Cheung D, van der Veen H, den Hartigh J, Dijkman J H, Sterk P J
Department of Pulmonology, University Hospital Leiden, The Netherlands.
J Appl Physiol (1985). 1994 Sep;77(3):1325-32. doi: 10.1152/jappl.1994.77.3.1325.
We tested the hypothesis that the inhaled tachykinin substance P (SP) can induce hyperresponsiveness to methacholine in asthmatic subjects in vivo. Nine atopic nonsmoking asthmatic males with normal forced expiratory volume in 1 s (FEV1; > 80% predicted) and increased methacholine sensitivity [provocative concn causing 20% fall in FEV1 (PC20) < 8 mg/ml] participated in a two-period placebo-controlled crossover study. Dose-response curves to SP (0.25-8 mg/ml) and placebo were recorded on 2 randomized days at least 1 wk apart, and methacholine tests were done 24 h before and 2 and 24 h after these challenges. The responses were measured by FEV1 (%fall from baseline). The position of the methacholine dose-response curves was expressed by the PC20 FEV1 and by the maximal response by the plateau level (MFEV1). SP caused a dose-dependent fall in FEV1 (P < 0.001). There was a slight increase in the PC20 FEV1 at 2 and 24 h, which was not significantly different between placebo and SP. Similarly, there was a reduction in MFEV1 at 2 h after both pretreatments. However, at 24 h after SP inhalation, MFEV1 increased compared with placebo. These changes in MFEV1 were significantly different between SP and placebo by 5.2 +/- 2.2% fall (SE) (P < 0.05). We conclude that 1) a bronchoconstrictive dose of SP, compared with placebo, enhances maximal airway narrowing to methacholine in asthma 24 h after inhalation and 2) tolerance develops to high doses of inhaled methacholine. These findings are suggestive of a role of SP in causing excessive airway narrowing in asthma by inflammatory mechanisms.
吸入速激肽P物质（SP）可在体内诱导哮喘患者对乙酰甲胆碱产生高反应性。9名患有特应性疾病的非吸烟男性哮喘患者，其1秒用力呼气量（FEV1；>预测值的80%）正常且对乙酰甲胆碱敏感性增加[引起FEV1下降20%的激发浓度（PC20）<8mg/ml]，参与了一项为期两个阶段的安慰剂对照交叉研究。在至少间隔1周的2个随机日记录对SP（0.25 - 8mg/ml）和安慰剂的剂量反应曲线，并且在这些激发试验前24小时以及激发试验后2小时和24小时进行乙酰甲胆碱试验。通过FEV1（相对于基线的下降百分比）来测量反应。乙酰甲胆碱剂量反应曲线的位置通过PC20 FEV1以及平台期的最大反应（MFEV1）来表示。SP导致FEV1呈剂量依赖性下降（P < 0.001）。在2小时和24小时时，PC20 FEV1略有增加，安慰剂组和SP组之间无显著差异。同样，两种预处理后2小时时MFEV1均降低。然而，吸入SP后24小时，与安慰剂相比MFEV1增加。SP组和安慰剂组之间MFEV1的这些变化差异显著，下降了5.2±2.2%（标准误）（P < 0.05）。我们得出结论：1）与安慰剂相比，支气管收缩剂量的SP在吸入后24小时可增强哮喘患者对乙酰甲胆碱的最大气道狭窄程度；2）对高剂量吸入性乙酰甲胆碱产生了耐受性。这些发现提示SP通过炎症机制在哮喘患者气道过度狭窄中发挥作用。
