permeability, impaired phagocytosis, and inhibited fibroblast proliferation and function
What does a foreign body do to the infection process?
Prolong the inflammatory phase, impair granulation tissue formation, inhibit proliferation of fibroblasts and deposition of collage, can contribute to pathogens by providing place for pathogens to hide and being barrier to wound closure
How is healing different for children?
They may lack reserves for proper tissue repair, may have a prolonged immune response due to an immature immune system, and have increased baseline metabolic nutritional demands
How is healing different for the elderly?
Decreased dermal thickness and collagen/elasticity of skin, decreased collagen and fibroblast synthesis, slower reepithelialization, and increased vulnerability to chronic wounds and slow wound healing
What is the difference in cellular infiltrate in acute vs chronic inflammation?
There are neutrophils early and monocytes/macrophages late in acute inflammation, in chronic inflammation you see monocytes/macrophages and lymphocytes
What is the extent of tissue injury in acute vs chronic inflammation?
Acute- mild, self-limited, minimal; chronic- severe, extensive and progressive
What are common causes of chronic inflammation?
Persistent injury or infection i.e ulcerations, pathogens, and foreign bodies; autoimmune conditions i.e rheumatoid arthritis, multiple sclerosis, and systemic lupus erythematosus
You may see the five cardinal signs and systemic manifestations as well as periods of remission in what type of inflammation?
Chronic
What are the five cardinal signs of inflammation?
Redness, heat, swelling, pain, loss of function
What are systemic manifestations of chronic inflammation?
Fever, malaise, fatigue and weakness, anemia, anorexia and weight loss
What is a period of remission?
Diminished or absent symptoms
Describe the process by which someone with chronic inflammation can get anemia
Prolonged inflammation can cause IL-6 production which increases hepcidin production by the liver. Hepcidin reduces iron by blocking ferroportin. If you have less iron, RBC formation is impaired. IL-1, TNF-a, and IFN-y inhibit erythropoietin release and augment phagocytosis
Describe the process by which the inflammatory process reacts to cancer
Tumor cells have abnormal markers and cause a inflammatory response. They may outgrow the supply of nutrients and cause other cell ischemia and distress. Cytokines lead to angiogenesis and influx of new nutrients which feeds cancer, and growth factors promote the reproduction of cancer cells and new vessels. Proteases and remodeling of ECM can enhance the ability of tumor cells to grow and spread
What happens in nonspecific chronic inflammation?
Macrophages and lumphocytes accumulate at site of injury, cytokines lead to persistent chemotaxis of leukocytes and fibroblasts, scar tissue forms and often replaces normal stromal and parenchymal tissues and loss of normal structure/function results
What is granulomatous inflammation?
Inflammatory lesions that encase substances that are not easily destroyed by inflammatory and immune response i.e foreign bodies and pathogens
How do macrophages adapt to address granulomatous inflammation?
giant cells (multinucleated, coalesced macrophages) surround large particles. Epitheloid cells surround and contain offending agent and macrophages processing it
What does fibrous tissue do with granulomatous inflammation?
Surrounds and encapsulates inflamed area. The macrophages continue to phagocytize harmful substances within to cause a pouch full of necrotic remains
