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Infection And Immunity > Inflammation > Flashcards

Inflammation Flashcards

0
Q

What are the 5 components of inflammation?

A

Heat, redness, swelling, pain, loss of function

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1
Q

What is the inflammatory process

A

Natural response of tissue to injury
Attack and remove cause of injury, repair damaged tissue
Beneficial, protective, self-limiting

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2
Q

What are the neurons involved in inflammation (pain)

A

Sensory neurons
Mediate nociception, release neuropeptides, contribute to redness and swelling, substance p, calcitonin gene related peptide

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3
Q

How does neuropeptides induced inflammation work?

A

Skin injury stimulates mast cells to release histamine
This sends signals to the brain
Also signals causes release of neuropeptides substance P and CGRP and this causes blood vessels to dilate and leak

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4
Q

Pg and CGRP

A 
PG= prostaglandins. Increase level of pain detected
CGRP= calcitonin gene related peptide. More potent than Pg
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5
Q

Inflammation involves complex interplay between… (5 things)

A 
Microvasculature (small blood vessels)
Leukocytes (white blood cells)
Nerves
Tissue cells (structural, immune)
Chemical mediators of inflammation (produced by all the above, plasma)
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6
Q

Rheumatoid arthritis background

A 
A chronic inflammatory joint disease
Affects 1-2% of uk population 
3:1 female:male
Variable onset 30-50 years
Complex pathology with unknown cause- genetic factors, immunological factors (autoantibodies), hormonal factors, neuronal factors, environmental factors
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7
Q

What is rheumatoid arthritis?

A

Affects numerous tissues and organs- predominant features of inflammation of the joints.
Loss of cartilage, bone erosion mediated by proteinases- predominantly Matrix Metallo Proteinases (MMP) secreted by tissue cells (synovial fibroblasts, chondrocytes).
Fibrous tissue formation (scarring) and loss of mobility

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8
Q

How are tissue cells activated in RA?

A

By infiltrating leukocytes, driven by inflammatory mediators and cytokines, particularly derived from macrophages (TNFalpha, IL-1beta).
T and B lymphocytes help to maintain cytokine production

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9
Q

What are the types of leukocytes? (white blood cells)

A

Granulocytes- neutrophils, eosinophils, basophils
Mononuclear cells- monocytes (macrophages), lymphocytes (T and B cells)
Mast cells

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10
Q

What is a macrophage?

A

’ big eater’
Defence against environment- phagocytosis, respiratory burst
Arise from blood monocytes
Long lived (months)
Major source of cytokines- IL-1, TNF, chemokines

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11
Q

What are lymphocytes?

A

Define by surface antigens, the cytokines they make and function
T cells and B cells

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12
Q

What are the types of T cells?

A 
T helper (CD4+)- TH1 and TH2 
T cytotoxic (CD8+)- Tc
Natural killer (NK, NKT)
Th17
Regulatory T cell (Treg)
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13
Q

What are B cells?

A

Mature to become antibody secreting ‘plasma cells’

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14
Q

What are T cells?

A

T cells are controllers of the specific immune system
T cells subsets secrete different cytokines
Different cytokines are associated with different immune responses
Imbalance or inappropriate activation of T-cell subsets leads to disease

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15
Q

What are the chemical mediators of inflammation?

A

Diverse molecules produced by the host in response to infection and immune reactions.
Low specificity (not antibodies)
Promote and effect inflammation

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16
Q

Why is inflammation beneficial?

A

Increase supply of cells and chemical mediators to site of inflammation- redness: increases blood flow, swelling: increased vascular permeability, allow removal of damaged tissue and infections agents, supply new materials for repair.
Tells body to rest- pain, loss of function

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17
Q

What is the mediator response to local injury? (5 things)

A

Release of pre-formed mediators- histamine
Rapid production of mediators from membrane lipids- eicosanoids (PGE2, PGI2), Leukotrienes (LTB4), PAF
Release of peptides from stimulated neurones- substance P, CGRP
Mediator production following proteinase activation- bradykinin, complement fragments (c3a, c5a)
Later (hours) production following protein synthesis- iNOS, COX2, cytokines

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18
Q

What mediators cause vasodilation?

A 
Histamine
Eicosanoids- PGE2, PGI2
Neuropeptides
Bradykinin
Nitric oxide
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19
Q

Which mediators increase vascular permeability?

A 
Histamine
Eicosanoids- LTB4, LTC4
PAF- platelet activating factor
Bradykinin 
C3a, c5a
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20
Q

What is plasma exudation?

A

Some agents increase plasma leakage via an action directly on the endothelium- histamine, bradykinin.
Neutrophil activators increase plasma leakage via a neutrophil dependent mechanism- LTB4, fmLP, interleukin-8

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21
Q

What is histamine synthesised from?

A

L-histidine goes to histamine using enzyme Histidine decarboxylase. Histamine goes inactive Imidazolyl acetic acid using enzyme histaminase

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22
Q

What inhibits histidine decarboxylase?

A

Tritotoqualine

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23
Q

Where is histamine stored?

A

Mainly in mast cells (in skin, lungs, gut and nasal mucosa)

Histamine is basic and is stored with acidic high molecular weight heparin

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24
Q

What is histamines stimuli for release?

A

Type 1 immediate hypersensitivity via IgE (allergy)
Chemicals: e.g. Insect bites
Mechanical injury to skin

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25
Q

What is the triple vascular response?

A

Redness (depends on soluble, chemical mediator)
Flare (depends on nerve supply)
Weal (depends on soluble, chemical mediator)

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26
Q

What is the cutaneous response to histamine or allergen?

A

Triple response:
Arterial vasodilation- local reddening
Oedema formation (WHEAL)
Axon reflex (FLARE)- release of neuropeptides

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27
Q

What are the actions of histamine (4 receptors)?

A

Potent vasodilators (arterioles) via H1 receptors
Increases vascular permeability (post-capillary venues) producing oedema swelling) via H1 receptors
The classic triple response following intra dermal injection
Potent stimulant of gastric acid secretion via H2 receptors
Role in chemo taxis via H4 receptors

28
Q

What is the pathopyshiological role of histamine?

A

Histamine release from mast cells important in immediate hypersensitivity responses: allergic rhinitis (hayfever), Urticaria (skin rashes), anaphylactic shock.
Histamine is the primary factor involved in the control of gastric acid secretion- hyper secretion of histamine results in excess acid production and formation of duodenal and peptic ulcers

29
Q

Describe H1 receptors

A 
Gq coupled- PLC--> Ca2+
Endothelial cell contraction- oedema 
EC release of NO- vasodilation
Neuropeptide release- vasodilation
airway and gut smooth muscle contraction.
30
Q

Describe H2 receptors

A

Gs coupled- adenylyl cyclase—-> cAMP

Vascular smooth muscle cell relaxation

31
Q

What are H1 receptor antagonists?

A

Antihistamines
Chlorphenamine
Newer drugs lower lipophilicity- astemizole, loratadine
Useful in urticaria and nasal congestion

32
Q

What are H2 receptor antagonists?

A

Histamine released from enterochromaffin-like cells
H2 receptors on parietal cells- gastric acid secretion
H2 antagonists block this action- cimetidine and raniditidine
Useful in peptic ulcer disease, oesophageal reflux
Inhibit p450 (especially cimetidine)- interaction with many other drugs

33
Q

What are Eicosanoids derived from?

A

A 20 carbon unsaturated fatty acid

34
Q

What is arachidonic acid?

A

An essential fatty acid derived from red meat, or indirectly via desaturation of linoleic acid
All cells of the body contain arachidonic acid, primarily as component of membrane phospholipids

35
Q

What are the physiological functions of prostaglandins?

A

1) initiation of labour (PGF2alpha 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 and vasoconstriction

36
Q

What are Eicosanoids?

A

Oxidation products of 20 carbon fatty acids:

Arachidonic acid, Dihomo gamma-linoleic acid, Eicosapentanoic acid

37
Q

What are classical Eicosanoids?

A

Prostaglandins, prostacyclins, thromoboxanes, Leukotrienes

38
Q

What are non-classical Eicosanoids?

A

Lipoxins, resolvins, isoprostanes, endocannabinoids

39
Q

Describe arachidonic acid metabolism

A

Membrane phospholipid goes to arachidonic acid using PLA2. Arachidonic acid goes to prostaglandins (PGI2, PGE2, TXA2) using COX
Arachidonic acid also goes to Leukotrienes (LTB4, LTC4, LTD4) using 5-lipoxygenase

40
Q

Describe prostaglandin receptors

A

Prostaglandins act via specific GPCRs on target cells
four PGE2 receptors- EP1-EP4
Prostacyclin (PGI2) receptor IP

41
Q

EP2 and IP

A

Are vasodilators
Enhance plasma extravasion
Gs coupled to adenylyl cyclase- increase cAMP

42
Q

PGD2 receptors

A

DP1 and DP2

DP2 also termed CRTH-2

43
Q

Thromoboxane receptor

A

TP

44
Q

PGF2 receptor

A

FP

Gq coupled to PLC —> IP3 and calcium

45
Q

Prostaglandins and pain

A

Prostaglandins sensitise peripheral C-fibres- increase pain response to other agents, increased algesic response to bradykinin
EP1 receptors in dorsal root ganglia- role in pain pathway
EP1 receptor knock out mice have decreased inflammatory pain responses

46
Q

Prostaglandins in fever

A

Fever results from elevation of thermoregulatory set point
Regulated by production and action of PGE2 in the anterior hypothalamus- cerebroventricular injection of PGE2 leads to fever (not sensitive to NSAIDs or paracetamol). Role for EP3 receptor

47
Q

Cyclo-oxygenases

A

Exists in two isoforms (encoded by separate genes)
COX-1 constitutive ‘housekeeping enzyme’- products important in normal function of stomach, intestine, kidney and platelets
COX-2 induced particularly in inflammatory cells exposed to inflammatory stimuli
COX-3 splice variant of COX-1 gene; expressed in CNS a. Relevance in human is questioned

48
Q

COX-1

A

Constitutive, widely expressed, I-523 critical residue

49
Q

COX-2

A

Inducible (by TNFalpha, IL-1) repressed by GC
Inflammatory cells
Critical reside- V-523

50
Q

Where are COX found?

A

Both COX-1 and COX-2 are homodimers found in inner membrane of ER

51
Q

Aspirin

A

Acetyl salicylic acid

Acetylated serine residue (530 in COX-1, 516 in COX-2)

52
Q

COX-2 selectivity

A

Inhibition of COX-2, but not COX-1, across the entire therapeutic dose range

53
Q

What drug is COX-1 selective?

A

Low dose aspirin

54
Q

What drugs are COX-2 selective?

A

Meloxicam, nimesulide, celecoxib (rofecoxib)

55
Q

What drugs are mixed COX-1 and COX-2 selective?

A

Indomethacin, diclofenac, piroxicam, ibuprofen, naproxen, flurbiprofen

56
Q

What are the side effects of aspirin like drugs?

A

Gastric irritation and bleeding, renal toxicity, bleeding tendency are due to blocking ‘housekeeping’ COX-1 and thus reducing the cytoprotective effects of PGs

57
Q

Rofecoxib

A

Withdrawn in 2004 due to 3.9x incidence of thromboembolic events.
Endothelial PGI2 derived mostly from COX-2, not COX-1
Rofecoxib suppresses this but has no effect on platelet COX-1 and so unbalances TXA2 v PGI2 production

58
Q

What are the anti-thrombotic actions of aspirin?

A 
Aspirin irreversibly acetylates cyclo-oxygenase, thus platelet TXA2 production ceases (lack of nucleus)
Endothelial cells make new COX and so PGI2 is still released
So useful in:
Acute MI
Coronary artery by-pass
After angioplasty and stenting
Acute thrombotic stroke 
Pulmonary embolism and thrombosis
59
Q

What are the actions of Leukotrienes?

A

Bronchoconstriciton- LTC4 and LTD4 constrict human bronchial smooth muscle
Oedema- LTC4 and LTD4 stimulate increased vascular permeability. LTB4 increases vascular permeability
Chemotaxis- LTB4 potent chemo tactic agent for inflammatory cells. BLT1 receptor.
Inflammation- high levels in synovial fluid of rheumatoid arthritis patients.

60
Q

What is the action of gluticorticoids on eicosanoids?

A

Inhibit PLA2 transcription
Induce synthesis of endogenous PLA2 inhibitor ‘lipocortin’
Inhibit COX-2 synthesis

61
Q

Why are Eicosanoids important?

A 
Potent vasodilators (PGE2, PGI2)
Increase vascular permeability (LTs)
Synergy with other mediators; with histamine, bradykinin, chemotaxis
Pain (PGE2, PGI2)
Fever (PGE2)
Important modulators of cell function
62
Q

What is leukocyte migration?

A

Leukocytes (and other cells) move from the 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 participate in host defence, inflammation and repair and resolution

63
Q

Leukocyte diapedesis

A
  1. Circulating
  2. Tethering/rolling
  3. Firm adhesion
  4. Transmigration
64
Q

What is tethering and rolling?

A

Fast moving leukocytes tethered to vessel wall

Guided by specific homing receptors and their ligands

65
Q

What are selectins?

A 
Lectin-like adhesion molecules (weakly bind CHO structures)
Expressed by 
L: leukocytes, 
P: (platelets) endothelium
E: endothelium,
66
Q

L-selectin

A

Constitutive expression on leukocytes.

Leukocyte activation leads to; transient increase in avidity, rapid shedding by proteolytic cleavage

67
Q

P-selectin

A

Constitutive in platelets and endothelium, stored in granules
Rapidly translocated to cell surface on cell activation

68
Q

E-selectin

A

Endothelial expression induced by cytokines or LPS
Expression requires denote protein synthesis
Expression inhibited by glucocorticoids

Infection And Immunity (1 decks)

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