Additive effect of nitric oxide and prostaglandin-E2 synthesis inhibitors in endotoxin-induced uveitis in the rabbit

Abstract

The involvement of nitric oxide (NO) and prostaglandin E2 (PGE2) was investigated in a model of intraocular inflammation induced by intravitreal injection of endotoxin (lipopolysaccharide, LPS, 10 ng) in rabbits. The severity of uveitis, the myeloperoxidase (MPO) activity in iris-ciliary body, and the protein concentration in aqueous humor were determined. Nitric oxide synthase (NOS) and cyclooxygenase (COX) activities were assessed respectively by nitrite and PGE2 levels in aqueous humor. Treatment with inhibitors of NOS (NG-nitro-L-arginine methyl ester, L-NAME, 50 mg/kp i.p.) or COX (diclofenac, 30 micrograms, topically), alone or in combination, were compared to a saline-treated group. Diclofenac or L-NAME alone reduced or delayed the intensity of uveitis, and partially decreased the protein concentration in aqueous humor; diclofenac, but not L-NAME, partially reduced the polymorphonuclear leukocyte infiltration in the iris ciliary body as indicated by the MPO activity. Treatment with both inhibitors in combination diminished the clinical uveitis, the disruption of the blood-aqueous barrier and the MPO activity in the iris-ciliary body. We conclude that NO and PGE2 have additive effects in endotoxin-induced uveitis in rabbits, and that the inhibition of both pathways would improve the therapeutical management of uveitis.

Captopril suppresses inflammation in endotoxin-induced uveitis in rats

“…The expression of the inducible enzymes, responsible for their synthesis (COX-2 and iNOS respectively), is also controlled by NF-κB. Bellot et al (Bellot et al, 1996) reported that PGE2 and NO have an additive effect in EIU in rabbits and that inhibition of both pathways would improve the therapeutic management of uveitis. Therefore our data suggest that the suppressed ocular inflammation can be attributed in part to the down-regulation of these mediators by captopril.…”

“…LPS triggers the secretion of a variety of inflammatory mediators, such as TNF-α (Tracey and Cerami, 1994), prostaglandin E2 (PGE2) (Bellot et al, 1996); Murakami et al, 2000), MCP-1 (Tuaillon et al, 2002), as well as the generation of ROS and excessive amounts of nitric oxide (NO) (Nathan and Xie, 1994), which all contribute to the pathophysiology of septic shock. The transcription of a significant number of these inflammatory mediators is triggered by the intracellular activation of NF-κB.…”

Therapeutic Effect of Melatonin in Experimental Uveitis

“…Despite the fact that uveitis is one of the main causes of eye morbidity and loss of visual functions, the complexity of the biochemical and immune mechanisms involved in its generation and development remain unknown. Several lines of evidence support that the disease is due to damage generated by infiltrated leukocytes, which release cytokines 1,2 and other inflammatory chemical mediators, like arachidonic acid metabolites, 3 reactive oxygen species, 4,5 and nitric oxide (NO), 6 among many others. Arachidonic acid metabolites regulate vascular permeability, chemotaxis, and contribute to uveitis amplification.…”

“…LPS enhances the expression of various inflammatory mediators, such as tumor necrosis factor (TNF)-␣, 1 interleukin (IL)-6, 1,2 prostaglandin E2, 3 and NO, 6,18 all of which contribute to the development of the disease. Several lines of evidence support that EIU mimics central features of human uveitis, such as the breakdown of the BOB, and infiltration of leukocytes.…”

“…3 is insoluble, and electron dense precipitates facilitate ultrastructural localization of lanthanum. After perfusion, the retina was dissected out and after several washings, and tissue blocks were postfixed in 1% aqueous osmium tetroxide for 1 hour and processed for electron microscopy.…”