Lü Han-Jing, Qiu Zhong-Min, Wei Wei-Li, Yu Li, Liu Rui-Lin, Zhang Min
Department of Respiratory Medicine, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China.
Chin Med J (Engl). 2004 Nov;117(11):1620-4.
There is currently considerable interest in the potential value of selective inhibitors of cyclic nucleotide phosphodiesterase 4 in the treatment of asthma. However, whether they influence eosinophilic airway inflammation-associated cough remains unclear. The objective of this study was to investigate the effects of selective phosphodiesterase 4 inhibitor SB207499 on cough response and airway inflammation in guinea pigs sensitized and challenged with ovalbumin.
Forty sensitized guinea pigs were randomly divided into four groups: control (n = 10), challenge (n = 10), SB207499 (n = 10) and aminophylline (n = 10), then challenged with aerosol of 1% ovalbumin or saline. Two hours later, animals were intraperitoneally injected with either saline, 25 mg/kg of SB207499 or aminophylline. At the 24th hour, the injection was repeated with 2.5 mg/kg and 25 mg/kg SB207499 or aminophylline, then cough response to inhaled capsaicin and airway responsiveness to methacholine inducing a 150% of the peak airway pressure to the baseline (PC150) was measured. Finally, total cell number and differentials in bronchoalveolar lavage fluid were analysed.
The cough frequency per 3 minutes and PC150 in the challenge group were (22 +/- 4) times/3 minutes and (198 +/- 54) microg/ml, which were significantly different from (6 +/- 2) times/3 minutes and (691 +/- 81) microg/ml in the control group (P < 0.05, respectively). The injection of 25 mg/kg SB207499 significantly inhibited the increased cough response and airway hyperresponsiveness, the cough frequency and PC150 in guinea pigs were (13 +/- 2) times/3 minutes and (680 +/- 81) microg/ml (P < 0.05), which differed significantly from (18 +/- 2) times/3 minutes and (400 +/- 86) microg/ml after the administration of the same dose of aminophylline (P < 0.05). The inhibition of SB207499 on cough response was dose-dependent. Similarly, SB207499 decreased the total cell number and percentage of eosinophils in bronchoalveolar lavage fluid to (2.1 +/- 0.5) x 10(6)/ml and (20 +/- 5)% respectively, which were significantly different from (3.2 +/- 0.5) x 10(6)/ml and (29 +/- 5)% in the aminophylline group (P < 0.05, respectively) or (4.2 +/- 0.7) x 10(6)/ml and (35 +/- 4)% in the challenge group (P < 0.05, respectively).
Phosphodiesterase 4 inhibitor may be more useful than aminophylline for cough associated with eosinophilic airway inflammation via inhibiting airway inflammation and airway hyperresponsiveness.
目前，环核苷酸磷酸二酯酶4选择性抑制剂在哮喘治疗中的潜在价值备受关注。然而，它们是否会影响嗜酸性粒细胞性气道炎症相关咳嗽尚不清楚。本研究旨在探讨选择性磷酸二酯酶4抑制剂SB207499对卵清蛋白致敏和激发的豚鼠咳嗽反应及气道炎症的影响。
将40只致敏豚鼠随机分为四组：对照组（n = 10）、激发组（n = 10）、SB207499组（n = 10）和氨茶碱组（n = 10），然后用1%卵清蛋白或生理盐水气雾剂进行激发。两小时后，动物腹腔注射生理盐水、25 mg/kg的SB207499或氨茶碱。在第24小时，重复注射2.5 mg/kg和25 mg/kg的SB207499或氨茶碱，然后测量对吸入辣椒素的咳嗽反应和对乙酰甲胆碱诱导气道压力峰值达到基线150%（PC150）的气道反应性。最后，分析支气管肺泡灌洗液中的总细胞数和分类细胞。
激发组每3分钟的咳嗽频率和PC150分别为（22±4）次/3分钟和（198±54）μg/ml，与对照组的（6±2）次/3分钟和（691±81）μg/ml有显著差异（P均<0.05）。注射25 mg/kg的SB207499可显著抑制豚鼠咳嗽反应增强和气道高反应性，咳嗽频率和PC150分别为（13±2）次/3分钟和（680±81）μg/ml（P<0.05），与给予相同剂量氨茶碱后的（18±2）次/3分钟和（400±86）μg/ml有显著差异（P<0.05）。SB207499对咳嗽反应的抑制呈剂量依赖性。同样，SB207499使支气管肺泡灌洗液中的总细胞数和嗜酸性粒细胞百分比分别降至（2.1±0.5）×10⁶/ml和（20±5）%，与氨茶碱组的（3.2±0.5）×10⁶/ml和（29±5）%（P均<0.05）或激发组的（4.2±0.7）×10⁶/ml和（35±4）%（P均<0.05）有显著差异。
磷酸二酯酶4抑制剂通过抑制气道炎症和气道高反应性，可能比氨茶碱更有效地治疗嗜酸性粒细胞性气道炎症相关咳嗽。
