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Infection & Immunity > Inflammation > Flashcards

Inflammation Flashcards

1
Q

what does inflammation involve

A

interplay between leukocytes (WBCs), tissue cells (immune, structural), microvasculature, nerves, chemical mediators of inflammation
plasma derived

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2
Q

what are the cardinal signs of inflammation

A

heat, redness, swelling, pain, loss of function

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3
Q

what causes heat and redness

A

arteriolar dilation, increased blood flow to inflamed tissue

increased blood flow due to relaxation of artieries

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4
Q

what causes swelling

A

leakage of plasma from blood vessels into tissue (plasma extravasation)
more chronic swelling due to tissue remodelling, cellular accumulation

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5
Q

what causes pain

A

external physical or chemical injury; endogenous generation of chemical mediators of inflammation trigger sensory nerves

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6
Q

what causes loss of function

A

due to chronic inflammation dur to tissue remodelling (tissue destruction/fibrin disposition-scarring)

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7
Q

what are the cellular components of the inflammatory response

A

leukocytes (WBCs)

granulocytes (neutrophils, eosinophils, basophils), lymphocytes (T,B,NK cells), monocytes

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8
Q

what are tissue mast cells

A

widely distributed throughout connective tissue and mucosal surfaces, similarities with circulating basophils, contain synthesise and release inflammaotry mediators

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9
Q

what are stimuli of tissue mast cells

A

mechanical injury to skin, hypersensitivity, chemicals

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10
Q

what is the role of the endothelium in inflammatory response

A

blood vessels lined in epithelium
endothelial-derived NO causes arteriolar dilation; endothelial contraction makes venules leaky due to increased permeability
causes oedema

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11
Q

what are chemical mediators of inflammation

A

diverse molecules produced by the host in response to infection and immune reactions
low specificity (not antibodies)
effectors of the innate immune response but modulate the specific response
promote inflammation and hopefully initiate repair

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12
Q

what is the triple response of histamine

A

redness due to vasodilation, flare (neuropeptide release causing itching), wheal (swelling)

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13
Q

what is the action of histamine on blood vessels

A

relaxation of arteriolar smooth muscle

contraction of venular endothelium leading to increased permeability

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14
Q

what category of drug is chlorphenamine

A

H1 receptor antagonist

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15
Q

what are some chemical mediators in inflammation

A

PGE2 and PGI2 cause vasodilation

histamine and bradykinin increase venule permeability

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16
Q

what is bradykinin

A

inflammatory substance formed from plasma precursor

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17
Q

what is PGE2 (prostaglandin)

A

inflammatory substance formed from membrane lipid

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18
Q

what pre-formed mediators are released in response to local injury

A

histamine, mediators from membrane lipids (PGE2, PGI2), release of peptides from neurokinins

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19
Q

what mediators are produced during inflammatory response

A

following proteinase activation, bradykinin and complementing fragments are formed, as well as products of infiltrating cells

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20
Q

what mediators take hours to produce after inflammatory response

A

transcription and translation of proteins

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21
Q

why is inflammation beneficial

A

increased supply of cells and chemical mediators to site of inflammation (redness, swelling, removal of damaged tissue or infectious agents)
tells body to rest to relieve pain and loss of function

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22
Q

what are eicosanoids

A 
oxidation products of 20-carbon fatty acids (arachidonic acid)
classical eicosanoids (prostaglandins), non-classical eicosanoids
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23
Q

what is the process of prostaglandin biosynthesis

A

membrane phospholipids react with phospholipase A to form arachidonic acid which reacts with cyclo-oxygenase to form PGH2
then forms tissue specific isomerases
synthesis is low under basal conditions
profile and rate dramatically altered in inflammation

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24
Q

what are prostaglandin receptors

A

prostaglandins act via specific GPCRs on target cells

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25
Q

what are some examples of prostaglandin receptors

A

PGE2 receptors, prostacyclin, thromboxane, PGD2 receptors

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26
Q

what are the hysiological functions of PGs

A

initiation of labour, inhibition of gastric acid secretion/increased gastric mucous production, inhibition of platelet aggregation and vasodilation, platelet vasodilation and aggregation

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27
Q

what is EP2

A

pro-inflammatory receptor
Gs/AC mediated elevation of cAMP in smooth muscle vasodilates
can inhibit leukocyte function and have anti-inflammatory properties

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28
Q

what is the Von Frey pain perception test

A

prostaglandin receptors are on sensory nerves; EP1 receptors knock-out mice have decreased pain perception
it increases pain signals to the brain

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29
Q

what does an EP3 receptor do

A

activates leukocytes and mast cells (Gi linked receptor reduces AC/cAMP signalling; enhances function)
enhances oedema formation

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30
Q

how to prostaglandins act in fever

A

protective against infection, dangerous if prolonged or severe, regulated by production of PGE2 in the hypothalamus

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31
Q

what is cyclo-oxygenase

A 
exists in two isoforms
COX1 constitutive (products important in normal function of stomach, intestine, kidney and platelets)
COX2 induced (especially during inflammation)
COX3 splice variant of COX1 expressed in CNA
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32
Q

what is the target of aspirin

A

cyclooxygenase (enzyme that converts arachidonic acid into prostaglandin)

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33
Q

what binding effects does aspirin have

A

covalent binding, acetylates COX, irriversible inhibition of COX, releases salicylate

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34
Q

what binding effects does ibuprofen have

A

competitive inhibitor of arachidonate binding to COX

non-selective COX inhibitor

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35
Q

what are the side effects of aspirin like drugs

A

gastric irritation, bleeding, renal toxicity, bleeding due to COX1 inhibition and reducing cytoprotective effects of PGs

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36
Q

what are the anti-thrombotic actions of aspirin

A

irriversibly acetylates cyclo-oxygenase, thus platelet TXA2 production ceases; endothelial cells make new COX and so PGI2 is still released

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37
Q

what happens when aspirin is used for anti-thrombotic effect

A

COX inactivated by low dose aspirin
platelet COX1 inactivated for the life of the platelet; blood vessel COX rapidly resynthesised
PGI levels maintained and decreased thrombus formation

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38
Q

what is the action of leukotrienes

A

bronchoconstriction, oedema, chemotaxis, present in inflammation

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39
Q

what is the action of leukotrienes on bronchoconstriction

A

LTC4 and LTD4 constrict human bronchial smooth muscle which increases effects of other constrictor agents

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40
Q

what is the action of leukotrienes on oedema

A

LTC4 and LTD4 stimulate increased vascular permeability

LTB4 increases vascular permeability (neutrophil dependent)

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41
Q

what is the action of leukotrienes on chemotaxis

A

LTB4 potent chemotactic agent for inflammatory cells

BLT1 receptor

42
Q

what is the action of leukotrienes in inflammation

A

high levels in synovial fluid of RA pts

43
Q

how do glutocorticoids work

A

inhibit PLA2 so arachidonic acid is not produced

44
Q

how does zileuton work

A

inhibits 5-lipoxygenase activity

45
Q

how does montelukast work

A

inhibits leukotrienes

46
Q

what action do glutocortecoids have on eicosanoids

A

inhibits PLA2 transcription, induces synthesis of endogenous PLA2 inhibitor ‘lipocortin’; inhibits COX2 synthesis

47
Q

why are eicosanoids important

A

potent vasodilators, increase vascular permeability, pain, fever, synergy with other medications, modulators of cell function

48
Q

what is leukocyte migration

A

leukocytes move from blood to sites of inflammation and immune activation
directional control is co-ordinated by tissue expression of adhesion molecules and chemical stimuli for leukocyte migration
on arrival at sites of inflammation, they precipitate in host defense, inflammation and repair/restoration

49
Q

what is leukocyte diapedesis

A
  1. circulation 2. tethering/rolling 3. firm adhesion 4. transmigration
50
Q

what happens in the tethering/rolling stage of leukocyte dispedesis

A

fast moving leukocytes tethered to blood vessel wall, guided by specific homing receptors and their ligands called selectins (binds carbohydrate structures with weak bonds)
most important stage is initial tethering of leukocytes to vascular cells

51
Q

what are selectins

A

lectin-like adhesion molecules that weakly bind CHO molecules

52
Q

where are L-selectins found

A

leukocytes

53
Q

where are P-selectins found

A

platelets and endothelium

54
Q

where are E-selectins found

A

endothelium

55
Q

what is L-selectin

A

constitutive expression on leukocytes
leukocyte activation leads to transient increase in avidity (molecules cluster on surface)
rapid shedding by proteolytic cleavage

56
Q

what is P-selectin

A

constituative in platelets and endothelium, stored in granules
rapidly translocated to cell surface on cell activation by thrombin or histamine

57
Q

what is E-selectin

A

endothelial expression induced by cytokines or LPS
expression required de novo protein synthesis (slow)
expression inhibited by glutocortecoids

58
Q

what is leukocyte adhesion deficiency II

A

patents suffer recurrent infections (no pus, neutrophilia)
normal phagocytosis and respiratory burst in vitro
defective fucose metabolism (leukocytes do not express selectin ligands)
decreased rolling response on E- or P-selectins
severely impaired neutrophil accumulation in skin inflammation
neutrophils stuck in vascular area (causes neutrophilia)
neutrophils do not escape circulatory system

59
Q

what happens in the firm adhesion and flattening stage of leukocyte dispedesis

A

rolling along endothelial cell surface which activates integrins
subsequent to receiving signals from chemokines on the endothelial surfaces

60
Q

what are integrins

A

firm adhesion occurs via integrins

heterodimeric proteins expressed on the surface of leukocytes and most other cells

61
Q

how is adhesion regulated

A

basal expression of integrins, leukocyte activation induces conformational change which increases affinity and clustering of integrins

62
Q

what is leukocyte adhesion deficiency I

A

patients suffer recurrant bacterial infection without pus
leukocytes do not adhere to extracellular material or endothelium in vitro
LAD I leukocytes are deficient in beta2 integrin

63
Q

what are integrin ligands

A

intracellular adhesion molecule (ICAM)
ICAM2 basally expressed on endothelium
ICAM1 induced by cytokines

64
Q

what is transmigration

A

involves CAMs and chemoattractants (chemotaxins)

65
Q

what are examples of leukocyte adhesion blockers in therapy

A

anti VLA-4

anti alphaL beta2 in dry eye symdrome

66
Q

what is natalizumab

A

monoclonal antibody against alpha4 integrin, inhibits T lymphocyte interactions with brain endothelium (decreased trafficking into the brain); trialled as therapy for MS
licenced in US for IBD

67
Q

what is chemotaxis

A

leukocyte movement

68
Q

what stimulates leukocyte movement (chemotaxis)

A

chemotaxins

they attract leukocytes - intigrin affinity and avidity change, movement

69
Q

what is the source of chemotaxis

A

site of inflammaion
some are immobilised and ‘presented’ to leukocytes; endothelial cell surface presentation, bound onto extracellular matrix

70
Q

what are some non-selective chemotaxins

A

LTB4, C3a, C5a, formyl peptides

71
Q

what are some selective chemotaxins

A

chemokines (large family of proteins)

72
Q

what are chemokines

A

structurally defined group of chemotaxins that are produced in response to IL-1, TNF and bacteria
G-protein coupled receptors
named according to ligand (-L) and receptor (-R)

73
Q

what are CXC chemokines

A

mainly neutrophil and T cell attachments
target CXCL8 ligand and CXCL12 ligand
their targets are neutrophils, lymphocytes and stem cells

74
Q

what are CC chemokines

A

not neutrophil attractants

ligands targeted are CCL2, CCL11 and targets are monocytes, eosinophil, activated T-cells

75
Q

what rate does each WBC move at

A

neutrophils>monocytes>lymphocytes
neutrophil-acute inflammation
monocytes, lymphocytes - chronic inflammation

76
Q

what is the tissue response in inflammation

A

different selectin and CAM expression, different chemokine expression

77
Q

what is the leukocyte response to inflammation

A

different integrin expression, different chemokine receptor expression

78
Q

where are integrins active

A

on CAM during adhesion part of leukocyte dispedesis

79
Q

what happens during leukocyte transmigration

A

leukocytes escape from circulation and accumulate at sites of injury
selectins tether leukocytes on endothelium near inflammatory site
integrins are used for stronger adhesion on chemokine activation of leukocytes
CAMs expressed by endothelium are ligands for integrins
leukocyte movement directed by chemotaxis

80
Q

what are proteases derived from

A

plasma zymogens, tissue cells, activated leukocytes

81
Q

what do proteases have a central role in

A

host defense, removal of damaged tissue, initiating repair, inflammation

82
Q

what are plasma proteins

A

interrelated systems activated by tissue injury, antibody complexes, foreign surfaces
generate inflammatory mediators from plasma precursors
kinins (vasodilation, increased permeability, pain)
complement (leukocyte activation, chemotaxis, mast cell degranulation, bacterial opsonisation and lysis)
clotting cascade (thrombosis, platelet activation)

83
Q

what is angioedema

A

deep cutaneous and mucosal swelling; lasts days and most pts also suffer mast cell degranulation, responsive to H1 antagonists
histamine-independent forms may be drug induced (like ACE inhibitors) or hereditory

84
Q

what proteases are involved in angioedema

A 
angiotensin converting enzyme inhibitor (blocks bradykinin degredation so increases inflammation)
hereditary angioedema (increases bradykinin, decreases protease inhibitors) trated with bradykinin receptor antagonist
85
Q

what are the families of proteolytic enzymes

A

matrix metalloproteinases, serine proteinases, cysteine proteinases

86
Q

what tissue damage occurs in RA

A 
cartilage proteoglycans (matrix material) lost rapidly in RA so shock absorption impaired and loss of function
proteoglycans have an open structre and are highly accessible and sensitive to breakdown by several proteinases
collagen is lost more slowly which causes loss of function of cartilage as smooth surface
87
Q

what are matrix metalloproteinases

A 
break down collagen and other matrix proteins
active at neutral pH, contains and requires Zn2+
major class of enzymes that degrade cartilage
inhibited by endogenous TIMPS (tissue inhibitors of metallo-proteinases)
88
Q

what activates metalloproteinases

A

removal of propeptide by other proteases
chemical modification of propeptide by RONS
active zinc site targeted by hydroxamate series of MMP inhibitors

89
Q

what is the cysteine switch mechanism

A

propeptide maintains MMP in an inactive state; interaction between conserved cysteine residue in pro-domain and active site zinc ion is disrupted; active site becomes accessible and MMP is activated; pro-domain does not need to be removed of a proMMP to acquire activity; only disruption of the zinc-thiol interaction is absolutely required

90
Q

what are peptidomimetics

A

synthetic MMP inhibitors used in inflammation

91
Q

how do peptidomimetics work

A

small hydroxamic acid based molecules used in zinc binding, based on collagen structre, inhibit MMP ativity
they lack specificity and act on most metalloenzymes

92
Q

how do non-peptide hydroxamates compare to peptidomimetica

A

they have better selectivity

93
Q

what are other inhibitors of MMPs

A

tetracycline derivatives, antibody therapies, endogenous inhibitors (TIMPs)

94
Q

what are some examples of serine and cysteins proteinases

A

neutrophil elastase - acive at neutral pH, breaks down matrix proteins like chondritin and proteoglycans
endogenous inhibition by serpins (serine protease inhibitors)
serpins are readily inactivated by oxidation

95
Q

what are some adverse effects of MMP inhibitors

A

muscoskeletal inhibitors, lack of specificity, key role in homeostatic connective tissue turnover

96
Q

what does RONS stand for

A

reactive oxygen and nitrogen species

97
Q

what is the role of RONS

A

essential for host defence

98
Q

how are RONS produced

A

infiltrating leukocytes and tissue resident cells
NADPH catalyses formation of O2- which forms H2O2 which is further metabolised to HClO (H+ and ClO-)
H2O2 inactivated by catalase
reactive nitrogen species formed from NOS derived NO- combining with oxygen species

99
Q

what is respiratory burst

A

leukocytes phagocytose bacteria, yeast, immune complexes, damaged tissue
proteases and ROS generated as part of host defence

100
Q

how do ROS’ cause joint damage

A

rheumatoid synovial tissue undergoes cycles of hypoxia and reperfusion (oxidative stress); immune complex formation in some diseases, generation of superoxide and RONS (tissue injury, modulation of cell function)

101
Q

what are the effects of RONS

A

activation of inflammatory gene transcription; amino acid modifications; matrix modifications; DNA damage; cell apoptosis and necrosis

102
Q

what are some resident RONS for inflammation

A

chondrocytes, osteoclasts, fibroblasts

Infection & Immunity (22 decks)

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