2.5 Chemical Mediators of inflammation Flashcards Preview

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Flashcards in 2.5 Chemical Mediators of inflammation Deck (152):
1

chemical mediators of inflammation

peptides,
lipids,
amines
- preformed or newly synthesized

2

where are these mediators found

in plasma
or cells

3

inflammatory mediators work by

binding receptors and many stimulate the release of other medeators

4

times life of inflammatory mediators

short lived
eg arachadonic acid

5

harmful to body

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

vasoactive amines

small molecular weight amines

7

vasoactive amines are found in

mast cells and platelets

8

vasoactive amines: preformed or synthesized

preformed and sequestered in cellular granules (active, not zymogens) ex histamine

9

Histamine found mostly in

mast cells

10

histamine is released by

physical injury,
IgE,
C3a and C5a,
cytokines (IL1 IL8)

11

fn of histamine

constricts large arteries,
vasodialation (small art)
and increased vascular permeability (venous)

12

histamine causes

itching pain

13

histamine works by

binding to H1 receptors

14

serotonin is found in

platelets but NOT mast cells

15

serotonin actions

same as histamine

16

role in inflammatory response of serotonin

in rats it is found in mast cells but we don't know its role in human inflammation. Mostly described in the CNS

17

complemet

proteases found in plasma that are preformed as zymogens

18

complement activation (cascade) paths

classical,
alternative,
lectin

19

classical complement

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

C3a C4a and C5a are

chemotactic, but mostly C5a

21

C3b is an

opsonin

22

alternative path

microbial surfaces --> C3 --> C3a and C3b,
C3b --> C5 --> C5a + C5b(-->MAC)

23

Lectin path

plasma lectin binds to microbe C2, C4 act - C3a and 5a are liberated _slide 99

24

C3a and C5a are

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