2.5 Chemical Mediators of inflammation Flashcards
1
Q
chemical mediators of inflammation
A
peptides,
lipids,
amines
- preformed or newly synthesized
2
Q
where are these mediators found
A
in plasma
or cells
3
Q
inflammatory mediators work by
A
binding receptors and many stimulate the release of other medeators
4
Q
times life of inflammatory mediators
A
short lived
eg arachadonic acid
5
Q
harmful to body
A
potentially - don’t have inflammation until you make the mediators so you only have it where you want it but some like IL1 and TNF float around causing systemic effects
6
Q
vasoactive amines
A
small molecular weight amines
7
Q
vasoactive amines are found in
A
mast cells and platelets
8
Q
vasoactive amines: preformed or synthesized
A
preformed and sequestered in cellular granules (active, not zymogens) ex histamine
9
Q
Histamine found mostly in
A
mast cells
10
Q
histamine is released by
A
physical injury,
IgE,
C3a and C5a,
cytokines (IL1 IL8)
11
Q
fn of histamine
A
constricts large arteries,
vasodialation (small art)
and increased vascular permeability (venous)
12
Q
histamine causes
A
itching pain
13
Q
histamine works by
A
binding to H1 receptors
14
Q
serotonin is found in
A
platelets but NOT mast cells
15
Q
serotonin actions
A
same as histamine
16
Q
role in inflammatory response of serotonin
A
in rats it is found in mast cells but we don’t know its role in human inflammation. Mostly described in the CNS
17
Q
complemet
A
proteases found in plasma that are preformed as zymogens
18
Q
complement activation (cascade) paths
A
classical,
alternative,
lectin
19
Q
classical complement
A
ag-aby complex–>C1qrs complex
that cleaves C2 and C4 liberating C4a and
froming C3 convertase,
C3 convertase cleaves C3 liberating C2a and C3 b,
C3b associates with C3 convertase and activates C5 liberating C5a,
activated C56789 forms the MAC
20
Q
C3a C4a and C5a are
A
chemotactic, but mostly C5a
21
Q
C3b is an
A
opsonin
22
Q
alternative path
A
microbial surfaces –> C3 –> C3a and C3b,
C3b –> C5 –> C5a + C5b(–>MAC)
23
Q
Lectin path
A
plasma lectin binds to microbe C2, C4 act - C3a and 5a are liberated _slide 99
24
Q
C3a and C5a are
A
anaphylatoxins –> C4a too a little
25
C5b and C6, 7, 8, 9
MAC complex
26
C3a
histamine release from mast cells (vasodialation and inc. vascular permeability indirectly)
27
C5a
```
histamine release from mast cell,
AA metabolism,
leukocyte chemotaxis,
adhesion,
activation
```
28
Plasmogen activator --> plasminogen --> plasmin
plasmin truns fibrin into split products, and
| cleaves C3 and C5 to relieve C3a and C5a
29
central and commited step of complement
formation fo C3a and C3b - this step is the focus of regulatin
30
DAF
decay accelerating factor
enhances disassociation of C3 convertase
(to inhibit further activation of complement)
31
factor 1
proteolytically cleaves C3b
32
C1 inhibitor
binds C1 to inhibit it
33
CD59
inhibits final assembly of MAC
34
C3 deficiency
death from infections if not treated
35
C2 and C4 deficiency
get autoimmune diseases especially lupus
36
MAC deficiencies
get Neisseria infections
37
defect in linking protein linking DAF and VD 59 to RBC
paroxysmal nocturnal hemoglobinuria-->red cells can't defend themselves_.
red cells normally have this linking protein binding this inhibitors of complement so activated complement doesn_t destroy your red cells
38
T cell deficiencies
really strange opportunistic infections
39
Kinin System
Peptieds in the plasma as zymogens
40
factor 12 involved in
the clotting cascade and prekallikrein (protein in plasma) pathway
41
factor 12a --> prekallikrein path
prekallikrein --> Kallikrein --> high MW Kiniogin --> Bradykinin
42
Kallikrein
involved in factor 12 regeneration, C5 cleavage to C5a, conversion to Plasmin (by plasminogen)
43
Bradykinin
peptide that acts like histamine
44
Bradykinin causes
inc vascular permeability, vasodilatation of small vessels, pain, contraction of large vessels
45
Coagulation system
factor 12, thrombin, fibrinopeptides generated, factor 10a
46
factor 12
kinin system
47
thrombin
binds protease activated receptors (PARs) on many cells stimulating many inflammatory reactions - if you're making thrombin you're not well so it makes sense to have crosstalk with inflammation, commited step of coagulation cascade
48
Factor 10a (Xa)
directly inflammatory
49
Fibrinolytic System
plasminogen --> plasminogen --> Plasmin
50
Plasmin involved in
C3/5 cleavage, Fibrin split product formation, factor 12a formation
51
activated factor 12(12a) / (XII) activates
kinins, thrombin, plasmin split products, C3a/5a formation via plasmin
52
C3a and 5a are fromed from
classic pathway, alternative pathway, microbes, plasmin
53
arachidonic acid metabolites
lipid in cells that are synthesized
54
Arachidonic acid is a
20 carbon unsaturated fatty acid (5 8 11 14 cicosatetraenoic acid)
55
AA is derived fomr
dietary sources or synthesized form linoleic acid
56
In phospholipids AA is
esterified especially at the 2 carbon position of phosphatidyl-choline, inositol and ethanolamine
57
different cells will have particular enzymes to creat AA metabolites such as
cyclooxygenases (prostaglandins),
| lipooxygenases (leukotrienes)
58
Phospholipases turn
phospholipids into AA
59
Steroids will inhibit
first commited stip shutting down AA synthesis and all its metabolites by extension
60
asprin and NSAIDS
only stop cyclooxygenases
61
how do we inhibit the synthesis of lipoxygenases
can only stop it from by steroids earlier in the path, preventing AA from forming
62
cyclooxygenases
COX1 and COX2
63
COX1/2 -->
PGG2 --> PGH2
64
PGH2 -->
```
PGI2 (prostacyclin),
TXA2,
PGD2,
PGE2,
PGF2alfpha
```
65
vasodialation
PG I2, E2, D2
66
inc vascular permeability
PGD2
67
vasoconstriction
TXA2
68
pain
PGE2
69
platelet aggregation
TXA2
70
inhibition of platelet aggregation
PGI2
71
fever
PGE2, fever enhances the actions of other mediators
72
TXA2 syn in
platelets
73
PGI2 syn in
endothelial cells
74
PGD2 syn in
mast cells
75
5HETE, LTB4 syn in
neutrophils and some macrophages
76
LTC4 LTD4 LTE4 syn in
mast cells
77
Lipoxins syn in
platelets (must cooperate with other cells to get LTA4)
78
lipoxygenases path starts with
5LO --> 5-PHETE
79
5PHETE -->
5HETE and LTA4
80
LTA4 -->
LTB4,C4, D4,E4, and lipoxin
81
LTA4 -->LTC4 via
adding glutathione
82
LTA4 -->LTD4 via
losing one aminoacid
83
LTA4 -->LTE4 via
losing one aminoacid
84
LTA4 -->lipoxins via
12-lipoxygenase in platelets
85
LTB4 is chemotactic fo
nformyl peptides
86
LT C D and E are
cystenyl leukotryines
87
LT C D and E actions
vasoconstriction,
bronchoconstriction,
inc vasc permeability
88
LTB4, lipoxins, and 5HETE actions
chemotaxis,
| leukocyte adhesion
89
lipoxins are required for
cell-cell contact
90
lipoxins are made from
LTA4 generated in other cells
91
lipoxins inhibit
vasoconstircion induced by LTC4,
| neutrophil chemotaxis and adhsion
92
Lipoxins stimulate
vasodialation,
| monocyte activities --> seen in switch from acute to chronic
93
Lipoxins vs leukotrienes relationship
inverse
94
Asprin and NSAIDs inhibit
COX1 and COX2
95
Celebrex inhibits
COX2 and later COX1 _.remeber fda study comparing celebrex and asprin
96
Zileuton inhibits
5LO
97
receptor antagonists for cysteinyl leukotrienes
montelukast (singulari) Zafirlukast, Pranlukast
98
glucocorticosteroids inhibit
phospholipases and downregulate COX2
99
Where is cox1 made
in the stomach - needed to protect against stomach acid
100
How does asprin work
acetylsiacilic acid causes irreversible shut down by acethylating cyclooxygenase
101
asprin also inhibits synthesis of
prostacyclin
102
give low dose asprin to
turn off platelets and prevent coagulation
103
fish oils
have less arachidonic acid and proinflammtory processes aer less
104
PAF - platelet activating factor
is made of lipd found in cells and are synthesized
105
PAF is a bioactive lipid called
acetyl-glyceryl-ether phosphorylcholine - glycerol backbone with long chain fatty acid in A position, short chain in B position and PC in C.
original long FA in B removed by phospholipase A2 then acetylated by acetyltransferase
106
PAF is found in
all infammatory cells and endothelial cells
107
PAF at high concentrations causes
constriction---an invitro arteaffect?
108
PAF at low concentrations causes
dialation, 10000 more potent than histamine
109
PAF induces
```
platelet aggregation,
leukocyte adhesion,
and chemotaxis,
degranulation,
and oxidative burst
```
110
PAF binds
a single G-protein coupled receptor
111
PAF in the oxididzed forms is found in
cigarette smokers that enhance platelet,
leukocyte,
and endothelial interactions
112
cytokines and chemokines
are proteins/peptides in cells that are both preformed and synthesized but usually synthesized
113
Interleukins
IL1, IL2 etc
114
Interferons
Type I alpha and beta, type 2 gamma
115
colony stimulating factors
GM-CSF, MCSF, GCSF
116
TNF
alpha and beta
117
TGF
beta
118
inflammatory cytokines
IL1 and TNFalpha and beta
119
IL1 and TNF are secreted by
macrophages
120
TNF beta is secreted by
T cells
121
IL1 is secreted by
many other cells
122
TNF and IL1 both can have
autocrine,
paracrine or
endocrine effects
123
TNF and IL1 mainly act on
leukocytes,
endothelium,
fibroblasts, and
systemic acute phase reactions
124
Endothelium can
```
inc syn of adhesion molecules,
inc PGI synthesis,
inc procoagulant activity,
dec anticoagulant activity,
inc IL1 secretion
```
125
leukocytes can
prime for enhanced activity,
inc cytokine secretion (TNF, IL1, IL2_IL6, IL8, PDGF),
inc affinity of adhesion molecules
126
fibroblasts cause
inc proliferation,
inc collagen synthesis,
inc collagenase and protease activity,
inc PGE2 secretion
127
in some fibrotic diseases scaring comes from
unregulated cytokine secretion
128
Systemic acute phase response
vasodialation, fever, dec appetite, inc sleep, acute phase proteins, neutrophilia
129
vasodialation can cause
shock
130
fever interacts with
PGE2
131
acute phase proteins are
```
C reactive protein,
SAA,
SAP,
C',
coagulants
```
132
TGF beta and IL10 are made by
many cell types including macrophages
133
TGF beta and IL10 have different effects
on different cells
134
TGF beta and IL10 are
antiinflammatory
135
TGF beta and IL10 stimulate
fibroblasts and healing reactions
136
Chemokines
chemokines are acctivators or attractants to specific types of leukocytes
137
fours subtypes pased on arangement of cysteins
CXC, C, CX3C, CC
138
CXC
one AA separating cysteins,
| act on neutrophils (IL8)
139
C-C
act on macorphages and monocytes (MCP1)
140
C act on
lymphoctyes
141
CX3C
on long stalk,
soluble and
cell bound endothelial cells.
Binds or attracts t-cell and monocytes
142
Nitric oxide
a soluble gas in cells that is synthesized
143
NO synthetase
constitutive or inducible found in
endothelial cells,
macrophages, and
neurons
144
3 forms of NO
eNOS,
nNOS,
iNOS
145
rezction of NO
arginine + o2 ----> NO + citruline
146
effects of NO
paracrine - generation of GMP,
vasodialation (shock),
antimicrobial,
with ROS yeilds peroxynitrite and other damaging compunds
147
vasodialation mediators
prostaglandins,
| NO
148
inc vasc permeability
```
vasoactive amines,
C3a and C5a,
bradykinin,
leukotrienes C4 D4 E4,
PAF,
Substance P
```
149
Chemotaxis and leukocyte activation
C5a,
LTB4,
Chemokines,
Bacterial products
150
Fever
IL1
IL6
TNF
151
Pain
prostaglandins,
| bradykinin
152
Tissue damage
neutrophils and macrophages lysosomal enzymes,
oxygen metabolites,
nitric oxide
