Evans D J, Barnes P J, Spaethe S M, van Alstyne E L, Mitchell M I, O'Connor B J
Clinical Studies Unit, Royal Brompton Hospital, London, UK.
Thorax. 1996 Dec;51(12):1178-84. doi: 10.1136/thx.51.12.1178.
Leukotriene (LT) B4 is a potent neutrophil chemoattractant and also stimulates eosinophils in vitro, but its role in asthmatic inflammation is unknown.
The effect of the novel LTB4 receptor antagonist, LY293111, was examined using allergen challenge as a model for asthmatic inflammation in 12 atopic asthmatic subjects in a double blind placebo controlled crossover trial. Subjects with an established early (EAR) and late asthmatic response (LAR) to allergen at screening received oral LY293111 in a dose of 112 mg three times daily for seven days or placebo before further allergen challenge. Each treatment was separated by a washout period of 28 days. Individuals underwent histamine challenge one hour before and three hours after allergen challenge. Bronchoalveolar lavage (BAL) fluid was obtained at bronchoscopy 24 hours after allergen challenge.
There was no difference in baseline lung function, EAR, LAR, or in airway responsiveness to histamine before and after allergen between placebo and LY293111. By contrast, treatment with LY293111 significantly reduced the number of neutrophils in BAL fluid expressed as both absolute cell numbers and percentage cell differential counts: absolute cell counts, median (range) 0.04 (0.02-0.15) x 10(6) after LY293111, 0.09 (0.02-0.43) x 10(6) after placebo; percentage differential cell counts 0.35 (0.1-2.0) after LY293111, 0.80 (0.1-3.6) after placebo (p < 0.05). Eosinophils, macrophages, and lymphocytes in BAL fluid did not differ between treatments. There was a significant reduction in the concentration of myeloperoxidase (MPO) with both placebo (16 (6.6) ng/ml) and LY293111 (3.5 (1.8) ng/ml) and of LTB4 (placebo 4.6 (1.2) pg/ml, LY293111 2.2 (0.2) pg/ml). Concentrations of LTC4 and interleukin 8 were reduced, although not significantly, whereas concentrations of interleukin 6, GM-CSF, and TNF-alpha were unchanged by LY293111.
These results demonstrate an influence of LTB4 on neutrophil influx and activation in the airway following allergen challenge. Despite this anti-inflammatory effect, there was no measured physiological benefit and this questions the functional role of the neutrophil in the pathophysiology of allergen induced asthma.
白三烯（LT）B4是一种强效的中性粒细胞趋化因子，且在体外也能刺激嗜酸性粒细胞，但它在哮喘炎症中的作用尚不清楚。
在一项双盲安慰剂对照交叉试验中，以12名特应性哮喘患者为研究对象，使用过敏原激发作为哮喘炎症模型，检测新型LTB4受体拮抗剂LY293111的效果。在筛查时对过敏原已出现早期（EAR）和晚期哮喘反应（LAR）的受试者，在再次进行过敏原激发前，接受口服LY293111，剂量为112mg，每日3次，共7天，或服用安慰剂。每次治疗间隔28天的洗脱期。在过敏原激发前1小时和激发后3小时，对个体进行组胺激发试验。在过敏原激发24小时后，通过支气管镜检查获取支气管肺泡灌洗（BAL）液。
安慰剂组和LY293111组在基线肺功能、EAR、LAR或过敏原激发前后气道对组胺的反应性方面无差异。相比之下，LY293111治疗显著降低了BAL液中中性粒细胞数量，以绝对细胞数和细胞分类计数百分比表示：绝对细胞计数，LY293111治疗后中位数（范围）为0.04（0.02 - 0.15）×10⁶，安慰剂治疗后为0.09（0.02 - 0.43）×10⁶；细胞分类计数百分比，LY293111治疗后为0.35（0.1 - 2.0），安慰剂治疗后为0.80（0.1 - 3.6）（p < 0.05）。各治疗组间BAL液中的嗜酸性粒细胞、巨噬细胞和淋巴细胞无差异。安慰剂（16（6.6）ng/ml）和LY293111（3.5（1.8）ng/ml）治疗后髓过氧化物酶（MPO）浓度均显著降低，LTB4浓度也降低（安慰剂4.6（1.2）pg/ml，LY293111 2.2（0.2）pg/ml）。LTC4和白细胞介素8浓度降低，尽管不显著，而白细胞介素6、粒细胞 - 巨噬细胞集落刺激因子（GM - CSF）和肿瘤坏死因子 - α（TNF - α）的浓度在LY293111治疗后未改变。
这些结果表明，LTB4对过敏原激发后气道中中性粒细胞的流入和激活有影响。尽管有这种抗炎作用，但未检测到生理益处，这对中性粒细胞在过敏原诱导哮喘病理生理学中的功能作用提出了质疑。
