Department of Anatomy, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
J Pharmacol Exp Ther. 2012 Jan;340(1):169-75. doi: 10.1124/jpet.111.186288. Epub 2011 Oct 17.
Bronchopulmonary dysplasia (BPD) remains a major cause of morbidity and mortality during the first year of life, and many infants have significant respiratory problems throughout childhood. Currently no effective therapy is clinically available to prevent the long-term pulmonary sequelae of BPD. Previous research has demonstrated that the renin-angiotensin system is up-regulated in human lung fibroblasts. Angiotensin II type 1 receptor (AT₁R) antagonists and AT₁R short interfering RNA diminished hyperoxia-increased collagen expression, whereas AT₂R antagonists did not have any effects on these hyperoxia-induced changes. The in vivo therapeutic effects of AT₁R antagonists on hyperoxia-induced lung fibrosis remain unknown. The present study assessed the effects of an AT₁R antagonist (losartan) on preventing hyperoxia-induced lung fibrosis in newborn rats. Rat pups were exposed to 7 days of > 95% O₂ and an additional 2 weeks of 60% O₂. AT₁R antagonist-treated pups were injected intraperitoneally with losartan at a dose of 10 mg/kg/day from postnatal days 1 to 7 and a dose of 5 mg/kg/day from postnatal days 8 to 21. Control group pups were injected with an equal volume of normal saline. AT₁R antagonist treatment attenuated the hyperoxia-induced lung fibrosis on postnatal days 7 and 21 and also decreased the hyperoxia-induced expression of extracellular signal-regulated protein kinase and α-smooth muscle actin. AT₁R antagonist treatment did not affect body weight or lung weight of the rats. These data suggest that AT₁R antagonist may offer a novel therapeutic strategy for preventing hyperoxia-induced lung fibrosis.
支气管肺发育不良 (BPD) 仍然是婴儿期发病和死亡的主要原因，许多婴儿在整个儿童期都有严重的呼吸系统问题。目前，临床上尚无有效的治疗方法可预防 BPD 的长期肺部后遗症。先前的研究表明，人类肺成纤维细胞中的肾素-血管紧张素系统被上调。血管紧张素 II 型 1 型受体 (AT₁R) 拮抗剂和 AT₁R 短干扰 RNA 可减少高氧诱导的胶原蛋白表达增加，而 AT₂R 拮抗剂对这些高氧诱导的变化没有任何影响。AT₁R 拮抗剂对高氧诱导的肺纤维化的体内治疗效果尚不清楚。本研究评估了 AT₁R 拮抗剂 (洛沙坦) 对预防新生大鼠高氧诱导肺纤维化的作用。新生大鼠暴露于 >95%的 O₂ 7 天，并在接下来的 2 周内暴露于 60%的 O₂。从出生后第 1 天到第 7 天，AT₁R 拮抗剂治疗组大鼠腹腔内注射洛沙坦 10 mg/kg/天，从出生后第 8 天到第 21 天注射洛沙坦 5 mg/kg/天。对照组大鼠注射等体积生理盐水。AT₁R 拮抗剂治疗减轻了高氧诱导的第 7 天和第 21 天的肺纤维化，并降低了高氧诱导的细胞外信号调节激酶和α-平滑肌肌动蛋白的表达。AT₁R 拮抗剂治疗不影响大鼠的体重或肺重。这些数据表明，AT₁R 拮抗剂可能为预防高氧诱导的肺纤维化提供一种新的治疗策略。
