Gout

Question 1

@ site of inflammation 1

Answer 1

Macrophages ingest urate and release inflammatory cytokine IL-1beta, and chemokine IL-8

Question 2

@ site of inflammation 2

Answer 2

IL-1b induces expression of adhesion molecules on endothelium

COX-2 in macs, monocytes, connective tissue and endothelium as well

Question 3

@ site of inflammation 3

Answer 3

TOGETHER (emphasizeD) IL-1beta and IL-8 recruit neutrophils from the blood toward site of inflammation/activated macs/monos

Question 4

@ site of inflammation 4

Answer 4

activated cells (monos/macs/connective tissue/neutrophils) increase enrichment of lipid mediators of inflammation + other factors (complement, coagulation, peptides).

Inflammatory environment manifests as redness/swelling, pain/heat

Question 5

@ sit of inflammation alternative version

Answer 5

IL-1b induces expression of COX-2 in cells at site of inflammation and in adjacent endothelium.

COX-1, COX-2 generate prostaglandin mediators that cause dilation+increase permeability of vessels, especially post-cap venules

Question 6

COX-2: where would you find this and how would it be affected by NSAIDs?

COX-1: compare to COX-2

Answer 6

This is the enzyme activated at sites of inflammaiton, and responsible for prostaglandin/leukotriene synthesis

NSAIDs block PG synthesis

COX-1 is constitutive
COX-2 is induced

Question 7

PG synthesis 1

Answer 7

IL-1b induces

Phospholipase A + membrane phospholipids –> arachidonic acid (AA)

AA + COX-2 or COX-1 –> Prostaglandin H2 (PGH2)

PGH2 + Tissue isomerases –> PG-D,F,G + Prostacyclin + Thromboxane (TxA2)

Question 8

How are prostaglandins degraded?

Answer 8

15-OH-dehydrogenase oxidizes them to inactive metabolites

Question 9

How are prostacyclins degraded?

Answer 9

a hydrolase enzyme

Question 10

Vasculature/Endothelium

Eicosanoid

Answer 10

PGI(2)

vasodilation, platelet aggregation

Question 11

Blood Platelets

Eicosanoid

Answer 11

TxA(2)

vasoconstriction
platelet aggregation

Question 12

Vasculature

Eicosanoid

Answer 12

PGE(2)

permeability

Question 13

GI

Eicosanoid

Answer 13

PGE(2)

mucosal cytoprotection
muscle tone
motility

Question 14

Renal

Eicosanoid

Answer 14

PGI(2), PGE(2)

Na+, H20 excretion

Question 15

Uterus

Eicosanoid

Answer 15

PGF(2)a, PGE(2)

muscle contraction

Question 16

CNS

Eicosanoid

Answer 16

PGE(2)

temperature

Question 17

PNS

Eicosanoid

Answer 17

PGE(2)

Pain sensitization

Question 18

Skeletal

Eicosanoid

Answer 18

PGE(2)

bone remodeling

Question 19

COX-1, PGs, & inflammation (3 things)

Answer 19

IL-1beta stimulates AA release
COX-1 converts AA into PGE2
PGE2 causes symptoms

Question 20

COX-2, PGs, & inflammation (3 things)

Answer 20

IL-1b induces COX-2 expression
COX-2 converts AA into PGE(2), PGI(2)
PGE(2), PG(I) amplifies symptoms

Question 21

PGE(2) and PGI() contribute functionally to….

Answer 21

vasodilation, vascular permeability, and local edema, and pain

Question 22

How do PGE2 and PGI2 contribute to edema?

Answer 22

PGE –> permeability of endothelia
PGI –> vasodilation of endothelia

together this causes “extravasation” of plasma into interstitial space

Question 23

“marginating pool”

Answer 23

neutrophils induced by Ig-1b to express adhesion molecules, making them “sticky”

Question 24

the Cytokine response and Involvement toward

LPS, bacterial components, fungal components

Answer 24

robust TNF-alpha, cytokines, and interleukins, IFN, IL-1, IL-8 etc

often system: sepsis possible

Question 25

The cytokine response and involvement toward uric acid buildup

Answer 25

IL-1b and IL-8

Question 26

Bacteria engulfed ---> inflammatory cytokines

Answer 26

TNF-alpha, IL-1, IFN, chemotactic sytokiens

Question 27

LPS itself ---> inflammatory cytokines

Answer 27

TNF-alpha/IL-1 --> adhesion molecules expression on endothelia + COX-2 expression in macs, monocytes, connective tissues, and endothelium

Question 28

systemic inflammation can be caused by

Answer 28

sepsis, during which time the entire body launches an inflammatory response the response overwhelms the body: organs, shock, death

Question 29

Sepsis: Physiology, Pathology

Answer 29

Phys: Autocoid mediators act locally, briefly Pathology: Autocoid mediators act systemically and persistently

Question 30

What two components cause systemic inflammation during sepsis? What then causes widespread damage to the host?

Answer 30

TNF-alpha in response to LPS induction of COX-2 and adhesion molecules, activation of myeloid cells extravasation of plasma from the blood to the interstitial spaces leads to a drop in blood pressure from a septic shock

Question 31

What does "Extravasation" do to the body?

Answer 31

when blood leaks out of the epithelium into the tissues and causes a drop in blood pressure

Question 32

COX-1 an Gout versus COX-2 and Gout

Answer 32

IL-1b stimulates release of AA Cox- 1 converts AA into PGE2 PGE2 causes symptoms (Erythema/Edema/Pain) L-1b induces COX-2 expression (inducible) Cox-2 converts AA into PGE(2) and PGI(2) PGE and PGI amplify symptoms (WORSE Erythema, Edema, Pain)

Question 33

PGI(2) on the endothelium | PGE(2) on the endothelum

Answer 33

PGI - vasodilation PGE - permeability they work together