Gout Flashcards
@ site of inflammation 1
Macrophages ingest urate and release inflammatory cytokine IL-1beta, and chemokine IL-8
@ site of inflammation 2
IL-1b induces expression of adhesion molecules on endothelium
COX-2 in macs, monocytes, connective tissue and endothelium as well
@ site of inflammation 3
TOGETHER (emphasizeD) IL-1beta and IL-8 recruit neutrophils from the blood toward site of inflammation/activated macs/monos
@ site of inflammation 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
@ sit of inflammation alternative version
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
COX-2: where would you find this and how would it be affected by NSAIDs?
COX-1: compare to COX-2
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
PG synthesis 1
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)
How are prostaglandins degraded?
15-OH-dehydrogenase oxidizes them to inactive metabolites
How are prostacyclins degraded?
a hydrolase enzyme
Vasculature/Endothelium
Eicosanoid
PGI(2)
vasodilation, platelet aggregation
Blood Platelets
Eicosanoid
TxA(2)
vasoconstriction
platelet aggregation
Vasculature
Eicosanoid
PGE(2)
permeability
GI
Eicosanoid
PGE(2)
mucosal cytoprotection
muscle tone
motility
Renal
Eicosanoid
PGI(2), PGE(2)
Na+, H20 excretion
Uterus
Eicosanoid
PGF(2)a, PGE(2)
muscle contraction
CNS
Eicosanoid
PGE(2)
temperature
PNS
Eicosanoid
PGE(2)
Pain sensitization
Skeletal
Eicosanoid
PGE(2)
bone remodeling
COX-1, PGs, & inflammation (3 things)
IL-1beta stimulates AA release
COX-1 converts AA into PGE2
PGE2 causes symptoms
COX-2, PGs, & inflammation (3 things)
IL-1b induces COX-2 expression
COX-2 converts AA into PGE(2), PGI(2)
PGE(2), PG(I) amplifies symptoms
PGE(2) and PGI() contribute functionally to….
vasodilation, vascular permeability, and local edema, and pain
How do PGE2 and PGI2 contribute to edema?
PGE –> permeability of endothelia
PGI –> vasodilation of endothelia
together this causes “extravasation” of plasma into interstitial space
“marginating pool”
neutrophils induced by Ig-1b to express adhesion molecules, making them “sticky”
the Cytokine response and Involvement toward
LPS, bacterial components, fungal components
robust TNF-alpha, cytokines, and interleukins, IFN, IL-1, IL-8 etc
often system: sepsis possible
The cytokine response and involvement toward
uric acid buildup
IL-1b and IL-8
Bacteria engulfed —> inflammatory cytokines
TNF-alpha, IL-1, IFN, chemotactic sytokiens
LPS itself —> inflammatory cytokines
TNF-alpha/IL-1 –> adhesion molecules expression on endothelia + COX-2 expression in macs, monocytes, connective tissues, and endothelium
systemic inflammation can be caused by
sepsis, during which time the entire body launches an inflammatory response
the response overwhelms the body: organs, shock, death
Sepsis: Physiology, Pathology
Phys: Autocoid mediators act locally, briefly
Pathology: Autocoid mediators act systemically and persistently
What two components cause systemic inflammation during sepsis?
What then causes widespread damage to the host?
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
What does “Extravasation” do to the body?
when blood leaks out of the epithelium into the tissues and causes a drop in blood pressure
COX-1 an Gout versus COX-2 and Gout
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)
PGI(2) on the endothelium
PGE(2) on the endothelum
PGI - vasodilation
PGE - permeability
they work together
