Infection/Inflammatory response

Question 1

What are the key signs of inflammation?

Answer 1

heat

redness

swelling

pain

loss of function

Question 2

describe the process of inflammation initiation

Answer 2

• microbe breaches barrier
• innate immune cells (macrophages, eutrophils, and dendritic cells) recognize ‘pathogen-associated molecular patterns’ (PAMP) using their ‘Pattern recognition receptors’ (PRR)
• once pathogen recognized, activate innate immune cells
• innate immune cells triger the production of cytokines and chemokines
• cytokines and chemokines initiate inflammaiton
  *

Question 3

What is the ‘Danger theory’ of tissue injury?

Answer 3

that cells (when damaged ) release self molecules, the “Danger signal” - these signals are then recognized by PRR and trigger the production of cytokines and chemokines - inflammaiton

Question 4

What cause the key stages of inflammation?

Answer 4

redness/heat - caused by vasodilation

pain - caused by release of inflammatory mediators

swelling - cuased by increased permeability

Question 5

in which (of the three) step of inflammation does activation of Macrophages, dendritic cells, and mast cells occur?

Answer 5

activation of tissue resident innate cells occurs in the first step of inflammation

Question 6

in what stage of inflammation are cytokines, lipids, and proteins released?

Answer 6

Cytokines, lipids, and proteins like histamine are released in the first step

Question 7

in what stage of inflammation does vasodilation and increased cell permeability occur?

Answer 7

in the second step - vasodilation and increased permeability allows for influx of neutrophils and monocytes

Question 8

in what stage of inflammation does activation of neutrophils/monocytes occur?

Answer 8

activation of neutrophils and monocytes occures in the third step

Question 9

in what stage of inflammation does redness, swelling, heat and pain occur?

Answer 9

in Step 3 - when the activation of neutrophils and monocytes releases cytokines

Question 10

describe the functions of lipids as inflammatory mediators

Answer 10

lipid inflammatory mediators include prostaglandings, leukotrienes, platelet activating factors…

they are responsible for vasodilation and permeabilisaiton

Question 11

describe the function of the cytokine inflammatory mediators

Answer 11

examples of cytokine inflammatory mediators are

IL1 and TNF alpha

they are responsible for activation, permeabilisation and cell adhesion

Question 12

describe the function of chemokine inflammatory mediators

Answer 12

example of chemokine inflammaotry mediators = IL 8

they are responsible for chemoattraction

Question 13

what chemical inflammatory mediators are there? What is their function?

Answer 13

Nitric oxide is a chemical inflammatory mediator - it is responsible for vasodilation

Question 14

what protein inflammatory mediators are there? what is their function?

Answer 14

histamin and C5a are both protein inflammatory mediators - they are responsible for permeabilisation

Question 15

what is the function of IL8?

Answer 15

IL-8 is a chemokine

chemokines are released by damaged cells and immune cells to bring more neutrophils to the infected region ‘chemoattractants’

they promote an increased expression of adhesion molecules on immune cells

Question 16

what is ‘Extravasation?’

Answer 16

it is how cells know to leave the circulation and traffic to the site of infection

it is the increased expression of adhesion molecules on endothelial cells of blood vessels close to the site of infection that enables interaction between selectin (endothelial) and carbohydrate (neutrophil)

Question 17

describe the key steps of extravasation

Answer 17

first step: loose binding between selectin (endothelial) and carbohydrate (neutrophil) enables neutrophils to slow down and ‘roll’ = rolling adhesion

second step = tight binding - facilitated by ICAM and integrin on the neutrophil

third step - neutrophil can ‘extravate’ through the vessel wall and into the surrounding tissue

Question 18

what is the function of neutrophils and macrophages once they reach the infection site?

Answer 18

phagocytosis - engulfment and killing of microorganism

phagocytic neutrophils respond to an epithelial chemokine interleukin 8

Question 19

what is the fist cell to migrate from the blood in the tissue into the underlying infection?

Answer 19

neutrophils are the first cells to migrate from the blood into the tissue underlying the infection - monocytes second

Question 20

how does phagocytosis kill the microorganism?

Answer 20

using the NADPH oxidase mechanism- Lysosomal enzymes indirectly kill phagocytosed microbes by making reactive oxygen species and nitric oxide

-once it has been ‘eaten’ the microorganism experiences lysosomal enzymes which make antimicrobial peptides - which make super oxygen radials and nitric oxide- when they react it causes a ‘respiratory burst’

it’s essentially a miniture ‘chemical explosion’ of the cell

Question 21

What is chronic granulomatous Disease?

Answer 21

phagocytes don’t function properly - leads to frequent severe infections of the skin, oral and intestinal mucosa

defect in NADPH oxidase system - a tissue biopsy may show granulomas -

Tests - nitroblue tetrazolium test - if NADPH oxidase is working then it will turn the WBC blue

Question 22

how does our body terminate an acute inflammation?

Answer 22

• short life of neutrophils and inflammaotry mediators
• neutrophils undergo apoptosis - macrophages ingest
• macrophages will change character and promote repair
• release inhibitory cytokines (IL10 and TGFbeta)
• limit inflammation
• grwoth factors promote repair
• act on fibroblasts
• lipid mediators- switch to production of anti-inflammatory lipoxins, resolvins, and protectins

Question 23

what causes chronic inflammation?

Answer 23

constant release of inflammatory mediators results in tissue injury - then macrophages constantly try to repair this ‘injury’ ending up with fibrosis of tissue instead of functional tissue

ex) COPD - lung fibrosis ,

Hepatitis = liver fibrosis

Question 24

What are we seeing here?

Answer 24

liver fibrosis

fibrosis = blue

liver tissue= red

Question 25

what characterises rheumatoid arthritis?

Answer 25

characterised by

• severe joint inflammation
• increased synovial fluid and thickened synovial membrane
• destruction of bone and cartilage in several joints
• elevated levels of pro-inflammatory cytokines

in the joints- lots of infiltrating macrophages and dendritic cells producing pro-inflmatory cytokines -

Question 26

what inflammatory mediator is targeted by NSAIDs?

Answer 26

lipid inflammatory mediators - which are normally responsible for vasodilation and permeabilisation

Question 27

what inflammatory mediator is targeted in anti-TNF therapies (etanercept or infliximab, as well as anti IL1 therapies like anakinra)

Answer 27

they target cytokines (hint anti - IL1) - which normally function to activate permeabilisation