Acute inflammation

Question 1

What is immunity?

Answer 1

Protection from infection or disease - includes autoimmunity where the target is one’s own tissues.

Question 2

What is infection?

Answer 2

Catching/spreading - involves microbes colonising a host.

Question 3

What is inflammation?

Answer 3

Part of immunity and is stimulated by infection and other injury.

Question 4

What is the common name of inflammatory diseases?

Answer 4

-itis e.g. arthritis, bronchitis, atherosclerosis, dermatitis, gastritis etc.

Question 5

What is involved in inflammation?

Answer 5

A complex interplay between leukocytes, tissue cells (immune and structural), microvasculature, nerves, chemical mediators of inflammation.

Question 6

What are the cardinal signs of inflammation?

Answer 6

Heat, redness, swelling, pain, loss of function

Question 7

What is heat and redness caused by?

Answer 7

Arteriolar dilation and increased blood flow to inflamed tissue.

Question 8

What is swelling caused by?

Answer 8

Leakage of plasma from blood vessels into the tissue (plasma extravasation).

Question 9

What are more chronic swelling diseases caused by?

Answer 9

Deposition of fibrin such as in arthritis.

Question 10

How is pain created?

Answer 10

There is a stimulus (such as external heat, pressure etc.) that will stimulate the central nerves directly or indirectly by elicitng the release of chemicals to the environment.

Question 11

What are the cellular components of the inflammatory response?

Answer 11

Granulocytes, lymphocytes, monocytes.

Question 12

What includes granulocytes?

Answer 12

Neutrophils, eosinophils and basophils.

Question 13

Where are tissue mast cells found?

Answer 13

They are widely distributed throughout connective tissue and mucosal surfaces.

Question 14

What do tissue mast cells do?

Answer 14

They contain, synthesise and release inflammatory mediators.

Question 15

What triggers tissue mast cells?

Answer 15

Mechanical injury to skin, type 1 immediate hypersensitivty via igE, chemicals such as insect bites.

Question 16

What is igE?

Answer 16

Immunoglobulin E - antibodies produced by the immune system

Question 17

What is th endothelium?

Answer 17

It lines blood vessels - contraction of the endothelium can make venules leaky (increased permeability) and oedema - swelling.

Question 18

What can cause arteriolar dilation?

Answer 18

Endothelial-derived nitric oxide.

Question 19

What are chemical mediators of inflammation?

Answer 19

Diverse molecules that are produced by the host in response to infection and immune reactions.

Question 20

Do chemical mediators of inflammation have high or low specificity?

Answer 20

Low specificity.

Question 21

What is the purpose of chemical mediators of inflammation?

Answer 21

Promote inflammation and initiate repair.

Question 22

What is a well known inflammatory mediator and what effects does it cause?

Answer 22

Histamine - redness (due to vasodilation), flare (activation of sensory nerves, pain and itch, neuropeptide release) and wheal (swelling).

Question 23

What are the histamine receptors in inflammation?

Answer 23

H1 and H4.

Question 24

What happens when the H1 receptor is activated?

Answer 24

It is Galphaq linked and causes phospholipase C stimulation. It causes vasodilation of arterioles via nitric oxide generation and causes endothelial cell contraction (leading to increased vascular permeability and oedema), and triggers pain and itch pathways.

Question 25

What does endothelial cell contraction result in?

Answer 25

Increased vascular permeability and oedema.

Question 26

What happens when the H4 receptor is activated?

Answer 26

It is Gi linked, and inhibits adenylyl cyclase and activates PLC via betagamma subunits. It activats pain and itch pathways and has a role in leukocyte chemotaxis.

Question 27

What happens when mast cells are triggered?

Answer 27

They release histamine as they are degranulated due to mechanical injury.

Question 28

What happens to smooth muscle when histamine is released?

Answer 28

There is relaxation of arteriolar smooth muscle

Question 29

When happens to the endothelium when histamine is released?

Answer 29

There is contraction of the venular endothelium which causes the opening of junctions and increased permeability.

Question 30

What else can histamine activate?

Answer 30

H1 receptors on sensory nerves (C fibres).

Question 31

What happens when C fibres are activated?

Answer 31

There are neuropeptides stored in the nerve endings that can be released in response to this activation. e.g. neurokinin A and calcitonin gene related peptide that act on their own cognate receptors.

Question 32

What effects do neurokinin A and calcitonin cause?

Answer 32

Dilation.

Question 33

What else does neurokinin do once being released by C fibres?

Answer 33

It reacts back on the mast cell to cause increased release of histamine in mast cells.

Question 34

What do NKA and CGRP act on?

Answer 34

They act on blood vessels (on specific receptors) to cause vasodilation.

Question 35

How is histamine involved in the pain response?

Answer 35

Mast cells release histamine that binds to H1 and H4 and sends signals back up to the brain to propagate pain signals.

Question 36

What are some common antihistamines?

Answer 36

Chlorpheniramine (Piriton), Astemizole, Loratidine.

Question 37

What can antihistamines be used for?

Answer 37

Allergy, urticaria (skin rashes), nasal congestion.

Question 38

What receptors to antihistamines act on?

Answer 38

H1 - currently no licensed H4 antagonists.

Question 39

Aside from histamine, what other chemical mediators cause inflammation?

Answer 39

Bradykinin, PGE2, PGI2

Question 40

Aside from histamine, what other chemical mediators cause increased permeability?

Answer 40

Bradykinin, NKA, fMLP, C5a, LTB4, IL-8.

Question 41

What is the idea of synergy between different inflammatory mediators?

Answer 41

Bradykinin alone doesn’t do much, but together with prostaglandin has a greater effect.

Question 42

What are the two ways in which inflammatory mediators can act on venules?

Answer 42

Neutrophil dependent and neutrophil independent.

Question 43

What is the neutrophil independent mechanism of inflammation?

Answer 43

Histamines/bradykinins/NKA act on venules to cause inflammation directly - the endothelial contracts and fluid can pass out on its own.

Question 44

What is the neutrophil dependent mechanism of inflammation?

Answer 44

Substances such as fMLP, C5a, LTB4 and IL-8 dependent on the neutrophil to be active and depend on the leukocyte for venular leakage.

Question 45

What is significant about the different mechanisms of inflammation?

Answer 45

Inhibiting/antagonising a single mediator is only effective in inflammation driven by one substance. e.g H1 antagonists only effective against the histamine aspect of allergic reactions.

Question 46

What may be a more effective strategy in inflammatory disease than histamine?

Answer 46

Inhibiting leukocytes.

Question 47

What is important in controlling the inflammatory response?

Answer 47

It is important to balance efficacy against off-target effects - need to leave host defence intact.

Question 48

What happens rapidly after local injury?

Answer 48

There is release of preformed substances, production of mediators from membrane lipids, and release of peptides from stimulated neurons.

Question 49

What happens seconds - minutes after local injury?

Answer 49

There is production of signalling molecules such as bradykinin and complement fragments after proteinase activation.

Question 50

What happens hours after local injury?

Answer 50

Transcription and translation of proteins such as iNOS, COX-2 and cytokines.

Question 51

Why is inflammation beneficial?

Answer 51

Increased supply of cells and chemical mediators to the site of inflammation - redness/swelling/removal of damaged tissues/supply of new materials for repair. It also tells the body to rest such as pain and loss of function.