10. inflammation and anti-inflammatory drugs Flashcards
three cytokines involved in longer term (>24hr) inflammation
IL1
TNFa
IL6
produced by activated neutrophils and macrophages
contribute to degradation of damaged tissue, preparation of site of injury for healing.
three principal biochemical changes that lead to degradation of damaged tissue and preparation for healing.
- Elevated corticosteroids as part of ‘stress response’ -promotes short term inflammation
- Increase hepatic protein (Heat Shock or Acute phase proteins eg: Lipopolysaccharide Binding Protein).
- Stimulate bone marrow
Acts centrally to elicit pyrogenic response. Evidence for specific cytokines receptors in the hypopthalamus
what happens in the late phase- 4-21 days of inflammation
what do proteolytic enzymes and oxygen radicals produced by leukocytes lead to
breakdown of tissue in preparation of repair
what happens in the proliferative/ granulation stage
macrophage and platelets produce growth factors that stimulate angiogenesis, fibroblast proliferation and collagen synthesis
Dense population of macrophages, fibroblasts and neovascularization (angiogenesis) in a loose matrix of collagen.
Various metalloproteinases stimulate cell movement in wound area
what influences proliferation?
sex hormones (gender)
how can granulation arise from proliferation?
Failure to stop the proliferative phase leads to granulomatous condition, eg. rheumatoid arthritis or Scleroderma.
Cartilage calcification and ossification.
Methotrexate may inhibit angiogenesis.
The hormonal regulation of cutaneous wound healing
Increased incidence of venous ulceration in the elderly - more so in men and post-menopausal women.
Major burden on NHS
Cutaneous healing is prolonged because:
Prolonged inflammatory response
Increased protease activity
Reduced matrix deposition
Is there a hormonal component?
Oestrogen, Testosterone & DHEA levels decline with age.
the effect of testosterone, oestrogen and DHEA in wound healing in mice
testosterone prolongs wound healing
Enhances cell infiltration and cytokine production, retards collagen production and re-epithelialization
reversed by oestrogen:
Reduced cell infiltration, pro-inflammatory cytokines, Increased production of TGF-β1
reversed by DHEA
Maturation phase: when does this happen?
21 days to 2 years
Cessation of proliferative phase leads to maturation phase and remodelling of the tissue
macrophages involved
effects after wound closure:
i) Reduced vascularisation. Lessens demand for nutrients as metabolic activity of tissue declines
ii) Remodelling of collagen and reinnervation by nerves.
Increases strength of tissues and the return of ‘sensation’ - but lack of elastin causes scar tissue.
which systems are involved in wound healing
Immune, Nervous, Endocrine and Cardiovascular
effects of NSAIDs
COX inhibitor: reduced prostaglandin synth
i) Reduced vasodilatation and hyperaemia.
ii) Reduced hydrostatic pressure in venules
iii) Reduced protein leakage into extracellular space
iv) Reduced pain.
what can topical NSAIDs reduce?
GI side effects
Non-COX-related benefit in inflammation-differences between NSAIDs
Indomethacin and aspirin reduce expression of L- selectin on neutrophils
An effect not seen with oxicam derivatives, eg. piroxicam.
• During activation of attached neutrophil L-selectin is cleaved and the expression of Mac-1 integrin increased to aid binding to ICAM-1.
Piroxicam but not indomethacin inhibits this process
glucocorticoids: long term effects
Reduction in:
- Prostanoid and llieukotriene production and, therefore, inflammatory synergy between humoral and cellular factors. Action at the level of phospholipase A2 (induction of lipocortin), COX-2 and iNOS.
- Expression of cell adhesion molecules
- Chemotaxis of neutrophils.
- Cytokine production.
- Potentiates vasoconstrictors
short terms effects may differ
