Pathophysiology of Inflammations

Question 1

What is inflammation?

Answer 1

A protective response to rid the organism from the cause of cell injury. There are 2 types of inflammation:
Acute and chronic

Question 2

Factors associated with acute inflammation:

Answer 2

1) rapid
2) short duration
3) associated with the presence of leukocytes
4) characterised by fluid and plasma protein secretion (edema production )

Question 3

Factors associated with chronic inflammation:

Answer 3

1) long duration
2) associated with the presence of lymphocytes and macrophages
3) characterised by proliferation of blood vessels, fibrosis and tissue disruption

Question 4

Clinical features of inflammation are…?

Answer 4

1) rubor (redness)
2) tumor (swelling)
3) calor (heat)
4) dolor (pain)
5) functio laesa (loss of function)

Question 5

What is acute inflammation?

Answer 5

A rapid host response that serves to deliver leukocytes and plasma proteins to the site of infection or tissue injury.

Question 6

Three stages of acute inflammation?

Answer 6

1) Vasodilation
2) Increased vascular permeability
3) Leukocyte migration

Question 7

Explain what happens in stage 1 of acute inflammation?

Answer 7

stage 1 is vasodilation. This is when the blood vessels dilate and alter the vascular calibre resulting in increased blood flow

Question 8

Explain what happens in stage 2 of acute inflammation?

Answer 8

stage 2 is increased vascular permeability. This is when the membrane of the blood vessels allow for plasma proteins and leukocytes (white blood cells) to leave the circulation and form an edema.

Question 9

Explain what happens in stage 3 of acute inflammation?

Answer 9

stage 3 is leukocyte migration from the microcirculation to the site of injury where they accumulate. They become activated and eliminate the cause of injury.

Question 10

Four stimuli for acute inflammation:

Answer 10

1) infections - microbial toxins
2) necrosis - molecules released by necrotic cells
3) foreign bodies - splinters, dirt
4) immune reactions - autoimmune diseases

Question 11

Explain how vascular permeability is increased?

Answer 11

1) endothelial cells contract due to histamine, NO and other mediators. This results in increased inter-endothelial spaces.
2) Endothelial injuries are caused by burns and microbial toxins and results in endothelial cell necrosis and detachment
3) Vascular injury caused by neutrophils attaching to endothelium.
4) Increased transport of fluids and proteins (transcytosis) induced by VEGF (vascular endothelial growth factor)

Question 12

Explain how leukocytes adhere to the endothelium?

Answer 12

1) Margination: redistribute along endothelium
2) Rolling: leukocyte adhere transiently (for a short time) then detach, the reattach firmly. Controlled by proteins called selectin.
3) Adhesion: Firmly adhere to endothelium by proteins called integrins.

Question 13

Explain how leukocyte migrate through the endothelium (aka diapedesis/transmigration).

Answer 13

leukocytes pierce the basement membrane of endothelial cells by secreting collagenase enzymes and enter the extravascular site. This is mediated by PECAM-1/CD31 (an adhesion molecule).

Question 14

Explain the chemotaxis process of leukocytes

Answer 14

They emigrate towards the site of tissue damage by following chemoattractants: exogenous and endogenous.

Question 15

What are endogenous and exogenous chemoattractants?

Answer 15

Exogenous: bacterial products
Endogenous: chemical mediators

Question 16

Three types of receptors on leukocytes for microbe recognition and attachment?

Answer 16

1) Mannose receptor
2) Scavenger receptor
3) Opsonin receptor

Question 17

What does the mannose receptor do?

Answer 17

Binds to terminal sugar residues which are part of the molecules found on microbial cell walls

Question 18

What does the scavenger receptor do?

Answer 18

binds to a variety of microbes.

Question 19

What does the opsonin receptor do?

Answer 19

Major opsonins are IgG antibodies and plasma lectins. The opsonin receptors detect opsonin around microbe coated in opsonin protein and leukocytes have a high affinity for this.

Question 20

What are the three stages of the phagocytosis of stimuli causing tissue damage?

Answer 20

1) recognition and attachment
2) engulfment
3) killing and degradation

Question 21

Explain the process of engulfment of microbe?

Answer 21

Plasma membrane of phagocyte (leukocyte) forms a vesicle that encloses the microbe (forming a phagosome). The phagosome fuses with the lysosome forming a phagolysosome.

Question 22

Explain the process of killing and degradation of microbe?

Answer 22

Accomplished by reactive oxygen species (ROS) and reactive nitrogen species derived from NO, or by lysosomal enzymes.

Question 23

What happens to the lymph flow during inflammation?

Answer 23

Increases and helps drain edema fluid into lymph nodes from lymphatic vessels.

Question 24

Two types of mediators of inflammation?

Answer 24

Cell-derived mediators and

plasma-protein-derived mediators

Question 25

What are Cell-derived mediators?

Answer 25

They are produced locally by cells at the site of inflammation. They’re either pre-accumulated in granules and rapidly secreted upon cellular activation, or they’re newly synthesised in response to a stimulus.

Question 26

What are plasma-protein-derived mediators?

Answer 26

They’re produced in the liver and circulate in the plasma. They become activated at the site of inflammation.

Question 27

What happens to mediators once activated?

Answer 27

They’re inactivated by enzymes or they’re eliminated or inhibited.

Question 28

Two examples of cell derived mediators of inflammation are?

Answer 28

Prostaglandin and Leukotrienes

Question 29

Explain the process of prostaglandin and leukotrienes formation?

Answer 29

Phospholipase A2 releases arachidonic acid (AA) from phospholipid membrane.
Prostaglandin: AA acts on COX enzymes and are converted to prostaglandins.
Leukotrienes: AA is converted to 5-HPETE and then leukotrienes.

Question 30

Explain thromboxane and prostacyclin formation?

Answer 30

Prostaglandin formed from AA and Cox interaction is PGG2, which gets converted to PGH2. PGH2 becomes Prostacyclin (PGI2) which is found in endothelial cells. PGH2 also becomes thromboxane (TXA2).

Question 31

Where are prostacyclin and thromboxane found and what do they cause?

Answer 31

Prostacyclin: found in endothelial cells. Causes vasodilation and inhibits platelet aggregation.
Thromboxane: found in platelets. Causes vasoconstriction and promotes platelet aggregation.

Question 32

What cause thrombus formation?

Answer 32

When there’s more thromboxane formed than prostacyclin.

Question 33

what are the effects of taking NSAIDs?

Answer 33

1) Anti-inflammatory - block prostaglandin production hence less vasodilation, hence less chance of edema formation.
2) Anti-pyretic - Lower high temperature
3) Analgesic - Reduce pain by inhibiting prostaglandin production that sensitise nociceptors to inflammatory mediators.

Question 34

Pro’s for using COX2 specific inhibitors?

Answer 34

E.g. celecoxib and Etoricoxib

1) more selective for inflammation as COX2 is mainly expressed in inflammatory cells after stimulation.
2) Less GI toxicity but increased risk of arterial thrombosis
3) potential role in colon cancer therapy

Question 35

Explain how lipoxygenase inhibitors reduce inflammation

Answer 35

By inhibiting leukotrienes production or by blocking leukotriene receptors. (useful for asthma)

Question 36

Explain how glucocorticoids reduce inflammation?

Answer 36

They reduce the transcription of genes encoding COX2, phospholipase A2, iNOS, pro-inflammatory cytokines and many more. This makes the most powerful anti-inflammatory drug. However, they have an immunosuppressive effect.

Question 37

What does NF-kB transcription factor do?

Answer 37

Regulates the expression of cytokines (IL-1, IL-6, TNF) and many other factors involved in inflammation. It is activated by a number of stimulus and causes the transcription of inflammatory gene in DNA to mRNA.

Question 38

Four inhibitors that can be used to prevent NF-kB from transcribing the inflammatory DNA gene?

Answer 38

1) IKK inhibitors
2) Proteasome inhibitors
3) Inhibitors to block nuclear translocation
4) Inhibitors to block NF-kB DNA-binding activity.

Question 39

What is chronic inflammation?

Answer 39

Inflammation of prolonged duration. Attempts at repair exists. Can develop from acute inflammation or emerge as a low-grade response without any acute reaction visible

Question 40

Three causes of chronic inflammation?

Answer 40

1) persistent infections
2) immune-mediated inflammatory diseases
3) prolonged exposure to toxic agents.

Question 41

Explain how persistent infections cause chronic inflammation?

Answer 41

microorganisms that are difficult to eradicate lead to granulomatous reactions (aggregation of macrophages transformed into epithelial cells surrounded by immune cells)

Question 42

Explain how immune-mediated inflammatory disease leads to chronic inflammation?

Answer 42

caused by excessive and inappropriate activation of the immune system. 3 types: 1) immune reactions against individuals own cells (autoimmune disease)

2) unregulated immune-reactions against microbes (IBDs)
3) immune response against harmless environmental substances (asthma)

Question 43

Explain how prolonged exposure to toxic agents cause chronic inflammation?

Answer 43

Long exposure to endogenous (toxic plasma lipids) and exogenous (silica) agents.

Question 44

Features of chronic inflammation?

Answer 44

1) Infiltration with mononuclear cells (macrophages, lymphocytes and plasma cells)
2) Tissue destruction induced by persistent offending agent
3) Attempts at healing (connective tissue replace damage tissue by proliferation of small blood vessels and fibrosis)

Question 45

Cells used in chronic inflammation?

Answer 45

1) Macrophages (to eliminate injury agents and initiate process of repair. Responsible for most of the tissue injuries)
2) Lymphocytes (Communicate with macrophages through the use of cytokines. Makes inflammatory reaction chronic and severe).
3) Plasma cells (Develop from B lymphocytes and produce antibodies against foreign body or self antigens at inflammatory site.)