inflammation

Question 1

• What is inflammation?

- What initiates inflammation?

Answer 1

Protective biological process that helps to remove damaged cells and clear toxins and infections
Non-specific response to cellular injury

Initiated when cellular damage (non-apoptotic cell death) leads to the release of damage associated molecular patterns (DAMPs) or the body detects pathogen associated molecular patterns (PAMPs)
causes cells in tissue to release a range of signals designed to induce inflammation

Question 2

• What can chronic inflammation lead to?
• What is acute inflammation characterised by?
• How does Chronic inflammation occur?

Answer 2

Scarring and loss of tissue function due to repetitive rounds of inflammation

Rapid onset, and recruitment of innate immune cells, particularly neutrophils.

When acute inflammation cannot get rid of the inflammatory signal
adaptive immune cells recruited

Question 3

• What are the 4 main signs of acute inflammation?

Answer 3

Redness (rubor)

Heat (calor)

Swelling (tumour)

Pain (dolor)

Question 4

• List causes of inflammation

Answer 4

Pathogens

Allergens 

Auto-antigens 

Physical damage

Extreme temperatures

Non-apoptotic cell death

Question 5

• What does the body release when there is damage done (e.g. wound in skin) ?
• What is the purpose of these chemicals?

Answer 5

Vasodilators (Histamine and nitric oxide)

Vascular changes:
    Increased permeability
    Dilation
    Reduced flow
    Plasma leakage into inflamed site

Question 6

• What benefits do increased leakage and vascular permeability have?

Answer 6

Increases antibodies to site

increased proteins (inc activation of immune cells and provides proteins for tissue repair)

physical barrier

increased leukocyte migration

Question 7

• What are the principle sources of Histamines and what are its actions?
• What are the principle sources of Prostaglandins and what are its actions?

Answer 7

Mast cells, basophils and platelets
Vasodilation, increased vascular permeability, endothelial activation

Mast cells & leukocytes
Vasodilation, pain, fever

Question 8

• What are the principle sources of Cytokines and what are its actions?
• What are the principle sources of Chemokines and what are its actions?

Answer 8

Macrophages, endothelial cells, mast cells
Endothelial activation, fever, malaise, pain, anorexia, shock

Leukocytes & activated macrophages
Chemotaxis & leukocyte activation

Question 9

• What are the principle sources of Complement and what are its actions?
• What is Exudate and what is it’s purpose?

Answer 9

Plasma (in liver)
Leukocyte chemotaxis & activation, opsonisation

Fluid containing proteins and cells that have seeped out of a blood vessel during inflammation
acts as barrier and prevents leakage of inflammatory stimuli and harmful pathogens to surrounding tissue

Question 10

• Outline the process of immune cell recruitment?

Answer 10

At the site of damage, inflammation and recruitment signals (e.g. chemokines) are produced, which diffuse out to form a gradient.

Leukocytes that have complementary chemokine receptors move to the chemokine source

Question 11

• What is CXCL8 also known as?
• What receptors bind to the chemokine CXCL8?
• Which cell type most prominently expresses these receptors that bind to CXCL8?

Answer 11

Interleukin-8 (IL-8)

CXCR1, CXCR2, These are g-coupled transmembrane proteins 

Neutrophils
This is why they are often the first cell type to be recruited to the site of inflammation

Question 12

• List and explain the 4 steps of neutrophil extravastion?

Answer 12

1. Chemo-attraction - production of cytokines and chemokines at the site of inflammation → endothelial up-regulation of adhesion molecules
   
   2. Rolling adhesion - Neutrophils have carbohydrate ligands in a low affinity state which bind to selectins (E.g. PSG1 - selectin P ligand)
   3. Tight adhesion - chemokines promote low→ high affinity switch integrins - enhances binding of neutrophil to endothelial wall
   4. Transmigration through endothelial wall → cytoskeletal rearrangement and extension of pseudopodia

Question 13

• What is the last step of neutrophil extravasation mediated by?
• What 3 main things do neutrophils do at the site of inflammation?

Answer 13

PECAM interactions on both endothelial side and neutrophil side

1. Pathogen recognition e.g. - use of TLR4 & CD14 to identify lipopolysaccharides present in gram-negative bacteria
2. Pathogen clearance - phagocytosis and netosis 
3. Cytokine secretion - Recruitment and activation of other immune cells

Question 14

what is the process of phagocytosis?

what else do phagocytes have that help with killing cells?

Answer 14

large particles are engulfed into a vesicle (phagosome)
phagosome fuses with a lysosome (vesicle containing elastase and lysozymes)
forms a phagolysosome

reactive oxygen species- phagocyte NADPH oxidase
antimicrobial peptides - eg defensin

Question 15

• What is the function of macrophages in the resolution of acute inflammation?

Answer 15

Clear apoptotic cells

Produce anti-inflammatory mediators

Question 16

• What is a hapten?
• What is the antigen type which independently can be capable of driving an immune response in the absence of additional substances?

Answer 16

Small molecule that alone does not act as an antigen but when bound to a larger molecule can create an antigen

Immunogen

Question 17

• What is the difference between acute and chronic inflammation?
• What makes chronic inflammation a vicious cycle?
• what is the distinct immune cell infiltrate from chronic inflammation

Answer 17

Chronic is a persistent inflammation → prolonged infection → persistent toxic stimuli

No clearance of inflammatory agent
Bystander tissue destruction
Concurrent repair processes (fibrosis and angiogenesis)

inflammatory macrophages
T cells
plasma cells

Question 18

what are examples of persistent inflammatory stimuli?

Answer 18

unclearable particulates eg silicon

allergens/ pollutants

persistent/ prolonged infection

autoimmunity

Question 19

What are examples of chronic inflammation?

Answer 19

Multiple sclerosis
Hepatitis
rheumatoid  arthritis
inflammatory bowel disease
asthma
psoriasis
glomerulonephritis

Question 20

• What form are macrophages recruited as in the site of inflammation?
• List some advantageous things about macrophages

Answer 20

monocytes

Phagocytic - good at clearing apototic cell bodies and foreign materials
Cytotoxic - can clear infection
Anti-inflammatory - suppress immune response
Wound repair

Question 21

• List some disadvantageous things about macrophages

Answer 21

Cytotoxic - if can’t clear infection they damage tissue

Inflammatory 

Pro-fibrotic - excessive formation of collagen → fibroblast proliferation

Question 22

• What can T cells do in inflammation?

Answer 22

Pro-inflammatory (eg TNF, IL-17, IFN gamma)

Regulatory (TGF- beta)

Cytotoxic (e.g. granzymes, perforin)

Question 23

• What do T cells allow in an immune response to inflammation?
• What do B cells do in inflammation?

Answer 23

Specificity to occur, (can also guide macrophages)

Generate plasma cells → antibodies
Protective - clearing infection
Also pro-inflammatory

Question 24

• What is granulomatous inflammation?

- What is a granuloma?

Answer 24

Chronic inflammation with distinct pattern of granuloma formation

Aggregation of activated macrophages → barrier designed for clearance

Question 25

- What triggers granulomatous inflammation? | - What are examples of granulomatous inflammation?

Answer 25

``` Strong T cell responses Resistive agents (e.g. mycobacterium, tumour) ``` ``` tumour formation Crohns disease Leprosy TB Sarcoidosis Foreign body granuloma ```

Question 26

- Compare the outcomes of acute and chronic inflammation? - What are released in acute and chronic inflammations respectively? - What leukocyte is dominant in each inflammation?

Answer 26

Acute - Complete resolution or Progression to Chronic Inflammation Chronic - Scarring & Loss of function Acute - histamine release Chronic - ongoing cytokine release Acute- neutrophil Chronic- monocyte/ macrophage

Question 27

- List some positives outcomes of acute and chronic inflammation - List some negatives outcomes of acute and chronic inflammation

Answer 27

Clear inflammatory agent Remove damaged cells Restore normal function Excess tissue damage Scarring Loss of organ function → organ failure

Question 28

- What is the major cause of these negatives of inflammation? - What does wound healing lead to?

Answer 28

The inflammatory agent not being removed Extracellular matrix (collagen) deposition