Inflammation

Question 1

What are the characteristics of inflammation?

Answer 1

Erythema/redness
Calor/heat
Oedema/swelling
Pain

Question 2

What is inflammation and what is the aim of the immune system it uses?

Answer 2

A response to tissue injury caused by trauma, burns or infection. The innate immune system aims to destroy the noxious agent and induce tissue repair.

Question 3

What are the characteristics of the innate immune system?

Answer 3

Rapid response as ready to activate at any time
No memory
Low specificity
Recognises pathogens via PAMP and PRRs

Question 4

How does the innate immune system recognise pathogens?

Answer 4

1) On breach of the barrier, the pathogen comes into contact with resident tissue macrophages.
2) The macrophages’ PRR (Pattern recognition receptor) detects PAMP (Pathogen associated molecular pattern) on the pathogen.
3) Activation of PRR releases cytokines and chemokines to activate the immune system.

Question 5

Which cytokines are involved in acute phase response?

Answer 5

TNFalpha
IL-1beta
IL-6

Question 6

What is the function of acute phase cytokines?

Answer 6

To upregulate acute phase protein production in the liver e.g. CRP.

Question 7

What is the function of CRP?

Answer 7

To opsonise pathogens and activate the complement cascade and other areas of the immune system.

Question 8

What is the function of APCs, phagocytes and granulocytes in inflammation?

Answer 8

APCs recognise nonself and escalate the inflammation.

Phagocytes and granulocytes contain and destroy the pathogen.

Question 9

What is the overall response of inflammation? (RRD)

Answer 9

Recognition - via innate immune cells
Response - Escalate response through cellular attraction and recruitment using cytokines and activating the complement cascade
Dealing - Phagocytosis, resolution of inflammation and recruitment of adpated immune response.

Question 10

What are mast cells?

Answer 10

Present in most tissues around vessels and nerves. Predominately under skin and mucosa. They initiate the inflammatory response by releasing preformed granules, in response to complement, inflammatory components, directly to pathogen derived factors or IgE.

Question 11

Which granules do mast cells release?

Answer 11

Histamine
Leukotrienes
Prostaglandins

Question 12

What is the function of histamine in the inflammatory response?

Answer 12

Induces vasodilation to increase blood flow to the area.
Endothelial junctional widening to increase permeability for immune cells.
Irritate nerve endings to cause itch/pain to alert consciously.

Question 13

What three things occur alongside increased movement of fluid into the tissue?

Answer 13

Leukocytes due to upregulation of adhesion molecules and cytokine secretion of IL CXCL-8.
Increased secretions
Smooth muscle constriction

Question 14

What factors are important for maintaining the inflammatory response and for its resolution?

Answer 14

PGs, thromboxane A2 and leukotrienes. Produced by arachidonic acid metabolism upon the release of granules.

Question 15

What do arachidonic metabolites cause?

Answer 15

Produced via COX pathway to induce vasodilation and therefore prolonging the oedema

Question 16

What drugs will block the COX pathway to reduce pain and fever?

Answer 16

Aspirin and NSAIDs

Question 17

What is the function of leukotrienes?

Answer 17

They are chemotaxins and vasoconstrictors causing vascular permeability and bronchospasm.

Question 18

What the cardial signs of an acute phase response?

Answer 18

erythema - vasodilation
oedema - vascular permeability
heat - cytokines
pain - mediators

Question 19

What causes anaphylactic shock?

Answer 19

Generalised mast cell activation leading to wide spread vasodilation and a dramatic fall in BP. Localised inflammatory response can cause systemic inflammation due to cytokines, PGs and leukotrienes.

Question 20

What is allergic disease?

Answer 20

Excessive activation of mast cells e.g. asthma and hayfever

Question 21

What is the function of inflammatory mediators?

Answer 21

Activate local endothelial cells to promote expression of adhesion molecules to increase permeability and cause vasodilation.

Question 22

How do leukocytes enter the tissue?

Answer 22

Leukocytes stick to the adhesion molecules to prevent further movement and are directed in to the tissue via chemotactic gradients.

Question 23

What is the purpose of coagulation in the inflammatory response?

Answer 23

To prevent spread of pathogen in the blood.

Question 24

What is the purpose of inducing a fever?

Answer 24

To change the environment and reduce optimal conditions for the pathogen.
To mobilse fat to provide energy for the response

Question 25

What therapies can block the acute phase response?

Answer 25

Anti-cytokine therapies:
Anti TNFalpha for IBD and RA
Anti IL-1 and IL-6 for RA and lupus

Question 26

What causes septic shock?

Answer 26

Spread of infection into the blood stream induces a systemic response. The release of systemic cytokines results in increase vascular permeability and a dramatic fall in BP, decreased CO and lack of tissue or organ perfusion due to intravascular coagulation, leading to organ failure.

Question 27

What are the 5 possible outcomes after an acute phase response?

Answer 27

Complete restitution (suppressed immune system and no damage)
Scar - where cells cannot regenerate
Abscess - encapsulated pathogen and formation of pus from dead neutrophils
Granuloma - Calcification around infection via TNFalpha
Chronic inflammation - failure to eradicate

Question 28

What is chronic inflammation?

Answer 28

Occurs when the acute phase cannot be resolved due to:
persistent injury/infection e.g. ulcer, TB
Prolonged exposure to toxic agent e.g. asbestos
AI e.g. RA
Lymphocytes, macrophages and plasma cells continuously infiltrate and results in granuloma formation, fibrosis, angiogensis and tissue damage from cytokine release

Question 29

How is inflammation resolved?

Answer 29

May be eradicated as most mediators or short lived and degrade. Anti-inflammatory cytokines inhibit production of proinflammatory cytokines e.g. TGFbeta, IL-10.
Clotting reduces blood loss from damaged vessels and scabs form as clot dries to reduce infection risk.
Fibroblasts from surrounding CT replace collage and ECM.
Angiogensis needed to form granulation tissue.
Clot dissolves as tissue repairs

Question 30

What is a scar?

Answer 30

Large volume of granulation tissue and loss of capillaries

Question 31

How can acute phase response be measured?

Answer 31

Acute phase proteins increase:
CRP - increase within 24-48hrs. Very high = bacterial
C3/4
Fibrinogen for clotting
Ferritin for iron metabolism
WBC and neutrophils

Negative control proteins decrease
A1 antitrypsin
Albumin
Transferrin

Question 32

What is the erythrocyte sedimentation rate?

Answer 32

The rate at which erythrocytes settle out of unclotted blood in one hour.
Normally settle slowly as -ve charged so repel each other, preventing aggregation.
Acute phase proteins cause them to lose -ve charge and aggregate, resulting in faster and increased sedimentation.

Question 33

When is CRP an ineffective marker?

Answer 33

With liver failure as synthesis is reduced despite rising levels of IL-6

Question 34

What is leukocytosis?

Answer 34

During an exaggerated reaction, IL-1 and IL-6 stimulate the bone marrow to release leukocytes, but due to inability to meet demand, there is a left shirt release of immature precursors.