Phases of healing Flashcards
Necrosis
The active degradation of death cells; end of pathologic process
Caused by injuries, infections, diseases, lack of blood flow, + extreme environment conditions
Need to be removed before healing can begin
Induces inflammation=danger signal
Types of necrosis
-Coagulative
-Caseous
-Liquefactive
-Fatty necrosis
-Fibrinoid
Coagulative necrosis
-Cause: Ischemia (lack of blood supply)
-Effect: Cell membrane preserved, nucleus undergoes pyknosis and karolysis (dissolution); organelles dissolve
-Areas: Solid internal organs (heart, liver, kidneys)
Caseous (Cheesy) necrosis
-Cause: TB; seen with other fungal infections
-Effect: Cell memb. destroyed; debris appears cheeselike and doesn’t disappear by lysis, persist indefinitely walled off in a fibrous calcified area forming a granuloma
Areas: Lungs, bronchopulmonary lymph nodes, skeletal bone (extrapulmonary TB)
Liquefactive necrosis
-Cause: Pygenic bacteria (Staphylococcus aureus)
-Effect: Death of neurons; lysosomes liquefy area, leaving pockets of liquid and cellular debris; shapeless amorphous debris remains
-Areas: Brain tissue (infarcts); skin, wound, joint infections
Fatty necrosis
-Cause: Acute pancreatitis, abdominal trauma
-Effect: formation of calcium soaps by the release of pancreatic lipases
-Areas: Abdominal area
Fibrinoid necrosis
-Cause: Trauma in blood vessel wall
-Effect: Plasma proteins accumulate; cellular debris and serum proteins form pink deposits
Areas: Blood vessels (tunica media, smooth muscle cells
Apoptosis
Programmed cell death, genetically mediated in a managed process that causes cells to die (TRIGGER/STIMULUS)
Physiologic
*NOT RELATED WITH INFLAMMATORY RESPONSE
During the remodeling phase, what is the maximal strength healing dermis attains?
80%
What type of tissue heals by regeneration?
epidermis
Proliferative phase of wound healing hallmark
New capillaries are created
Structural network that supports and surrounds cells within connective tissue
Extra cellular matrix
Neutrophil cell is responsible for:
ingesting debris and bacteria
Acute Inflammation
-Sudden and short duration of inflammation
-Exudation of fluid and plasma proteins (edema) and migration of leukocytes (neutrophils)
Chronic Inflammation
-Inflammation that doesn’t resolve but persists over time
-Presence of lymphocytes and macrophages, the proliferation of blood vessels and fibrosis, and tissue destruction
Clinical manifestations of inflammation
-Redness
-Swelling
-Increased temperature
-Pain
-Decreased function of the affected site
What causes the redness and heat during inflammation?
arteriolar vasodilation
What causes the swelling during inflammation?
the exudation and leukocyte infiltration
What causes the loss of function and pain during inflammation?
increased pressure from the edema on the peripheral nerves
In the presence of what does chronic inflammation occur?
extensive necrosis or if regeneration of parenchymal cells is not possible
T/F Inflammatory reaction may become chronic if underlying cause is not addressed.
True; injurious agent persists for a prolonged period
Repeated episodes of acute inflammation in the same tissue over time causes what?
Chronic inflammation
Chronic inflammation develops…
Common morphologic features of granulation tissue, macrophages, lymphocytes, and plasma cells
Acute Inflammation results in either…
Restitution of normal structure and function; if labile or stable cells or little necrosis occurs after injurious agent removed OR
Persistent abnormal structure and (possibly) function; if permanent cells or extensive necrosis is organized in scarring
Cellular Aging
Aging and age-related changes can significantly influence homeostasis and the recovery process
What does age-associated cell deterioration lead to?
leads to tissue or organ weakness aging or disease
What does the cell’s recovery depend on for recovery?
healthy cells
What is the prime target of age-related changes?
Mitochondrial DNA
What is the most well-described age associated change in postmitotic cells?
Presence of lipofuscin; an aging pigment granule found in high concentrations in older cells
Why is lipofuscin suspected to interfere with cellular function?
pressure from pigmented lipid on the cells nucleus
Free radical theory of aging
Excess amounts of free radicals causes DNA damage and cellular oxidative stress
Telomere aging clock theory
Telomeres at the end of chromosomes act as a molecular clock signaling the onset of cell senescence (deterioration)
Accumulation of these cells contributes to the aging process (Does NOT cause it)
Major cell type in the Inflammatory phase of Healing
Platelets
Monocytes
Neutrophils
Macrophages
Mast cells
Major cell type in the Proliferative phase of Healing
Fibroblasts
Myofibroblasts
Endothelial Cells
Keratinocytes
Remodeling
Fibroblasts
Platelets
small, irregular shaped clear cell fragments which circulate in the blood and are involved in hemostasis
Neutrophils
phagocytic cells that clean up debris and bacteria
Monocytes
white blood cell that in response to inflammation will differentiate into macrophages
Endothelial cells
cells that form the endothelium (lining of blood vessels)
Fibroblasts
produce protein fibers (collagen, elastin) and extracellular matric (ECM)
Myofibroblasts
cells that is differentiated from a fibroblast; contains an actin and myosin contractile system similar to what is found in smooth muscle
Keratinocytes
predominant cell found in epidermis
Mast cells
specialized secretory cell that helps to promote fibroblast proliferation
Growth Factors (GFs) and other Regulatory Proteins
Growth Factors
-Naturally occurring proteins (polypeptides)
-Mediate and regulate tissue deposition
-Can act on distant cells, adjacent cells, or themselves
-Can cause cell growth, cell migration, regulatory functions
Inflammatory Phase
-Begins at time of injury + can last 2-5 days
-Clotting takes place in order to obtain hemostasis
-Factors are released to rid wound of debris, bacteria and damaged tissue
-Wound characterized by redness, warmth, pain, edema, decreased ROM
Inflammatory Phase-
Hemostasis (clotting cascade)
-Clotting and vasoconstriction reduces blood loss
Breaks down pre-existing tissue scaffolding
Clean-up of cellular, extracellular, pathogen debris
Inflammatory Phase-Signals to other cells of Damage
Epidermal barrier is disrupted
-Keratinocytes release IL-I (1st signal to other cells of damage)
-Platelets are activated by collagen that is exposed when injury occurs
-triggers vasoconstriction of
injured vessels
Inflammatory Phase- Hemostasis
Hemostasis
-Clot is formed of cytokines, GFs, fibrin molecules, clotting cascade proteins
-Serves as a scaffolding for the migration of leukocytes, keratinocytes, fibroblasts, and endothelial cells
-Reservoir of GFs
Inflammatory Phase- Platelets
Platelets secrete multiple cytokines and GFs
-Attracts neutrophils to the wound
-Monocytes are transformed into macrophages
Inflammatory Phase- Neutrophils
Neutrophils - cell that cleanses the wound
-Migrate into the wound within 24hr of injury
-Phagocytic cells that clean debris and bacteria
-Hypoxic (low oxygen levels) environment
Inflammatory Phase- Macrophages
Macrophage-important throughout all phases of healing
-Activities in the inflamm. phase initiate angiogenesis and granulation tissue formation during proliferation
-Phagocytosis of debris- excrete lactic acid
-Secrete collagenases-debridement in preparation for new collagen
-Secrete GFs
Inflammatory Phase-Mast celss
-promote fibroblast proliferation
-release histamine-vascular dilation (permeability and slight edema)
-produce heparin-stimulates endothelial cells
Inflammatory Phase-Temperature
-Vasodilation of surrounding tissue-increased tissue perfusion aids in moving cells to the injury (up T)
-Injured nerve endings cause reflex hyperemia (up T)
-Increases in cellular metabolism (up T)
In general, if by the 4th day there isn’t a decrease in T-possible sing of infection
Proliferative Phase
Begins around 3rd-5th day and can last up to 21 days
Characterized by:
-Angiogenesis
-Granulation tissue formation
-Collagen deposition
Epithelization
-Wound contraction
Proliferative Phase-New tissue and Contraction
Fill in the defect with new tissue
-Collagen synthesis-fibroplasia
-Angiogenesis
Contraction
-Make the defect smaller
Restore the integrity of the epidermis
Proliferative Phase-Fibroblasts
Macrophages release GFs and cytokines that attract fibroblasts to the wound
Fibroblasts produce collagen and elastin molecules; building blocks of connective tissue
Acts as a scaffolding that will support blood vessel growth by the endothelial cells
Proliferative Phase-Extra Cellular Matrix
ECM
-Intricate structural network that supports and surrounds cells within connective tissue
-Contains elastic fibers (elastin), collagen, and ground substance
Proliferative Phase-Elastin and Collagen
Elastin-forms a network of fibers that stretch and recoil
-Gives ECM of connective tissue its elasticity
-decreases with age (skin tears)
Collagen-predominant fiber in connective tissue
-rope-like macromolecule that aggregates in long fibrils and resists stretching forces
Ground substance-fill the space
Proliferative Phase-Ground substance
-Occupies space between cells and fibers
-Viscous, clear substance with high water content
-Consists of glycosaminoglycans, proteoglycans, and multi-adhesive glycoproteins
Proliferative Phase-Angiogenesis
-Restoration of vascular integrity
-Macrophages induce this process by releasing TNF-beta, VEGF
-New capillary buds arise from intact blood vessels
-Endothelial cells proliferate and grow into the wound space
-Angioblasts are endothelial
precursor cells
Proliferative Phase-New Capillaries
-New capillary bed fills the wound space
-Supplies oxygen and nutrients to heal wound
-Capillary loops have the appearance of granules
-Granulation tissue: Matrix
metalloproteases (MMPs)
-Proteases produced by
neutrophils, macrophages,
fibroblasts, and keratinocytes
-Degrade the debris formed
during inflammation
-Very fragile
-Trauma may induce bleeding; reinitiate inflammatory phase
Proliferative Phase-Contraction
DERMIS
-Myofibroblasts connect to the wound margin to pull the dermal layer inward
-Closes the wound
Proliferative Phase-Re epithelization
EPIDERMIS
-Re establishment of an intact epidermis over the newly formed tissue
-Keratinocytes near the basal lamina migrate across the granulation tissue
-Epithelial migration from intact hair follicles and sebaceous glands
Remodeling Phase
Occurs for 6 months - 3 years post injury
Collagen becomes parallel and creates stronger bonds
Most endothelial cells, macrophages, and myofibroblasts undergo apoptosis
Remodeling Phase- Collagen
Created during proliferation -Type III
Type II is lysed by tissue collagenases and replaced with Type I
Type I is a stronger collagen fibril
Finely tuned balance between collagen synthesis and collagen lysis
Remodeling Phase-Stress
Significant effect on scar remodeling (shape, strength, and Pliability)
Collagen, elastin, and ground substance are affected by the direction and magnitude of mechanical stress applied to the scar (Wolfe’s Law)
Remodeling Phase- Stress cont’d
Connective tissue is laid down in response to lines of stress
Tension causes an increase in collagen fibers
-need stress to increase the population of connective tissue cells to remodel the tissue
-too much stress will cause newly formed scar to pull apart
Remodeling Phase-Scar formation
Vascularity and cellularity diminish
Scar becomes less red and flattens out
Ratio of collagen breakdown to production determines types of scar
-Breakdown>=rate of production=
flat scar
-Breakdown<= rate of production=
hypertrophic scar
Hypertrophic scar
Red, itchy, elevated
Confined to original area of injury
Keloid scar
Type of hypertrophic scar
Extends outside the area of injury
Tumor like appearance
Type I Collagen
Most common
Strong thick bundle found in all body tissues
Predominant structural collagen of the body; constitutes 80%–85% of dermal collagen; prominent in mature scars, tendon, bone, and dentin; joints; labrum (capsular side)
Type II Collagen
Thin supporting filaments
Predominant component of physis (growth plate) and hyaline cartilage (e.g., outer ear, end of nose, joint); not present in skin; found in nucleus pulposus external annulus; labrum (capsular side)
Type III Collagen
Thin filaments that make tissues strong but supple and elastic
Prominent in vascular and visceral structures (e.g., blood vessels, GI tract, liver, uterus) but absent in bone and tendon; constitutes 15%–20% of dermal collagen; abundant in embryonic tissues; first collagen deposited in wound healing (granulation tissue)
More prevalent in newborns
Describe regeneration in terms of the different cells in the body
Main cell = Epithelial cells
Within hours of lethal injury, epithelial cells (viable cells around necrotic tissue) detach from ECM site and separate from other cells
Epithelial cells involvement in regeneration
After separating from other cells, the rest flatten out to cover the area left bare by necrotic cells
Divide and migrate to tissue using ECM support provided by proteins secreted by the fibroblasts
What is the process of replacing dead parenchymal cells by new cells called?
Regeneration
What exactly does regeneration do?
It restores normal tissue structure and function
How is healing of tissue achieved?
By both cell regeneration and replacement by connective tissue (scarring) called repair
In what conditions can regeneration happen?
Only if parenchymal cells can undergo mitosis; ability to divide
Only in labile or stable tissues where inflammatory reaction followed and is short-lived and don’t disrupt the basement membranes
What are some examples of labile cells?
Epithelial cells of the skin and GI system and bone marrow
