Fiber Chaper 13. INFLAMMATION AND CYTOKINES Flashcards
1
Q
Three phases of inflammation
A
- 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)
2
Q
PDGF
A
- 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
3
Q
EGF
A
epidermal growth factor
- chemotactic and activates fibroblasts
- angiogenesis
- epithelialization
4
Q
FGF
A
fibroblastic growth factor
- chemotactic and activates fibroblasts, which leads to collagen and ECM proteins
- angiogenesis
- epithelialization
5
Q
PAF
A
platelet activating factor
- is not stored, generated by phospholipase in endothelium, is a phospholipid
- chemotactic for inflammatory cells; increases adhesion molecules
6
Q
Chemotactic factors
A
For inflammatory cells: PDGF, IL-8, LTB-4, C5a, C3a, PAF
For fibroblasts: PDGF, EGF, FGF
7
Q
Angiogenesis factors
A
PDGF, EGF, FGF, IL-8, hypoxia
8
Q
Epithelialization factors
A
PDGF, EGF, FGF
9
Q
PMNs last how long?
A
1-2 days in tissues, 7 days in blood
10
Q
Platelets last how long?
A
7-10 days
11
Q
Lymphocytes do what?
A
Chronic inflammation (T cells) and antibody productions (B cells)
12
Q
Type 1 Hypersensitivity (allergic reactions)
A
- 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)
13
Q
What is the main source of histamine in blood? Tissues?
A
Blood: basophils
Tissue: mast cells
14
Q
What does histamine do?
A
- 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
15
Q
What causes peripheral vasodilation, increased permeability, pain, and pulmonary vasoconstriction in a type 1 hypersensitivity reaction?
A
Bradykinin
16
Q
What inactivates bradykinin?
A
ACE; located in lung
17
Q
Nitric oxide
A
also called endothelium derived relaxing factor
arginine -> (via NOS) -> nitric oxide
NO activates guanylate cyclase and increases cGMP resulting in vascular smooth muscle dilation
18
Q
What is the precursor to nitric oxide?
A
arginine
19
Q
What does NO do?
A
activated guanylate cyclase and increases cGMP to cause vascular smooth muscle dilation
20
Q
What does the opposite of NO?
A
Endothelin (causes vascular smooth muscle constriction)
21
Q
Main initial cytokine response to injury and infection
A
TNF-alpha and IL-1 release
22
Q
TNF-alpha
A
- 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
23
Q
IL-1
A
- 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
24
Q
What cytokine causes fever?
A
IL-1
25
What cytokine causes cachexia?
TNF-a
26
IL-6
Increases hepatic acute phase proteins (CRP and amyloid A)
27
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
28
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)
29
Cell adhesion molecules
-Selectins, bet-2 integrins, ICAM, VCAM, PECAM, ELAM
30
Selectins
L-selectins on leukocytes, bind to E- (endothelial) and P- (platelet) selectins all causing ROLLING ADHESIONS
31
Beta-2 integrins
(CD 11/18 molecules) on leukocytes bind ICAMs, etc., ANCHORING ADHESION
32
ICAM, VCAM, PECAM, ELAM
On endothelial cells, bind beta-2 integrin molecules located on leukocytes and platelets ; also involved in TRANSENDOTHELIAL MIGRATION
33
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)
34
Convergence cytokine in complement pathways
C3
35
Factors C1, C2, C4 are in what pathway?
Classic
36
Factors B, D, P are in what pathway?
Alternative
37
What molecule do both pathways need?
Mg
38
Anaphylatoxins
C3a, C4a, C5a (C3a and C5a are also chemotaxis)
-increase vascular permeability, bronchoconstriction, activate mast cells and basophils (to release histamine)
39
Membrane attack complex
C5b-C9b; causes cell lysis (usually bacteria) by creating a hole in cell membrane
40
Obsonization
Targets Ag for immune response
C3b and C4b
41
C3b and C4b do what?
Opsonizatoin
42
Prostaglandins come from what?
Arachidonic precursors (by COX?)
43
What do PGI2 and PGE2 do?
Vasodilation, bronchodilation, permeability, inhibit platelets
44
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
45
NSAIDs MoA
Inhibit COX reversibly
46
Aspirin MoA
Inhibits COX irreversibly and inhibits platelet adhesion by decreasing TXA2
47
Steroids MoA
Inhibits phospholipase, which converts phospholipids to arachidonic acid, therefore inhibits inflammation
48
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
49
How long after injury do catecholamines peak?
24-48 hours
50
Where is epi and norepi released?
Epi: adrenal medulla
Norepi: sympathetic postganglionic neurons and adrenal medulla
51
Neuroendocrine response to injury
Afference nerves from site of injury stimulate CRF, ACTH, ADH, GH, Epi, and Norepi release
52
Does thyroid hormone play a major role in injury and inflammation?
No
53
CXC chemokines (C= cysteine, X= another amino acid)
- Chemotaxis, angiogenesis, wound healing
| - IL-8 and PF4 are CXC chemokines
54
Oxidants generated in inflammation
Superoxide anion radical (O2-); main producer oxidase is NADPH oxidase
Hydrogen peroxide (H2O2); main producer oxidase is canthine oxidase
55
Cellular defense against superoxide anion radial O2-?
Superoxide dismutase, which converts it to hydrogen peroxide H2O2
56
Cellular defense against Hydrogen peroxide H2O2
Glutathione peroxidase, catalase
57
What is the primary mediator in reperfusion injury?
PMNs
58
What is chronic granulomatous disease?
NADPH oxidase system enzyme defect in PMNs, resulting in decreased superoxide O2- radical formation
