Intra-airway administration of small interfering RNA targeting plasminogen activator inhibitor-1 attenuates allergic asthma in mice

• Published in: American journal of physiology. Lung cellular and molecular physiology Vol. 301; no. 6; pp. L908 - L916
• Main Authors: Miyamoto, Shintaro, Hattori, Noboru, Senoo, Tadashi, Onari, Yojiro, Iwamoto, Hiroshi, Kanehara, Masashi, Ishikawa, Nobuhisa, Fujitaka, Kazunori, Haruta, Yoshinori, Murai, Hiroshi, Yokoyama, Akihito, Kohno, Nobuoki
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.12.2011
• Subjects: Airway Remodeling - genetics; Animals; Asthma; Asthma - pathology; Asthma - prevention & control; Bronchitis - prevention & control; Bronchoalveolar Lavage Fluid - chemistry; Correlation analysis; Drug Evaluation, Preclinical; Female; Hepatocyte Growth Factor - metabolism; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Molecular Targeted Therapy; Ovalbumin; Pathogenesis; Plasminogen Activator Inhibitor 1 - genetics; Plasminogen Activator Inhibitor 1 - metabolism; Pulmonary Eosinophilia - pathology; Pulmonary Eosinophilia - prevention & control; Ribonucleic acid; RNA; RNA Interference; RNA, Small Interfering - administration & dosage; RNA, Small Interfering - therapeutic use; Rodents; Sputum - metabolism
• ISSN: 1040-0605; 1522-1504; 1522-1504
• DOI: 10.1152/ajplung.00115.2011

Recent studies suggest that plasminogen activator inhibitor-1 (PAI-1), a major inhibitor of the fibrinolytic system, may promote the development of asthma. To further investigate the significance of PAI-1 in the pathogenesis of asthma and determine the possibility that PAI-1 could be a therapeutic target for asthma, this study was conducted. First, PAI-1 levels in induced sputum (IS) from asthmatic subjects and healthy controls were measured. In asthmatic subjects, IS PAI-1 levels were elevated, compared with that of healthy controls, and were significantly higher in patients with long-duration asthma compared with short-duration asthma. PAI-1 levels were also found to correlate with IS transforming growth factor-β levels. Then, acute and chronic asthma models induced by ovalbumin were established in PAI-1-deficient mice and wild-type mice that received intra-airway administrations of small interfering RNA against PAI-1 (PAI-1-siRNA). We could demonstrate that eosinophilic airway inflammation and airway hyperresponsiveness were reduced in an acute asthma model, and airway remodeling was suppressed in a chronic asthma model in both PAI-1-deficient mice and wild-type mice that received intra-airway administration of PAI-1-siRNA. These results indicate that PAI-1 is strongly involved in the pathogenesis of asthma, and intra-airway administration of PAI-1-siRNA may be able to become a new therapeutic approach for asthma.