Fujimoto K, Kubo K, Shinozaki S, Okada K, Matsuzawa Y, Kobayashi T, Sugane K
First Department of Internal Medicine, Shinshu University School of Medicine, Matsumoto, Japan.
Respir Physiol. 1995 Apr;100(1):91-100. doi: 10.1016/0034-5687(94)00123-h.
To determine the role of neutrophil elastase in asthmatic responses, we studied the effect of ONO-5046, a specific neutrophil elastase inhibitor, on antigen-induced asthmatic responses in allergic sheep. Pulmonary resistance (RL) was measured for 8 h after antigen challenge. Measurements of airway responsiveness to methacholine and bronchoalveolar lavage fluid (BALF) were obtained 8 h after challenge. Antigen challenge caused early and late increases in RL, airway hyperresponsiveness (AHR), and recruitment of neutrophils and eosinophils along with increases in TXB2 and LTB4 in BALF. ONO-5046 treatment significantly reduced both early and late bronchoconstriction, neutrophil recruitment, increases in LTB4 in BALF, and AHR. ONO-5046 post-treatment significantly reduced the increase in RL 8 h after antigen challenge. Another neutrophil elastase inhibitor, FR 134043, significantly reduced both early and late bronchoconstriction. ONO-5046 had little effect on calcium ionophore-induced LTB4 release from isolated neutrophils and whole blood obtained from drug-treated sheep. These findings suggest that neutrophil elastase is involved in antigen-induced bronchoconstriction and AHR mediated by neutrophil accumulation and 5-lipoxygenase products in allergic sheep.
为了确定中性粒细胞弹性蛋白酶在哮喘反应中的作用，我们研究了特异性中性粒细胞弹性蛋白酶抑制剂ONO-5046对变应性绵羊抗原诱导的哮喘反应的影响。抗原激发后8小时测量肺阻力（RL）。激发后8小时测量气道对乙酰甲胆碱的反应性和支气管肺泡灌洗液（BALF）。抗原激发导致RL、气道高反应性（AHR）早期和晚期增加，中性粒细胞和嗜酸性粒细胞募集，以及BALF中TXB2和LTB4增加。ONO-5046治疗显著降低了早期和晚期支气管收缩、中性粒细胞募集、BALF中LTB4增加以及AHR。抗原激发后8小时，ONO-5046治疗后显著降低了RL的增加。另一种中性粒细胞弹性蛋白酶抑制剂FR 134043显著降低了早期和晚期支气管收缩。ONO-5046对钙离子载体诱导的从分离的中性粒细胞和从药物处理的绵羊获得的全血中LTB4释放几乎没有影响。这些发现表明，中性粒细胞弹性蛋白酶参与变应性绵羊中由中性粒细胞聚集和5-脂氧合酶产物介导的抗原诱导的支气管收缩和AHR。
