title: ISO-1, a macrophage migration inhibitory factor antagonist, inhibits airway remodeling in a murine model of chronic asthma.
abstract: Airway remodeling is the process of airway structural change that occurs in patients with asthma in response to persistent inflammation and leads to increasing disease severity. Drugs that decrease this persistent inflammation play a crucial role in managing asthma episodes. Mice sensitized (by intraperitoneal administration) and then challenged (by inhalation) with ovalbumin (OVA) develop an extensive eosinophilic inflammatory response, goblet cell hyperplasia, collagen deposition, airway smooth muscle thickening, and airway wall area increase, similar to pathologies observed in human asthma. We used OVA-sensitized/challenged mice as a murine model of chronic allergic airway inflammation with subepithelial fibrosis (i.e., asthma). In this OVA mouse model, mRNA and protein of macrophage migration inhibitory factor (MIF) are upregulated, a response similar to what has been observed in the pathogenesis of acute inflammation in human asthma. We hypothesized that MIF induces transforming growth factor-β1 (TGF-β1) synthesis, which has been shown to play an important role in asthma and airway remodeling. To explore the role of MIF in the development of airway remodeling, we evaluated the effects of an MIF small-molecule antagonist, (S,R)3-(4-hy-droxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester (ISO-1), on pathologies associated with the airway-remodeling process in the OVA mouse model. We found that administration of ISO-1 significantly mitigated all symptoms caused by OVA treatment. In addition, the treatment of OVA-sensitized mice with the MIF antagonist ISO-1 significantly reduced TGF-β1 mRNA levels in pulmonary tissue and its protein level in bronchial alveolar lavage fluid supernatants. We believe the repression of MIF in the ISO-1 treatment group led to the significant suppression observed in the inflammatory responses associated with the allergen-induced lung inflammation and fibrosis in our murine asthma (OVA) model. Our results implicate a possible function of MIF in the pathogenesis of chronic asthma and suggest that MIF might be an important therapeutic target for airway remodeling.
authors.affiliation: Departments of Respiratory Diseases and ShenZhen Third People Hospital, Guangdong, China.
authors.forename: Pei-Fen
authors.initials: PF
authors.lastname: Chen
authors.forename: Ya-ling
authors.initials: YL
authors.lastname: Luo
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Jiang-xin
authors.initials: JX
authors.lastname: Wang
authors.forename: Wen-yan
authors.initials: WY
authors.lastname: Lai
authors.forename: Si-ming
authors.initials: SM
authors.lastname: Hu
authors.forename: Kai Fan
authors.initials: KF
authors.lastname: Cheng
authors.forename: Yousef
authors.initials: Y
authors.lastname: Al-Abed
mesh_terms: D056151:Airway Remodeling / Q000187:drug effects*; D000818:Animals; D001249:Asthma / Q000150:complications / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002452:Cell Count; D002908:Chronic Disease; D003907:Dexamethasone / Q000494:pharmacology; D004195:Disease Models, Animal; D005260:Female; D005355:Fibrosis; D005786:Gene Expression Regulation / Q000187:drug effects; D020397:Goblet Cells / Q000187:drug effects / Q000473:pathology; D006801:Humans; D006984:Hypertrophy; D007150:Immunohistochemistry; D007555:Isoxazoles / Q000494:pharmacology* / Q000627:therapeutic use*; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008263:Macrophage Migration-Inhibitory Factors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009130:Muscle, Smooth / Q000187:drug effects / Q000473:pathology; D010047:Ovalbumin; D011014:Pneumonia / Q000150:complications / Q000188:drug therapy / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism
chemical_list: C462499:3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazoleacetic acid methyl ester; D007555:Isoxazoles; D008263:Macrophage Migration-Inhibitory Factors; D012333:RNA, Messenger; D053773:Transforming Growth Factor beta1; D003907:Dexamethasone; D010047:Ovalbumin