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FoundSci II Unit 1 > Acute Inflammation II > Flashcards

Acute Inflammation II Flashcards

1
Q

What are the 4 functional responses induced on leukocytes upon activation?

A
  1. Modulation of leukocyte adhesion molecules
  2. Activation of oxidative burst and degranulation and secretion of lysosomal enzymes
  3. Production of arachiodonic acid metabolites
  4. Secretion of cytokines
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2
Q

What are the steps of phagocytosis of a microorganism? What mediates it?

A
  1. Recognition and Attachment - enhanced by Opsonins (IgG, C3b)
  2. Engulfment - pseudopods surround object forming phagosome that fuses with lysosome creating a phagolysosome
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3
Q

What are the paths of metabolic killing of microorganisms?

A

Aerobic and anaerobic pathways:
- Oxygen Dependent (respiratory/oxidative burst)
- Oxygen Independent

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4
Q

What is the aerobic pathway of killing microorganisms? Aka respiratory burst

A
  1. Oxygen reduced to superoxide via NADPH oxidase
  2. Superoxide is converted to hydrogen peroxide by superoxide dismutase
  3. Myelo-peroxidase from neutrophilic granules catalyze reaction between Cl- and hydrogen peroxide forming HOCl (hypochlorous acid)
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5
Q

What is HOCl?

A

Powerful antioxidant and antimicrobial

Product of respiratory burst

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6
Q

What is the anaerboic pathway for metabolic killing of organisms?

A

Leukocyte granule proteins and enzymes e.g. lysozyme, acid hydrolases, lactoferrin, cationic proteins

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7
Q

What are the characteristics of mediators of inflammation?

A

Originate from plasma (in precursor form that must be activated) or cells (sequestered in granules or synthesized)

Bind to specific receptors on target cells

Can stimulate the release of other (or same) mediators from target cells

Most are short lived

Most have potential to cause harmful effects

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8
Q

What are examples of vasoactive amines?

A

Histamine and Serotonin

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9
Q

What are characteristics of vasoactive amines like histamine and serotonin?

A

Binding to H1 receptors on endothelium

Causing increased permeability of postcapillary venules and capillaries

Immediate but transient effect

Stored in preformed granules of mast cells and basophils and platelets

Cause arteriolar dilation by constricting large arteries

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10
Q

What stimulates mast cell release of histamine and serotonin?

A

trauma, cold, heat

Platelet aggregation

C3a, C4a, C5a (anaphylatoxins)

Neuropeptides - substance P

Cytokines - IL-1 and IL-8

Histamine releasing proteins from platelets and neutrophils

IgE binding to mast cells

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11
Q

What are the 4 plasma mediator systems?

A
  1. Complement System
  2. Kinin System
  3. Clotting System
  4. Fibrinolytic System
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12
Q

What is the critical step in complement activation?

A

Cleavage of C3

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13
Q

What is the classical complement pathway?

A

Initiated by binding of an antigen antibody complex (IgG) to C1

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14
Q

What is the alternate complement pathway?

A

C3 directly activated by bacterial endotoxins, complex polysaccharides, aggregated globulins, e.g. IgA

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15
Q

What is the lectin complement pathway?

A

C1 activation by binding of mannose-binding lectin to carbohydrates on microbes

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16
Q

What do C3a, C4a, and C5a do?

A

Anaphylatoxins

Stimulate histamine release from mast cells leading to increased vascular permeability and vasodilation

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17
Q

What does C5a do?

A

Chemotaxis of monocytes and granulocytes

Increases surface expression of leukocyte CAM

Activates lipoxygenase pathway in neutrophils and monocytes

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18
Q

What does C3b do?

A

Opsonization with recognition by receptors on neutrophils, macrophages, and eosinophils

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19
Q

What does C5-9 do?

A

Membrane attack complex that inserts into lipid bilayer forming macropores that increase cell permeability and lead to lysis

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20
Q

What is Hageman factor?

A

Factor XII of the intrinsic clotting system

Activated by direct contact with activated platelets, endotoxins, collagen, or basement membrane.

Triggers the kinin and clotting systems.

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21
Q

What are the steps of the Kinin System? What does kallikrein lead to?

A

Activated Hageman factor converts Prekallikrein into Kallikrein which:

-amplifies activation of Hageman factor
- cleaves high molecular weight kininogen, forming the kinins, including Bradykinin
-Converts plasminogen to plasmin
- Chemoattractant for neutrophils and converts C5 to C5a, which is chemoattractant for leukocytes
- increases cell adhesion molecule expression on endothelium

22
Q

What is Bradykinin? What are its functions?

A

Short lived vasoactive peptide - inactivated by plasma kininase

Increases vascular permeability (capillary/venule)

Dilates blood vessels - arterioles, capillaries

Contracts non-vascular smooth muscle

Causes pain - been venom is bradykinin largely

23
Q

What is the clotting system and fibrinolytic system?

A

Cascade of reactions resulting in a fibrin clot which is then dissolved by fibrinolytic system

Hageman factor forms clotting factors that leads to thrombin. Thrombin helps convert fibrinogen to fibrin

Kallikrein helps with conversion of plasminogen to plasmin

24
Q

What is thrombin?

A

A protease that cleaves circulating soluble fibrinogen to generate insoluble fibrin

25
How does thrombin link to inflammation?
Coagulation system produces thrombin which leads to inflammation Thrombin binds to protease activated receptors (PARs) on platelets, endothelium, smooth muscle cells, that then: Mobilize P-selectin Produce chemokines - PAF, NO Stimulate endothelial adhesion molecule formation Induce COX-2 and production of prostaglandins Induce changes in endothelial shape
26
What is plasmin?
Lyses fibrin clots Formed by cleaving of plasminogen by kallikrein or plasminogen activator released by endothelia and leukocytes
27
How does plasmin play into inflammation?
In inflammation, plasmin Activates Hageman factor Cleaves C3 to C3a Degrades fibrin to form fibrin split products that increase vascular permeability in skin and lung
28
What does Hageman factor induce the generation of?
Bradykinin Fibrin Fibrin split products Anaphylatoxin - C3a, C4a, C5a
29
What is arachidonic acid?
A polyunsaturated fatty acid present in cell membrane phospholipids Released by action of cellular phospholipases by physical and chemical stimuli including C5a
30
What are two key pathways to form arachidonic acid metabolites?
Cyclooxygenase (COX) pathway Lipoxygenase (LOX) pathway
31
What is the COX pathway?
COX converts arachidonic acid into prostaglandin intermediates that form several inflammation related products: TXA2 - Thromboxane A2 PGI2 PGE2 PGD2, PGE2, and PGF2a
32
What are the functions of the COX pathway products? TXA2 - Thromboxane A2 PGI2 PGE2 PGD2, PGE2, and PGF2a
TXA2 - Thromboxane A2 - potent platelet aggregator and vasoconstrictor PGI2 - vasodilator and inhibitor of platelet aggregation PGE2 - sensitizes skin to painful stimuli and plays role in cytokine induced fever PGD2, PGE2, and PGF2a - causes vasodilation and potentiate edema
33
What is the LOX pathway?
Covnerts arachidonic acid into leukotrienes (LT) and lipoxins
34
What are the functions of LTB4 and LT C4, D4, and E4? *From LOX pathway
LT B4 - potent chemoattractant causing neutrophil 1. aggregation 2. Adhesion to endothelial cell 3. Generation of ROS 4. Release of lysosomes enzymes LT C4, D4, and E4 1. Cause intense vasodilation 2. Cause intense bronchospasm 3. Increase vascular permeability
35
What are lipoxins?
Endogenous Negative regulators of Leukotriene action Principal actions are to inhibit leukocyte recruitment and the cellular activities of inflammation
36
What do Lipoxin A4 and B4 do?
Inhibit neutrophil adhesion to endothelium and neutrophil chemotaxis
37
What is platelet activating factor (PAF) and its function?
Generated by stimulated basophils, mast cells, neutrophils, macrophages, platelets, and endothelial cells Causes platelet aggregation and release of platelet products (histamine, serotonin) Induces vasoconstriction and bronchoconstriction, but induces vasodilation and increased venular permeability at low concentration
38
What are cytokines and chemokines?
Polypeptides which function as cellular hormones or locally acting cell to cell mediators Participate in intricate "networks" to achieve their effect Those with strong chemotactic properties are referred to as chemokines
39
What are key cytokines of inflammation?
Interleukin-1 (IL-1) and Tumor Necrosis Factor (TNF) - produced mainly by activated macrophages
40
What reactions do IL-1 and TNF cause?
Acute phase reactions Endothelial effects Fibroblast effects Leukocyte effects
41
What do acute phase reactions induce?
Fever Affect sleep and appetite Induce acute phase proteins Cause neutrophilia Hemodynamic effects in shock
42
What are the endothelial effects that IL-1 and TNF produce?
Increase leukocyte adherence Stimulate PGI synthesis Increase procoagulant activity Increase production of IL-1, IL-6, IL-8, and PDGF
43
What are the fibroblast effects produced by IL-1 and TNF?
Increase proliferation Increase collagen synthesis and PGE synthesis Increases protease and collagenase synthesis
44
What are the leukocyte effects produced by IL-1 and TNF?
Increase cytokine secretion of IL-1 and IL-6
45
What are chemokines and what do they do?
Stimulate leukocyte recruitment in inflammation Small proteins classified according to conserved cysteine residues in the protein
46
What does the chemokine C-X-C or alpha -chemokines do? Examples?
Act primarily on neutrophils Ex. IL-8
47
What does the chemokine C-C or Beta-chemokines do? Examples?
Attract other cells but not neutrophils Ex. Monocyte chemoattractant protein (MCP-1), macrophage inflammatory protein-1a (MIP-1a), and eotaxin (for eosinophils)
48
What does the chemokine C or gamma-chemokines do? Examples?
Specific for lymphocytes Ex. Lymphotactin
49
What does the CX3C chemokines do?
Fractalkine is strong attractant for monocytes and T cells
50
What are mediators in inflammation for vasodilation, vascular permeability, chemotaxis and leukocyte activation, fever, pain, and tissue damage?
Vasodilation - PG, NO Vascular permability - vasoactive amines, C3a and C5a via histamine, Bradykinin, Leukotrienes (C4, D4, E4), PAF, Substance P Chemotaxis and leukocyte activation - C5a, Leukotriene B4, Chemokines Fever - IL-1, IL-6, TNF, PG Pain - PG, Bradykinin Tissue damage - Lysosomal enzymes, ROS, NO

FoundSci II Unit 1 (9 decks)

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