Inflammation and Anti-Inflammatory Drugs

Question 1

Late phase local changes in inflammation

Answer 1

Cytokines produced by activated neutrophils and cytokines contribute to degradation of damaged tissue and preparation of injured site for healing

These WBCs release mediators like reactive oxygen species or proteins like TNFα or Hydrolytic alpha

Question 2

Systemic action of cytokines in response to inflammation

Answer 2

Site of infection has WBCs which release cytokines into body: IL-1, TNFα and IL-6

Once in circulation, they can go into hypothalamus (HT) and produce prostaglandins which raise body temperature to kill microbes

HT also releases ACTH (hormone) which acts on adrenal cortex to produce corticosteroids that act on the liver (in addition to other cytokines) to make it produce acute-phase proteins like C-reactive protein

Cytokines stimulate bone marrow to increase leukocytosis

Question 3

Describe changes 1 day after colorectal and cardiac surgery

In platelets, neutrophils, lymphocytes, monocytes

Answer 3

Reduction in platelets

Increase in neutrophils

Reduction in Lymphocytes

Increase in Monocytes

Question 4

Tissue regeneration methods that occur after inflammation

Answer 4

Angiogenesis - Formation of new blood vessels
Fibroblast Proliferation - Most common cell type in connective tissue
Collagen Synthesis

Question 5

Granulation of Tissue

Answer 5

Caused by dense population of macrophages, fibroblasts and neovascularisation in a loose matrix of collagen after inflammation

Characterised by:

• fibroblast production of collagen
• Proliferation of blood vessels to ensure nutrient/O2 supply
• Metalloporteinases stimulate cell movement in wound area

Question 6

Which type of hormones affect granulation

Answer 6

Sex hormones

Question 7

What happens if there is a failure to stop proliferative phase (post inflammation)

Answer 7

Granulomatous conditions; e.g. rheumatoid arthritis or scleroderma

• Cartilage calcification/ossification

Loss of function and pain

These 3 drugs treat such conditions:
Methotrexate (may inhibit angiogenesis)

Etanercept & Adalimumab (Monoclonal antibodies)
(adalimumab gives the drug company the most revenue of all drugs)

Question 8

Differences in cutaneous wound healing between sexes

Answer 8

Venous ulceration (which is more common in the elderly) in is more common in men and post-menopausal women (thought to be lack of oestrogen)

Prolonged Cutaneous healing is attributed to:

• Prolonged inflammatory response
• Increased protease activity
• Reduced matrix heealing

Question 9

Experimental observations in mice of sex hormones on wound healing

Answer 9

Basically:

Testosterone prolongs wound healing

Overiectomy gives enhanced inflammation which is reversed by oestrogen and reduces inflammatory response

Question 10

What was the effect of vaginal oestrogen application for 6 weeks preoperatively

Answer 10

Increased synthesis of various factors that lead to improved outcome in terms of surgical repair

Question 11

Maturation phase (post inflammatory)

Answer 11

From 21 days to two years

Reduction in cell proliferation at site of inflammation and remodelling (macrophage involved)

Closure of wound is not end point:

Reduction in vascularisation as less nutrients are needed (since metabolic activity declines)

Remodelling of collagen and reinnervation by nerves to increase strength of tissues after return of sensation (lack of elastin causes scar tissue)

Question 12

Phosphalipase A

Answer 12

Enzyme that converts phosphatidylcholine into arachidonic acid which is then libterated into the extracellular space

Upregulated by inflammatory mediators

Question 13

How can arachidonic acid be metabolised

Answer 13

By two major sets of enzymes:

• Cyclo-oxygenase
• Lipoxygenase (into leukotrienes)

Question 14

Forms of COX enzymes

Answer 14

COX-1 (Physiological); functions for stuff like mucosal protection, renal blood flow and haemostasis

COX-2 (Inducible); functions for stuff like inflammation, pain and fever

Question 15

How does asprin affect COX

Answer 15

Non-competitive inhibitor of cyclooxygenase

Question 16

Competitive inhibitors of COX

Answer 16

Indomethacin and other NSAIDS

Question 17

Examples of NSAIDS (also what is abbreviation)

Answer 17

Non-steroidal anti-inflammatory drugs

Ibuprofen
Piroxicam
Diclofenac

Inhibit synthesis of prostaglandins by preventing the metabolism of arachadonic acid through COX-2 inhibition which reduces inflammatory response;

They tend to be applied topically as they can inhibit prostaglandin functions that protect stomach mucosa

Question 18

What drug changes were made to reduce the side effects of COX-2 inhibitors and NSAIDS; what happened afterwards

Answer 18

Production of selective COX-2 inhibitors that do not target COX-1

Initial results were promising as the drugs had much more selectivity for the inflammtory mediator COX-2 as opposed to COX-1 (physiological).

Turned out to have bad side effects though as COX-2 has beneficial effects on the heart and other things like affecting ovulation

Question 19

Glucocorticoids

Answer 19

SHort-term steroids that enhance inflammatory response; in the long term they inhibit inflammation though by reducing:

• mediator production with action at the level of phospholipase A2 and COX-2
• Expression of cell adhesion molecules
• Chemotaxis of neutrophils
• Cytokine production