Inflammatory mediators Flashcards
(76 cards)
1
Q
what do inflammatory mediators serve to do?
A
activate cells
localize the process
communicate between the cells
sequential activation of the inflammatory process
2
Q
how can inflammation be inhibited?
A
enzyme inhibition
decrease enzymatic substrates
activate or block receptors
activate or block signal transduction pathways
3
Q
activated cells are able to do what?
A
- expression of adhesion molecules
- contraction of cytoskeleton-> increases vascular permeability and increase chemotaxis
- chemotaxis
- synthesis of arachidonic acid derived mediators
- gene transcription-> NFk-B
- cell division
4
Q
where to mediators of inflammation generally act?
A
only in the immediate area
- only cells in immediate area are activated
- cells leave the blood stream only at sites of increased vascular permeability
- inactivate precursors activated only a site of inflammation
5
Q
what are the two exception to mediators acting locally?
A
IL-1/IL-6 and TNF
-can have systemic responses
6
Q
what is the evolution in inflammation resulting from inflammatory mediator synthesis?
A
- ) vasodilation and increased vascular permeability
- ) chemotaxis and cellular activation
- ) phagocytosis
- ) activation of immune processes
- ) resolution and regeneration
7
Q
what are pre-formed mediators?
A
1st
Histamine, Serotonin, Lysozymes
-initiations (minutes)
8
Q
what are plasma derived mediators
A
2nd
complement, coagulation, factors, kinins
-present but inactive state
-initiation and augmentation (minutes to hours)
9
Q
what are arachidonic acid derived and chemokines (membrane lipids)
A
3rd
prostaglandins, leukotrienes, PAF (hours to days)
-must be synthesized
-mainly of vasodilation and vascular permeability; chemotaxis
10
Q
what are cytokines and growth factors (protein/gene transcription)
A
4th
cytokines, chemokines, growth factors (days to weeks)
-formed by activation by nuclear transcription by NFk-B
-Cytokines/chemokines: cell activation and intercellular signaling
-GF: cell division and tissue regeneration (days weeks, colony-stimulating factors, growth factors)
11
Q
Pre-formed mediators
A
packaged into vesicles
- available for immediate release at site of injury or inflammatory focus
- involved in earliest events of inflammation, vasodilation and increased vascular permeability and often initiate the response
12
Q
Histamines
A
- Derived from histidine, synthesized in mast cells
- source: mast cells and basophils
- released from mast cells-> trauma or cold
- immunologic reactions-> cross-linking of IgE
- C3a, C5a-> complement receptors
- histamine-releasing factors from neutrophils, monocytes and platelets
- IL-1
- important in IgE-mediated hypersensitivity reactions
13
Q
Serotonin
A
derived from tryptophan
synthesized in platelets
14
Q
histamine and serotonin
A
diffuse rapidly and are metabolized rapidly
15
Q
histamine receptors
A
7 transmembrane G-coupled receptors
-4 types:
H1: mediated inflammatory reactions and increased vascular permeability
H2: increases gastrointestinal secretion
H3: central nervous system
H4: bone marrow and white blood cells
-Most antihistamines are block H1, cross-reactivity with H3 leads to drowsiness
16
Q
what is the inflammatory response to histamine?
A
- Vasodilation-> “axonal reflex”, of “flare response” resulting in arterial vasodilation
- Increased vascular permeability (venous)-> local tissue swelling (hive or wheal in skin)
- Potent stimulators of pain, itch
- Contraction of smooth muscle->bronchial smooth muscle: asthma
17
Q
Plasma derived mediators
A
derived from large amounts of inactive precursors
- coagulation proteins-> Hageman factor/Factor XII
- complement proteins-> C3a, C5a, C3b
- Fibrinolytic peptides-> activation of plasmin
- Kinins
18
Q
what is inactive plasma serine protease precursor (Factor XII-Hageman factor) activated by?
A
local signals
- ) negatively charged surfaces (basement membranes, collagen, etc)
- ) bacterial lipopolysaccharides
- ) enzymes (trypsin, plasmin)
19
Q
Plasma proteins
A
activated by serine proteases
- hageman factor plays central role
- occurs within mintues-hours-> increased vascular permeability and initiation of cell migration
20
Q
products of plasma proteins do what?
A
- augmentation and maintenance of histamine response
- coordinate inter-related activities-> includes coagulation, endothelial cell activation, leukocyte adhesion and migration, enhancement of phagocytosis
21
Q
coagulation components are?
A
- Hageman Factor (Factor XIIa)
- Plasmin
22
Q
Hageman factor (factor XIIa)
A
central to activation of coagulation, fibrinolytic, kinin, and complement pathways
23
Q
Plasmin
A
cleaves fibrin into fibrin degradation products which augment vascular permeability in both the skin and the lung
- also cleaves complement components generating C3a and C5a, which also increase
- also activates hageman factor, kininogens, and itself, thus amplifying the response
24
Q
what does the Kallikrein/Kinin system do?
A
- increased vascular permeability
- contraction of smooth muscle
- dilation of blood vessels
- causes pain when injected into the skin
25
Bradykinin
part of Kallikerin/Kinin system
- thought to be inactivated by angiotensin converting enzyme (ACE)
- in the presence of ACE inhibitors-> bradykinin levels increase
- associated with side effect of eliciting a "dry cough" with ACE inhibitor therapy
26
what are complement proteins involvement in inflammation
- C3a, C4a, C5a "anaphylatoxins"
- mast cells, basophils degranulation via complement receptors-> resulting in increased histamine release
- smooth muscle contraction
- increased vascular permeability
- C5a-> chemotactic factor for PMN's, neutrophil degranulation, superoxide production
- C3b-> opsoinzation
27
newly synthesized productions
protein and lipid mediators produced on activation of inflammatory cells
- newly synthesized proteins (cytokines, chemokines, growth factors) (days to weeks)
- activate other cells, enhance cell migration, and ehance phagocytosis, production of cytokines follow migration of cells into the area and mediate inflammatory cell functions
28
newly synthesized productions: Lipid-derived mediators
from membrane-released fatty acids (hours to days)
- derived from fatty acids release from cell membrane on cellular activation
- membranes serve as source of large amounts of free arachidonic acid-> acetylated lipids, synthesis of PG, LT, and platelets activating factor
- released within minutes of cell activation, quickly metabolized
29
what do newly synthesized products mediate?
latter phase of inflammation (18-72 hours), why?: b/c production of larger cytokines increases after migration of cells into area, activation of those cells, induction of new protein synthesis
30
what produces newly synthesized products?
endothelial cells, monocytes (macrophages), lymphocytes and fibroblasts
31
Review: initiation of vascular response?
Histamine, within minutes
32
Review: augmentation of vascular response?
Plasma proteins (minutes to hours)
33
Review: cell migration and vascular maintenance?
Lipid-derived (PG's, LT's)
| hours-days
34
Review: resolution and healing
Growth factors
| -weeks to months
35
Eicosanoids
PG, LT, thomboxanes
- derived from arachidonic acid release from cell membrane on cell activation
- arachidonic acid has 20 carbons and 4 double bonds-> eicosatrtraenoic acid
36
release of arachidonic acid
every cell can release arachidonic acid-> but make different mediators
- resides in 2nd position of phospholipid-> released from phospholipids by lipases
- cells have different different enzymes for metabolizing
37
release of arachidonic acid-> cellular activation
activated-> lipases are activated to release large amounts of phosphoinositol and arachidonic acid
-activation of phospholipases occurs through ligand/receptor linked mechanism
38
what are two mechanisms of release of arachidonic acid?
1. ) direct action of phospholipase A2
2. ) action of diacylglyercol lipase after phosphoinositol is removed by phospholipase C
- inhibited by steroids
39
arachidonic acid metabolites
prostaglandin/thromoboxanes and leukotrienes
40
prostaglandin/thromoboxanes pathway
Cyclo-oxygenases results in the formation of prostanoic acid that contains a 5-carbon ring (cyclo)
-further metabolism results in prostaglandins and thromboxanes
41
leukotrienes pathway
lipoxygenase result in the formation of leukotriene A
| -further metabolism results in formation of LBT4 or the LTC/LTD/LTE results
42
Arachidonic acid derivatives in inflammation: Macrophages
Mediators-> PGE, PGF-> vasodilation, increased vascular permeability
43
Arachidonic acid derivatives in inflammation: Neutrophils
LTB4-> chemotaxis of neutrohils
44
Arachidonic acid derivatives in inflammation: Mast cells
LTC, LTD, LTE->bronchoconstriction
45
Arachidonic acid derivatives in inflammation:Platelets
thromboxanes (TXA2)-> platelets aggregation, blood clotting
46
Arachidonic acid derivatives in inflammation: endothelial cells
prostacyclin (PGI2)-> anti-thrombotic
47
prostaglandins
Macrophages form PGD and PGE/PGF
- first 24-72 hours-> prostaglandins synthesis by macrophages-> PGD, PGE synthesis-> maintain vasodilation and increased vascular permeability as earlier mediators are metabolized , enhance pain (hyperalgesia)
- Platelets form thromboxanes (TXA2, TXB2)-> potent aggregator of platelets
- endothelial cells for PGI2-> anti-thrombotic substances
48
Leukotrienes
- lipoxygenase forms leukotriene A which is further metabolize either to LTB4 or the LTC/LTD/LTE series
- enhance neutrophil chemotaxis and activity
- slow-reacting substances of anaphylaxis
- important role in asthma
49
Lipoxins
derived from arachidonic acid
- induced in resolution of inflammation
- binds cys-LT receptor and acts as an antagonist blocking LTC/LTC/LTE activity
- aspirin promotes lipoxin synthesis
- can also be formed from LT precursors or acetylated cyclo-oxygenase (aspirin therapy)
50
Platelet activating factor
- acetylated lysophospholipid
- sources: mast cells, basophils, neutrophils, macrophages
- induces platelets aggregation and degranulation, enhances the release of histamine and serotonin, increased vascular permeability, increases leukocyte adhesion, chemotaxis
51
what causes synthesis of inflammatory mediators?
activation of mast cells, macrophages, and arriving neutrophils
52
cytokines
signals between cells
- large proteins
- usually require days for induction and peak synthesis
- require specific receptors on target cells
- secreted at sites of inflammation (autocrine and paracrine)
- long-lived
53
what are the chief sources of cytokines?
macrophages and monocytes
| -orchestrate cell migration, activation and proliferation after first 24-48 hours
54
activation of macrophages control whether?
initiation and maintenance of cellular phases of inflammation including cell migration and phagocytosis, chronic inflammatory reactions, healing and regeneration and immune responses
-transcription through NFk-B
55
interleukins
NONspecific nomenclature for cytokines
56
what do IL-1, TNF and IL-6 have in common?
synthesized by activated macrophages
- overlapping functional profiles
- mediate cellular phase, systemic responses, immune responses, healing and regeneration
57
local effects of interleukins
if reach sufficient levels-> can act systemically
- activate EC's-> increased VP
- induction of adhesion molecules on EC's, neutrophils and monocytes
- induction of synthesis of other cytokines and GF
58
role of interleukins in inflammation
induction of fever, malaise, synthesis of acute phase protein, increase in white blood cells, lymph node swelling
59
TNF alpha
made by activated M
- similar to IL-1 and IL-6
- also activation of apoptotic death domain-> TNF-R1, TRADD signaling
60
what are monoclonal antibodies of TNF used to treat?
chronic inflammation disorders (Crohn's, rheumatoid, psoriasis)
61
IL-6
synthesized by activated M
-similar to IL-1 and TNF
-synthesis of acute phase proteins
-induction of fever
-local production of IL-6 by osteoblasts results in increased osteoclast activity and bone loss
(IL-6 inhibitors may have some role in post-menopausal osteoporosis)
62
chemokines
family of chemotactic molecules
- produced locally to mediate chemotaxis of specific types
- adjacent cysteines known as C-C
- separating two cysteins C-X-C
- role in movement of inflammatory and immune cells
63
IL-8 (CXCL8)
- inflammatory chemokines
- neutrophil chemotactic-> bind CXCR-1
- synthesized by activation macrophages, endothelial cells (cell migration)
- required for neutrophil chemotaxis during acute inflammation
64
MCP-1
inflammatory chemokines
- from M
- chemotactic for monocytes
- induces histamine release from mast cell
65
RANTES, MIP-1
eosinophil chemotaxis (allergic responses)
66
inflammatory lymphokines
IL-2, IL-4, IL-5, IL-10, IL-13, (Th2 4,5,10,13)
| IFN-gamma, Type 1 interferons (alpha, beta)
67
IFN-gamma
from T cells, and NK cells
- activates M
- induces expression of MHC I and II
- inhibits Th2 responses
- enhances leukocyte-endothelial adherence
68
type I interferons
various cells
- induce resistance to viral replication in all cells
- increase MHC class I expression
- activates NK cells to kill virus-infected cells
69
IL-2
inflammatory cytokine
-synthesized by M, MC
cell mediated immune responses
-activates T cells-> induction of naive T cells Th1 cells, inhibits Th2 pathways
70
inflammatory growth factors
fibroblast growth factor, TNFalpha
angiogenic factors
colony stimulating factors-> GM-CSF
71
fibroblast growth factor, TNFalpha
stimulates fibroblasts in healing and regeneration
| -causes fibrosis in chronic inflammation
72
angiogenic factors
VEGF (vascular endothelial growth factor), FGF, PDGF,
73
colony stimulating factors-> GM-CSF
promotes differentiation of granulocytes in bone marrow
| stimulates neutrophils, E, M
74
activation of signaling of cytokine transcription
IL-1, TNF, IL-6 signaling further activate transcription of other inflammatory cytokines
- induction NFk-B mediated gene transcription
- LPIS from gram - bacteria to TLR4-> pro-inflammatory cytokines synthesis through similar pathways-> septic shock
75
Nitric Oxide
synthesized from L-arginine by NOS
- iNOS induced in inflammation-> increased levels of NO
- eNOS and nNOS
- short half life
- enhance vasodilation, platelet aggregation/adhesion, bactericidal activity
- leukocyte migration
76
two main sources of inflammation from NO?
endothelial cell-> vasodilation
| activated M
