thromboxane-b2 and Uveitis

Since prostaglandins (PGs) were originally discovered in the eye in a search for the mediators of the ocular irritative responses, it is not surprising that the first decade of research on the ocular effects of these autacoids concentrated on their potential role in inflammation and other pathological processes. It is clear that PGs, like most other biologically active compounds, can have pathological effects when introduced into the eye in sufficiently high doses. More recent studies indicate, however, that PGs are also involved in the normal physiological processes of the eye, and that some PGs effectively reduce intraocular pressure and may actually moderate rather than mediate ocular inflammation. We must therefore consider the eicosanoids as a new class of potential ocular therapeutic agents. This paper reviews the evidence that these autacoids are actively transported by some tissues, including the ciliary epithelium, and considers the role of such transport processes in the ocular and systemic pharmacokinetics of endogenous eicosanoids and their therapeutically applied prodrugs.

Topics: Animals; Aqueous Humor; Biological Transport, Active; Cats; Cell Membrane Permeability; Ciliary Body; Epithelium; Eye; Female; Glaucoma; Intraocular Pressure; Kinetics; Macular Edema; Prostaglandins; Rabbits; Retinal Vessels; Thromboxane A2; Thromboxane B2; Uveitis

The anti-inflammatory effects of vitamin E were investigated using the S antigen model of uveoretinitis. Thirty-six 3-week-old Lewis rats were separated into three groups and maintained on a specially formulated diet. One group of animals received a diet deficient in vitamin E; a second group received a normal diet containing vitamin E, and the third group, in addition to receiving the normal diet, received vitamin E supplementation. At 9 weeks of age, all rats were sensitized to S antigen. Six animals in each group were killed on day 14 and the remaining animals on day 21 following immunization. Both histopathologic and biochemical studies were conducted to evaluate the tissue damage observed in animals maintained on different dietary levels of the vitamin. The intraocular inflammation in the vitamin E-supplemented group was considerably smaller than in the other two groups (p less than 0.01). The former group had the highest level of vitamin E in both the eye and plasma (mean value 1.13 micrograms/mg protein and 23.9 micrograms/ml, respectively), while the vitamin E-deficient group had the lowest levels (mean values of 0.16 micrograms/mg protein and 0.48 micrograms/ml in the eye and plasma, respectively). Results of the radioimmunoassay for the determination of the arachidonic acid metabolites revealed significantly lower levels of thromboxane B2 in the vitamin E-supplemented group (2.04 +/- 0.45 pg/mg) than in the normal (4.33 +/- 0.98 pg/mg) or the vitamin E-deficient (5.21 +/- 1.12 pg/mg) groups (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Antigens; Arrestin; Autoantigens; Choroid; Diet; Dinoprostone; Disease Models, Animal; Eye Proteins; Female; Leukotriene B4; Membrane Proteins; Phosphodiesterase Inhibitors; Radioimmunoassay; Rats; Rats, Inbred Lew; Retinitis; Thromboxane B2; Uveitis; Vitamin E

Endotoxin-induced uveitis (EIU) can be produced by systemic injection of endotoxin (ET). It is not clear yet why exclusive ocular involvement occurs in this model. To clarify this question and to establish the sequence of inflammatory events, EIU was induced in Lewis rats by footpad injection of Salmonella ET. Ocular inflammatory response (anterior chamber cells and proteins), aqueous inflammation mediators (thromboxane B2, prostaglandin E2, leukotriene B4 and substance P) and MHC class 2 (Ia) antigen expression in the ciliary body were monitored for 72 hours. Thromboxane B2 was detected early in the aqueous humor, peaking already 1 hour after ET injection. Prostaglandin E2 & leukotriene B4 peaks and a second peak of thromboxane B2 were recorded 18 hours after ET-injection, at the time of maximal ocular inflammation. MHC-class 2 expression was first detected in the ciliary body stroma at the vascular level 6 hours after ET injection and was massively expressed in the ciliary body epithelium at 18 and 72 hours. It is hypothesized that ciliary body endothelium is particularly sensitive to the effect of ET and is the site of thrombocyte adherence. Vascular damage leads in succession to cellular infiltration, release of inflammation mediators and disruption of blood-ocular barrier. MHC-class 2 expression is a secondary phenomenon and is probably at the origin of additional tissue damage from immune effector mechanisms.

Topics: Animals; Aqueous Humor; Bacterial Toxins; Cell Count; Ciliary Body; Dinoprostone; Endotoxins; Enterotoxins; Eye Proteins; Histocompatibility Antigens Class II; Inflammation; Leukotriene B4; Male; Rats; Rats, Inbred Lew; Substance P; Thromboxane B2; Uveitis

Intraocular inflammation was induced in the rat by footpad injection of salmonella endotoxin in order to study the influence of chemical inflammation mediators in this uveitis model. Ocular inflammation was assessed 1, 6, 18, 24 and 72 h after endotoxin administration as well as in control rats, by measuring aqueous protein concentration, aqueous inflammatory cell content, and pupillary diameter. Thromboxane B2 (TXB2), prostaglandin E2 (PGE2), prostaglandin F2 alpha (PGF2-alpha), leukotriene B4 (LTB4), and substance P were simultaneously measured in the aqueous humor by radioimmunoassay. Inflammation parameters peaked at 18 h. TXB2 was already significantly elevated at 1 h. PGE2 peak values of 2.7 ng/ml were reached at 18 h. PGF2-alpha was never significantly raised over control values. LTB4 peaked at 18 h, together with a polymorphonuclear peak. Substance P was significantly elevated after 6 h. It is concluded that maximal uveitis in this model occurs at 18 h. TXB2 is an early mediator, and PGE2 is probably implicated in blood-ocular barrier disruption for which levels as high as 2.7 ng/ml in aqueous seem necessary. PGF2-alpha does not play a major role in this model, while LTB4 seems to be the main chemotactic factor for polymorphonuclears (PMNs) in the anterior chamber and substance P is clearly related to pupil miosis.

Topics: Animals; Aqueous Humor; Dinoprost; Dinoprostone; Endotoxins; Leukotriene B4; Male; Pupil; Rats; Rats, Inbred Lew; Salmonella; Substance P; Thromboxane B2; Uveitis

Animals and humans undergoing treatment with ciclosporin (CS) show a reversible increase in renal vascular resistance and a decrease in glomerular filtration rate. The causes of these abnormalities have not yet been established. We evaluated the effects of a 1-week treatment with CS on creatinine clearance, renal arachidonic acid metabolites, plasma renin activity (PRA), plasma aldosterone levels, urinary excretion and plasma levels of catecholamines in 7 patients with idiopathic uveitis. We show that CS treatment induces a significant (p less than 0.05) decrease in creatinine clearance (from 132 +/- 0.5 to 108 +/- 8 ml/min); urinary 6-keto-PGF1 excretion (from 17.8 +/- 4.9 to 10.9 +/- 3.3 ng/mmol creatinine), urinary thromboxane B2 excretion (from 7.0 +/- 1.0 to 3.6 +/- 0.9 ng/mmol creatinine), upright PRA (from 4.2 +/- 0.9 to 2.3 +/- 0.8) and supine PRA (from 2.0 +/- 0.5 to 1.1 +/- 0.3). We found no change in plasma aldosterone levels and plasma levels and urinary excretion of catecholamines. We suggest that the reversible renal vasoconstriction observed in patients treated with CS may be induced by inhibition of renal prostacyclin synthesis. In this setting inhibition of PRA and angiotensin II formation may impair autoregulation of effective filtration pressure and therefore glomerular filtration rate.

Topics: Adult; Aged; Catecholamines; Cyclosporins; Epoprostenol; Female; Humans; Kidney; Male; Middle Aged; Prostaglandins; Renin; Thromboxane B2; Uveitis