title: Intra-airway administration of small interfering RNA targeting plasminogen activator inhibitor-1 attenuates allergic asthma in mice.
abstract: 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.
authors.affiliation: Department of Molecular and Internal Medicine, Graduate School of Biomedical Sciences, Hiroshima University, Japan.
authors.forename: Shintaro
authors.initials: S
authors.lastname: Miyamoto
authors.forename: Noboru
authors.initials: N
authors.lastname: Hattori
authors.forename: Tadashi
authors.initials: T
authors.lastname: Senoo
authors.forename: Yojiro
authors.initials: Y
authors.lastname: Onari
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Iwamoto
authors.forename: Masashi
authors.initials: M
authors.lastname: Kanehara
authors.forename: Nobuhisa
authors.initials: N
authors.lastname: Ishikawa
authors.forename: Kazunori
authors.initials: K
authors.lastname: Fujitaka
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Haruta
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Murai
authors.forename: Akihito
authors.initials: A
authors.lastname: Yokoyama
authors.forename: Nobuoki
authors.initials: N
authors.lastname: Kohno
mesh_terms: D056151:Airway Remodeling / Q000235:genetics; D000818:Animals; D001249:Asthma / Q000473:pathology / Q000517:prevention & control*; D001991:Bronchitis / Q000517:prevention & control; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D004353:Drug Evaluation, Preclinical; D005260:Female; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058990:Molecular Targeted Therapy; D010047:Ovalbumin; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics* / Q000378:metabolism; D011657:Pulmonary Eosinophilia / Q000473:pathology / Q000517:prevention & control; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000627:therapeutic use*; D013183:Sputum / Q000378:metabolism
chemical_list: C553307:HGF protein, mouse; D017395:Plasminogen Activator Inhibitor 1; D034741:RNA, Small Interfering; D017228:Hepatocyte Growth Factor; D010047:Ovalbumin