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Flashcards in Inflammation and Repair Deck (230):
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Characteristics of acute inflammation

redness, swelling, heat, pain, loss of function

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First step of acute inflammation

vasoconstriction followed immediately by vasodilation - increased vascular flow and caliber

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Vasodilation following trauma results in

warmth and redness and edema

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Vasodilation causes __________ in hydrostatic pressure and

increase; protein poor fluid enters tissue

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Vascular permeability

endothelial cells separate (due to shrinkage and high hydrostatic pressure) allowing leakage into ECS

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Initially the fluid leaked into the ECS is _________ in protein content, then becomes ______

low/poor, high/rich

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High protein fluid in the ECS causes

increased osmotic pressure causing more fluid to accumulate

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Pain receptors are triggered by

released chemical mediators

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Immediate transient response

Mild tissue injury; within5-10min; lasts 15-30min; mediated by histamine; involves small-medium venules

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Immediate sustained response

severe injury; endothelial necrosis; lasts for days; involves venues and capillaries

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Delayed prolonged response

delayed by hours-days; response to burns, X-ray damage, UV damage, bacterial toxins, Type IV hypersensitivity

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Primary cellular mediator of acute inflammation

segmented neutrophils

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neutrophils engulf

bacteria, cellular debris, and immune complexes

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neutrophils breakdown engulfed materials by

phagosomes + lysosome (hydrolytic and proteolytic enzymes)

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Prolonged inflammation may result from

segmented neutrophil's releasing lysosomal enzymes and toxic free radicals (toxic)

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Margination

attracting segmented neutrophils to the endothelial lining of vessels where they congregate by PAVEMENTING

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Adhesion

neutrophils adhere to endothelial cells via adhesion molecules

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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

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How long after injury do segmented neutrophils first appear in extravascular tissue?

6-24hrs

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Monocytes emigrate to the injury site once they have

become activated

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How long after injury do monocytes first appear in extravascular tissue?

24-48hrs

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Chemotaxis definition

unidirectional movement of cells along a chemical gradient toward an attractant/chemotactic factor

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Chemotactic factors include

bacterial products, components of the complement system (C5a), and leukotriene B4

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What percentage of the leukocyte receptors must be bound by chemotactic factors in order for activation and migration to occur

20%

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The motion (chemotaxis) is facilitated by

pseudopod formation + pulling with actin-myosin filaments

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What acts as a mediator in the interaction of contractile elements and cell movement

intracellular Ca2+

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Chemokinesis definition

accelerated random locomotion of cells - not related to migration along a specific gradient

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How does a neutrophil recognize cell debris or bacteria in the ECS?

opsonization by serum factors

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2 key opsonins

IgG (subtypes 1 and 3) and complement factor C3b

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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

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How does a neutrophil engulf bacteria/debris?

sends out cytoplasmic extensions/pseudopods which envelop bacteria and trap it in a vesicle

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Phagosome

engulfed debris contained in a vesicle within the cell

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Degradation of material within the phagosome occurs by

fusion of a lysosome and phagosome and degranulation releasing lysosomal digestive enzymes and free radicals

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Phagolysosome

lysosome + phagosome fusion

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Leakage of free radicals or phagolysosomal digestive enzymes contribute to

further injury (cellular or regional)

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2 Oxygen dependent bactericidal mechanisms

break down of material within a lysosome that requires OXYGEN: Hydrogen peroxide-Myeloperoxidase Halide System, Myeloperoxidase Independent System

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Hydrogen peroxide-Myeloperoxidase Halide System in PMN granules

(requires O2) uses the enzyme myeloperoxidase to destroy bacteria

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Myeloperoxidase catalyzes

H2O2 + halide (Cl-) = HOCl- which acts as an antimicrobial and oxidant

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Myeloperoxidase Independent System

use free radicals formed by alternative enzymes to kill bacteria

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Myeloperoxidase Independent System is predominantly used by

macrophages and myeloperoxidase deficient segmented neutrophils

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Oxygen Independent Bactericidal Mechanisms include:

Bactericidal permeability increasing protein (BPI), Lysozyme, Lactoferrin, Major Basic Protein

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Major Basic Protein is produced by

Eosinophils and toxic to parasites

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What may efflux from a neutrophil and cause further tissue damage?

lysosomal enzymes, oxygen-derived metabolites, and products of arachidonic acid metabolism

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Release of effluxed material from neutrophils may be due to:

regurgitation during phagocytosis, reverse endocytosis, cytotoxic release, heterolysis

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Defective leukocytes result in

impaired acute inflammatory response

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Causes of defective leukocytes include

decreased numbers of circulating leukocytes, defects in adherence mechanisms, defects in migration/chemotaxis

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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

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Leukocyte defects in microbiocidal activity include

decreased hydrogen peroxide production, myeloperoxidase deficiency, G-6-PD deficiency

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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

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Vasoactive amines include:

histamine and serotonin (5-hydroxytryptamine)

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Vasoactive amines are produced by

mast cells, basophils, and platelets

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Vasoactive amine stimuli:

physical factors (heat, trauma), immune reactions (IgE factors), C3a, C5a (compliment anaphylotoxins), histamine releasing factors (neutrophils, monocytes, platelets), IL-1

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complement system's role

increase vascular permeability, mediate chemotaxis, facilitate opsonization and lysis of microbial organisms

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2 complement cascades

Classic (fast) and alternative (slow)

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Complement components of acute inflammation

C3a, C5a, C3b, iC3b, C5b-9

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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

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C3a and C5a effects on mast cells and platelets

stimulate the release histamine (anaphylotoxins)

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C3a and C5a act as chemotactic factors to

neutrophils, basophils, eosinophils, and monocytes

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C3a and C5a activate which pathways in neutrophils and macrophages

lipoxygenase/arachidonic acid pathways

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Which compounds of the complement system mediate leukocyte adhesion to blood vessel endothelium?

C3a and C5a

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C3b and iC3b role

act as opsonins for neutrophils, macrophages, and eosinophils

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C5b-9 role

Membrane Attack Complex: direct lytic action on bacteria, injures parenchymal cells stimulating arachidonic acid metabolism and producing ROS metabolites

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What initiates the classical complement pathway?

an immune complex binds C1 and activates it

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What initiates the alternative complement pathway?

microbial surface polysaccharides interact with C3

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the kinin system produces

bradykinin

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bradykinin's role

increases vascular permeability, causes smooth muscle contraction in the INITIAL vasoconstriction, subsequent vasodilation and pain

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Is bradykinin a chemotactic factor?

NO

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Are C3a and C5a chemotactic factors?

YES

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The coagulation cascade's main role in acute inflammation is to

activate the Hageman Factor

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Downstream to the Hageman factor, fibrinogen is converted to fibrin, releasing

fibrinopeptides

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Fibrinopeptides role

increase blood vessel permeability and act as chemotactic factors for leukocytes

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Downstream to the Hageman factor, plasminogen is converted to _______ by ____________

PLASMIN by plasminogen activator or Kallikrein and

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Kallikrein

converts plasminogen to plasmin

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Plasmin's role

Fibrinolysis (fibrin to fibrinopeptides), activation of Hageman factor (subsequently produces bradykinin), cleaves C3 to C3a

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Arachidonic acid is derived from

dietary sources or produced by the metabolism of linoleic acid into arachidonic acid

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Phospholipase A2 converts

linoleic acid to arachidonic acid

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Steroids effect

steroids inhibit phospholipase and therefore prevent arachidonic acid synthesis

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Arachidonic acid metabolites are formed by

esterification of phospholipids via the 5-lipoxygenase or cyclooxygenase pathways

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Arachidonic acid metabolites produced by the COX pathway

Thromboxane (TXA2), Prostacyclin (PGI2), Prostaglandins (PGD2, PGE2, and PGF2)

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Thromboxane (TXA2) role

promote platelet aggregation and cause vasoconstriction

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Prostacyclin (PGI2) role

inhibit platelet aggregation and cause vasodilation

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Prostaglandins (PGD2, PGE2, and PGF2) role

cause vasodilation and potentiate edema

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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)

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Lipoxygenase pathway

converts arachidonic acid into leukotrienes with the enzyme: lipoxygenase

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Leukotriene B4 role

Chemotactic, stimulates aggregation of leukocytes

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Leukotrienes C4, D4, and E4 role

Vasoconstriction, bronchospasms, increased vascular permeability

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Segmented neutrophils contain _________ and ___________ granules

primary and secondary

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Degranulation follows

phagocytosis and involves fusion of lysosome and phagosome

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Neutrophil granule contents cause

bacterial lysis and breakdown of debris when released into phagolysosomes

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Primary granules of neutrophils contain:

Myeloperoxidase, lysozyme, bactericidal factors, cationic proteins, acid hydrolyses, elastases

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Secondary granules of neutrophils contain:

lactoferrin, lysozyme, alkaline-phosphatase, leukocyte adhesion molecules and collagenase

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If lysosome granules leak into the ECS

further increase in vascular permeability, increased chemotaxis, and additional tissue damage

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ROS may cause

damage to endothelial cells, inactivate anti-proteases, injure tumor cells, RBCs, and parenchymal cells

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ROS may be inactivated by

anti-oxidants

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Platelet activating factor (PAF) is released by

IgE sensitive basophils

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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

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Acute inflammation chemical mediators of pain

Prostaglandins and Bradykinin

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IL-1 is produced by what cell type

ALL cells

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IL-1 is produced in response to

endotoxins, trauma, immune reaction, and inflammation

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Tumor Necrosis Factor is released by what cell type

Stimulated macrophages

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Tumor Necrosis Factor role

induction and synthesis of adhesion molecules (PGI2 and PAF) and stimulation of coagulation cascade

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Cytokines involved in acute inflammation

TNF, IL-1, IL-6, Chemokines

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IL-1 and TNF have what acute phase reaction effects

fever, fatigue, decreased appetite, increased acute phase proteins, shock, neutrophilia

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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

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IL-1 and TNF have what effects on fibroblasts

increased: proliferation, collagen synthesis, collagenase, protease, PGE synthesis

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Growth Factors that play a role in acute inflammation include:

EGF, TGF-alpha, Hepatocyte GF, platelet derived GF, vascular endothelial GF, FGF, TGF-beta

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TGF-beta's role

growth inhibition of epithelial cells, fibrinogenic agent, anti-inflammatory, enhance immune function

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Vasodilators of acute inflammation:

prostaglandins, NO, and histamine

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Mediators of increased permeability in acute inflammation:

Histamine, serotonin, C3a and C5a, Leukotrienes C4, D4, and E4, PAF, Substance P (neuropeptide)

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Mediators of Chemotaxis, Leukocyte recruitment and activation in acute inflammation include:

TNF, IL-1, chemokines, C3a and C5a, Leukotriene B4, bacterial products

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Mediators of fever in acute inflammation:

IL-1, TNF, prostaglandins

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Mediators of pain in acute inflammation:

prostaglandins and bradykinin

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Mediators of tissue damage in acute inflammation:

lysosomal enzymes of leukocytes, ROS, NO

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Lymphangitis

inflammation of the lymphatic vessel when bacteria gain access

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Lymphadenitis

inflammation of lymph nodes if bacteria gains access

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Bacteremia/Sepsis

bacterial infection gains access to blood

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Mononuclear phagocyte system includes which cells

monocytes and macrophages

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Monocytes

defense mechanism against bacteria in the blood

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Macrophages

defense mechanism against bacteria in the tissues

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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

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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)

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Major cellular components of chronic inflammation

macrophages, lymphocytes, plasma cells, eosinophils, fibroblasts

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Tissue changes involved in chronic inflammation

tissue destruction, vascular proliferation, fibrosis

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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

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In chronic inflammation, progressive tissue damage occurs via

continued cell stimulation and release of chemical inflammatory mediators

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Plasma cells contribute to chronic inflammation by releasing

antibodies (derived from B cells)

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Lymphocytes contribute to chronic inflammation by releasing

lymphokines, which serve as chemotactic factors for more monocytes/macrophages

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Eosinophils contribute to chronic inflammation by releasing

Major basic protein (parasitic infections) and mediate IgE immune reactions

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Neutrophils contribute to chronic inflammation by

persisting in low numbers at injury site

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Granuloma

specialized form of chronic inflammation characterized by an area containing lymphocytes, plasma cell, macrophages, and multinucleate giant cells

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Cell types involved in granuloma formation

lymphocytes, plasma cell, macrophages, and multinucleate giant cells

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Caseating Granuloma

central area of caseating necrosis with a peripheral rim of lymphocytes, macrophages, and Langahns giant cells

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Disease processes generally associated with caseating granulomas

Tuberculosis, fungal infections

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Cell types involved in caseating granuloma formation

lymphocytes, macrophages, and Langahns giant cells

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Non-caseating Granuloma

Granuloma lacking the caseating necrotic center

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Disease processes generally associated with non-caseating granulomas

Sarcoidosis, Fungi, Brucellosis, Leprosy, foreign body reaction, cat scratch disease, syphilis, and parasites

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Serous inflammation produces

thin, cloudy, watery fluid produced

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Serous inflammation is generally found

in body cavities (pleural spaces, peritoneum)

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Fibrinous Inflammation produces

response composed of fibrin and plasma proteins

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Fibrinous Inflammation is generally found

in body spaces and potential spaces (pericardial, pleural, peritoneal)

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Suppurative/Purulent Inflammation is generally found

surfaces of epithelial or mesothelial structures and underlying tissue

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Suppurative/Purulent Inflammation predominant cell type

segmented neutrophils (acute process)

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Suppurative/Purulent Inflammation produces

pus (pyogenic), acute inflammatory exudate

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Abscess

cavity containing pus surrounded by tissue

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Ulceration

sloughing or shedding of the epithelial cells and underlying tissue that are infiltrated by inflammatory cells

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Acute ulcers contain primarily what cell type

segmented neutrophils

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Chronic ulcers contain primarily what cell type

macrophages, lymphocytes, plasma cells, fibroblasts

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During inflammation, fever is generated by

IL-1 and TNF effects on thermoregulatory center of the brain

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During inflammation, rigors is characterized by

shaking chills during fever, especially associated with bacteremia, viremia, parasitemia

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Acute phase reactions include:

fever, rigors, appetite suppression, sleep changes, protein degradation, hypotension, hematologic effects, and release of acute phase proteins

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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

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Leukocytosis

WBC count over 10,000

154

Acute Phase proteins include

C reactive protein, Serum amyloid A, Complement factors, Coagulation factors

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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

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Serum amyloid A role

recruitment of immune cells to inflammatory sites, and the induction of enzymes that degrade extracellular matrix

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Irreversibly damaged cells must be replaced by

new cells and supporting tissue matrix

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Labile Cells

capable of mitotic division throughout life

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Labile cells include:

epithelial, splenic, lymphoid, and hematopoietic cells

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In order for epithelial cells to replicate there must be

an intact basement membrane

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Stabile Cells

Normally only replicate under specific stimuli

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Stabile cells include:

parenchymal, mesenchymal, and vascular endothelial cells

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In order for stabile cells to replicate there must be

intact basement membrane

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Permanent cells

limited (if any) ability to replicate

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damaged permanent cells

are replaced by scar tissue

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Permanent cells include:

neurons, skeletal muscle, and myocardium

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Granulation tissue

formed by the regenerative process through which injured or necrotic tissue is gradually replaced and repaired (angiogenesis, macrophage localization, edema, collagen deposition)

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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

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Edema occurs in granulation tissue due to

high permeability of parent vessel and new developing vessels

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Fibroblasts play what role in granulation formation

collagen formation to provide structure to repaired tissues

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Collagen's role

increase strength and stability of the tissue undergoing repair

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Granulation tissue has a high number of __________ and a low number of ___________

high number of macrophages; low number of segmented neutrophils, eosinophils, and lymphocytes

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Primary Union

clean with straight margins which can easily be approximated (larger wounds require sutures)

174

The first 24 hours a primary union wound is infiltrated with

neutrophils

175

Within 24-48 hours a primary union wound is infiltrated with

epithelial cells from adjacent tissue (re-epithelialization) and macrophages

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By 72 hours, segmented neutrophils have been replaced by

macrophages

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By 72 hours, primary union wounds are

almost entirely composed of granulation tissue with marked neovascularization

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By 2 weeks, primary union wounds are

completely replaced by collagen

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Secondary Union

large gaping wounds in which the margins cannot be approximated, requiring significant re-epithelialization and stromal repair

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Secondary Union wounds include

trauma, burns, infarctions, ulcerations, and large surface wounds (lacerations)

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Granulation tissue in a secondary wound appears as

pink, moist granular surface within the wound

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Cicatrization

scar formation by collagen in secondary union wounds

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Fibrosis

collagen deposition (scaring) involving non-epithelial/parenchymal tissue

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Fibrous Adhesions

collagen deposition (scaring) involving mesothelial surfaces of viscera

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Collagen is constantly remodeled, it may take ______ for final remodeling process

9-12 mo

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Hypertrophic Scars

excessive production and deposition of collagen in a developing scar, resulting in a keloid

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Keloid

large nodular mass within a developing scar

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Competence Factors

prepare cells for mitotic division

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Progression Factors

stimulate cell division

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EGF is a

progression factor

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Platelet derived GF (PDGF) is a

competence factor

192

PDGF is released with activation of

platelets, macrophages, endothelial cells, smooth muscle cells, and tumor cells

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PDGF's role in healing

stimulate migration and proliferation of fibroblasts and smooth muscle

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FGF's role in healing

stimulate angiogenesis

195

TGF-alpha's role in healing

bind EGF receptors stimulating EGF release

196

TGF-beta's role in healing

inhibits growth of parenchymal cells; inhibits macrophages; chemotactic for fibroblasts and mediates collagen production

197

IL-1's role in healing

chemotactic for fibroblasts; increases collagen and collagenase synthesis

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TNF's role in healing

chemotactic for fibroblasts; increases collagen and collagenase synthesis

199

Contact inhibition

cells grow until coming into contact with each other

200

Surface receptors

recognize extracellular matrix proteins

201

Collagenization

the FINAL mechanism of healing

202

Tropocollagen

main unit of all types of collagen, 3 attached alpha chains cross-linked for tensile strength

203

Skin contains predominantly Type ___ collagen

Type I

204

Granulation tissue initially contains predominantly Type ___ collagen

Type III

205

Following remodeling, granulation tissue contains predominantly Type ___ collagen

Type I

206

Non-collagen components of the ECM

elastin, laminin, proteoglycans, fibronectin

207

Primary union wounds have ____% of their original strength if sutures are used

70-80

208

Primary union wounds have ____% of their original strength when sutures are removed

10

209

How long would it take to regain 70-80% of strength in a primary union wound

3 months

210

How long would it take to regain 100% of strength in a primary union wound

6-12 months

211

Wound Dehiscence

Delayed wound healing: opening of a partially healed wound (large wounds with sutures prematurely removed, infection, or tensile pressure)

212

For PMN adhesion, neutrophil _________ receptors bind to endothelial ______ receptors

Sialyl-Lewis X (PMN); Selectins (endothelial)

213

For PMN transmigration, neutrophil _________ receptors bind to endothelial ______ receptors

Integrins (PMN); CAM (Endothelial)

214

What cells may be present at both acute and chronic inflammatory sites?

macrophages

215

Cell type indicative of early acute inflammation

segmented neutrophil

216

Chemical Mediator involved in DIRECT bacterial lysis

C5b-9

217

Segmented neutrophils leave blood vessels by

emigration through tight junctions

218

Healing by primary union involves

approximation of wound margins (with or without sutures)

219

Local Causes of delayed wound healing

Infection, inadequate blood supply, forge in body, type of tissue

220

Systemic causes of delayed wound healing

Old age, poor nutrition, bleeding disorder, diabetes, Hypertension, Atherosclerosis, Collagen-Vascular Disease, NSAID or steroid use

221

Eosinophils are increased under what conditions

Parasitic infections, allergic reactions, hypersensitivity reactions, and some chronic inflammation

222

Erythema and warmth is indicative of

increased vascular flow (vasodilation)

223

Example: Red streaks in the skin from the site of infection on the arm extending to the axilla

lymphangitis

224

Swelling in acute inflammation is due to

increased vascular permeability, increased hydrostatic pressure, followed by increased TISSUE oncotic pressure

225

Acute wound with thick yellow pus

acute inflammatory exudate

226

Acute wound with thick yellow pus, but surround by tissue and enclosed within a cavity

abscess

227

Main function of the neutrophil in a pyogenic acute infection

to kill G(+) and G(-) bacteria via phagocytosis

228

Anaphylatoxin Chemical Mediators

C3a and C5a

229

Opsins for phagocytosis

IgG (Fc fragment), C3b

230

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