The authors tested the hypothesis that
platelet-activating factor (PAF) and
cyclooxygenase metabolites of
arachidonic acid mediate the ocular inflammatory response to intravitreally injected
tumor necrosis factor-alpha (
TNF alpha). Rabbits were treated with the PAF receptor antagonist
SRI 63-441, the
cyclooxygenase inhibitors indomethacin and
naproxen, or
SRI 63-441 and
indomethacin. At 24 hr after
intravitreal injection of TNF (20,000 U), the severity of
inflammation was assessed based on
iridal hypermia, aqueous humor leukocyte number and aqueous humor
protein, immunoreactive-
prostaglandin E (I-
PGE), and
leukotriene B4 (
LTB4) concentrations. Although all of the treatments significantly reduced the severity of
anterior uveitis,
SRI 63-441 plus
indomethacin was the most effective,
indomethacin and
naproxen were intermediately effective, and
SRI 63-441 was the least effective. The results of this study are consistent with an important role for
cyclooxygenase metabolites of
arachidonic acid in the inflammatory response to
TNF alpha, particularly with respect to dilation of
iridal blood vessels. Although
naproxen was nearly as effective as
indomethacin in reducing aqueous humor I-
PGE levels,
indomethacin conferred significantly more protection to the blood-aqueous barrier as shown by lower
protein levels in the aqueous humor. Thus, although
cyclooxygenase inhibition may partially explain the protection afforded the blood-aqueous barrier by these
nonsteroidal anti-inflammatory agents, the data suggest that
indomethacin may also exert anti-inflammatory effects that are independent of
cyclooxygenase inhibition. Furthermore, the data are consistent with
TNF alpha releasing PAF in the eye and PAF acting both directly, by increasing vascular permeability, and indirectly, by promoting release of
cyclooxygenase and
lipoxygenase metabolites of
arachidonic acid.