Inflammation and Repair Flashcards
Characteristics of acute inflammation
redness, swelling, heat, pain, loss of function
First step of acute inflammation
vasoconstriction followed immediately by vasodilation - increased vascular flow and caliber
Vasodilation following trauma results in
warmth and redness and edema
Vasodilation causes __________ in hydrostatic pressure and
increase; protein poor fluid enters tissue
Vascular permeability
endothelial cells separate (due to shrinkage and high hydrostatic pressure) allowing leakage into ECS
Initially the fluid leaked into the ECS is _________ in protein content, then becomes ______
low/poor, high/rich
High protein fluid in the ECS causes
increased osmotic pressure causing more fluid to accumulate
Pain receptors are triggered by
released chemical mediators
Immediate transient response
Mild tissue injury; within5-10min; lasts 15-30min; mediated by histamine; involves small-medium venules
Immediate sustained response
severe injury; endothelial necrosis; lasts for days; involves venues and capillaries
Delayed prolonged response
delayed by hours-days; response to burns, X-ray damage, UV damage, bacterial toxins, Type IV hypersensitivity
Primary cellular mediator of acute inflammation
segmented neutrophils
neutrophils engulf
bacteria, cellular debris, and immune complexes
neutrophils breakdown engulfed materials by
phagosomes + lysosome (hydrolytic and proteolytic enzymes)
Prolonged inflammation may result from
segmented neutrophil’s releasing lysosomal enzymes and toxic free radicals (toxic)
Margination
attracting segmented neutrophils to the endothelial lining of vessels where they congregate by PAVEMENTING
Adhesion
neutrophils adhere to endothelial cells via adhesion molecules
Emigration - how does a neutrophil traverse the blood vessel
insert pseudopods between endothelial cell tight junctions, squeeze through and exit via developing gaps in the basement membrane
How long after injury do segmented neutrophils first appear in extravascular tissue?
6-24hrs
Monocytes emigrate to the injury site once they have
become activated
How long after injury do monocytes first appear in extravascular tissue?
24-48hrs
Chemotaxis definition
unidirectional movement of cells along a chemical gradient toward an attractant/chemotactic factor
Chemotactic factors include
bacterial products, components of the complement system (C5a), and leukotriene B4
What percentage of the leukocyte receptors must be bound by chemotactic factors in order for activation and migration to occur
20%
The motion (chemotaxis) is facilitated by
pseudopod formation + pulling with actin-myosin filaments
What acts as a mediator in the interaction of contractile elements and cell movement
intracellular Ca2+
Chemokinesis definition
accelerated random locomotion of cells - not related to migration along a specific gradient
How does a neutrophil recognize cell debris or bacteria in the ECS?
opsonization by serum factors
2 key opsonins
IgG (subtypes 1 and 3) and complement factor C3b
In order to phagocytose debris, neutrophil and macrophage receptors bind/are specific for
Fc fragment of IgG or DIRECTLY bind to C3b following its activation
How does a neutrophil engulf bacteria/debris?
sends out cytoplasmic extensions/pseudopods which envelop bacteria and trap it in a vesicle
Phagosome
engulfed debris contained in a vesicle within the cell
Degradation of material within the phagosome occurs by
fusion of a lysosome and phagosome and degranulation releasing lysosomal digestive enzymes and free radicals
Phagolysosome
lysosome + phagosome fusion
Leakage of free radicals or phagolysosomal digestive enzymes contribute to
further injury (cellular or regional)
2 Oxygen dependent bactericidal mechanisms
break down of material within a lysosome that requires OXYGEN: Hydrogen peroxide-Myeloperoxidase Halide System, Myeloperoxidase Independent System
Hydrogen peroxide-Myeloperoxidase Halide System in PMN granules
(requires O2) uses the enzyme myeloperoxidase to destroy bacteria
Myeloperoxidase catalyzes
H2O2 + halide (Cl-) = HOCl- which acts as an antimicrobial and oxidant
Myeloperoxidase Independent System
use free radicals formed by alternative enzymes to kill bacteria
Myeloperoxidase Independent System is predominantly used by
macrophages and myeloperoxidase deficient segmented neutrophils
Oxygen Independent Bactericidal Mechanisms include:
Bactericidal permeability increasing protein (BPI), Lysozyme, Lactoferrin, Major Basic Protein
Major Basic Protein is produced by
Eosinophils and toxic to parasites
What may efflux from a neutrophil and cause further tissue damage?
lysosomal enzymes, oxygen-derived metabolites, and products of arachidonic acid metabolism
Release of effluxed material from neutrophils may be due to:
regurgitation during phagocytosis, reverse endocytosis, cytotoxic release, heterolysis
Defective leukocytes result in
impaired acute inflammatory response
Causes of defective leukocytes include
decreased numbers of circulating leukocytes, defects in adherence mechanisms, defects in migration/chemotaxis
Leukocyte defects in migration/chemotaxis may be due to:
intrinsic leukocyte abnormalities, defective production of chemotactic factors, inhibition of chemotactic factors, suppressed leukocyte locomotion, defective phagocytosis, defective microbiocidal activity, mixed defects in leukocyte function
Leukocyte defects in microbiocidal activity include
decreased hydrogen peroxide production, myeloperoxidase deficiency, G-6-PD deficiency
Vasoactive amines role
released in response to injury and cause immediate vasodilation and increased blood vessel permeability in acute inflammation, they also mediate IgE immune response
Vasoactive amines include:
histamine and serotonin (5-hydroxytryptamine)
Vasoactive amines are produced by
mast cells, basophils, and platelets
Vasoactive amine stimuli:
physical factors (heat, trauma), immune reactions (IgE factors), C3a, C5a (compliment anaphylotoxins), histamine releasing factors (neutrophils, monocytes, platelets), IL-1
complement system’s role
increase vascular permeability, mediate chemotaxis, facilitate opsonization and lysis of microbial organisms
2 complement cascades
Classic (fast) and alternative (slow)
Complement components of acute inflammation
C3a, C5a, C3b, iC3b, C5b-9
C3a and C5a role
increase vascular permeability, anaphylotoxins (stimulate mast cells and platelets to release histamine), chemotactic to neutrophils, basophils, eosinophils, and monocytes, mediate leukocyte adhesion to bv’s, activate lipoxygenase/arachidonic acid pathways in PMNs and macrophages
C3a and C5a effects on mast cells and platelets
stimulate the release histamine (anaphylotoxins)
C3a and C5a act as chemotactic factors to
neutrophils, basophils, eosinophils, and monocytes
C3a and C5a activate which pathways in neutrophils and macrophages
lipoxygenase/arachidonic acid pathways
Which compounds of the complement system mediate leukocyte adhesion to blood vessel endothelium?
C3a and C5a
C3b and iC3b role
act as opsonins for neutrophils, macrophages, and eosinophils
C5b-9 role
Membrane Attack Complex: direct lytic action on bacteria, injures parenchymal cells stimulating arachidonic acid metabolism and producing ROS metabolites
What initiates the classical complement pathway?
an immune complex binds C1 and activates it
What initiates the alternative complement pathway?
microbial surface polysaccharides interact with C3
the kinin system produces
bradykinin
bradykinin’s role
increases vascular permeability, causes smooth muscle contraction in the INITIAL vasoconstriction, subsequent vasodilation and pain
Is bradykinin a chemotactic factor?
NO
Are C3a and C5a chemotactic factors?
YES
The coagulation cascade’s main role in acute inflammation is to
activate the Hageman Factor
Downstream to the Hageman factor, fibrinogen is converted to fibrin, releasing
fibrinopeptides
Fibrinopeptides role
increase blood vessel permeability and act as chemotactic factors for leukocytes
Downstream to the Hageman factor, plasminogen is converted to _______ by ____________
PLASMIN by plasminogen activator or Kallikrein and
Kallikrein
converts plasminogen to plasmin
Plasmin’s role
Fibrinolysis (fibrin to fibrinopeptides), activation of Hageman factor (subsequently produces bradykinin), cleaves C3 to C3a
Arachidonic acid is derived from
dietary sources or produced by the metabolism of linoleic acid into arachidonic acid
Phospholipase A2 converts
linoleic acid to arachidonic acid
Steroids effect
steroids inhibit phospholipase and therefore prevent arachidonic acid synthesis
Arachidonic acid metabolites are formed by
esterification of phospholipids via the 5-lipoxygenase or cyclooxygenase pathways
Arachidonic acid metabolites produced by the COX pathway
Thromboxane (TXA2), Prostacyclin (PGI2), Prostaglandins (PGD2, PGE2, and PGF2)
Thromboxane (TXA2) role
promote platelet aggregation and cause vasoconstriction
Prostacyclin (PGI2) role
inhibit platelet aggregation and cause vasodilation
Prostaglandins (PGD2, PGE2, and PGF2) role
cause vasodilation and potentiate edema
Aspirin and Indomethacin have what effect on arachidonic metabolism
they are COX1 and COX2 inhibitors and they inhibit PROSTAGLANDIN production (preventing TXA, PGI, and Prostaglandins)
Lipoxygenase pathway
converts arachidonic acid into leukotrienes with the enzyme: lipoxygenase
Leukotriene B4 role
Chemotactic, stimulates aggregation of leukocytes
Leukotrienes C4, D4, and E4 role
Vasoconstriction, bronchospasms, increased vascular permeability
Segmented neutrophils contain _________ and ___________ granules
primary and secondary
Degranulation follows
phagocytosis and involves fusion of lysosome and phagosome
Neutrophil granule contents cause
bacterial lysis and breakdown of debris when released into phagolysosomes
Primary granules of neutrophils contain:
Myeloperoxidase, lysozyme, bactericidal factors, cationic proteins, acid hydrolyses, elastases
Secondary granules of neutrophils contain:
lactoferrin, lysozyme, alkaline-phosphatase, leukocyte adhesion molecules and collagenase
If lysosome granules leak into the ECS
further increase in vascular permeability, increased chemotaxis, and additional tissue damage
ROS may cause
damage to endothelial cells, inactivate anti-proteases, injure tumor cells, RBCs, and parenchymal cells
ROS may be inactivated by
anti-oxidants
Platelet activating factor (PAF) is released by
IgE sensitive basophils
Platelet activating factor (PAF) role
cause release of histamine and serotonin, vasoconstriction, bronchoconstriction (vasodilation/increased perm. at low concentrations), increased adhesion, leukocyte chemotaxis, degranulation, stimulation of oxidative burst
Acute inflammation chemical mediators of pain
Prostaglandins and Bradykinin
IL-1 is produced by what cell type
ALL cells
IL-1 is produced in response to
endotoxins, trauma, immune reaction, and inflammation
Tumor Necrosis Factor is released by what cell type
Stimulated macrophages
Tumor Necrosis Factor role
induction and synthesis of adhesion molecules (PGI2 and PAF) and stimulation of coagulation cascade
Cytokines involved in acute inflammation
TNF, IL-1, IL-6, Chemokines
IL-1 and TNF have what acute phase reaction effects
fever, fatigue, decreased appetite, increased acute phase proteins, shock, neutrophilia
IL-1 and TNF have what effects on endothelial cells
increased: leukocyte adhesion, PGI production, coagulation cascade, production of IL-1, IL-8, IL-6, PGDF
IL-1 and TNF have what effects on fibroblasts
increased: proliferation, collagen synthesis, collagenase, protease, PGE synthesis
Growth Factors that play a role in acute inflammation include:
EGF, TGF-alpha, Hepatocyte GF, platelet derived GF, vascular endothelial GF, FGF, TGF-beta
TGF-beta’s role
growth inhibition of epithelial cells, fibrinogenic agent, anti-inflammatory, enhance immune function
Vasodilators of acute inflammation:
prostaglandins, NO, and histamine
Mediators of increased permeability in acute inflammation:
Histamine, serotonin, C3a and C5a, Leukotrienes C4, D4, and E4, PAF, Substance P (neuropeptide)
Mediators of Chemotaxis, Leukocyte recruitment and activation in acute inflammation include:
TNF, IL-1, chemokines, C3a and C5a, Leukotriene B4, bacterial products
Mediators of fever in acute inflammation:
IL-1, TNF, prostaglandins
Mediators of pain in acute inflammation:
prostaglandins and bradykinin
Mediators of tissue damage in acute inflammation:
lysosomal enzymes of leukocytes, ROS, NO
Lymphangitis
inflammation of the lymphatic vessel when bacteria gain access
Lymphadenitis
inflammation of lymph nodes if bacteria gains access
Bacteremia/Sepsis
bacterial infection gains access to blood
Mononuclear phagocyte system includes which cells
monocytes and macrophages
Monocytes
defense mechanism against bacteria in the blood
Macrophages
defense mechanism against bacteria in the tissues
Monocytes and macrophages produce what chemical mediators of acute inflammation
neutrophil proteases, chemotactic factors, arachidonic acid metabolites, ROS, complement, coagulation factors, growth factors, cytokines, PAF, and interferon
Chronic inflammation occurs as
sequela to acute inflammation, repeated episodes of acute inflammation, low grade inflammation from a long standing injury (persistent intracellular infection or toxins, autoimmune reactions)
Major cellular components of chronic inflammation
macrophages, lymphocytes, plasma cells, eosinophils, fibroblasts
Tissue changes involved in chronic inflammation
tissue destruction, vascular proliferation, fibrosis
In chronic inflammation, monocytes play what role
they arrive at the injury site by chemotaxis, become activated into macrophages, divide and remain localized at site
In chronic inflammation, progressive tissue damage occurs via
continued cell stimulation and release of chemical inflammatory mediators
Plasma cells contribute to chronic inflammation by releasing
antibodies (derived from B cells)
Lymphocytes contribute to chronic inflammation by releasing
lymphokines, which serve as chemotactic factors for more monocytes/macrophages
Eosinophils contribute to chronic inflammation by releasing
Major basic protein (parasitic infections) and mediate IgE immune reactions
Neutrophils contribute to chronic inflammation by
persisting in low numbers at injury site
Granuloma
specialized form of chronic inflammation characterized by an area containing lymphocytes, plasma cell, macrophages, and multinucleate giant cells
Cell types involved in granuloma formation
lymphocytes, plasma cell, macrophages, and multinucleate giant cells
Caseating Granuloma
central area of caseating necrosis with a peripheral rim of lymphocytes, macrophages, and Langahns giant cells
Disease processes generally associated with caseating granulomas
Tuberculosis, fungal infections
Cell types involved in caseating granuloma formation
lymphocytes, macrophages, and Langahns giant cells
Non-caseating Granuloma
Granuloma lacking the caseating necrotic center
Disease processes generally associated with non-caseating granulomas
Sarcoidosis, Fungi, Brucellosis, Leprosy, foreign body reaction, cat scratch disease, syphilis, and parasites
Serous inflammation produces
thin, cloudy, watery fluid produced
Serous inflammation is generally found
in body cavities (pleural spaces, peritoneum)
Fibrinous Inflammation produces
response composed of fibrin and plasma proteins
Fibrinous Inflammation is generally found
in body spaces and potential spaces (pericardial, pleural, peritoneal)
Suppurative/Purulent Inflammation is generally found
surfaces of epithelial or mesothelial structures and underlying tissue
Suppurative/Purulent Inflammation predominant cell type
segmented neutrophils (acute process)
Suppurative/Purulent Inflammation produces
pus (pyogenic), acute inflammatory exudate
Abscess
cavity containing pus surrounded by tissue
Ulceration
sloughing or shedding of the epithelial cells and underlying tissue that are infiltrated by inflammatory cells
Acute ulcers contain primarily what cell type
segmented neutrophils
Chronic ulcers contain primarily what cell type
macrophages, lymphocytes, plasma cells, fibroblasts
During inflammation, fever is generated by
IL-1 and TNF effects on thermoregulatory center of the brain
During inflammation, rigors is characterized by
shaking chills during fever, especially associated with bacteremia, viremia, parasitemia
Acute phase reactions include:
fever, rigors, appetite suppression, sleep changes, protein degradation, hypotension, hematologic effects, and release of acute phase proteins
IL-1 and TNF cause what hematological change
Left shift: an increase in the percentage of immature segmented neutrophils “Neutrophilic Leukocytosis” due to a stimulation of neutrophil release from bone marrow
Leukocytosis
WBC count over 10,000
Acute Phase proteins include
C reactive protein, Serum amyloid A, Complement factors, Coagulation factors
C reactive protein role
bind to phosphocholine expressed on the surface of dead or dying cells (and some types of bacteria) in order to activate the complement system
Serum amyloid A role
recruitment of immune cells to inflammatory sites, and the induction of enzymes that degrade extracellular matrix
Irreversibly damaged cells must be replaced by
new cells and supporting tissue matrix
Labile Cells
capable of mitotic division throughout life
Labile cells include:
epithelial, splenic, lymphoid, and hematopoietic cells
In order for epithelial cells to replicate there must be
an intact basement membrane
Stabile Cells
Normally only replicate under specific stimuli
Stabile cells include:
parenchymal, mesenchymal, and vascular endothelial cells
In order for stabile cells to replicate there must be
intact basement membrane
Permanent cells
limited (if any) ability to replicate
damaged permanent cells
are replaced by scar tissue
Permanent cells include:
neurons, skeletal muscle, and myocardium
Granulation tissue
formed by the regenerative process through which injured or necrotic tissue is gradually replaced and repaired (angiogenesis, macrophage localization, edema, collagen deposition)
Angiogenesis following irreversible tissue damage steps:
enzyme degradation of endothelial cell basement membrane of parent vessel, migration of endothelial cells to inflamed tissue, endothelial proliferation, endothelial maturation
Edema occurs in granulation tissue due to
high permeability of parent vessel and new developing vessels
Fibroblasts play what role in granulation formation
collagen formation to provide structure to repaired tissues
Collagen’s role
increase strength and stability of the tissue undergoing repair
Granulation tissue has a high number of __________ and a low number of ___________
high number of macrophages; low number of segmented neutrophils, eosinophils, and lymphocytes
Primary Union
clean with straight margins which can easily be approximated (larger wounds require sutures)
The first 24 hours a primary union wound is infiltrated with
neutrophils
Within 24-48 hours a primary union wound is infiltrated with
epithelial cells from adjacent tissue (re-epithelialization) and macrophages
By 72 hours, segmented neutrophils have been replaced by
macrophages
By 72 hours, primary union wounds are
almost entirely composed of granulation tissue with marked neovascularization
By 2 weeks, primary union wounds are
completely replaced by collagen
Secondary Union
large gaping wounds in which the margins cannot be approximated, requiring significant re-epithelialization and stromal repair
Secondary Union wounds include
trauma, burns, infarctions, ulcerations, and large surface wounds (lacerations)
Granulation tissue in a secondary wound appears as
pink, moist granular surface within the wound
Cicatrization
scar formation by collagen in secondary union wounds
Fibrosis
collagen deposition (scaring) involving non-epithelial/parenchymal tissue
Fibrous Adhesions
collagen deposition (scaring) involving mesothelial surfaces of viscera
Collagen is constantly remodeled, it may take ______ for final remodeling process
9-12 mo
Hypertrophic Scars
excessive production and deposition of collagen in a developing scar, resulting in a keloid
Keloid
large nodular mass within a developing scar
Competence Factors
prepare cells for mitotic division
Progression Factors
stimulate cell division
EGF is a
progression factor
Platelet derived GF (PDGF) is a
competence factor
PDGF is released with activation of
platelets, macrophages, endothelial cells, smooth muscle cells, and tumor cells
PDGF’s role in healing
stimulate migration and proliferation of fibroblasts and smooth muscle
FGF’s role in healing
stimulate angiogenesis
TGF-alpha’s role in healing
bind EGF receptors stimulating EGF release
TGF-beta’s role in healing
inhibits growth of parenchymal cells; inhibits macrophages; chemotactic for fibroblasts and mediates collagen production
IL-1’s role in healing
chemotactic for fibroblasts; increases collagen and collagenase synthesis
TNF’s role in healing
chemotactic for fibroblasts; increases collagen and collagenase synthesis
Contact inhibition
cells grow until coming into contact with each other
Surface receptors
recognize extracellular matrix proteins
Collagenization
the FINAL mechanism of healing
Tropocollagen
main unit of all types of collagen, 3 attached alpha chains cross-linked for tensile strength
Skin contains predominantly Type ___ collagen
Type I
Granulation tissue initially contains predominantly Type ___ collagen
Type III
Following remodeling, granulation tissue contains predominantly Type ___ collagen
Type I
Non-collagen components of the ECM
elastin, laminin, proteoglycans, fibronectin
Primary union wounds have ____% of their original strength if sutures are used
70-80
Primary union wounds have ____% of their original strength when sutures are removed
10
How long would it take to regain 70-80% of strength in a primary union wound
3 months
How long would it take to regain 100% of strength in a primary union wound
6-12 months
Wound Dehiscence
Delayed wound healing: opening of a partially healed wound (large wounds with sutures prematurely removed, infection, or tensile pressure)
For PMN adhesion, neutrophil _________ receptors bind to endothelial ______ receptors
Sialyl-Lewis X (PMN); Selectins (endothelial)
For PMN transmigration, neutrophil _________ receptors bind to endothelial ______ receptors
Integrins (PMN); CAM (Endothelial)
What cells may be present at both acute and chronic inflammatory sites?
macrophages
Cell type indicative of early acute inflammation
segmented neutrophil
Chemical Mediator involved in DIRECT bacterial lysis
C5b-9
Segmented neutrophils leave blood vessels by
emigration through tight junctions
Healing by primary union involves
approximation of wound margins (with or without sutures)
Local Causes of delayed wound healing
Infection, inadequate blood supply, forge in body, type of tissue
Systemic causes of delayed wound healing
Old age, poor nutrition, bleeding disorder, diabetes, Hypertension, Atherosclerosis, Collagen-Vascular Disease, NSAID or steroid use
Eosinophils are increased under what conditions
Parasitic infections, allergic reactions, hypersensitivity reactions, and some chronic inflammation
Erythema and warmth is indicative of
increased vascular flow (vasodilation)
Example: Red streaks in the skin from the site of infection on the arm extending to the axilla
lymphangitis
Swelling in acute inflammation is due to
increased vascular permeability, increased hydrostatic pressure, followed by increased TISSUE oncotic pressure
Acute wound with thick yellow pus
acute inflammatory exudate
Acute wound with thick yellow pus, but surround by tissue and enclosed within a cavity
abscess
Main function of the neutrophil in a pyogenic acute infection
to kill G(+) and G(-) bacteria via phagocytosis
Anaphylatoxin Chemical Mediators
C3a and C5a
Opsins for phagocytosis
IgG (Fc fragment), C3b
You get slapped in the face and your face turns red, feels warm, and throbs, but this goes away in 30 min, this is an example of
Immediate transient response
