Inflammation: the molecular basis Flashcards
What is inflammation?
Localised, protective response to injury or infection, characterised by:
- Pain - Dalor
- Heat - Calor
- Swelling - Tumor
- Redness - Rubor
- Loss of function - Functio laesa
- Mediated primarily by cells present in the blood stream
What’s the purpose of inflammation?
Physical protection
- Increase in blood flow to the site of trauma/infection - allows defence cells present in the blood to then attack and destroy invading pathogens
What’s acute inflammation?
- Initial response to injury or infection
- Lasts for days/weeks
- Protective response which leads to healing and resolution
What are the constituents of “inflammatory soup”?
- Cytokines: superfamily of humoral substances released from cells associated with the immune system, that exhib autocrine/paracrine activity. E.g. IL, chemokines, lymphokines, TNF
- Prostanoids: substances produced via action of cyclo-oxygenase (COX) e.g. prostaglandins, prostacyclins, TXA2
- Nitric Oxide
- Bradykinin
- Histamine
What’s the primary inflammatory response?
- The initiation of the primary inflammatory response is via the recognition of Pathogen associated molecular patterns (PAMP’s) and Damage associated molecular patterns (DAMP’s)
- PAMP’s are common products produced by bacteria/fungi/virus infected cells (lipopolysaccharides LPS) and they are detected by Pathogen Recognition Receptors (PRR’s = TLR’s) on innate immune cells (monocytes/macrophages, dendritic cells, monocytes, fibroblasts, epithelial and endothelial cells)
2b. DAMPs are products of self cells which are either secreted or expressed by damaged or dead cells (RNA/DNA/heat shock protein (HSP/ high-mobility group box 1 (HMGB-1) - detected by TLR’s and Node-like receptors (NLRs) expressed on phagocytes - PAMP and DAMP detect causes non-immune cells to secrete MCP-1 chemokine which acts as a chemoattractant and recruits monocytes to the area of injury
3b. PAMPs and DAMPs also activate Caspase-1 which cleave pro-IL-1 (inflammatory cytokines) and allow them to be secreted and TNF secretion
3c. IL-1 increase blood vessel vasodilation & upregultion of ICAM-1 for leukocyte adhesion and transmigration / increased permeability of post capillary venule (PCV) - Increased vascular permeability allows fluid exudate containing components of:
+ Coagulation cascade
+ Complement system
+ Fibrinolytic cascade
+ Kinin system
- to enter the interstitial fluid surround cells - These exudate components cause an increase in Thrombin (clots), bradykinin - causes endothelial smooth muscle cells to secrete nitric oxide and prostacyclin which causes vasodilation and activate Phospholipase A2 (LPA2)
- LPA2 converts phospholipids into Arachadonic Acid
- Cells at the site of injury possess a Nuclear Factor - Kappa B (nf-kb) transcription factor which is normally under inhibition from IKB
7b. IL-1 and TNF-alpha cause signal induced degradation of IKB, freeing NF-kB – enters the nucleus and activates genes coding for COX2 and iNOS - COX2 converts Arachadonic acid into Prostaglandins and is INDUCIBLE - Found in cells assocaited with inflammation
8b. Prostaglandins don’t cause pain themselves; they potentiate the pain-producing effect of bradykinin ( and sensitise nerve terminals to other agents by partly inhibiting potassium ion channels (bradykinin itself causes prostaglandin release (self-sensitising” )) (Hyperalgesia)
What is the physiological process behind a fever?
- IL-1 secretion into the bloodstream travels to the hypothalamus in the brainstem
- Cause an COX2 expression = production+increase in Prostaglandin E2 (pge2)
3, PGE2 binds to EP3 in the pre-optic nucleus of the hypothalamus slowing the firing rate of the warm sensitive neurons and resulting in an increase in body temperature
- The increase in core body temperature is supposed to kill off the pathogenic cells but it will also cause self cell death
How can we inhibit the Cyclo-oxygenase (COX) pathway?
- Glucocoriticoids
2. Non-steroidal Anti-inflammatory Drugs (NSAID’s)
What are Glucocoriticoids and how do they function?
- Family of steroid homones produced by the adrenal cortex
Glucocorticoid = Regulation of glucose metabolism (increases blood glucose)
- Very potent anti-inflammatory agent which is typically prescribed in Oral Maxillofacial Surgery
- Binds to intracellular receptors = changes gene expression
- Potent inhibitor of nuclear factor kappa B (NF-kappa B) activation - inhibition is mediated by induction of the I kappa B alpha inhibitory protein, which traps activated NF-kappa B in inactive cytoplasmic complexes
- Prevents gene expression for COX2 and iNOS & blocks genes coding for IL-1 and TNF-a = non creation of prostaglandins
How do Glucocorticoids interact with Macrophages?
They annex on the surface of macrophages which reduces the production of Phospholipase A2 which decrease the conversion of Phospholipids to Arachadonic acid
What’s the mechanism of action for NSAID’s
- Inhibit COX directly to reduce the production of prostaglandins
Different NSAIDs target different COX 1/2/3
- Possess anti-pyrogenic properties - in the hypothalamus they will inhibit the production of prostaglandin E - NO inhibition of WARM SENSING NEURONS
How is inducible nitric oxide produced and what is its function?
- Gene expression increased by NF-kB and is expressed by cells in response to inflammatory stimuli (IL-1 family and TNF-a)
- Has same qualities as endothelial NO
1. Vasodilation
2. Increased vascular permeability
3. Increased production of pro-inflammatory prostanoids (prostaglandins)
4. Inhibition of platelet aggregation
5. . Cytoxic - Killer T-cells relsease a high concentration dose of NO which kills nearby cells.
What’s Bradykinin?
- Potent pain producing agent which sensitises nociceptive fibres
- Produced as a by-product of clotting cascade activation
1. Activated factor XII converts Prekallikrein = Kallikrein
2. Kallikrein cleaves HMW-Kininogen to Bradykinin
What’s Histamine?
Amine agent predominantly found in mast cells and basophils (allergic reaction)
- Stored in granules, released by exocytosis in response to inflammatory stimuli (mainly complement proteins and Antibodies)
H1 = Contraction of most smooth muscle BUT cause relaxation of vascular smooth muscle cells = vasodilation
- Itching
H2 = Gastric acid secretion
H3 = plasticity in CNS
What occurs after unsuccessful/inappropriate acute inflammation initiation?
- Chronic inflammation - mononuclear cells, localised tissue damage, proliferation of new (abnormal) cells and CT
- Tuberculosis, Rheumatoid and Osteo-arthritis, atherosclerosis, autoimmune disease, hypersensitivity
