Cellular Interactions

Question 1

What is the inflammatory response for?

Answer 1

1. First line of defence that’s part of the inate immune system
2. Protects against injury
3. Protects against infections
4. Promotes healing

Question 2

What are the 5 cardinal signs of inflammation?

Answer 2

1. Redness
2. Heat
3. Swelling
   (due to increase blood flow to the area)
4. Loss of function
5. Pain

Question 3

What is the 3 sections of the skin structure?

Answer 3

1. Epidermis
   - Keratinocytes
2. Dermis
   - Fatty tissue - connective tissue
   - Capillaries
3. Subcutaneous Layer
   - Fat
   - Larger blood vessel and nerves

Question 4

What occurs when there’s an injury to the surface of the skin?

Answer 4

1. Clots and exudate- neutrophils gather and haemorrhage too
2. Mitosis (dividing cells)
   - Fibroblasts- create tissue to heal and create new scar tissue
   - New capillaries and macrophages
3. Complex cascade of events occur that recruit many other cell types from the circulation

Question 5

What is the purpose of inflammation occurring in injury?

Answer 5

1. Protect from invading pathogen
2. Penetration
3. Burn
4. For both part of healing process

Question 6

What is the purpose of inflammation occurring in insect bite?

Answer 6

1. Protects against infection

2. Heals wound

Question 7

What clinical problems may an inflammation response have?

Answer 7

1. Insect bite: Hypersensitivity- out of controlled response
2. Contact dermatitis: allergy
3. Atopic Dermatitis (eczema)
4. Urticaria (allergy/adverse reaction)- give someone a drug rash

Question 8

Give examples of when the inflammation response goes wrong?

Answer 8

1. Hypersensitivity (insect bite)
2. Failure to heal
3. Chronic inflammation (Rheumatoid arthritis- cells attacking themselves and lose function in cell)

Question 9

How do chemical signals cause cardinal signs of inflammation?

Answer 9

Changing cellular functions and each mediator has slightly different effects by targeting different receptors and cells

2. Many mediators are complex as most act as drug targets
   - Receptors
   - Enzymes
   - Steroid receptors and protein expression

Question 10

What mediators act as drug targets?

Answer 10

1. Receptors
2. Enzymes
3. Steroid Receptors and protein expression

Question 11

What are mast cells and give examples of what they release?

Answer 11

1. Cells that contain or make numerous inflammatory mediators (reside in every tissue site of the body)
2. Histamine, 5-HT (serotonin), proteases
3. Lipid derived mediators (prostaglandins)
4. Cytokines (peptide mediators)

Question 12

How are mast cells activated ?

Answer 12

1. Pathogens
2. IgE (antibodies) (immunoglobins)
3. Complement Cascade (clotting system)
4. Physical damage

Question 13

What do the terms Wheal and Flare mean? And what can this lead to?

Answer 13

1. Wheal- Swelling
2. Flare- Reddening
3. Leads to itch or pain- release of inflammatory mediators and activation of sensory nerves

Question 14

Where is histamine released? And what does an injection of it cause?

Answer 14

1. Released by mast cells

2. Causes wheal and flare of the cells

Question 15

How do anti-histmaines work?

Answer 15

They block the Histamine H1 receptors

Question 16

How do drugs target lipid mediators?

Answer 16

1. Target the phospholipids from cell membranes which can stop inflammatory responses
2. Targeting one pathway can stop many other pathways
3. Example: Glucosteroids stops the production of Phospholipase A2 altogether which stops the inflammatory reaction altogether

Question 17

How do NSAIDS work in targeting the lipid mediators?

Answer 17

They inhibit the cyclooxygenase (COX) enzyme and prevent prostaglandin formation

Question 18

How does ibuprofen work in lipid mediators?

Answer 18

1. Inhibits the cyclooxygensae (COX) which converts arachidonic acid to prostaglandins
2. Prostaglandins work by mediating pain, inflammation and fever

Question 19

How does Aspirin work in lipid mediators?

Answer 19

Non selective inhibition of COX1 and COX2 (anti-inflammatory effect) and the irreversible inhibition of COX1 (anti-platelet)

Question 20

What side effects can NSAIDS cause and why?

Answer 20

1. Gastric problems- prostaglandins in gut wall involved in gastric mucosa (protects GI tract) reduction which can cause GI bleeding
2. Kidney problems- prostaglandins important in controlling blood flow to kidneys
3. Cardiovascular problems- imbalance in prostaglandins can lead to stroke
4. Contraindiction in ASTHMA (reducing prostaglandins)

This is mainly due to inhibition of COX 1

Question 21

What can glucosteroids (corticosteroids) do to lipid mediators for inflammation? And how do they work?

Answer 21

1. Lipid mediators: They inhibit the induction of cycle-oxygenase which means it has a stronger effect than the NSAIDS
2. Alter expression of proteins involved in inflammation by altering DNA transcription
3. Promotes expression of anti-inflammatory proteins and suppresses expression of pro-inflammatory

Question 22

What is the mechanism of action of glucocorticoid?

Answer 22

1. They normally circulate in the blood if they take are taken in orally or topically (based on the steroid of cortisol
2. They bind to the glucocorticoid receptors into the cytoplasm which go through the nucleus to bind to different genes
3. This affects the transcription of these different genes
4. The activated glucocorticoid receptor complex can interfere with cell signalling pathways
5. So doesn’t have to get translocated into the nucleus

Question 23

What does binding of the glucocorticoid do to the DNA binding dependent?

Answer 23

1. Increases expression of the genes

2.

Question 24

What does binding of the glucocorticoid do to the DNA binding independent?

Answer 24

1. Suppresses inflammation induced dependent gene transcription
2. It essentially blocks the intracellular signals which stimulate gene transcription and downstream of the receptors
3. This is stimulated by inflammatory mediators

Question 25

Explain at a lipid mediator level (by corticosteroids) how you would induce a therapeutic effect of an anti-inflammatory?

Answer 25

1. Increase lipocortin-1 (annexin-1) synthesis | 2. Block induction of COX-2

Question 26

Explain at a lipid mediator level (by corticosteroids) how you would induce a therapeutic effect of immune suppression?

Answer 26

1. Decreases T and B cells | 2. Inhibits cytokine production which are involved in recruiting and starting the immune response

Question 27

Explain the indication of hydrocortisone and the mechanism of action?

Answer 27

1. Indication: - Eye- local treatment of inflammation (short term) - Skin- mild inflammatory disorders (eczema, nappy rash) - Anaphylaxis- IV with adrenaline as emergency treatment 2. MoA: - Glucocorticoid receptor agonist - Binds to mineral corticoid receptors that regular blood pressure and volume (can cause many side effects hence why preferred to be used topically)

Question 28

Explain the indication of Dexamethasone and the mechanism of action?

Answer 28

1. Indication: nurmerous, where reducing inflammation or immune suppression is beneficial e.g. joint inflammation 2. MoA - Glucocorticoid receptor agonist - 40x more potent than hydrocortisone - Doesn't bind to mineral corticoid receptors - Has a longer half-life than hydrocortisone

Question 29

What are some of the unwanted effects of glucosteroids being taken orally?

Answer 29

1. Suppress proliferation of skin cells- blocks scarring- can cause permanent scarring 2. Effects on skeleton- decreased bone density 3. Muscle- reduces it - Reduce glucose uptake - Stimulate protein breakdown - Inhibit protein synthesis 4. Adrenal suppression - atrophy of adrenal gland - Abrupt withdrawal can lead to acute adrenal insufficiency hypotension or death

Question 30

What can long term topical treatment of glucosteroids do?

Answer 30

1. Can induce a cutaneous side effect such as atrophy of the epidermis and the dermis (skin shrinking) 2. Disturbed wound healing

Question 31

What can long term topical treatment of glucosteroids do?

Answer 31

1. Can induce a cutaneous side effect such as atrophy of the epidermis and the dermis (skin shrinking) 2. Disturbed wound healing

Question 32

Which drugs target the sensory nerves?

Answer 32

1. Opiates directly block the nerve signals that cause pain- won't get rid of the information such as the inflammatory response 2. Prostaglandins can reduce pain signalling by sensing the nerve

Question 33

Explain how pain occurs from the brain? And what does this cause?

Answer 33

1. Noxious stimuli causes a C fibre activity 2. This causes excitation of the transmission neuron which leads to pain 3. Inflammatory response is caused