Physiology + Pharmacology of Inflammation + Autoimmunity

Question 1

Describe inflammation

Answer 1

Protective response
Response of blood vessels + leukocytes

Question 2

Describe acute inflammation

Answer 2

Rapid
Presence of leukocytes
Exudation of fluids + plasma proteins

Question 3

Describe chronic inflammation

Answer 3

Longer
Presence of lymphocytes + macrophages
Fibrosis + tissue disruption

Question 4

What happens in acute inflammation?

Answer 4

Vasodilation = mediators - eg. histamine binds
Increased blood flow
Increases permeability of microvasculature
Increase viscosity of blood
Stasis = slows moving RBCs = fluid leaves capillary
Neutrophil accumulation

Question 5

What are the stimuli for acute inflammation?

Answer 5

Infections
Tissue necrosis
Foreign bodies
Immune reactions

Question 6

How do leukocytes adhere to endothelium?

Answer 6

Leukocytes redistribute along endothelium
Detach + adhere = mediated by selectins
Firmly adhered = mediated by integrins
Transmigration
Emigrate to site of tissue, followed by chemoattractant

Question 7

How do leukocytes respond?
(Phagocytosis)

Answer 7

Particle bound to phagocyte receptor
Plasma membrane form vesicle
Phagosome fuses with lysosomal granule
ROS + NO + lysosomal enzymes = kill + degrade

Question 8

Describe cell-derived mediators

Answer 8

Produced locally
Pre-accumulated or synthesised de novo

Question 9

Describe plasma protein-derived mediators

Answer 9

Produced in liver
Circulate in plasma as inactive precursors

Question 10

What mediators does anti-inflammatories target?

Answer 10

Prostaglandins
Leukotrienes

Question 11

Describe prostaglandin + leukotrienes

Answer 11

Phospholipase release arachidonic acid COX-1 + COX-2 convert AA in prostaglandin
OPTION 1: Thromboxane synthetase convert PGH2 to thromboxane
OPTION 2: prostacyclin synthetase convert PGH2 to prostacyclin

Question 12

What are COX-1/2 inhibitors?

Answer 12

Aspirin
Ibuprofen
Paracetamol

Question 13

What is the anti-inflammatory effect of COX-1/2 inhibitors?

Answer 13

Block PGs production = reduce vasodilation

Question 14

What is analgesic effect of COX-1/2 inhibitors?

Answer 14

Reduce pain by inhibiting PGs production

Question 15

What is anti-pyretic effect COX-1/2 inhibitors?

Answer 15

Lower higher temperature

Question 16

Describe COX-2 specific inhibitors

Answer 16

More selective for inflammation
Less GI toxicity
eg. celecoxib

Question 17

Describe 5-lipoxygenase

Answer 17

Present in neutrophils
Convert AA to 5-HPETE
Precursor to leukotrienes
Cause vasoconstriction

Question 18

How do lipoxygenase reduce inflammation?

Answer 18

Inhibit LTs production
Or block leukotriene receptors

Question 19

Describe glucocorticoids

Answer 19

Reduce transcription of genes encoding phospholipase A2
eg. cortisone

Question 20

Describe NF-kB transcription factor

Answer 20

Activated by huge number of stimuli
Master regulator of inflammation
Regulates expression of cytokines

Question 21

What is the outcome of acute inflammation for short-lived injury?

Answer 21

Damaged tissue can regenerate
Complete removal of debris by macrophages
Complete resolution

Question 22

What is the outcome of acute inflammation for extended injury?

Answer 22

Damaged tissue cannot regenerate
Connective tissue grows in area of damage
Fibrosis

Question 23

What is the outcome of acute inflammation for persistence injury?

Answer 23

Damage interferes with repair process
Persistent inflammation
Chronic inflammation

Question 24

What is chronic inflammation?

Answer 24

Prolonged duration

Question 25

What are the causes of chronic inflammation?

Answer 25

Persistent infections Immune-mediated inflammatory diseases

Question 26

What are the features of chronic inflammation?

Answer 26

Infiltration with mononuclear cells Tissue destruction Attempts at healing

Question 27

What are the cells involved in chronic inflammation?

Answer 27

Macrophages Lymphocytes Plasma cells

Question 28

What is autoimmunity?

Answer 28

Genetic susceptibility, breakdown in natural tolerance + environmental triggers

Question 29

What are examples of autoimmunity diseases?

Answer 29

Pathogenic effects of autoantibodies T cell-mediated autoimmunity

Question 30

Describe pathogenic effects of autoantibodies

Answer 30

Affect molecular function (type 2 hypersensitivity) = antibodies bind to antigens on top of cell a) ABs to Ach receptor in myasthenia gravis = receptor internalisation + remove muscle surface b) ABs to TSH receptor in Grave's disease = mimics effect of TSH = excess thyroid hormone secretion

Question 31

Describe T cell-mediated autoimmunity

Answer 31

Insulin dependent diabetes = cells of pancreas destroyed by CD8 T cells

Question 32

How do you develop chronic autoimmune disease?

Answer 32

Self-antigen cannot be eliminated Constant presence = chronic inflammation Tissue damage = release of more self-antigens Leukocytes attracted by cytokines (released by damaged tissue) Self-destructive process continues