Inflammation

Question 1

What is inflammation?

Answer 1

Universal, non-specific response to cellular injury / non-apoptotic cell death
Remove cause and consequence of injury
Complex yet tightly regulated process

Question 2

How is inflammation triggered?

Answer 2

Sublethal cellular damage releases DAMPs (damage associated molecular patterns)
Cells in the damaged tissue secretes a range of signals molecules that induce inflammation

Question 3

How does the body induce inflammation?

Answer 3

Alter structure of nearby blood vessels

Release chemokines that recruit immune cells

Question 4

4 main signs of inflammation? (And why)

Answer 4

Redness - blood flow is slower
Heat - histamine mediated vasodilation
Swelling - histamine mediated increase in permeability of cells and oedema
Pain - many of the same mediators that signal to endothelial cells and other immune cells during inflammation, also signal on local nerve cells
Bonus 5th, obscure point: Loss of function - usually due to swelling and pain

Question 5

Why is inflammation useful / necessary?

Answer 5

Protects against infection and trauma

Question 6

What is acute inflammation?

Answer 6

Quick / instantaneous
Rapid change in local blood flow, structural change in the microvasculature (arterioles,venules, capillaries)
Starting point for the progression of major/chronic inflammation

Question 7

Where does it occur?

Answer 7

Process applies to any viable vascularised tissue

Anywhere the blood vessel has an endothelium

Question 8

What is the normal / steady state of all the immune cells? (E.g. on the skin)

Answer 8

Normally : Inside interstitium (AKA between the epithelium and vascular endothelium) resident immune cells are present - macrophages, mast cells, dendritic cells etc.
Inside the vascular bundle (AKA inside the blood vessel) lymphocytes are present - many neutrophils, some macrophages etc.

Question 9

How does the normal change when there is damage?

Answer 9

1. Non apoptotic cell death releases inflammatory signals - foreign material detected
2. Vessels dilate as vasodilator are released - e.g. histamine and nitric oxide
3. Accumulation of blood and fluid in that site results in: dilation, slowed vascular speed, increased permeability, increased plasma leakage

Question 10

What benefits does increased vascular permeability and leakage bring?

Answer 10

Increase vascular permeability and leakage = increased access to lymphocytes and antibodies, access to more coagulation factors/ plasma based proteins, increased blood flow = increased heat, acts as a barrier

Question 11

What is exudate?

Answer 11

Fluid barrier - high protein content and cellular debris that has escaped from blood vessels and deposited in/on tissues
Harder for pathogen to penetrate and cause damage to tissue below

Question 12

What are other soluble mediators released at an injury?

Answer 12

Histamines released by mast cells, basophils and platelets - cause vasodilation + increased vascular permeability
Prostaglandins released by mast cells and leukocytes - cause vasodilation, pain, fever
Cytokines released by macrophages, endothelial cells and mast cells - cause endothelial activation (adhesion molecules), fever, pain, anorexia, shock
Chemokines released by leukocytes and activated macrophages - cause chemotaxis and leukocyte activation
Complement produced by plasma in the liver - cause leukocyte chemotaxis and activation, vasodilation and opsonisation (pathogen marked as to be engulfed)

Question 13

How are immune cells recruited to the site of inflammation?

Answer 13

1. Recruitment and inflammation signals are produced at the site (e.g.) chemokines
2. Chemokines diffuse out to form a gradient
3. Leukocytes expressing complementary chemokine receptors migrate towards the chemokine source

Question 14

What do chemokines do?

Answer 14

Chemical gradient to recruit immune cells

Question 15

How are neutrophils extravated?

Answer 15

1. Chemokine signals released - cause endothelial upregulation of adhesion molecules (such as selectin) + neutrophils to upregulate their complementary molecules
2. Engagement with endothelial cells + roll adhesion - selectins on the neutrophils can bind to endothelial cells
3. Exposure to integrins causes strong binding of neutrophil to tissue site
4. Transmigration - neutrophils squeeze through between cell membranes, through the gaps into the interstitium

Question 16

What is the roll adhesion process?

Answer 16

Selectins are loose at first, but as the neutrophil rolls along the side of the blood vessel and slows, permanent bonds are formed, which fix the neutrophil to the endothelial cell

Question 17

What do neutrophils do at the site of inflammation?

Answer 17

TLRs (T-cell receptors) recognise polysaccharides on pathogens e.g. TLR4 and CD14 to identify lipopolysaccharides (LPS) present in gram-negative bacteria
Phagocytosis
Expose pathogens to reactive oxygen species
Antimicrobial peptides released
Lymphocytosis - increased release of cytokines for increased neutrophil recruitment

Question 18

How does phagocytosis work?

Answer 18

Large particles engulfed into membrane bound vesicles (phagosomes)
Phagosome fuses with lysosome (vesicles containing enzymes e.g. elastase and lysozyme) to form a phagolysosome
The large particles are digested, and some antigens are presented on the cell surface
Reactive oxygen species (ROS) – phagocyte NADPH oxidase
Antimicrobial peptides – e.g. defensins

Question 19

How does the inflammation / neutrophil stop being recruited?

Answer 19

Neutrophils have a short half life
Once they pass away, no recruitment
Histamine and nitric acid also have short half lives
Macrophages - clear apoptotic cells and produce anti-inflammatory mediators
Repair and wound healing

Question 20

Examples of chronic inflammation

Examples of diseases with granulomatous

Answer 20

Chronic
Rheumatoid Arthritis
Asthma
Hepatitis

Granulomatous - foreign body stuck to tissue
TB
Leprosy
Copy off slide

Question 21

What is chronic inflammation and how is it different to acute inflammation?

Answer 21

Both are quite similar, but whilst acute is instantaneous, chronic inflammation lasts much longer and has prolonged /persistent inflammatory stimulii e.g.
persistent/prolonged infection (e.g. TB, hepatitis B/C)
Persistent toxic stimulii e.g. allergens, pollutants
Unclearable particulates e.g. silica
Autoimmunity e.g. self antigens

Question 22

How is the response different to chronic than acute inflammation?

Answer 22

Inflammatory macrophages rather than neutrophils
T cells
Plasma cells - produce antibodies against persistent infections

Question 23

What happens to the tissues that are chronically inflamed?

Answer 23

No clearance of the persistent inflammatory stimuli
Results in continuous damage to surrounding tissues and a concurrent repair process (fibrosis - formation of excess fibrous connective tissue during repair and angiogenesis - formation of new blood vessels)

Question 24

Good and bad of macrophages

Answer 24

Recruited as monocytes at site of inflammation
Good :
Cytotoxic = kill cell
Phagocytosis
Anti inflammatory - shut down response by releasing suppressive cytokines to promote sound heating and suppress activity of immune cells
Wound repair
Bad:
Cytotoxic = not just kill bacteria but healthy cells too
Inflammatory or regulatory are often the wrong way round at the site, e.g. cause an inflammatory response instead of the regulatory one (and vice versa). Inflammatory response, especially chronic, can cause fibrosis of tissue resulting in permanent damage to tissue function

Question 25

What are some other cells involved in the innate and adaptive immune response that work together?

Answer 25

Macrophages and T cells which signal to each other
T cells are pro inflammatory and so are good for viral infections and wound repair, cytotoxic so can kill viral infected cells solely and not damage healthy tissue, regulatory
B cells can differentiate to plasma cells that generate antibodies. Can result in autoimmune disorders

Question 26

On scan granulomatous

Answer 26

Circular space that doesn’t match the surrounding tissue
Aggregation of activated macrophages
Fuse around stimulus
Triggered by strong T cell/ resistant agents

Question 27

Key differences between acute and chronic inflammation are?

Answer 27

ACUTE:
Immediate onset/ lasts a few days
Vasodilation, increased vascular permeability, leukocyte response
Neutrophils predominate
Histamine release
Prominent necrosis
Outcomes include:
Complete resolution
Progression to Chronic Inflammation

CHRONIC:
Delayed onset; may last weeks, months or years
Persistent inflammation, ongoing tissue injury, attempts at healing
Monocytes / Macrophages predominate
Ongoing cytokine release
Prominent scarring
Outcomes include:
Scarring
Loss of function

Question 28

What is granulomatous inflammation?

Answer 28

A specialised type of chronic inflammation, with a distinct pattern of granules formed. It can stem from strong T cell responses and/or resistant agents (e.g. mycobaterium, tumour)

Granulomatous accompanied by chronic
Generally does not cause necrosis, at least not to the cells surrounding the granulomatous

Question 29

What are the outcomes of acute inflammation?

Answer 29

Change in vascular network
Neutrophil recruitment
Afterwards, it may go back to the way it looked originally
Or the neutrophil breaks down tissue which results in slight scarring, but new blood vessels form and it goes back to normal
So ultimately: clears inflammatory agent, removes damaged cells and restores normal tissue function

Question 30

What are the outcomes of chronic inflammation?

Answer 30

Excessive tissue damage
Continuous tissue damage
Scarring
Loss of organ function — in serious circumstances can result in organ failure

Question 31

What are the stages of wound healing?

Answer 31

Haemostasis
Inflammation
Proliferation
Matrix formation (mesh network) and remodelling