Chapter 1 Inflammatory Response

Question 1

4 hallmarks of inflammation

Answer 1

Heat (calor) Swelling (tumor) Erythema (rubor) Pain (dolor)

Question 2

In acute vascular response to inflammation, ithe response can be broken down into 4 ‘mechanisms’

Answer 2

Vasodilation

Permeability

Stasis

Leukocyte extravasation

Question 3

In acute vascular response to inflammation, which vasoactive agents (4) cause initial, transient vasoconstriction? And which (5) cause vasodilation?

Answer 3

Vasoconstriction: Catecholamines, serotonin, bradykinin, PGs

Vasodilation: NO, histamine, leukotrienes, PGs, complement factors.

Question 4

Which two vasoactive agents mediate increased vascular permeability, in acute vascular response to inflammation And broadly speaking, how is permeability increased?

Answer 4

Histamine and serotonin. Increased size of intracellular endothelial gaps i.e. trans cytoplasmic channels.

Question 5

Briefly outline leukocyte extravasation, with regard to 1) margination and rolling 2) adhesion 3) diapedesis

Answer 5

• Margination + rolling mediated through endothelial selectins (E-selectin) and corresponding leukocyte ligand (e.g. Sialyl-Lewis X-modified glycoprotein). Weak, transient bonds, increasing affinity as rolls and bond from/re-form.
• Leukocyte adhesion to vascular wall through integrin on leukocyte surface (alpha- subunit (CD11a/CD11b/CD11c) and beta-subunit (CD18)) to corresponding endothelial adhesion molecule (e.g. intercellular adhesion molecule-1 (ICAM-1)). High affinity bonds.

o E.g. Lymphocyte function associated antigen 1 (LFA-1 = CD11a/CD18) and macrophage antigen 1 (Mac-1 = CD11b/CD18)

• Diapedesis = migration of leukocytes through inter-endothelial junctions. Mediated via endothelial adhesion molecules (e.g. ICAM-2 and platelet-endothelial cell adhesion molecule-1 (PECAM-1). • Adhesion molecules/integrin expression upregulated by inflammatory mediators.

Question 6

How long are peak populations of neutrophils present for during inflammation?

Answer 6

24-48 hours

Question 7

3 mechanisms by which neutrophils provide local killing

Answer 7

1) phagocytosis
2) release of superoxide radicals
3) formation of neutrophil extracellular traps (inc antimicrobial peptides)

Question 8

Name the three types of neutrophil granule + basic functions

Answer 8

Primary (azurophil): microbicidal polypeptides

Secondary: metalloproteases

Tertiary (“gelatinase”): gelatinase granules

Question 9

What are the two types of macrophages and basic roles

Answer 9

Tissue-derived: detection + early pro-inflammatory

Monocyte-derived: main type in inflammatory conditions, also effector cells for vascular ingrowth

Question 10

Macrophage polarisation = ability of macrophages to assume two distinct functional phenotypes. What are they and their basic functions?

Answer 10

M1 and M2. M1 = pro-inflammatory + debride. M2 = anti-inflammatory + aid healing by secreting growth factors.

Question 11

What is the life-span of tissue macrophages vs monocytes?

Answer 11

Tissue: Months-years

Monocytes: < 1d.

Question 12

Briefly outline lymphocyte ‘family tree”

Answer 12

B cell (antibodies) or T cell.

T cell –> T helper (CD4+) or cytotoxic (CD8+)

CD4+ –> Th1, Th2, Treg or Th17.

Question 13

Define a reactive oxygen species

Answer 13

Reactive oxygen species = unstable molecules that initiate chain reactions to perpetuate further reactive oxygen species e.g. hydrogen peroxide (H2O2). i.e. has paired electrons

Question 14

Define free radical

Answer 14

Free radical = reactive oxygen species with unpaired electrons that accept electrons from other molecules (proteins, lipids, carbohydrates) e.g. superoxide anion (O2-) and hydroxyl radical (OH-).

Question 15

Define acute phase protein

Answer 15

Acute phase protein = those whose concentration change significantly (>25%) in response to inflammation

Question 16

What does SOD (as in the anti-oxidant enzyme/SOD gene mutation) stand for + what does it do?

Answer 16

Superoxide dismutase

Metabolises superoxide (O₂^-) to hydrogen peroxide (H₂O₂)

i.e. metabolised free radical to just reactive oxygen species

Question 17

List pro-inflammatory and anti-inflammatory cytokines

Answer 17

Proinflammatory:

IL-1ß

IL-6

TNF

Chemokines (=chemotactic cytokines responsible for attraction of cells across a concentration gradient)

Anti-inflammatory:

IL-10

Question 18

What is frustrated phagocytosis?

Answer 18

If phagocyte fails to engulf its traget and releases damaging material into extracellular milleu.

Question 19

List 3 gaseous mediators of inflammation

Answer 19

• NO (from amino acid L-arginine). Anti-and pro inflammatory. Can react with superoxide to form powerful oxidant peroxynitrite = cytotoxic!)
• Carbon Monoxide (produced from breakdown of haem to bilirubin). Anti-inflammatory
• Hydrogen Sulfide. Pro-inflammatory.

Question 20

Name 1 negative acute phase protein and 6 positive ones

Answer 20

Negative:

• Albumin

Positive:

• CRP. Pro- and anti-inflammatory. Binds to bacteria and necrotic/apoptosed cells.
• Serum Amyloid A –> production of pro-inflammatory cytokines
• Serum Amyloid P
• Complement proteins (=hepatically synthesised proteases that circulate inactive, become cleaved = active). –> Membrane Attack Complex (MAC)
• Coagulation Factors
• Kallikrein-Kinin System (i.e. brady- and tachykinin (e.g. substance P, released from neurons and inflammatory leukocytes))

Question 21

What is MODS?

Answer 21

Multiple organ dysfunction syndrome i.e. failure of two or more organ systems distant from original insult e.g. GI, renal, heart, lungs, liver.

N.B. “Disease of modern medicine”

“Two-hit” theory i.e. neuts and macs primed for exagerated response by initial insult then surgery/ventilation/interventions –> marked deterioration.