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Flashcards in Watson Deck (156)
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1
Q

Define immunity

A

Protection from infection or disease

2
Q

What is autoimmunity

A

When the target is ones own tissues

3
Q

Define inflammation

A

“Set alight” - part of immunity and stimulated by infection and other injury

4
Q

What’s the point of the inflammatory response?

A

Natural response of tissue to injury- attacks and removes cause of injury, repair damaged tissue, beneficial, protective, self limiting

5
Q

What are the two heat sources during inflammation?

A

Heat in individual tissues

Fever to eliminate infectious agents

6
Q

What is arthritis

A

Autoimmune inflammation of joints

7
Q

Why is there swelling but less redness in arthritis

A

Because you can’t see increased blood flow, the swelling is due to irreversible tissue remodelling

8
Q

How do sensory Neurons contribute to the pain during inflammation

A

Release Neuropeptides which contribute to redness and swelling, substance P, calcitonin gene related peptide

9
Q

What is substance P

A

Is a neuropeptide responsible for pain and leaks

10
Q

What is calcitonin gene related peptide

A

Neuropeptide responsible for vasodilation and also stimulates mast cells further enhancing signal (+ve feedback)

11
Q

Role of ATP?

A

Extra cellular mediator of inflammation

12
Q

What are prostaglandins released for

A

Vasodilation

13
Q

Name two Neuropeptides

A

Calcitonin gene related peptide

Substance P

14
Q

What is rheumatoid arthritis

A

A chronic inflammatory joint disease

15
Q

In rheumatoid arthritis what is the loss of cartilage and bone erosion mediated by?

A

Proteinases

16
Q

Name the proteinase predominantly responsible for the loss of cartilage and bone erosion in RA

A

Matrix metalloproteinase (MMP)

17
Q

What is matrix metalloproteinase secreted by?

A

Tissue cells- synovial fibroblasts and Chondrocytes

18
Q

What are synovial fibroblasts

A

They are around the joints and secrete proteinases

19
Q

Which stains with acidic dye:
Basophil
Eosinophil

A

Eosinophil

20
Q

Name three PMN granulocytes

A

Neutrophils
Eosinophil
Basophils

21
Q

Are macrophages short lived?

A

No bbe they live for months

22
Q

Name 5 types of T cell

A
T helper (1+2) 
T cytotoxic 
Natural killer
Th17 
Regulatory T cell
23
Q

What do B cells do?

A

Mature to become antibody secreting plasma cells

24
Q

Name 3 mediators rapidly produced from membrane lipids

A

Eicosanoids (PGE2, PGI2)
Leukotrienes (LBT4)
PAF

25
Q

Name two ways to increase plasma leakage

A

1) agents increase plasma leakage via action directly on the endothelium e.g histamine, bradykinin
2) neutrophil activators increase plasma leakage via a neutrophil dependent mechanism

26
Q

Name 4 substances that increase plasma leakage via a neutrophil dependent mechanism

A

LTB4
fMLP
C5a
Interleukin-8

27
Q

What is tritoqualine

A

Antihistamine- inhibits the enzyme histidine decarboxylase

28
Q

Name the process of histamine synthesis

A

L-histidine
Histamine
Imidazolyl acetic acid

29
Q

Name two enzymes involved in the process of histamine production

A

Histidine decarboxylase

Histaminase

30
Q

Define infection

A

Catching, spreading- involves microbes colonising a host e.g man

31
Q

What is the triple vascular response

A

1) local reddening
2) oedema- wheal
3) axon reflex - flare

32
Q

How many histamine receptors are there?

A

4

33
Q

What’s the role of the H1 receptors?

A

PLC linked- Ca2+elevation
Vasodilator via nitric oxide
Increased vascular permeability- oedema via endothelial contraction

34
Q

What’s the H2 receptor responsible for

A

Adenylyl cyclase leading to cAMP elevation
Vasodilator
Potent stimulant of gastric acid secretion

35
Q

What does the H4 receptor have a role in?

A

Chemotaxis

36
Q

Hyper secretion of histamine results in what

A

Excess acid production and formation of duodenal and peptic ulcers

37
Q

Is the H2 receptor Gs coupled?

A

Yeh

38
Q

Is the H1 receptor Gs coupled

A

NO it’s Gq

39
Q

Name a key H1 receptor antagonist

A

Chlorpheniramine (chlorphenamine- piriton)

40
Q

Name two newer H1 antagonists that have lower lipophilicity

A

Astemizole

Loratidine

41
Q

What are H1 receptor antagonist useful in?

A

Urticaria

Nasal congestion

42
Q

Name 2 H2 receptor antagonists

A

Cimetidine

Ranitidine

43
Q

Do H2 receptor antagonists interact with other drugs?

A

Yes especially cimetidine as they inhibit P450

44
Q

What are eicosanoids derived from

A

C20 unsaturated fatty acid

45
Q

What is arachidonic acid?

A

An essential fatty acid derived from red meat or indirectly via desaturation of linoleic acid

46
Q

Name the steps and enzymes in the making of prostaglandin H2

A
Arachidonate 
-cyclooxygenase 2O2
Prostaglandin G2
-peroxidase 2H+ 2e-
Prostaglandin H2
47
Q

Name the enzyme that converts prostaglandin H2 to prostacyclin

A

Prostacyclin synthase

48
Q

What’s the enzyme that converts prostaglandin H2 to thromboxanes

A

Thromboxane synthases

49
Q

Name 4 physiological functions of PGs

A

1) initiation of labour (PGF2a and PGE2)
2) inhibition of gastric acid secretion, increased gastric mucus production (PGE2)
3) vascular PGI2 from endothelium, inhibition of platelet aggregation, vasodilator
4) vascular TXA2 from platelets, causes platelet aggregation, vasoconstrictor

50
Q

Name 3 leukotrienes

A

LTB4
LTC4
LTD4

51
Q

What enzyme converts arachidonate to leukotrienes

A

Lipoxygenases

52
Q

Name 3 oxidation products of 20 carbon fatty acids

A

Arachidonic acid
Dishomo gamma-linoleic acid
Eicosapentanoic acid

53
Q

Name 4 classical eicosanoids

A

Prostaglandins
Prostacyclins
Thromboxanes
Leukotrienes

54
Q

Name 4 non classical eicosanoids

A

Lipoxins
Resolvins
Isoprostanes
Endocannabinoids

55
Q

Do non classical eicosanoids have short or long half life?

A

Short half life

56
Q

Thromboxanes are produced by what

A

Platelets

57
Q

Prostaglandins act via what

A

Specific GPCRs on target cells

58
Q

How many PGE2 receptors

A

There’s 4

EP1-EP4

59
Q

What’s the receptor for prostacyclin (PGI2)

A

IP

60
Q

Name the two PGD2 receptors

A

DP1 and DP2

DP2 also termed CRTH2

61
Q

Where are EP2 and IP receptors found

A

Found on vascular smooth muscle - vasodilator a increase blood flow

62
Q

What’s the thromboxane receptor

A

TP on platelets

63
Q

What’s the PGF2 receptor

A

FP

64
Q

If leukocytes are present are EP2 receptors anti or pro inflammatory

A

Anti-inflammatory

65
Q

What fibres do prostaglandins sensitise

A

Peripheral C-fibres

66
Q

How are prostaglandins involved in fever

A

Thermoregulatory set point regulated by production and action of PGE2 in the anterior hypothalamus

67
Q

Cerebroventriclar injection of PGE2 leads to what?

A

Fever

68
Q

How many isoforms of cyclo-oxygenase are there?

A

2- encoded by separate genes

69
Q

How many COX enzymes are there

A

3
COX 1
COX 2
COX 3

70
Q

What does the enzyme COX1 do

A

Constitutive housekeeping enzyme- products important in normal function of stomach, intestine, kidney and platelets

71
Q

What’s the enzyme COX2 important in

A

Induced particularly in inflammatory cells exposed to inflammatory stimuli

72
Q

Are COX1 and 2 homodimers

A

Yes

73
Q

Where are COX1 and 2 found

A

On the inner membrane of endoplasmic reticulum

74
Q

COX enzymes are made up of what two sites?

A

Peroxidase site

Cyclooxygenase site

75
Q

What serine residue on COX2 is targeted by aspirin

A

S516

76
Q

What serine residue on COX1 is targeted by aspirin

A

S530

77
Q

NSAIDs selectivity for COX1 and COX2 can be studied pharmacologically as what?

A

‘Potency ratios’

- the IC50 values for blocking the two enzymes

78
Q

Name a COX1 selective drug

A

Flurbiprofen; low dose aspirin

79
Q

Name 3 COX2 selective drugs

A

Meloxicam
Celecoxib
Rofecoxib

80
Q

Name 4 physiological functions of prostaglandins?

A

1) initiation of labour
2) inhibition of gastric acid secretion, increased gastric mucous production
3) inhibition of platelet aggregation and vasodilation
4) platelet aggregation and vasoconstriction

81
Q

Why do you have a tendency to bleed using aspirin like drugs?

A

Due to blocking of housekeeping COX1 and thus reducing the cytoprotective effects of prostaglandins

82
Q

Platelet COX1 inhibition is beneficial in what?

A

Thrombosis

83
Q

Why are selective COX 2 inhibitors bad in thrombosis

A

Because they affect PGI2 more than TXA2

84
Q

Name four actions of leukotrienes

A

Bronchoconstriction
Oedema
Chemotaxis
Present in inflammation

85
Q

Name two leukotrienes involved in bronchoconstriction

A

LTC4 and LTD4

86
Q

Name two leukotrienes involved in oedema independent of neutrophils

A

LTC4 and LTD4

87
Q

Name a leukotriene involved in oedema neutrophil dependent

A

LTB4

88
Q

Name a leukotriene involved in chemotaxis

A

LTB4

89
Q

Name 4 anti leukotriene drugs

A

Glucocorticoids
Zileuton
Zafirlukast
Montelukast

90
Q

Name 5 anti eicosanoid therapies

A
Glucocorticoids
Zileuton
Zafirlukast
Montelukast
NSAIDs
91
Q

Name three ways in which glucocorticoids act on eicosanoids

A

Inhibit PLA2 transcription
Induce synthesis of endogenous PLA2 inhibitor lipocortin
Inhibit COX2 synthesis

92
Q

What determines the directional control of leukocyte migration?

A

Tissue expression of adhesion molecules and chemical stimuli

93
Q

Name 4 steps of leukocyte diapedesis

A

Circulating
Tethering/rolling
Firm adhesion
Transmigration

94
Q

What are selectins important for?

A

Initial ‘tethering’ of leukocytes to vascular cells

95
Q

Name the letters of three selectins and state what they’re expressed by:

A

L- leukocytes
P- platelets (endothelium)
E- endothelium

96
Q

How is expression of endothelial E-selectin induced?

A

By cytokines or LPS and expression requires de novo protein synthesis which is slow take 2-6hrs

97
Q

What are integrins

A

When the leukocytes roll along endothelial cell surfaces they activate integrins which are Luganda expressed on leukocyte surfaces

98
Q

What type of protein are integrins?

A

Heterodimeric proteins

99
Q

How many heterodimer integrins are formed for leukocytes

A

3
aL/B2
aM/B2
aX/B2

100
Q

What’s LAD-2

A

Leukocyte adhesion deficiency

101
Q

How is adhesion of leukocytes regulated

A

Basal expression of integrins
Leukocyte activation induces
1) conformational change- affinity
2) clustering of integrins- avidity

102
Q

What does ICAM stand for and what are they

A

Intercellular adhesion molecules

Integrin Ligands

103
Q

ICAM2

A

Intercellular adhesion molecule basally expressed on endothelium

104
Q

ICAM1

A

Intercellular adhesion molecule induced by cytokines IL1 and TNF

105
Q

Name an integrin that binds vascular cell adhesion molecule (VCAM)

A

a4B1 (VLA4) expressed on Eosinophils, monocytes, Tcells

106
Q

What induces VCAM1

A

Cytokines

107
Q

What is natalizumab?

A

Monoclonal antibody against a4 integrin, it inhibits T lymphocyte interactions with brain endothelium, best results in multiple sclerosis when combined with IFN-B

108
Q

Chemoattractants are produced by what

A

Tissues and bacteria

109
Q

What’s a chemokine

A

Chemotactic cytokine

110
Q

Chemokines are produced in response to what?

A

IL1, TNF, bacteria

111
Q

Name two classes of chemokine

A

CXC

CC

112
Q

Which class of chemokine are neutrophil attractants?

A

CXC chemokines

113
Q

In RA, activated tissue cells produce _________ which attract ____________ to the ___________

A

Chemotaxins (esp chemokines)
Leukocytes
Synovium

114
Q

In RA, tissue cells and leukocytes are further activated and produce what 4 things

A

Cytokines
Chemoattractants
Proteases
Reactive oxygen & nitrogen species

115
Q

What is cartilage?

A

Connective tissue made up of cells and extra cellular matrix

116
Q

What is the role of cartilage

A

Provides smooth robust surface over the bone ends:

  • low friction movement
  • protects bone from mechanical wear
117
Q

Cartilage is made up of what cells

A

Chondrocytes

118
Q

Joint cartilage comprised mainly what two things?

A

Fibrous protein

Proteoglycan

119
Q

What is bone?

A

Dense connective tissue made up of cells and matrix

  • mineralised calcium phosphate matrix
  • fibrous protein(collagen)
120
Q

What is proteoglycan?

A

Part of cartilage structure: chondroitin sulphate (polysaccharide) linked to aggrecan (core protein), it’s charged (highly sulphated) and bind water

121
Q

What do synovial fibroblasts secrete?

A

Lipid mediators (PGE2)
Cytokines
Enzymes
Matrix materials

122
Q

What makes bone?

A

Osteoblasts

123
Q

What’s osteoclasts?

A

Activated by cytokines, they break down bone

124
Q

Proteoglycans are lost rapidly in RA which leads to what?

A

Shock absorption impaired- loss of joint function= pain

125
Q

Proteoglycans have an open structure which makes them what?

A

Highly accessible and thus sensitive to breakdown by several proteinases

126
Q

In RA which is lost more slowly: proteoglycans or collagen

A

Collagen but loss is irreversible

127
Q

Is native collagen susceptible to breakdown by all enzymes that can degrade collagen?

A

NO native collagen only susceptible to collagenases but once it’s damaged other enzymes can degrade it

128
Q

What does MMP stand for?

A

Matrix metalloproteinase

129
Q

Name the three MMPs that are collagenases?

A

MMP-1 -8 -13

130
Q

What MMP is gelatinase A

A

MMP 2

131
Q

Is matrix metalloproteinase active at neutral pH?

A

YES

132
Q

What do matrix metalloproteinases contain and require

A

Zn2+

133
Q

What inhibit matrix metalloproteinases?

A

Tissue inhibitors of metalloproteinases (TIMPs)

134
Q

How is matrix metalloproteinase activated?

A

Activated by removal of propeptide and hence the cysteine motif- activated by serine proteases

135
Q

On matrix metalloproteinases what is the c terminus important for?

A

Substrate specificity and regulation

136
Q

How do matrix metalloproteinases inhibitors work?

A

The active site Zn2+ is targeted by hydroxamate series: E.g marimastat

137
Q

Name two types of MMP inhibitors

A

Peptidomimetics

Non-peptide hydroxamates

138
Q

Name a type of peptidomimetics MMP inhihitor

A

Marimastat

139
Q

Name a type of non-peptide hydroxamate MMP inhihitor

A

Prinomastat

140
Q

Which type of MMP inhibitor has better selectivity for collagenases?

A

Non-peptide hydroxamates e.g prinomastat

141
Q

Name 4 classes of proteolytic enzymes

A

Matrix metalloproteinases
Serine proteinases
Cysteine proteinases
Aspartate proteinases

142
Q

Name 3 other approaches to inhibiting Matrix metalloproteinases?

A

Tetracycline derivatives
Antibody based therapeutics
Endogenous inhibitors of MMPs

143
Q

Name 4 matrix proteins that serine and cysteine proteinases break down

A

Elastin
Laminin
Chondroitin sulfate
Proteoglycans

144
Q

Serine protease inhibitors are also called what?

A

SERPINS

145
Q

What are SERPINS readily inactivated by?

A

Oxidation

146
Q

Name three adverse effects of matrix metalloproteinases

A

Musculoskeletal syndrome
Lack specificity
Role in homeostatic connective tissue turnover

147
Q

What’s the process of reactive oxygen and nitrogen species formation?

A

NADPH –> O2- –> H2O2 –> OH. + HOCl-

Then nitrogen species formed from NOS derived NO combining with oxygen species

148
Q

What is reactive oxygen and nitrogen species essential for?

A

Host defence

149
Q

What does RONS activate?

A

Activation of inflammatory gene transcription

-NFkB

150
Q

The shared epitope carried by rheumatoid arthritis patients is what?

A

A 5aa sequence motif in the third allelic hypervariable region of the HLA-DRBeta chain

151
Q

What is rheumatoid factor

A

The first antibody associated with rheumatoid disease

152
Q

What does ACPA stand for

A

Anti-citrullinated protein antigen

153
Q

What’s citrulline?

A

A post translational modification of arginine, it’s up regulated in joints

154
Q

Are anti-citrulline protein antibodies highly specific for RA?

A

Yeh they are and they’re found up to 14yrs before onset of symptoms in RA

155
Q

What does HAQ stand for

A

Health assessment questionnaire

156
Q

What does the HAQDI score?

A

How difficult patients can carry out activities