RGD Reference Report - ISO-1, a macrophage migration inhibitory factor antagonist, inhibits airway remodeling in a murine model of chronic asthma. - Rat Genome Database

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ISO-1, a macrophage migration inhibitory factor antagonist, inhibits airway remodeling in a murine model of chronic asthma.

Authors: Chen, PF  Luo, YL  Wang, W  Wang, JX  Lai, WY  Hu, SM  Cheng, KF  Al-Abed, Y 
Citation: Chen PF, etal., Mol Med. 2010 Sep-Oct;16(9-10):400-8. Epub 2010 May 14.
RGD ID: 4145113
Pubmed: PMID:20485865   (View Abstract at PubMed)
PMCID: PMC2935952   (View Article at PubMed Central)
DOI: DOI:10.2119/molmed.2009.00128   (Journal Full-text)

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-beta1 (TGF-beta1) 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-beta1 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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
asthma  ISOTgfb1 (Mus musculus)4145113; 4145113mRNA:increased expression:lungRGD 
asthma  IEP 4145113mRNA:increased expression:lungRGD 

Objects Annotated

Genes (Rattus norvegicus)
Tgfb1  (transforming growth factor, beta 1)

Genes (Mus musculus)
Tgfb1  (transforming growth factor, beta 1)

Genes (Homo sapiens)
TGFB1  (transforming growth factor beta 1)


Additional Information