L11- Acute inflammation

Question 1

What does the inflammatory response involve?

Answer 1

• Acute microvascular changes
• Release of inflammatory mediators
• Accumulation of inflammatory cells
• Repair and healing

Question 2

What are examples of inflammatory mediators that trigger the microvascular effects?

Answer 2

• Nitric oxide
• Histamine
• Bradykinin
• Prostaglandins
• Neuropeptides e.g substance P
• Complement, PAF, Cytokines

Cause increased microvascular permeability (gaps between endothelial cells) leading to plasma extravasation and oedema formation

Question 3

What is the microcirculation?

Answer 3

• Arteriole (blood flow changes)
• Capillaries (unimportant in inflammation)
• Venule (oedema formation and cell accumulation- lymphocytes)

Question 4

What are the sources of vasodilators?

Answer 4

• Endothelial cells- prostaglandins, NO
• Inflammatory cells- prostaglandins, NO
• Sensory nerves acting on endothelium- neuropeptides

Question 5

What are direct acting oedema mediators?

Answer 5

• Histamine
• Substance P
• Bradykinin
• PAF
• Leukotrienes

Question 6

What are neutrophil dependent oedema mediators?

Answer 6

Agents that stimulate neutrophil activation causing neutrophils to adhere to endothelium

Question 7

What are the neutrophil-endothelial cell interactions?

Answer 7

1. Rolling of neutrophil along post-capillary venule
2. Cell adhesion molecule expression (CAM)
3. Adherence by flattening of neutrophil
4. Extravasation by making gaps between endothelial cells
5. Phagocytosis of bacterium

Question 8

What are neutrophil activating agents?

Answer 8

• LTB4
• C5a
• IL-8
• TNF 
Act on receptors on neutrophil's to stimulate them

Question 9

What are endothelial adhesion molecule stimulants?

Answer 9

• TNF
• IL-1
Makes endothelial cells more adhesive so neutrophils can stick to them

Question 10

What is histamine?

Answer 10

• Major inflammatory mediator
• Mast cells and basophils release
• Preformed and released in allergic/IgE hypersensitivity responses
• When IgE antibodies become cross-linked they activate the release of histamine by Ca2+ influx into cells

Question 11

What do H1 receptors do?

Answer 11

• Found on endothelial cells
• Increased blood flow
• Increased microvascular permeability- oedema
• itch

Question 12

What are 1st gen H1 antagonists?

Answer 12

• CHLORPHENIRAMINE
• DIPHENYDRAMINE
• PROMETHAZINE
sedating, short acting, rapid onset

Question 13

What are the steps in histamine release?

Answer 13

1. Histidine broken down into histamine by histidine decarboxylase
2. Histamine stored in vesicles
3. Allergic IgE mediated reaction causes degranulation
4. Histamine acts on its receptors

Question 14

What are the effects of histamine?

Answer 14

• Itching and pain
• Bronchoconstriction, nasal congestion
• Increases blood flow and vascular permeability leading to erythema, edema and flare (triple resp)

Question 15

What are second gen H1 antagonists?

Answer 15

• LORATADINE
• CETIRIZINE
• TERFENADINE
• ASTEMIZOLE
non sedating, longer acting, slow onset, less side effects

Question 16

What are sensory nerves?

Answer 16

• C fibres- slow
• A δ fibres- fast
• Transmit sensory info to CNS and initiate reflexes, noiception (pain and itch)
• Release neuropeptides

Question 17

What are stimulants of sensory nerves?

Answer 17

• Mechanical (pressure)
• Temperature (cold and heat)
• Chemical (mediators and capsaicin)

Question 18

What is nitric oxide?

Answer 18

Another inflammatory mediator

• Produced from arginine + O2 to produce citrulline + NO, mediated by nitric oxide synthase enzyme

Question 19

What are the types of NOS?

Answer 19

Constitutive:
• Endothelial- eNOS
• Neurons- nNOS  
Inducible:
• Macrophages- iNOS

Question 20

What are the roles of NO?

Answer 20

• Regulation of blood flow and pressure (eNOS)
• Immune response (iNOS)
• Neurotransmitter, pain (nNOS)
• Radicals (cytotoxic)

Question 21

What is bradykinin?

Answer 21

• Inflammatory mediator formed in plasma by activity of enzymes on tissue fluid substrates called kininogens
• Metabolised by ACE enzyme and carboxypeptidases

Question 22

What to B2 receptors mediate?

Answer 22

• Increased blood flow and microvascular permeability
• Noiception (enhanced sensitisation of pain and itch)
• Bronchoconstriction and nasal blockage
*B1 receptors similar in inflammation

Question 23

How are prostaglandins and thromboxanes produced?

Answer 23

Arachidonic acid breakdown by cyclo-oxygenase enzyme

Question 24

How are leukotrienes produced?

Answer 24

Arachidonic acid breakdown by lipoxygenase enzyme

Question 25

What are the eicosanoids?

Answer 25

• PGE2, PGI2= released from endothelial cells and lymphocytes, increase blood flow, hyperalgesia

PGD2= released from mast cells, less potent

LTC4, LTD4= increase microvascular permeability, bronchconstrictors

LTB4= chemotaxin that recruits neutrophils to inflammatory sites

Question 26

What do NSAIDs do?

Answer 26

Non-steroidal anti-inflammatory strugs

• Inhibit arachidonic acid metabolism- inhibit COX- prevent eicosanoids being produced

Question 27

What are non selective NSAIDs?

Answer 27

• Aspirin
• Ibuprofen
• Indomethacin
side fx on gut and kidney

Question 28

What are COX2 selective NSAIDs?

Answer 28

• Celecoxib
• Rofecoxib
• Meloxicam
fewer gut side fx
adverse cardiac fx