title: Roflumilast Ameliorates Airway Hyperresponsiveness Caused by Diet-Induced Obesity in a Murine Model.
abstract: Obese patients with asthma respond poorly to conventional asthma medications, resulting in severe symptoms and poor prognosis. Roflumilast, a phosphodiesterase-4 inhibitor that lowers the levels of various substances that are implicated in obese subjects with asthma, may be effective in the treatment of those subjects. We evaluated the potential of roflumilast as a novel therapeutic agent for obese subjects with asthma. We designed three models: diet-induced obesity (DIO); DIO with ovalbumin (OVA); and OVA. We fed C57BL/6J mice a high-fat diet for 3 months with or without OVA sensitization and challenge. Roflumilast or dexamethasone was administered orally three times at 2-day intervals in the last experimental week. Airway hyperresponsiveness resulting from DIO significantly improved in the roflumilast-treated group compared with the dexamethasone-treated groups. Although DIO did not affect the cell proliferation in bronchoalveolar lavage fluid, increased fibrosis was seen in the DIO group, which significantly improved from treatment with roflumilast. DIO-induced changes in adiponectin and leptin levels were improved by roflumilast, whereas dexamethasone aggravated them. mRNA levels and proteins of TNF-α, transforming growth factor-β, IL-1β, and IFN-γ increased in the DIO group and decreased with roflumilast. The reactive oxygen species levels were also increased in the DIO group and decreased by roflumilast. In the DIO plus OVA and OVA models, roflumilast improved Th1 and Th2 cell activation to a greater extent than dexamethasone. Roflumilast is significantly more effective than dexamethasone against airway hyperresponsiveness caused by DIO in the murine model. Roflumilast may represent a promising therapeutic agent for the treatment of obese patients with asthma.
authors.affiliation: 1 Department of Internal Medicine, Division of Allergy and Immunology, and.|2 Institute of Allergy, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Hye Jung
authors.initials: HJ
authors.lastname: Park
authors.affiliation: 1 Department of Internal Medicine, Division of Allergy and Immunology, and.|2 Institute of Allergy, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Jae-Hyun
authors.initials: JH
authors.lastname: Lee
authors.affiliation: 2 Institute of Allergy, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Yoon Hee
authors.initials: YH
authors.lastname: Park
authors.affiliation: 2 Institute of Allergy, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Heejae
authors.initials: H
authors.lastname: Han
authors.affiliation: 1 Department of Internal Medicine, Division of Allergy and Immunology, and.|2 Institute of Allergy, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Da Woon
authors.initials: da W
authors.lastname: Sim
authors.affiliation: 1 Department of Internal Medicine, Division of Allergy and Immunology, and.|2 Institute of Allergy, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Kyung Hee
authors.initials: KH
authors.lastname: Park
authors.affiliation: 1 Department of Internal Medicine, Division of Allergy and Immunology, and.|2 Institute of Allergy, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Jung-Won
authors.initials: JW
authors.lastname: Park
mesh_terms: D052242:Adiponectin / Q000378:metabolism; D000631:Aminopyridines / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001549:Benzamides / Q000494:pharmacology / Q000627:therapeutic use*; D049109:Cell Proliferation / Q000187:drug effects; D003521:Cyclopropanes / Q000494:pharmacology / Q000627:therapeutic use; D016207:Cytokines / Q000378:metabolism; D004032:Diet / Q000009:adverse effects*; D004195:Disease Models, Animal; D020738:Leptin / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D009765:Obesity / Q000150:complications* / Q000473:pathology; D010047:Ovalbumin; D011658:Pulmonary Fibrosis / Q000150:complications / Q000188:drug therapy; D017382:Reactive Oxygen Species / Q000378:metabolism; D012130:Respiratory Hypersensitivity / Q000188:drug therapy* / Q000209:etiology* / Q000473:pathology; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism
chemical_list: D052242:Adiponectin; D000631:Aminopyridines; D001549:Benzamides; D003521:Cyclopropanes; D016207:Cytokines; D020738:Leptin; D017382:Reactive Oxygen Species; C424423:Roflumilast; D010047:Ovalbumin
keywords: airway hyperresponsiveness; asthma; obesity; phosphodiesterase-4 inhibitor; roflumilast