Acute inflammation

Question 1

What are the 5 cardinal features of acute inflammation?

Answer 1

1. Calor (Heat).
2. Rubor (Redness).
3. Tumor (Swelling).
4. Dolor (Pain).
5. Functio Laesa (Loss of Function).

Question 2

List 4 causes of acute inflammation

Answer 2

1. Infection.
2. Tissue necrosis.
3. Foreign bodies.
4. Immune reactions.

Question 3

How specific is the immediate response to a pathogen?

Answer 3

The immediate response activates the innate immune system and therefore has limited specificity.

Question 4

Name 3 cell types which act as sentinel cells in tissues ready to react to invading microorganisms or to cell damage.

Answer 4

1. Macrophages.
2. Dendritic cells.
3. Mast cells.

Question 5

What are the molecules which pathogens and damaged cells produce which can activate cells of the innate immune system?

Answer 5

PAMPS and DAMPS (Pathogen Associated Molecular Patterns and Damage Associated Molecular Patterns)

Question 6

What is the main cytokine produced by sentinel cells when they are activated by DAMPs and PAMPs?

Answer 6

Interleukin 1 (IL-1).

Question 7

List the 5 steps of acute inflammation (the 5 R’s)

Answer 7

Recognition (of the injurious agent).
Recruitment (of leucocytes).
Removal (of the agent).
Regulation (of the response).
Resolution.

Question 8

What is the difference between a cytokine and a chemokine?

Answer 8

Cytokines are proteins produced by many cell types that can mediate and regulate inflammatory reactions. Cyto means cell and kine refers to kinesis or movement. Chemokines are chemotactic cytokines. These are produced as a chemical cloud which spreads out from the source of inflammation and can attract specific white blood cells.

Question 9

List the 5 important mediators of acute inflammation.

Answer 9

1. Hageman factor (Factor XII).
2. The complement system.
3. Mast cells.
4. Arachidonic acid metabolites.
5. Toll-like receptors.

Question 10

What is the Hageman Factor?

Answer 10

This is a factor produced by the liver as an inactive protein. It circulates in the blood stream until it is activated by exposure to collagen.

Question 11

What is the link between the clotting system and the inflammatory system?

Answer 11

Hageman factor activates the coagulation cascade and also activates the kinin system.

Question 12

What are the 3 main functions of bradykinin?

Answer 12

1. Vasodilation.
2. Increased vascular permeability.
3. Pain.

Question 13

What is the Complement System?

Answer 13

A system of pro-inflammatory proteins produced by the liver which circulate as inactive precursors until they are activated by 1 of 3 pathways.

Question 14

Name the 3 complement system activation pathways and explain how they are activated.

Answer 14

1. Classical pathway. Activated by antigen binding to IgG or IgM which activates C1.
2. Alternative pathway. Activated by microbial components directly.
3. Mannose-binding lectin pathway. Activated by mannose-binding lectin binding to mannose on the surface of a bacterium.

Question 15

List 4 consequences of complement system activation.

Answer 15

1. Formation of anaphylatoxins (C3a, C4a + C5a) which cause histamine to be released from mast cells. C5a is a chemotactic + activation agent for neutrophils, monocytes, eosinophils and basophils.
2. Opsonisation. C3b is the main opsonin (an ‘eat-me’ signal for neutrophils and macrophages which have C3b receptors).
3. Cell lysis. The final stage of the complement cascade results in the formation of a membrane attack complex (C5b, C6, C7, C8 and C9) flooding the cell with water and ions and causing lysis.
4. Immunoglobulin clearance. Removal of immune complexes from the circulation.

Question 16

List 3 ways in which mast cells can be activated

Answer 16

1. Tissue trauma.
2. Complement components C3a and C5a.
3. Cross-linking of IgE bound to the mast cell surface by antigen.

Question 17

Describe the consequences of mast cell activation

Answer 17

Mast cells contain pre-formed histamine granules which can be quickly released causing blood vessels to dilate and to leak. Mast cells also cause a delayed response by producing leukotrienes.

Question 18

What enzyme is required to generate arachidonic acid from membrane phospholipids and what drug class can stop this reaction?

Answer 18

Phospholipase A2 and steroids

Question 19

What enzymes are required to generate Prostaglandins from Arachidonic acid and name 2 drugs which can block these enzymes?

Answer 19

Cyclooxygenase 1+2 (COX 1+2) and Aspirin/Non-steroidal anti-inflammatory drugs

Question 20

What is produced when 5-lipooxygnease acts on Arachidonic acid?

Answer 20

Leukotrienes

Question 21

List 4 effects of prostaglandin production in the context of acute inflammation

Answer 21

1. Vasodilation.
2. Increased vascular permeability.
3. Pain (PGE2).
4. Fever (PGE2).

Question 22

List 4 consequences of leukotriene production in the context of acute inflammation

Answer 22

1. Vasoconstriction.
2. Bronchospasm.
3. Increased vascular permeability.
4. Attraction and activation of neutrophils (LTB4).

Question 23

How do steroids reduce inflammation?

Answer 23

Corticosteroids are broad-spectrum anti-inflammatory agents that reduce the transcription of genes encoding phospholipase A2, COX-2, proinflammatory cytokines (interleukin-1 and tumour necrosis factor) and iNOS.

Question 24

What are Toll-like receptors?

Answer 24

These are receptors present on macrophages and dendritic cells which can be activated by PAMPs. TLR activation upregulates NF-ƙß which activates immune response genes producing cytokines. TLRs are also present on cells of adaptive immunity (lymphocytes).

Question 25

List 4 mediators which can cause redness and heat (rubor and calor).

Answer 25

1. Histamine. 2. Prostaglandins. 3. Bradykinin. 4. Nitric oxide.

Question 26

What causes fever in the context of acute inflammation?

Answer 26

Pyrogens (eg. lipopolysaccharide) cause macrophages to release interleukin 1 (IL-1) and tumour necrosis factor (TNF) which increase COX activity in perivascular cells of the hypothalamus. This causes production of PGE2 which raises the temperature set point.

Question 27

What causes the swelling seen in acute inflammation?

Answer 27

Histamine (from mast cells) causes endothelial cells to contract and endothelial cells can also be disrupted. This results in leakage of fluid from post-capillary venules into the interstitial space.

Question 28

What is oedema?

Answer 28

An excess of fluid in the interstitial tissue or serous cavities. Can be an exudate (a fluid high in protein containing cell debris) or a transudate (a fluid low in protein).

Question 29

What is pus?

Answer 29

A purulent exudate which is an inflammatory exudate rich in leucocytes (mostly neutrophils), the debris of dead cells and in many cases microbes.

Question 30

What causes pain in the context of acute inflammation?

Answer 30

Bradykinin and PGE2 sensitise sensory nerve endings.

Question 31

Describe the 5 steps which neutrophils follow to get from the post-capillary venule to the site of infection.

Answer 31

1. Margination. 2. Rolling (selectins on endothelial cells weakly bind to sialyl Lewis X on neutrophils). 3. Adhesion (mediated by adhesion molecules eg. ICAM and VCAM strongly binding to integrins on neutrophils). IL-1 and TNF induce the expression of selectins and adhesion molecules. 4. Transmigration (histamine contracts endothelial cells allowing neutrophils to squeeze through the gaps, helped by PECAM1 (CD31)). 5. Chemotaxis (neutrophils are attracted by bacterial products, IL-8, C5a and LTB4).

Question 32

Describe the steps involved in phagocytosis.

Answer 32

Consumption of pathogens is enhanced by opsonins/eat me signals (IgG and C3b). Phagocytosis involves binding to receptors on the neutrophil membrane, engulfment and fusion of phagocytic vacuoles with lysosomes. This is followed by destruction of ingested particles within the phagolysosomes by lysosomal enzymes and by reactive oxygen and nitrogen species. In activated leucocytes, cytoplasmic components of the phagocyte oxidase enzyme assemble in the membrane of the phagosome to form the active enzyme which catalyses the conversion of oxygen into superoxide and hydrogen peroxide. Myeloperoxidase which is present in the granules of neutrophils converts hydrogen peroxide into hypochlorite. Microbiocidal reactive oxygen species and nitric oxide then kill the ingested microbes.

Question 33

What is the consequence of myeloperoxidase deficiency?

Answer 33

There is defective conversion of hydrogen peroxide to hypochlorite. This leads to an increased risk of candida infection. The conversion of oxygen to hydrogen peroxide remains intact.

Question 34

Which inflammatory cell predominates in acute inflammation and which can be raised in a full blood count in the setting of acute inflammation, such as in the setting of an acute bacterial infection?

Answer 34

Neutrophil.

Question 35

Which cell dominates 3 days after acute inflammation begins?

Answer 35

Macrophage.

Question 36

How do macrophages kill organisms?

Answer 36

They ingest via phagocytosis helped by opsonins (C3b) and destroy phagocytosed material using enzymes (lysozyme) in secondary granules (Oxygen-independent killing).

Question 37

List 3 organs which mediate the systemic protective effects seen in acute inflammation and the cytokines which mediate these effects.

Answer 37

1. Brain. Fever (mediated by TNF IL-1 and IL-6). 2. Liver. Production of acute phase proteins (mediated by IL-1 and IL-6). 3. Bone marrow. Leukocyte production (mediated by TNF, IL-1 and IL-6).

Question 38

List the 4 possible outcomes to acute inflammation.

Answer 38

1. Resolution and healing (mediated by IL-10 and TGF-beta). 2. Continued acute inflammation (mediated by IL-8 with persistent pus production). 3. Abscess formation. 4. Chronic inflammation (macrophages present antigen to activate CD4+ helper T-cells).