Lipid mediators of tumor necrosis factor-alpha-induced uveitis.
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.
Fleisher
L N
LN
Department of Anatomy, North Carolina State University, College of Veterinary Medicine, Raleigh, North Carolina 27606.
Ferrell
J B
JB
Smith
M G
MG
McGahan
M C
MC
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001082:Aqueous Humor / Q000378:metabolism; D015777:Eicosanoids / Q000502:physiology*; D005136:Eye Proteins / Q000378:metabolism; D007213:Indomethacin / Q000494:pharmacology / Q000627:therapeutic use; D007958:Leukocyte Count; D007975:Leukotriene B4 / Q000378:metabolism; D008297:Male; D009288:Naproxen / Q000494:pharmacology / Q000627:therapeutic use; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors; D011458:Prostaglandins E / Q000378:metabolism; D011806:Quinolinium Compounds / Q000494:pharmacology / Q000627:therapeutic use; D011817:Rabbits; D011994:Recombinant Proteins / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*; D014606:Uveitis, Anterior / Q000188:drug therapy / Q000209:etiology*; D014822:Vitreous Body / Q000187:drug effects
D000894:Anti-Inflammatory Agents, Non-Steroidal; D015777:Eicosanoids; D005136:Eye Proteins; D010972:Platelet Activating Factor; D011458:Prostaglandins E; D011806:Quinolinium Compounds; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; C050531:SRI 63-441; D007975:Leukotriene B4; D009288:Naproxen; D007213:Indomethacin