Ricciardolo F L M, Timmers M C, Sont J K, Folkerts G, Sterk P J
Department of Pulmonology, Leiden University Medical Center, The Netherlands.
Thorax. 2003 Oct;58(10):840-5. doi: 10.1136/thorax.58.10.840.
Exposure of patients with atopic asthma to allergens produces a long term increase in exhaled nitric oxide (FENO), probably reflecting inducible NO synthase (NOS) expression. In contrast, bradykinin (BK) rapidly reduces FENO. It is unknown whether BK suppresses increased FENO production after allergen exposure in asthma, and whether it modulates FENO via NOS inhibition.
Levels of FENO in response to aerosolised BK were studied before (day 3) and 48 hours after (day 10) randomised diluent (diluent/placebo/BK (Dil/P/BK)), allergen (allergen/placebo/BK (All/P/BK), and allergen/L-NMMA/BK (All/L/BK)) challenges (day 8) in 10 atopic, steroid naïve, mild asthmatic patients with dual responses to inhaled house dust mite extract. To determine whether BK modulates FENO via NOS inhibition, subjects performed pre- and post-allergen BK challenges after pretreatment with the NOS inhibitor L-NMMA in the All/L/BK period.
Allergen induced a fall in FENO during the early asthmatic reaction (EAR) expressed as AUC(0-1) (ANOVA, p=0.04), which was followed by a rise in FENO during the late asthmatic reaction (LAR) expressed as AUC(1-48) (ANOVA, p=0.008). In the Dil/P/BK period, FENO levels after BK on pre- and post-diluent days were lower than FENO levels after placebo (difference 23.5 ppb (95% CI 6.2 to 40.9) and 22.5 ppb (95% CI 7.3 to 37.7), respectively; p<0.05). Despite the long lasting increase in FENO following allergen challenge in the LAR, BK suppressed FENO levels at 48 hours after allergen challenge in the All/P/BK period, lowering the increased FENO (difference from placebo 54.3 ppb (95% CI 23.8 to 84.8); p=0.003) to the baseline level on the pre-allergen day (p=0.51). FENO levels were lower after L-NMMA than after placebo on pre-allergen (difference 10.85 ppb (95% CI 1.3 to 20.4); p=0.03) and post-allergen (difference 36.2 ppb (95% CI 5.5 to 66.9); p=0.03) days in the All/L/BK and All/P/BK periods, respectively. L-NMMA did not significantly potentiate the pre- and post-allergen reduction in BK induced FENO.
Bradykinin suppresses the allergen induced increase in exhaled NO in asthma; this is not potentiated by L-NMMA. Bradykinin and L-NMMA may follow a common pathway in reducing increased NO production before and after experimental allergen exposure. Reinforcement of this endogenous protective mechanism should be considered as a therapeutic target in asthma.
特应性哮喘患者暴露于变应原会导致呼出一氧化氮（FENO）长期增加，这可能反映了诱导型一氧化氮合酶（NOS）的表达。相比之下，缓激肽（BK）能迅速降低FENO。目前尚不清楚BK是否能抑制哮喘患者变应原暴露后FENO的增加，以及它是否通过抑制NOS来调节FENO。
在10名对吸入屋尘螨提取物有双重反应的特应性、未使用过类固醇的轻度哮喘患者中，研究了在随机给予稀释剂（稀释剂/安慰剂/BK（Dil/P/BK））、变应原（变应原/安慰剂/BK（All/P/BK））和变应原/L - N - 甲基精氨酸/BK（All/L/BK）激发（第8天）前（第3天）和激发后48小时（第10天），雾化BK后FENO的水平。为了确定BK是否通过抑制NOS来调节FENO，在All/L/BK阶段，受试者在使用NOS抑制剂L - N - 甲基精氨酸预处理后进行变应原激发前后的BK激发试验。
变应原在早期哮喘反应（EAR）期间导致FENO下降，以AUC(0 - 1)表示（方差分析，p = 0.04），随后在晚期哮喘反应（LAR）期间FENO上升，以AUC(1 - 48)表示（方差分析，p = 0.008）。在Dil/P/BK阶段，稀释剂前和后BK后的FENO水平低于安慰剂后的FENO水平（差异分别为23.5 ppb（95% CI 6.2至40.9）和22.5 ppb（95% CI 7.3至37.7）；p < 0.05）。尽管在LAR中变应原激发后FENO持续升高，但在All/P/BK阶段，BK在变应原激发后48小时抑制了FENO水平，将升高的FENO降低（与安慰剂的差异为54.3 ppb（95% CI 23.8至84.8）；p = 0.003）至变应原激发前一天的基线水平（p = 0.51）。在All/L/BK和All/P/BK阶段，变应原激发前（差异10.85 ppb（95% CI 1.3至20.4）；p = 0.03）和变应原激发后（差异36.2 ppb（95% CI 5.5至66.9）；p = 0.03），L - N - 甲基精氨酸后的FENO水平均低于安慰剂后的FENO水平。L - N - 甲基精氨酸并未显著增强BK诱导的FENO在变应原激发前后的降低。
缓激肽抑制哮喘患者变应原诱导的呼出一氧化氮增加；L - N - 甲基精氨酸并未增强这种作用。缓激肽和L - N - 甲基精氨酸在实验性变应原暴露前后减少一氧化氮产生增加方面可能遵循共同途径。增强这种内源性保护机制应被视为哮喘的治疗靶点。
