Eynott Paul R, Paavolainen Niko, Groneberg David A, Noble Alistair, Salmon Michael, Nath Puneeta, Leung Sum-Yee, Chung K Fan
National Heart and Lung Institute, Imperial College School of Science, Technology and Medicine, London, United Kingdom.
J Pharmacol Exp Ther. 2003 Jan;304(1):22-9. doi: 10.1124/jpet.102.040295.
Chronic cellular inflammation and airway wall remodeling with subepithelial fibrosis and airway smooth muscle thickening are features of chronic asthma. We determined the role of nitric oxide in the pathogenesis of allergen-induced airway cell proliferation and inflammation by studying the effects of a relatively selective prodrug inhibitor of nitric-oxide synthase type 2 (NOS2), L-N6-(1-iminoethyl)-lysine-5-tetrazole amide (SC-51). Brown-Norway rats were sensitized to ovalbumin and were exposed to ovalbumin aerosol every 3rd day on six occasions and were treated orally with either vehicle or SC-51 (10 mg. kg(-1); 12 doses). We measured inflammatory cell accumulation in the airways and proliferation of cells by incorporation of bromodeoxyuridine. There was an increase in the total number of airway smooth muscle cells expressing bromodeoxyuridine from 1.3% of airway smooth muscle cells in saline exposed to 5.4% after allergen-exposure (P < 0.001) and airway epithelial cells from 3.3 cells/mm basement membrane to 9.6 after allergen-exposure (P < 0.001). SC-51 had no effect on airway smooth muscle or epithelial cell proliferation. SC-51 attenuated the allergen-induced increase in major basic protein (MBP+) eosinophil (P < 0.05) and CD4+ T-cell (P < 0.05) accumulation. We conclude that nitric oxide derived during allergic inflammation is involved in the expression of eosinophilic inflammation and not in epithelial or airway smooth muscle cell DNA synthesis induced by chronic allergen exposure.
慢性细胞炎症以及伴有上皮下纤维化和气道平滑肌增厚的气道壁重塑是慢性哮喘的特征。我们通过研究相对选择性的2型一氧化氮合酶（NOS2）前药抑制剂L-N6-(1-亚氨基乙基)-赖氨酸-5-四唑酰胺（SC-51）的作用，确定了一氧化氮在变应原诱导的气道细胞增殖和炎症发病机制中的作用。将棕色挪威大鼠对卵清蛋白致敏，每隔3天暴露于卵清蛋白气雾剂中，共6次，并口服给予溶剂或SC-51（10 mg·kg⁻¹；12剂）。我们通过掺入溴脱氧尿苷来测量气道中的炎症细胞积聚和细胞增殖。表达溴脱氧尿苷的气道平滑肌细胞总数从盐水暴露组气道平滑肌细胞的1.3%增加到变应原暴露后的5.4%（P<0.001），气道上皮细胞从每毫米基底膜3.3个细胞增加到变应原暴露后的9.6个（P<0.001）。SC-51对气道平滑肌或上皮细胞增殖没有影响。SC-51减弱了变应原诱导的主要碱性蛋白（MBP⁺）嗜酸性粒细胞（P<0.05）和CD4⁺T细胞（P<0.05）积聚的增加。我们得出结论，变应性炎症过程中产生的一氧化氮参与嗜酸性炎症的表达，而不参与慢性变应原暴露诱导的上皮或气道平滑肌细胞DNA合成。
