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Inflammation Flashcards

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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
What is histamines stimuli for release?
Type 1 immediate hypersensitivity via IgE (allergy) Chemicals: e.g. Insect bites Mechanical injury to skin
25
What is the triple vascular response?
Redness (depends on soluble, chemical mediator) Flare (depends on nerve supply) Weal (depends on soluble, chemical mediator)
26
What is the cutaneous response to histamine or allergen?
Triple response: Arterial vasodilation- local reddening Oedema formation (WHEAL) Axon reflex (FLARE)- release of neuropeptides
27
What are the actions of histamine (4 receptors)?
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
What is the pathopyshiological role of histamine?
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
Describe H1 receptors
``` Gq coupled- PLC--> Ca2+ Endothelial cell contraction- oedema EC release of NO- vasodilation Neuropeptide release- vasodilation airway and gut smooth muscle contraction. ```
30
Describe H2 receptors
Gs coupled- adenylyl cyclase----> cAMP | Vascular smooth muscle cell relaxation
31
What are H1 receptor antagonists?
Antihistamines Chlorphenamine Newer drugs lower lipophilicity- astemizole, loratadine Useful in urticaria and nasal congestion
32
What are H2 receptor antagonists?
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
What are Eicosanoids derived from?
A 20 carbon unsaturated fatty acid
34
What is arachidonic acid?
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
What are the physiological functions of prostaglandins?
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
What are Eicosanoids?
Oxidation products of 20 carbon fatty acids: | Arachidonic acid, Dihomo gamma-linoleic acid, Eicosapentanoic acid
37
What are classical Eicosanoids?
Prostaglandins, prostacyclins, thromoboxanes, Leukotrienes
38
What are non-classical Eicosanoids?
Lipoxins, resolvins, isoprostanes, endocannabinoids
39
Describe arachidonic acid metabolism
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
Describe prostaglandin receptors
Prostaglandins act via specific GPCRs on target cells four PGE2 receptors- EP1-EP4 Prostacyclin (PGI2) receptor IP
41
EP2 and IP
Are vasodilators Enhance plasma extravasion Gs coupled to adenylyl cyclase- increase cAMP
42
PGD2 receptors
DP1 and DP2 | DP2 also termed CRTH-2
43
Thromoboxane receptor
TP
44
PGF2 receptor
FP | Gq coupled to PLC ---> IP3 and calcium
45
Prostaglandins and pain
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
Prostaglandins in fever
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
Cyclo-oxygenases
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
COX-1
Constitutive, widely expressed, I-523 critical residue
49
COX-2
Inducible (by TNFalpha, IL-1) repressed by GC Inflammatory cells Critical reside- V-523
50
Where are COX found?
Both COX-1 and COX-2 are homodimers found in inner membrane of ER
51
Aspirin
Acetyl salicylic acid | Acetylated serine residue (530 in COX-1, 516 in COX-2)
52
COX-2 selectivity
Inhibition of COX-2, but not COX-1, across the entire therapeutic dose range
53
What drug is COX-1 selective?
Low dose aspirin
54
What drugs are COX-2 selective?
Meloxicam, nimesulide, celecoxib (rofecoxib)
55
What drugs are mixed COX-1 and COX-2 selective?
Indomethacin, diclofenac, piroxicam, ibuprofen, naproxen, flurbiprofen
56
What are the side effects of aspirin like drugs?
Gastric irritation and bleeding, renal toxicity, bleeding tendency are due to blocking 'housekeeping' COX-1 and thus reducing the cytoprotective effects of PGs
57
Rofecoxib
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
What are the anti-thrombotic actions of aspirin?
``` 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
What are the actions of Leukotrienes?
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
What is the action of gluticorticoids on eicosanoids?
Inhibit PLA2 transcription Induce synthesis of endogenous PLA2 inhibitor 'lipocortin' Inhibit COX-2 synthesis
61
Why are Eicosanoids important?
``` 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
What is leukocyte migration?
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
Leukocyte diapedesis
1. Circulating 2. Tethering/rolling 3. Firm adhesion 4. Transmigration
64
What is tethering and rolling?
Fast moving leukocytes tethered to vessel wall | Guided by specific homing receptors and their ligands
65
What are selectins?
``` Lectin-like adhesion molecules (weakly bind CHO structures) Expressed by L: leukocytes, P: (platelets) endothelium E: endothelium, ```
66
L-selectin
Constitutive expression on leukocytes. | Leukocyte activation leads to; transient increase in avidity, rapid shedding by proteolytic cleavage
67
P-selectin
Constitutive in platelets and endothelium, stored in granules Rapidly translocated to cell surface on cell activation
68
E-selectin
Endothelial expression induced by cytokines or LPS Expression requires denote protein synthesis Expression inhibited by glucocorticoids

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