Radomski A, Sawicki G, Olson D M, Radomski M W
Department of Pharmacology, University of Alberta, Edmonton, Canada.
Br J Pharmacol. 1998 Dec;125(7):1455-62. doi: 10.1038/sj.bjp.0702216.
The effects of nitric oxide (NO) and metalloproteinases (MMP-2 and MMP-9) in the pathogenesis of hyperoxia-induced lung damage in newborn rats were examined. Three-day-old rat pups were subjected to hyperoxia (> or = 95% O2) or room air for 7 and 14 days. Some animals were treated with NG-L-nitro-L-arginine methyl ester (L-NAME, 10 mg kg(-1), s.c., daily). Histology, morphometry, oedema, Ca2+-dependent and -independent NO synthase (NOS) activities, expression of NOS isoforms and the activities of MMP-2 and MMP-9 were measured in lungs of hyperoxic and control animals. Exposure of rats to hyperoxia for 7 days resulted in alveolar sac injury characterized by the presence of cellular debris, red cell extravasation and inflammatory infiltration with mononuclear cells. Lung water content, epithelial, smooth muscle layers and total airway thickness was similar to controls. In contrast, exposure of rats to hyperoxia for 14 days resulted in lung oedema, inflammation and epithelial proliferation. Hyperoxia caused a decrease in Ca2+-dependent NOS activity, an effect that was associated with increased expression of eNOS protein. In control rats, Ca2+-dependent NOS activity and expression of eNOS were reduced at 14 days. Hyperoxia caused 10 fold increase in the activity of Ca2+-independent NOS that remained significantly elevated after 14 days of exposure to hyperoxia. The activity of this enzyme was unchanged in control rats. In lungs of hyperoxic rats, the immunoblot showed time-dependent, biphasic expression (peak at 7 days) of iNOS. The profile of expression of iNOS in control rats was similar. The activities of MMPs were increased in lungs of hyperoxic animals. The L-NAME treatment of hyperoxic animals reduced lung oedema and epithelial proliferation, but enhanced the activities of MMPs. L-NAME exerted no significant effects in control rats. It is concluded that increased generation of NO contributes to the pathogenesis of hyperoxia-induced lung damage in newborn rats.
研究了一氧化氮（NO）和金属蛋白酶（MMP - 2和MMP - 9）在新生大鼠高氧诱导肺损伤发病机制中的作用。将3日龄的幼鼠置于高氧环境（≥95% O₂）或空气中7天和14天。部分动物每日皮下注射NG - L - 硝基 - L - 精氨酸甲酯（L - NAME，10 mg kg⁻¹）。检测高氧组和对照组动物肺组织的组织学、形态学、水肿情况、Ca²⁺依赖性和非依赖性一氧化氮合酶（NOS）活性、NOS亚型的表达以及MMP - 2和MMP - 9的活性。将大鼠暴露于高氧环境7天导致肺泡囊损伤，其特征为存在细胞碎片、红细胞外渗以及单核细胞炎性浸润。肺含水量、上皮层、平滑肌层和气道总厚度与对照组相似。相比之下，将大鼠暴露于高氧环境14天导致肺水肿、炎症和上皮细胞增殖。高氧导致Ca²⁺依赖性NOS活性降低，这一效应与eNOS蛋白表达增加有关。在对照大鼠中，14天时Ca²⁺依赖性NOS活性和eNOS表达降低。高氧导致Ca²⁺非依赖性NOS活性增加10倍，在暴露于高氧14天后仍显著升高。该酶活性在对照大鼠中未发生变化。在高氧大鼠肺组织中，免疫印迹显示诱导型一氧化氮合酶（iNOS）呈时间依赖性双相表达（7天时达到峰值）。对照大鼠中iNOS的表达模式相似。高氧动物肺组织中金属蛋白酶的活性增加。对高氧动物进行L - NAME治疗可减轻肺水肿和上皮细胞增殖，但增强了金属蛋白酶的活性。L - NAME对对照大鼠无显著影响。结论是，NO生成增加在新生大鼠高氧诱导的肺损伤发病机制中起作用。
