Inflammation and the vascular response

Question 1

Aims of inflammation

Answer 1

1) kill or sequester microbes and neoplastic cells: neutrophils kill pathogenic bacteria, one of their main jobs is to phagocytose bacteria
2) to help removed damaged tissue e.g. phaogcytosis of cellular debric by macrophages
3) provides wound healing factors to traumatized tissue

Question 2

Cardinal signs of inflammation

Answer 2

redness (rubror), heat (calor), swelling (tumor), pain (dolor) and loss of function

Question 3

5 R’s of the process of inflammation

Answer 3

Recognition of injurious agent

Recruitment of White blood cells

Removal of the injurious agent

Regulation of the response

Resolution/Repair

Question 4

Components of the inflammatory response

Answer 4

1) blood leukocytes: polymorphonuclear leukocytes (neutrophils, eosinnophils, basophils) and mononuclear leukocytes (monocytes (macs in tissue), lymphocytes, plasma cells and mast cells)
2) plasma proteins
3) vascular endothelial proteins
4) extracellular matrix

Fibroblasts involved in chronic inflammation

Question 5

Acute inflammatory reaction

Answer 5

Exposure to injurious agent:

1) modification of plasma proteins–> release of chemical mediators–> recruitment of WBCs from circulation and exudation of fluids and proteins from blood vessels (vascular response)
2) macrophages–>release of chemical mediators–> recruitment of leukocytes from circulation–> phagocytosis
nb: macrophages also phagocytose.

Question 6

Vascular changes in inflammation

Answer 6

NB: usually in acute inflammation (1st 12-24 hours post injury)

1. initial transient vasoconstriction
2. vasodilation of arterioles and small vessels
   - local increase in blood flow( hyperemia); engorgement of capillary beds; erythema (redness)
3. increased intravascular pressure
   - intravascular hydrostatic pressure forces fluid OUT of vessels
   - low protein fluid- formation of transudate (ultrafiltrate) which gets pushed out of vessels.

Question 7

Local manifestation in acute inflammation

Answer 7

1) increased blood flow leading to arteriole dilation, expansion of capillary bed and venule dilation
2) increased leakage of plasma proteins (which bring fluid along with it)–>oedema
3) neutrophil emigration

Question 8

Causes of increased vascular permeability (i.e. movement of protein rich (exudate) fluid into interstitium

Answer 8

1st: endothelial cell contraction (reversible)
- intracellular gaps result from contraction, chemical mediator (histamine), “immediate transient response” i.e. vasoconstriction
2nd: endothelial cell retraction
- end effect is also an increase in intracellular gaps
- mediated by cytokines- TNF and IL1

causes changes in the cytoskeleton

takes 4-6 hours and persists longer ~24 hours

Question 9

other causes of increased vascular permeability

Answer 9

a. endothelial cell injury: cell necrosis and detachment- immediate onset and persists several hours- “immediate sustained injury”
b. leukocyte-mediated endothelial injury: neutrophils line up along walls (loaded with enzymes) and can damage endothelial cells when activated.
c. increased transcytosis: movement of proteins by an intracellular vesicular pathway
d. high permeability of new vessels during angiogenesis (immature, new young BVs are leaky)

Question 10

Summary of changes in vascular permeability

Answer 10

Short lived vasoconstriction, then vasodilation induced by chemical mediators.

Increased vascular permeability induced by chemical mediators, gaps produced between endothelial cells

Plasma proteins and WBCs enter sites of damage or infection; fluid leakage into tissues results in oedema.

Question 11

Transudate vs. exudate

Answer 11

Transudate: leakage of fluid containing water and electrolytes but low protein and cells

Modified transudate: leakage of fluid containing water and electrolytes , high protein but few cells

Exudate: leakage of fluid containing water, electrolytes, high protein and numerous inflammatory cells.

Question 12

When do transudate and exudate form?

Answer 12

under normal conditions: hydrostatic pressure draws fluid OUT of blood vessels. Oncotic pressure draws fluid into blood vessels (albumin specifically)

Transudate: increased hydrostatic pressure due to venous outflow obstruction (i.e. congestive heart failure); decreased oncotic pressure due to decreased albumin caused by i.e. liver disease or leaky glomeruli

Exudate: intracellular gaps in endothelial cells are MUCH larger, so WBCs and proteins can squeeze through. Fluid and protein leakage results–> this happens during inflammation.

Question 13

Typical appearances of transudates and exudates

Answer 13

Transudate: clear, colorles fluid

Exudate: turbid fluid, sometimes accompanied by pus/purulent material; can be caseous (thickened or dried)

Histopath of purulent exudate: intracellular bacteria, degenerate, lots of n’phils, v. active macrophages with vacuoles.

Question 14

Inflammatory exudates

Answer 14

suppurative (purulent) exudate: contains abundant neutrophils

mucopurulent exudate: mucus and abundant neutrophils

fibrinous exudate: high protein fluid with abundant deposition of fibrin– caused by more severe injury causing greater vascular permeability

NB: fibrin indicates pretty severe damage

Fibronecrotic exudate: necrotic cellular debris with abundant fibrin and degenerate neutrophils- presence of diphtheritic pseudomembrane

Question 15

Inflammation: sequence of events

Answer 15

Acute: vascular changes (redness and oedema), neutrophil migration; short duration

Chronic: mononuclear cell infiltrate–> increase in lymphocytes, plasma cells, and macrophages; angiogenesis; fibrosis; long duration

Basic forms of inflammation can overlap; can get chronic active inflammation for example with abundant neutrophils (acute inflammation), many macrophages (chronic response) and +/- lymphocytes and plasma cells.

Question 16

Consequences of acute inflammation

Answer 16

modified by nature and intensity of injury

site and tissue affect

ability of host to mount a response

Question 17

Outcomes of acute inflammation

Answer 17

1. resolution: neutralization, decay, degradation of chemical mediators; normalization of vascular permeability; cessation of WBC emigration
2. progression to chronic inflammation (if offending agent not removed); may be seen at onset of injury in some cases; return to normalcy dependent on initial and continued injury and ability of tissue to regenerate
3. scarring and fibrosis: results from substantial tissue destruction (i.e abscess formation where tissue structure has been destroyed) or where tissues can’t regenerate.
   nb: johne’s disease (mycobacterium avium ssp paratuberculosis) : insidious smoldering macrophage chronic response, not really any acute inflammation seen.

Question 18

Events in resolution of inflammation

Answer 18

1. return to normal vascular permeability
2. drainage of oedema and proteins into lymphatics or drainage of oedema and protein by pinocytosis into macrophages
3. phagocytosis of apopototic neutrophils
4. phagocytosis of necrotic debris
5. disposal of macrophages

Macrophage is main cell of inflammation: tidy up necrotic debris, leukocytes; produce growth factors which encourage re-growth and healing.

Question 19

Undesireable consequences of inflammation

Answer 19

• uncontrolled, severe inflammation (i.e. hot water burn)
• prolonged persisten inflammation (injurious agent can’t be removed)- johne’s disease- intracellular location (in macrophages)- constant stimulus of chronic inflammatory response- result in thickened rugae of GI tract
• inflammatory response is inappropriate i.e. autoimmune disease (directed against self-antigen), allergic disease (excessive response to harmless environmental antigens).