Brindicci Caterina, Ito Kazuhiro, Torre Olga, Barnes Peter J, Kharitonov Sergei A
Section of Airway Disease, National Heart and Lung Institute, Imperial College, London, UK.
Section of Airway Disease, National Heart and Lung Institute, Imperial College, London, UK.
Chest. 2009 Feb;135(2):353-367. doi: 10.1378/chest.08-0964. Epub 2008 Aug 21.
Nitric oxide (NO) is produced by resident and inflammatory cells in the respiratory tract by the enzyme NO synthase (NOS), which exists in three isoforms: neuronal NOS (nNOS), inducible NOS (iNOS), and endothelial NOS. NO production is increased in patients with COPD, and the production of NO under oxidative stress conditions generates reactive nitrogen species that may amplify the inflammatory response in COPD.
To examine the role of increased NO in COPD, we administered a relatively selective iNOS inhibitor, aminoguanidine, by nebulization in a double-blind, placebo-controlled study in COPD patients, healthy smokers, and healthy nonsmoking subjects. We investigated whether aminoguanidine had any effect on exhaled NO produced in the central lung (flux of NO from the airways [Jno] and peripheral lungs (concentration of NO in peripheral lung [Calv], on NO metabolites (nitrite [NO(2)(-)]/nitrate [NO(3)(-)], peroxinitrite [ONOO(-)], nitrotyrosine), and on a marker of oxidative stress (8-isoprostane) in exhaled breath condensate (EBC) and in sputum.
Aminoguanidine administration resulted in a significant reduction in Jno compared with administration of the saline solution control in healthy subjects, smokers, and COPD patients. Calv in smokers and in COPD patients was not completely inhibited 1 h after aminoguanidine inhalation, in marked contrast to previous results in asthma. Moreover, ONOO(-) and NO(2)(-)/NO(3)(-) levels were also increased in EBC and in sputum of smokers and COPD and were not completely inhibited following aminoguanidine inhalation. 8-Isoprostane levels were also increased in smokers and in COPD patients but were not reduced after aminoguanidine inhalation.
These results suggest that the constitutive NOS isoform as well as iNOS might be involved in NO release and contribute to the high Calv and ONOO(-) production in patients with COPD.
Clinicaltrials.gov Identifier: NCT00180635.
呼吸道中的驻留细胞和炎症细胞通过一氧化氮合酶（NOS）产生一氧化氮（NO），该酶存在三种同工型：神经元型NOS（nNOS）、诱导型NOS（iNOS）和内皮型NOS。慢性阻塞性肺疾病（COPD）患者的NO生成增加，氧化应激条件下NO的生成会产生活性氮物质，这可能会放大COPD中的炎症反应。
为了研究NO增加在COPD中的作用，我们在一项针对COPD患者、健康吸烟者和健康非吸烟受试者的双盲、安慰剂对照研究中，通过雾化给予一种相对选择性的iNOS抑制剂氨基胍。我们研究了氨基胍对中央肺产生的呼出NO（气道NO通量[Jno]）、外周肺产生的呼出NO（外周肺中NO浓度[Calv]）、NO代谢产物（亚硝酸盐[NO(2)(-)]/硝酸盐[NO(3)(-)]、过氧亚硝酸盐[ONOO(-)]、硝基酪氨酸）以及呼出气体冷凝物（EBC）和痰液中氧化应激标志物（8-异前列腺素）的影响。
与在健康受试者、吸烟者和COPD患者中给予盐溶液对照相比，给予氨基胍导致Jno显著降低。在吸烟者和COPD患者中，吸入氨基胍1小时后Calv未被完全抑制，这与先前在哮喘中的结果形成显著对比。此外，吸烟者和COPD患者的EBC和痰液中ONOO(-)以及NO(2)(-)/NO(3)(-)水平也升高，吸入氨基胍后未被完全抑制。吸烟者和COPD患者的8-异前列腺素水平也升高，但吸入氨基胍后未降低。
这些结果表明，组成型NOS同工型以及iNOS可能参与NO释放，并导致COPD患者中高Calv和ONOO(-)的产生。
Clinicaltrials.gov标识符：NCT00180635。
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