This Article Full Text Full Text (PDF) Online Supplement All Versions of this Article: 200806-905OCv1 179/4/271    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Nakanishi, Y. Articles by Takayama, K. Search for Related Content PubMed PubMed Citation Articles by Nakanishi, Y. Articles by Takayama, K.

Clarithromycin Prevents Smoke-induced Emphysema in Mice

¹ Research Center, Taisho Pharmaceutical Co., Ltd., Saitama, Japan; ² Division of Pharmaceutical Sciences, Kanazawa University Graduate School of Natural Science and Technology, Ishikawa, Japan; ³ Department of Medicine, Washington University in St. Louis School of Medicine, St. Louis, Missouri; ⁴ Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pennsylvania; ⁵ Research Center, NB Health Laboratory Co., Ltd., Saitama, Japan

Correspondence and requests for reprints should be addressed to Kiyoshi Takayama, Ph.D., Research Center, Taisho Pharmaceutical Co., Ltd., 403, Yoshino-Cho 1-Chome, Kita-Ku, Saitama City, Saitama, Japan 3319530. E-mail: ktakayama{at}nbhl.co.jp

Rationale: Modulating the low-grade chronic inflammation in chronic obstructive pulmonary disease remains challenging. Clarithromycin (CAM), a macrolide antibiotic, reportedly ameliorates chronic inflammation via mechanisms independent of its antibacterial activity.

Objectives: The aim of this study was to examine whether CAM can prevent or reduce emphysema induced by chronic cigarette smoke exposure.

Methods: Mice were exposed to cigarette smoke daily for 6 months and treated with orally administered CAM at doses of 25 to 100 mg/kg twice a day throughout the course of the experiment to test the preventive effects. The administration of CAM at 50 or 100 mg/kg was performed during the second half of a 6-month exposure period to assess the therapeutic effects. Histologic analysis was performed to evaluate the effect of CAM.

Measurements and Main Results: CAM treatment for 6 months decreased airspace enlargement and the destruction of the alveolar walls and impaired the accumulation of macrophages in bronchoalveolar lavage fluid in a dose-related fashion. The administration of clarithromycin at 100 mg/kg in the therapeutic protocol reduced emphysema compared with the smoke-exposed group without treatment. An immunohistologic analysis revealed that CAM reduced the number of F4/80-positive macrophages in the lung parenchyma. In an in vitro test, CAM at 5 to 20 µM directly suppressed the activation of macrophages stimulated with tumor necrosis factor-.

Conclusions: Our data demonstrated that CAM at a clinically achievable dose prevented cigarette smoke–induced emphysema by modulating lung inflammation. This study supports the possibility that low-dose CAM treatment might provide a new therapeutic strategy for chronic obstructive pulmonary diseases.

Key Words: macrolides • chronic obstructive pulmonary disease • anti-inflammatory agents

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Modulating inflammation in chronic obstructive pulmonary disease remains challenging. Clarithromycin is effective for treating patients with diffuse panbronchiolitis independently from its antibacterial activity. However, the effects of clarithromycin on emphysema remain uncertain. What This Study Adds to the Field This study demonstrates that clarithromycin prevents emphysema evoked by cigarette smoke by modulating lung inflammation in mice, supporting the possibility that low-dose clarithromycin treatment might provide a new therapeutic strategy for pulmonary emphysema.