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.
Highlights
Asthmatic airway remodeling, characterized by structural and morphometric changes of the airway epithelium, is believed to be the result of chronic inflammation in the bronchial wall
We studied the effect of ISO-1 administration on transforming growth factor-β1 (TGF-β1) mRNA in lung tissue and TGF-β1 levels in bronchial alveolar lavage fluid (BALF) to determine if TGF-β1 was a possible downstream target of migration inhibitory factor (MIF) inhibition and played a role in the process of airway remodeling
To determine whether MIF is expressed in this model, we first evaluated the expression of MIF at mRNA and protein levels in mouse pulmonary tissue
Summary
Asthmatic airway remodeling, characterized by structural and morphometric changes of the airway epithelium, is believed to be the result of chronic inflammation in the bronchial wall. Airway remodeling has been speculated to be one of the factors that makes asthma difficult to cure [3]. Current guidelines for asthma treatment emphasize the use of bronchodilators to rescue or delay exacerbation of symptoms, and inhaled corticosteroids to minimize the underlying inflammation. Despite the role of inhaled corticosteroids in prevention of inflammation [4] and reduction of airway remodeling [5], these drugs have potential adverse side effects, such as oral candidiasis and dysphonia [6]. It is estimated that a subset of asthmatic patients (10% to 25%) do not respond to glucocorticoid therapy [7,8,9,10]. There is urgent need for additional therapies in asthma because such a large number of asthmatic patients remain symptomatic with glucocorticoid therapy
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