Effects of U74389G on pulmonary macrophage influx and lung development in 95% O2 exposed newborn rats / 中华儿科杂志

<p><b>OBJECTIVE</b>Oxygen toxicity is believed to play a critical role in the pathogenesis of bronchopulmonary dysplasia (BPD). U74389G, a potent 21-aminosteroid antioxidant, was applied to the 95% O(2) induced acute lung injury in newborn rat model. The present study aimed to investigate the mechanism of hyperoxic lung injury and the interaction of possible mediators, and to explore the effect of antioxidant intervention.</p><p><b>METHODS</b>Newborn Sprague-Dawley rats were randomly divided into four groups: air-exposed control, air-exposed treated with U74389G, hyperoxia-exposed control, hyperoxia-exposed treated with U74389G. Hydroxyl radical formation (2,3-DHBA and 2,5-DHBA) was assessed by an aromatic hydroxylation assay using GC/MS with salicylate as the probe. The 8-isoprostane, a specific marker for in vivo lipid peroxidation, was quantitated by enzyme immunoassay. Pulmonary macrophage influx and nitrotyrosine formation were measured by means of immunohistochemistry. (3)H-TdR (autoradiography) incorporation was assessed as an index of active lung cell growth.</p><p><b>RESULTS</b>Exposure to 95% O(2) for 7 days induced significant lung injury and mortality. The contents of hydroxyl radical in the hyperoxia-exposed lungs were dramatically increased [(2,3-DHBA 49.2 +/- 3.5 pmol/mg), (2,5-DHBA 55.8 +/- 2.3 pmol/mg), P < 0.05) and were decreased by treatment with U74389G [(2,3-DHBA 37.9 +/- 2.4 pmol/mg), (2,5-DHBA 31.3 +/- 1.9 pmol/mg), P < 0.05). The level of 8-isoprostane in the lungs of 95% O(2)-exposed newborn rats was significantly raised (546.6 +/- 32.2 pg/mg, P < 0.05) and lowered down by U74389G (358.5 +/- 24.1 pg/mg, P < 0.05). This phenomenon was also observed in the air-exposed animals. Remarkable pulmonary macrophage infiltration was evident in hyperoxia-exposed newborn rats and was attenuated by U74389G treatment. Nitrotyrosine distributed in the lung parenchyma and epithelial cells of large airway of hyperoxia-exposed newborn rats. The extent of protein nitration was reduced by U74389G, but the oxygen induced morphological change was not significantly improved by U74389G treatment. Exposure to 95% O(2) induced lung growth arrest as shown by (3)H-TdR incorporation. U74389G partially preserved active lung cell growth in hyperoxia-exposed rats, but showed an inhibitory effect on normal lung cell growth.</p><p><b>CONCLUSION</b>Through scavenging hydroxyl radical and lipid peroxides, U74389G could block pulmonary macrophage influx and partly avert alveolar development arrest in hyperoxia-exposed newborn rats. Antioxidant intervention holds promising in hyperoxic lung injury though cautions should be taken as possible interference on normal cell development.</p>

Effect of U74006F (Tirilazad Mesylate) in rabbit eyes after argon laser trabeculoplasty.

A new free radical scavenger, U74006F (Upjohn Company, Kalamazoo, MI, USA) was studied to determine if it would have a beneficial effect on preventing intraocular pressure (IOP) spikes and reducing blood-aqueous barrier (BAB) breakdown in rabbits after argon laser trabeculoplasty (ALT). The post-ALT IOP averaged 24.7 mm Hg (+/- 3.8 mm Hg; N = 6) and 30.3 mm Hg (+/- 6.9 mm Hg; N = 7) at 1 hour (p = 0.097) and 22.7 mm Hg (+/- 1.9) and 27.3 mm Hg (+/- 7.0 mm Hg) at 3 hours in the U74006F and vehicle groups (p = 0.137), respectively. By 48 hours, the IOP averaged 12.8 +/- 2.2 mm Hg in the U74006F group and 12.4 +/- 2.4 mm Hg in the vehicle group (P = 0.757). The aqueous fluorescein permeability (AFP) between lasered and unlasered eyes was determined for the U74006F and vehicle-treated groups by aqueous fluorophotometry. Prelaser or baseline AFP was determined for the U74006F (-0.236 +/- 0.236) and vehicle (-0.145 +/- 0.237) groups (p = 0.505). At day 2 posttreatment, the U74006F group and the placebo group both reported similar AFP of 5.109 +/- 4.831 and 5.680 +/- 4.280 (p = 0.827), respectively. At one week post-ALT, AFP for the U74006F group (0.109 +/- 0.367) had returned close to baseline, while that of the vehicle group (0.426 +/- 0.511) was still quite elevated (p = 0.220). U74006F appears to be beneficial in the prevention of acute elevation of IOP following ALT but not in the prevention of Blood-Aqueous Barrier (BAB) breakdown.(ABSTRACT TRUNCATED AT 250 WORDS)