A Novel Oral Neutrophil Elastase Inhibitor (ONO-6818) Inhibits Human Neutrophil Elastase-induced Emphysema in Rats

Abstract

We investigated the effects of a novel oral neutrophil elastase inhibitor (ONO-6818) on acute lung injury and pulmonary emphysema induced by human neutrophil elastase (HNE). Young male Wistar rats were divided into four treatment groups: (1) control group (saline); (2) HNE group (HNE 200 U + 0.5% carboxymethyl-cellulose [solution for ONO-6818]); (3) low-dose ONO-6818 group (HNE 200 U + ONO-6818 10 mg/kg); and (4) high-dose ONO-6818 group (HNE 200 U + ONO-6818 100 mg/kg). Saline and HNE were applied via the trachea using a microsprayer. ONO-6818 was administered orally 1 hour before HNE application. Six hours after HNE application, neutrophil counts and hemoglobin concentration in bronchoalveolar lavage fluid and lung tissue myeloperoxidase activity were determined. Eight weeks after the application, FRC, TLC, lung compliance, and mean linear intercept were estimated. ONO-6818 attenuated dose-dependently HNE-induced increases in lung myeloperoxidase activity, hemoglobin, and neutrophil count in bronchoalveolar lavage fluid. Furthermore, it significantly attenuated HNE-induced increases in FRC, TLC, lung compliance, and mean linear intercept. ONO-6818 inhibited acute lung injury induced by HNE by minimizing lung hemorrhage and accumulation of neutrophils in the lung. ONO-6818 also inhibited the development of HNE-induced emphysematous changes including lung hyperinflation, degradation of elastic recoil, and airspace enlargement.

Risk Factors for Bronchiectasis in Children With Cystic Fibrosis

“…Such therapies are available or are under investigation in clinical trials, [24][25][26] highlighting the relevance of understanding the role that neutrophil elastase may play in disease initiation and progression. Studies of ibuprofen in older children and adults have shown a delayed decrease in lung function and improved maintenance of weight, with these findings attributed to antiinflammatory activity.…”

In vivo animal models for drug delivery across the lung mucosal barrier☆

“…Hormonally and immunologically guinea pigs are more like humans than other rodents; thus they are often used to model human infectious diseases [58]. Although rats are not as similar to humans they have been used to study a range of diseases such as emphysema [59], influenza [60] and pulmonary fibrosis [61]. Other systemic diseases such as diabetes can be induced in rats by administration of streptozocin [62].…”

Niacinamide mitigated the acute lung injury induced by phorbol myristate acetate in isolated rat's lungs

“…The neutrophil elastase (NE) was determined with a synthetic substrate, N-methoxysuccinyl-Ala-Ala-Pro-Val-p-nitroanilide as described previously [15,18]. In brief, samples were incubated in 0.1 M Tris-HCl buffer (pH 8.0) containing 0.5 M Nacl and 1 mM substrate at 37°C for 24 hrs.…”