• neutrophils
• macrophages

• basophils
• eosinophils
• lymphocytes

• prostaglandins
• leukotrienes
• histamine
• (cytokines)
• (kinins: bradykinin, killidin)

what mediator(s) primarily causes VASODILATION in inflammatory response?

PGs (PGI2, PGE2, PGD2)

vasodilation

what mediator(s) primarily causes INCREASED VASCULAR PERMEABILITY in inflammatory response?

• HISTAMINE
• BRADYKININ
• LTS
• COMPLEMENT (C5A, C3A)

what mediator(s) primarily causes CHEMOTAXIS/LEUKOCYTE ACTIVATION in inflammatory response?

• C5A
• LTB4

what mediator(s) primarily causes TISSUE DAMAGE in inflammatory response?

• NEUTROPHIL AND MACROPHAGE LYSOSOMAL PDCTS
• O-
• NO

what mediator(s) primarily causes FEVER in inflammatory response?

• PGS
• IL 1
• IL 6
• TNF

what mediator(s) primarily causes PAIN in inflammatory response?

• PGE2
• PGI2

PAIN

what drug blocks conversion of essential fatty acid into AA?

what cytokines stimulate the conversion of EFA into AA?

TNF a

IFN gamma

*prof-inflammatory mediators*

what drug blocks 5-LOX from converting AA into LTs?

what enzymes are responsible for the range of PGs produced from EFA?

PG synthases create the range of PGs which all result from the common structure PGH2 (which comes from PGG2)

PGH and PGG are rapidly converted to the active PGs and are difficult to measure

a generic term for PGG and PGH, the precursors of the active PGs

you can tell the source of the initial phospholipid by the number of double bounds in active PGs. In PGE:

• 1 DB: plant source
• 2 DB: endogenous
• 3 DB: fish source

what are the COX forms? Which is inducible vs constitutive?

• COX 1: constitutive, responsible for PGs and TX, which function towards fever, pain, GI protection, platelet aggregation
• COX 2: inducible, responsible for INFLAMMATORY mediators (ie: LTs)

• series of oxidations and reductions
• double bonds broken
• polarity increased
• increased polarity enables trapping in kidney filtrate and easy excretion

• AA precursor acted on by 5-LOX to produce 5-HPETE
• various LT synthases act sequentially, starting on 5-HPETE, to produce the various LTs
• the active forms:
  • LTC4
  • LTD4
  • LTE4

• a different receptor for each PG (D, E, F, I, T)
• employ second messengers
• G protein coupled (as is histamine)
• short half life (mins) and act in secs to mins
• cross reaction possible (each PG can bind to others' receptors, but potency of reaction is much less to any receptor but own specific one)

TXA2 INCREASES

PG I2 DECREASES

vascular tone

PG F2

increase in GI tone

what eicosanoid mediates increase in bronchial tone?

LT C

LT D

both greatly increase bronchial tone

what eicosanoid mediates increase in uterine tone?

what eicosanoid mediates increase in platelet aggregation?

TXA2 INCREASES platelet aggreg

PG I2 DECREASES platelet aggreg

what eicosanoid mediates leukocyte chemotaxis?

LT B4 is the ONLY eicosanoid involved in leukocyte chemotaxis (primarily involved in neutrophil migration to particular tissue)

normally closes after 24 hrs, but can be maintained by PGE and PGI

treated by ligation (clip) or with IBUPROFEN or INDOMETHACIN via cardiac cath

• mast cells
• vasodilation
• anti aggregator
• sensitive nerve endings --> enhances pain

• role in acute inflammtion (w/ PGIs in pain/fever)
• EP1
  • bronchocontrictor
  • GI contraction
• EP2
  • bronchodilator
  • GI relaxation
• EP3
  • inhibit GI secretion/contraction
  • at term, uterine contraction

• smooth muscle!!!!
• corpus luteum
• contracts uterus

• found in vascular endothelium
• anti-aggregator
• vasodilator

• platelet aggregation
• vasoconstrictor

• induction of labor
• abortifacient

• Me-PGE + MTX -->
• ABORTIFACIENT

• used to maintain the DA

• some cases of ED

alprostadil = PGE

inhibit platelet aggregation;

vasodilator, esp in pulmonary HT

epoprostanol (PGI)

what is the major contributor to bronchial hyper-reactivity in asthmatics?

LTD4 (bronchial hyper reactivity)

• zafirlukast (LTD4 antagonist)
• montelukast (LTD4 anatagonist)
• zileuton (5-LOX inhibitor)

all treatments for asthma that target LTs

• allergens, drugs (ie: vancomycin), contrast media, etc  BIND TO IgE Ab on mast cell surface -->
• mast cell release of PGs, LTs, histamine, and IL-4, TNFa
• granules contain:
  • histamine
  • heparin
  • tryptase

• skin (face)
• nasal epithelia
• lungs
• upper GI tract

mast cells and basophils are primary sites of histamine release

• release via DEGRANULATION
  • cytolytic:due to damage or drugs, Ca2+/ATP INDEPENDENT, leakage
  • non-cytolytic: due to multiple stimuli, requires change in Ca2+, ATP, receptor, and involves enocytosis; mechanism used in ANAPHYLAXIS

intradermal injection of histamine causes these characteristic signs:

• erythema (localized red spot due to dilation of arterioles and pre-cap sphincters)
• flare (bright red flush that extends sev mms)
• wheal (due to increased permeability of post-cap venules)

• cetirizine
• chlorpheniramine
• diphenhydramine
• hydroxyzine

compare LTs and Histamine's effect on airway conductances

histamine produces an immediate yet transient decrease in airway conductance

Lts action is slower and longer lasting

histamine and LTs produce around the same level of conductance reduction...timing simply different

histamine blocked with H1 antagonist

LTs (once released) blocked by montelukast and zafirlukast (but NOT zileuton, which is 5-Lipox inhibitor)

• bronchoconstriction
• vasodilation
• vascular permeability
• GI acid secretion
• cardiostimulatory

stored in mast cells/basophils

induces triple response of Lewis (erythema, flare, wheal)

vasoactive peptides formed from action of kallikrein on circulating plasma proteins, kininogens

act on receptors in vascular bed to cause:

• vasodilation
• pain (nociceptive)
• vasc perm
• smooth muscle spasm

inactivated by kininase I and II