Exam #1: Acute Inflammation II Flashcards
Generally, how are organisms phagocytosed?
1) Recognition of the offending agent & activation of leukocytes
2) Engulfment
What are the mediators of recognition and attachment.
- Mannose receptors= recognize mannose and fucose on microbial cell walls
- Scavenger receptors
- Opsonins= IgG & C3b
Describe the process of engulfment.
After a microbe has bound to a phagocyte receptor:
1) Pseudopods, or extensions of the cytoplasm, surround the object forming a phagosome
2) Phagosome that fuses with the lysosome, creating a phagolysosome
What are the two systems for killing organisms?
Once the phagolysosome has formed, killing is mediated by two pathways:
1) Oxygen-dependent
2) Oxygen-independent
What is the oxygen-dependent/ aerobic process for killing organisms?
Respiratory burst
1) Oxygen–>superoxide via NADPH oxidase
2) Superoxide–>Hydrogen peroxide via superoxide dismutase
3) Myelo-peroxidase from neutrophilic granules catalyzing reaction between Cl- & Hydrogen peroxide, forming hypochlorus acid
What reaction is carried out by NADPH oxidase?
Oxygen–>Superoxide
What reaction is carried out by Superoxide Dismutase?
Superoxide–>Hydrogen peroxide
What is myelo-peroxidase from? What reaction does it catalyze?
Neutrophils
CL- & H2O2–>HOCl
(Hypochlorous acid i.e. bleach)
Describe the oxygen-independent mechanism for killing organisms.
The oxygen-independent mechanisms of killing include leukocyte granule proteins and enzymes
What is leukocyte activation?
Initiating secretion or production of cell surface proteins by leukocytes
What are the functional responses induced on leukocytes upon activation?
1) Production of arachidonic acid (AA) metabolites
2) Degranulation & secretion of lysosomal enzymes & activation of oxidative burst
3) Secretion of cytokines
4) Modulation of adhesion molecules
List the general characteristics of inflammatory mediators.
- Originate from plasma proteins or cells
- Bind to specific receptors on target cells
- Can stimulate the release of other mediators from target cells
- Most are short lived
- Most have the potential to cause harmful effects
What are the vasoactive amines?
Histamine
Serotonin
What is the function of the vasoactive amines?
- ARTERIOLAR dilation (vasodilation)
- Increased permeability of POSTCAPILLARY VENULES
Where do the vasoactive amines come from?
Stored in preformed granules of mast cells, basophils, and platelets
What causes the release of vasoactive amines from mast cells?
- Trauma
- Platelet aggregation
- C3a, C4a, C5a
- Neuropeptides
- Cytokines
- Histamine releasing proteins
- IgE binding to mast cells
Review the three pathways of complement activation.
1) Classic= binding of antigen- antibody complex to C1
2) Alternate= C3 directly activated by bacterial endotoxins, complex polysaccharides, & aggregated globulins
3) Lectin= C1 activation by mannose
What is the center of complement activation?
C3
What is the function of C3a, C4a, and C5a in imflammation?
Stimulate histamine release from mast cells leading to increased vascular permeability & vasodilation
What is the function of C5a?
- Chemotaxis of monocytes & granulocytes
- Increases surface expression of leukocyte CAM
- Activates LOX pathway in neutrophils & monocytes
What is the function of C3b?
Opsonization
What is the function of C5-9?
Membrane attack complex (MAC) that inserts into the lipid bilayer forming macropores tha ticnrease the cell permeability & leads to lysis
What is Hageman Factor?
Factor XII of the intrinsic clotting system
- Activated by direct contact with endotoxins, collagen, basememnt membrane i.e. any NEGATIVELY charged surface
Triggers:
- Kinin system
- Clotting cascade
Outline the Kinin System.
1) Activated Hageman Factor (XII) converts Prekallikrein to Kallikrein
2) Kallikrein:
- Amplifies activation of Hageman Factor
- Cleaves kininogen to form kinins including bradykinin
- Converts plasminogen to plasmin
- Converts C5 to C5a, a chemoattractant for luekocytes
- Increases cell adhesion molecule expression
What is bradykinin? What is the function of bradykinin?
Bradykinin= a short-lived vasoactive peptide
- Increases vascular permeability
- Dilates blood vessels
- Contracts non-vascular smooth muscle
- Causes pain
*Note that bradykinin is inactivated by plasma kininase
What is thrombin?
- Thrombin is a protease that cleaves fibrinogen to generate insoluble fibrin
- It is the link between inflammation and coagulation
What is the function of thrombin?
Binds protease-activated receptors (PARs) that
- Mobilize P-selectin
- Produce chemokines, PAF, and NO
- Stimulate enothelial adhesion molecule formation
- Induce COX-2 and production of prostaglandins
- Induces changes in endothelial shape
What is plasmin?
Protease formed by cleaving plasminogen by kallikrein or plasminogen activator released by endothelium and leukocytes
What is the function of plasmin?
Lyses fibrin clots
- Activates Hageman Factor (XII)
- Cleaves C3 to C3a
- Degrades fibrin to form fibrin split products that increase vascular permeability in skin and lung
What is Arachidonic acid?
- Normally bound to cell membrane phospholipids
- Released by the action of cellular phospholipases
What are the two key pathways that stem from AA?
1) COX
2) LOX
Outline the COX pathway.
COX converts AA into protaglandin intermediates that form several inflammation related products including:
- Thromboxane A2 (TXA2)
- Prostacyclin (PGI2)
- PGE2
- PGD2, PGF2a, PGE2
What is TXA2 & what is its function?
Thromboxane A2= potent platelet aggregator and vasoconstrictor
What is PGI2 & what is its function?
PGI2= protacyclin, a vasodilator and inhibitor of platelet aggregation
What is the function of PGD2, PGF2a, and PGE2? What is unique about PGE2?
All three cause vasodilation and potentiate edema
- pGE2= also sensitizes skin to painful stimuli and plays a role in cytokine induced fever
What is the mechanism of action of aspirin? What is the mechanism of action of glucocorticoids?
Aspirin & NSAIDS= inhibits COX-1 & OCX-2, reducing platelet aggregation & vasoconstriction
Clucocorticoids= inhibit phospholipases and the release of AA
Outline the LOX pathway.
Lipoxygenase converts AA into HPETE compounds, and then leukotrienes & lipoxins
What is the function of Leukotriene B4 (LTB4)?
Potent chemoattractant causing
- neutrophil aggregation & adhesion to endothelial cells
- generation of ROS
- release of lysosomes
What is the function of Leukotrienes C4, D4, E4?
Cause intense vasoconstriction, bronchopasm & increase vascular permeability
*Allergic reaction
What are lipoxins?
- Endogenous negative regulators of leukotriene action
- Principal actions are to inhibit leukocyte recruitment and the cellular activities of inflammation
What is the function of Lipoxin L4 & B4?
Inhibition of neutrophil adhesion to endothelium and neutrophil chemotaxis
What is PAF?
Platelet Activating Factor
- Causes platelet aggregation
- Has multiple inflammatory effects
What is the function of PAF dependent on?
Concentration- dependent:
- Low= vasodilation & venular permeability
- High= vasoconstriction & bronchoconstriction
What are cytokines?
Polypeptides that function as cellular hormones or locally acting cell-to-cell mediators
What are chemokines?
Cytokines with strong chemotactic properties
What cells produce IL-1 & TNF-a?
Activated macrophages
What are the functions of IL-1 & TNF-a?
These are two cytokines that work synergistically to mediate inflammation, including:
- Acute phase reactions
- Endothelial effects
- Fibroblast effects
- Leukocyte effects
What are the acute phase reactions produced by IL-1 & TNF-a?
- Fever
- Affect sleep and appetite
- Acute phase proteins
- Neutrophilia
- Hemodynamic effects in shock
What are the endothelial effects of IL-1 & TNF-a?
- Increased expression of leukocyte adhesion molecules
- Stimulate PGI synthesis
- Increase procoagulant activity
- Increased production of IL1, IL-6, IL-8, and PDGF
What Fibroblast effects of IL-1 & TNF-a?
- Increases proliferation, collagen synthesis, and PGE synthesis
- Increases protease and collagenase production
What are the Leukocyte effects of IL-1 & TNF-a?
Increased cytokine secretion (IL-1 & IL-6)
How are chemokines classified?
Classified according to conserved cysteine residues in the protein
What is the difference between C-X-C or alpha chemokines, C-C or beta-chemokines, C or gamma chemokines, and CX3C?
Alpha= act primarily on neutrophils e.g. IL-8, which is important for neutrophil chemotaxis
Beta= attract monocytes, eosinophils, basophils, and lymphocytes, but NOT NEUTROPHILS
Gamma= specific for lymphocytes
CX3C= attractant for monocytes and T-cells
What is NO? List the functions of NO.
Nitric Oxide
- Soluble free radical gas that is produced by: macrophages, endothelium, and some neurons
- Strong vasodilator
- Reduces platelet aggregation
- Microbicidal
What are ROS?
Reactive Oxygen Species released from neutrophils & macrophages
What is the function of antioxidants?
Protection from free radicals
What are neuropeptides?
Substance P & Neurokinin A
What are the biological functions of substance P?
- Transmission of pain signals
- Regulation of blood pressure
- Increasing vascular permeability
