Fiber Chaper 13. INFLAMMATION AND CYTOKINES Flashcards
Three phases of inflammation
- Injury: causes exposed collagen, PAF and TF release
- Platelets bind collagen: release growth factors (platelet derived growth factor PDGF) and leads to PMN and macrophage recruitment
- Macrophages: dominant role in wound healing; release important growth factors (PDGF) and cytokines (IL-1 and TNF-a)
PDGF
- chemotactic and activated inflammatory cells (PMHs and macrophages) and fibroblasts, which leads to collagen and ECM proteins
- angiogenesis
- epithelialization
- chemotactic for smooth muscle cells
- has been shown to accelerate wound healing
EGF
epidermal growth factor
- chemotactic and activates fibroblasts
- angiogenesis
- epithelialization
FGF
fibroblastic growth factor
- chemotactic and activates fibroblasts, which leads to collagen and ECM proteins
- angiogenesis
- epithelialization
PAF
platelet activating factor
- is not stored, generated by phospholipase in endothelium, is a phospholipid
- chemotactic for inflammatory cells; increases adhesion molecules
Chemotactic factors
For inflammatory cells: PDGF, IL-8, LTB-4, C5a, C3a, PAF
For fibroblasts: PDGF, EGF, FGF
Angiogenesis factors
PDGF, EGF, FGF, IL-8, hypoxia
Epithelialization factors
PDGF, EGF, FGF
PMNs last how long?
1-2 days in tissues, 7 days in blood
Platelets last how long?
7-10 days
Lymphocytes do what?
Chronic inflammation (T cells) and antibody productions (B cells)
Type 1 Hypersensitivity (allergic reactions)
- Eosinophils: IgE receptors that bind to allergen, release major basic protein, which stimulates basophils and mast cells to release histamine; increased in parasitic infections
- Basophils: main source of histamine in blood; not found in tissue
- Mast cells: primary cell in type 1 hypersensitivity reactions; main source of histamine in tissues
- Histamine: vasodilation, tissue edema, postcapillary leakage; primary effector in type 1 hypersensitivity reactions
- Bradykinin: peripheral vasodilation, increased permeability, pain, pulmonary vasoconstriction (inactivated by ACE)
What is the main source of histamine in blood? Tissues?
Blood: basophils
Tissue: mast cells
What does histamine do?
- Released by basophils (in blood) and mast cells (in tissue) in response to major basic protein released by eosinophils (which have IgE receptos which bind allergen)
- Vasodilation, tissue edema, postcapillary leakage
What causes peripheral vasodilation, increased permeability, pain, and pulmonary vasoconstriction in a type 1 hypersensitivity reaction?
Bradykinin
What inactivates bradykinin?
ACE; located in lung
Nitric oxide
also called endothelium derived relaxing factor
arginine -> (via NOS) -> nitric oxide
NO activates guanylate cyclase and increases cGMP resulting in vascular smooth muscle dilation
What is the precursor to nitric oxide?
arginine
What does NO do?
activated guanylate cyclase and increases cGMP to cause vascular smooth muscle dilation
What does the opposite of NO?
Endothelin (causes vascular smooth muscle constriction)
Main initial cytokine response to injury and infection
TNF-alpha and IL-1 release
TNF-alpha
- Macrophages are largest producers of TNF-a
- Increases adhesion molecules
- Procoagulant
- Cachexia in cancer patients
- Activates neutrophils and macrophages -> more cytokine production and cell recruitment
- High concentrations can cause circulatory collapse and multisystem organ failure
IL-1
- Macrophages are main source
- Effects similar to TNF-a and synergized TNF-a
- Responsible for fever (PGE2 mediated in hypothalamus): raises thermal set point, NSAIDs can decrease fever by reducing PGE2 synthethis
- Alveolar macrophages: cause fever with atelectasis by releasing IL-1
What cytokine causes fever?
IL-1
What cytokine causes cachexia?
TNF-a
IL-6
Increases hepatic acute phase proteins (CRP and amyloid A)
What are interferons?
Released by lymphocytes in response to viral infection or other stimulants
- Activate macrophages, natural killer cells, and cytotoxic T cells
- Inhibit viral replication
Hepatic acute phase response proteins
- IL-6: most potent stimulus
- CRP: opsonin, activates complement
- Amyloid A and P
- Fibrinogen
- Haptoglobin
- Ceruloplasmin
- Alpha-1 antitrypsin
- C3
- (albumin, pre-albumin, and transferrin are DECREASED)
Cell adhesion molecules
-Selectins, bet-2 integrins, ICAM, VCAM, PECAM, ELAM
Selectins
L-selectins on leukocytes, bind to E- (endothelial) and P- (platelet) selectins all causing ROLLING ADHESIONS
Beta-2 integrins
(CD 11/18 molecules) on leukocytes bind ICAMs, etc., ANCHORING ADHESION
ICAM, VCAM, PECAM, ELAM
On endothelial cells, bind beta-2 integrin molecules located on leukocytes and platelets ; also involved in TRANSENDOTHELIAL MIGRATION
Complement pathways
Classic (IgG or IgM): antigen-antibody complex activates; factors C1, C2, C4
Alternative: endotoxin, bacteria, other stimulus activates; Factors B, D, P (properdin)
Convergence cytokine in complement pathways
C3
Factors C1, C2, C4 are in what pathway?
Classic
Factors B, D, P are in what pathway?
Alternative
What molecule do both pathways need?
Mg
Anaphylatoxins
C3a, C4a, C5a (C3a and C5a are also chemotaxis)
-increase vascular permeability, bronchoconstriction, activate mast cells and basophils (to release histamine)
Membrane attack complex
C5b-C9b; causes cell lysis (usually bacteria) by creating a hole in cell membrane
Obsonization
Targets Ag for immune response
C3b and C4b
C3b and C4b do what?
Opsonizatoin
Prostaglandins come from what?
Arachidonic precursors (by COX?)
What do PGI2 and PGE2 do?
Vasodilation, bronchodilation, permeability, inhibit platelets
Prostaglandin pathway
Phospholipids -> (phospholipase) -> Arachidonic acid -> (COX) -> PGG2 -> (peroxidase) -> PGH2 which either goes to PGI2, PGD2, PGE2, or (via thromboxane synthase) to TXA2
-Prostaglandins are vasodilatory and inhibit platelet adhesions, while TXAs are thrombotic and vasoconstrictors
NSAIDs MoA
Inhibit COX reversibly
Aspirin MoA
Inhibits COX irreversibly and inhibits platelet adhesion by decreasing TXA2
Steroids MoA
Inhibits phospholipase, which converts phospholipids to arachidonic acid, therefore inhibits inflammation
Leukotrienes
LTC2, LTD4, LTE4: slow reacting substances of anaphylaxis; bronchoconstriction, vasoconstriction followed by increased permeability (wheal and flare)
LTB4: chemotactic for inflammatory cells
-Produced from arachidonic precursors
How long after injury do catecholamines peak?
24-48 hours
Where is epi and norepi released?
Epi: adrenal medulla
Norepi: sympathetic postganglionic neurons and adrenal medulla
Neuroendocrine response to injury
Afference nerves from site of injury stimulate CRF, ACTH, ADH, GH, Epi, and Norepi release
Does thyroid hormone play a major role in injury and inflammation?
No
CXC chemokines (C= cysteine, X= another amino acid)
- Chemotaxis, angiogenesis, wound healing
- IL-8 and PF4 are CXC chemokines
Oxidants generated in inflammation
Superoxide anion radical (O2-); main producer oxidase is NADPH oxidase
Hydrogen peroxide (H2O2); main producer oxidase is canthine oxidase
Cellular defense against superoxide anion radial O2-?
Superoxide dismutase, which converts it to hydrogen peroxide H2O2
Cellular defense against Hydrogen peroxide H2O2
Glutathione peroxidase, catalase
What is the primary mediator in reperfusion injury?
PMNs
What is chronic granulomatous disease?
NADPH oxidase system enzyme defect in PMNs, resulting in decreased superoxide O2- radical formation
