Week 10 SAIDs and Inflammation Flashcards
Innate immune system activation = inflammation
Innate immune cells recognise and are activated by molecular patterns associated with injury (ischaemia, trauma) or infection
- Cellular damage (cell contents): - e.g. K+, DNA, H+, ATP, warning proteins
= (DAMPs)
and / or - Pathogen (non-self)
components, e.g.
- viral proteins,
- bacteria cell wall
=> PAMPs
Innate immune system definition and purpose
a “non-specific” first line body defence response to cell injury or infection
purpose:
- localise and eliminate the injurious agent
- remove damaged tissue components
- body can begin to heal
5 cardinal signs of inflammation
redness
heat
swelling
pain
decreased function
(systemic = fever)
Acute inflammation (2 phases)
- Vascular phase
- cellular phase
Vascular phase
1.Injured cells, sensory neurons & resident immune cells release chemical mediator
2. Chemical mediators induce vasodilation (warmth) & increase capillary permeability => influx of plasma proteins that propagate inflammation (swelling, redness)
3. Plasma proteins lead to blood clotting, complement system and kinin production
4. The ‘complement system’ plus inflammatory mediators (chemokines) attract phagocytic white blood cells (e.g. monocytes and neutrophils) to the injury site =>
Cellular phase
Neutrophils & macrophages enter infl. tissue through the leaky blood capillaries
Phagocytic cells :
- ingest invading pathogens, dead cells and cellular debris
- release cytokines (enhance inflamm.) & ‘pyrogens’ & induce fever.
Chronic inflammation
Inflammation that lasts for 2 weeks or more.
*Results from an inability of the inflammatory response to remove the cause of inflammation
*Eg. chronic inflammatory diseases include
- arthritis (osteo / rheumatoid),
- Crohn’s disease & IBD
- asthma / COPD
- tuberculosis
*Can be dominated by lymphocytes & monocytes/macrophages
*Persistent inflammation causes local tissue damage and high fibroblast activity at the site causes local deposition of fibrin and formation of ‘fibrotic’ (dead/ cell-free) tissue (scarring)
inflammatory
mediators
eicosanoids = (Greek for “20” as derived from C20 fatty acids) arachidonic acid metabolites, including prostaglandins (PGs) and leukotrienes (LTs), thromboxane
- histamine = stored in mast cells (the major role of histamine in inflammation is to mediate allergic reactions)
- platelet activating factor (PAF) and C5a
Except for histamine, inflammatory mediators are not stored; they are synthesized and released in response to inflammatory stimuli, thus inflammation takes time.
What is the inflammatory synthetic process?
Inflammatory stimulus
->
Arachidonic acid - esterified to membrane phospholipids
->
[phopholipase A2]
->
free cytosolic Arachidonic Acid
=
Prostanoids: PGs, prostacyclin (PGI2),
thromboxanes.
Inflammatory mediator overview
Products of cyclooxygenase (COX) enzymes: prostaglandins (PGs), prostacyclin (PGI2)
COX = cyclo-oxygenase enzyme
LOX = lipoxygenase enzyme
CYP = cytochrome P450
PG = prostaglandin
LT = leukotriene
EET = epoxyeicosatrienoic acid
HETE = hydroxyeicosatetraenoic acid
Prostaglandins (PGs)
Inflammatary roles:
- vasodilation
- altered platelet function
- hyperalgesia (abnormally increased sensitivity to pain)
- bronchoconstriction
- uterine contraction
- fever
How do prostanoids bring about their effects?
- G-protein coupled receptors (GPCRs), Table 33-1;
- Great diversity in receptor structures and G-protein interactions.
- e.g. PGE2, PGI2 and PGD2 each cause local vasodilation and reduced BP; PGF2a causes constriction of pulmonary arteries and veins, no change in BP.
- These effects may differ by tissue, e.g. contraction of GI and uterine smooth muscle, increased gastric secretions.
Endogenous agents which reduce PLA2 activity
Endogenous corticosteroids are made in the adrenal cortex:
* Mineralocorticoids are involved in water and electrolyte balance (aldosterone);
* Glucocorticoids have widespread effects on
metabolism, as well as mechanisms of
defense (hydrocortisone (“aka” cortisol)).
Exogenous glucocorticoids are most commonly used for their anti-inflammatory effects, hopefully with reduced mineralocorticoid activity
– very lipophilic.
- Common drugs used are hydrocortisone, prednisolone, and dexamethasone.
SAIDs
Glucocorticosteroids
Steroid hormones
e.g. Prednisolone - synthetic GCS
Hydrocortisone - endogenous GCS
Physiological role
= glucose homeostasis under stress
SAIDs reduce inflammation, but also have strong immunosuppressive and wider effects on the body
=> most potent anti-inflammatories BUT many side effects
Main anti-inflammatory mechanisms:
- increase synthesis of anti inflammatory proteins
- decrease synthesis of pro-inflammatory mediators
Main anti-inflammatory mechanism of action of SAIDs
Lipocortin-1 inhibits phospholipase A2
AND
Reduces the expression of COX enzymes
Overall result is the reduced production of prostaglandins + a lot more.
SAIDs (corticosteroids): Summary
- Bind to intracellular glucocorticoid receptors in cytoplasm
- enter the cell nucleus, alter inflammatory gene expression
- SAIDs upregulate anti-inflammatory genes e.g. IL-10, b2-adrenoceptor,
lipocortin-1 (annexin) (inhibits prostaglandin synthesis) - Inhibit pro-inflammatory pathways : synthesis and release (cytokines, chemokines, enzymes e.g. < iNOS, < COX2 … )
- Decrease inflammatory cell number (proliferation) = allergies
- Inhibition of IL2 & Th cell
proliferation = immunosuppression
Anti-inflammatory Indications of corticosteroids
- Transplant rejection (in combination with other immunosuppressants)
- Rheumatoid arthritis (injected into joints)
- Inflammatory bowel disease / Crohn’s disease / Ulcerative colitis
- Psoriasis & Systemic lupus erythematosus
- Asthma / allergies
- Septic shock… (can restore cardiac output and increase BP)
Potential side effects of corticosteroids
Immunosuppressive activity increases risk of microbial infections.
- Worsen diabetes (promote hyperglycaemia by lowering glucose uptake and promoting gluconeogenesis)
- Some drugs can activate mineralocorticoid receptor and thus cause Na+ and water retention, leading to hypertension and heart failure.
- May increase the risk of peptic ulcers (greater gastric acid, less gut protection)
- May increase osteoporosis, as Ca2+ absorption is decreased and vit D is blocked,
NSAIDs
Non-Steroidal Anti-Inflammatory Drugs
NSAIDs inhibit prostaglandin synthesis by inhibiting COX-1 & 2
- All* NSAIDs have the following
effects, - Anti-inflammatory*
– Anti-pyretic (lower body temp)
– Analgesic (reduce pain) magnitude of these effects vary for each drug and pain indication - NSAIDs provide relief from
- swelling in arthritis,
- bone fractures,
- soft tissue injury,
- postoperative & dental pain,
- menstrual pain,
- headaches and migraines.
- Used extensively to control mild pain and inflammation
- NSAIDs are the most prescribed medications in the world
- Use of NSAIDs is on the rise due to:
– availability without a prescription
– use of aspirin for prevention of thrombotic disorders
– the ageing population
COX enzymes
COX-1: produces protective prostaglandins that :
* Coat the stomach lining with mucus (=protection), PGE2
* Aid in platelet aggregation (prevent
excessive bleeding), TXA
* Regulate renal blood flow
* Induce parturition, PGF + PGE2
COX 2: produces inflammatory
prostaglandins that:
- sensitise skin nociceptors
- increase body temperature by acting on the hypothalamus
- recruit inflammatory cells
towards injured parts of the body
Antipyretic effects of NSAIDs
- Body temperature controlled by
a hypothalamic “thermostat” which ensures that heat production and heat loss are in balance around a set-point. - Fever occurs when hypothalamic
interleukin-1 (IL-1), an inflammatory mediator, stimulates production of PGE2 that elevates the set-point. - In the POAH, neurons with PGE
receptors change the firing rate of
neurons in the febrile response,
raising the set-point. - NSAIDs act by interrupting this
synthesis of PGE2, returning the
set-point to normal temperature. - The body then adjusts dilation of
blood vessels, sweating, etc. to
restore normal body temperature.
Antithrombotic effects
At low concentrations of aspirin
PERMANENTLY acetylate blood platelet COX-1 enzyme, leading to inactivation of thromboxane production.
- Thromboxane is a vasoconstrictor and aids in platelet aggregation. By
inactivating it, there is a marked
reduction in blood clotting. - Platelets are cell fragments without
a nucleus- so cannot replace COX-1
once acetylated. It may take a week
for the platelets to be regenerated.
Aspirin thus prolongs clotting time of the blood; a single dose of aspirin doubles clotting time.
Side effects common to most NSAIDs
(mainly due to inhibition of COX1?)
- Gastrointestinal disturbances:
– Inhibition of gastric mucosal production by PGs
– Blockage of the ‘acid secreting inhibitory’ effects of PGs
=> Due to systemic exposure to NSAIDs, NOT gastric exposure
– Direct irritation of the gastric mucosa may contribute - Renal effects:
– Reduce renal blood flow, increase toxic effects of drugs
=> Inhibition of PG/prostacyclin production that maintains high renal blood flow - Cardiovascular effects:
– anticoagulant effects of some NSAIDs can prolong bleeding time - Uncommon effects:
– Skin reactions: idiosyncratic rashes, erythematosus and photosensitivity
Severity of side effects correlates to effectiveness as an anti-inflammatory
Aspirin
(Class: salicylates)
Irreversibly inhibits COX 1 & 2 through COX acetylation (COX1:COX2 ratio is >10:1)
Effects on pain and fever:
– decreases hyperalgesia after tissue injury => analgesic
– Anti-inflammatory in arthritis
– PGs in the hypothalamus change the ‘set point’ for body temp
– Aspirin ‘resets’ the body’s internal thermostat to normal => decreases fever.
Effects on blood clotting: (antiplatelet activity)
* Inhibits platelet thromboxane synthesis – slows clotting
* Single 0.5 g dose doubles clotting time for ~5 days
* Don’t use 1 week before surgery
(risk of operative and post-operative bleeding)
* Used to prevent arterial clotting in at risk patients (elderly)
* Limited effect on venous clotting (DVT)
