ISO-1, a Macrophage Migration Inhibitory Factor Antagonist, Inhibits Airway Remodeling in a Murine Model of Chronic Asthma
ISO-1, a Macrophage Migration Inhibitory Factor Antagonist, Inhibits Airway Remodeling in a Murine Model of Chronic Asthma
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DOI：
10.2119/molmed.2009.00128
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发表时间：
2010-09-01
影响因子：
5.7
通讯作者：
Al-Abed, Yousef
中科院分区：
文献类型：
--
作者：
Chen, Pei-Fen;Luo, Ya-ling;Al-Abed, Yousef
气道重塑是哮喘患者对持续性炎症反应的气道结构变化过程，导致疾病严重程度增加。减少这种持续性炎症的药物在控制哮喘发作中起着至关重要的作用（通过腹膜内给药），然后激发（通过吸入）与卵清蛋白（OVA）发生广泛的嗜酸性炎症反应、杯状细胞增生、胶原沉积、气道平滑肌增厚和气道壁面积增加，与人类哮喘中观察到的病理相似我们使用OVA致敏/激发小鼠作为慢性过敏性气道炎症伴上皮下纤维化的小鼠模型在该OVA小鼠模型中，巨噬细胞迁移抑制因子（MIF）的mRNA和蛋白质被上调，这一反应类似于在人类哮喘急性炎症发病机制中观察到的反应。我们假设MIF诱导转化生长因子β 1（TGF-β 1）的合成，这已被证明在哮喘和气道重塑中起重要作用。为了探索MIF在气道重塑发展中的作用，我们评估了MIF小分子拮抗剂（S，R）3-（4-羟基苯基）-4，5-二氢-5-异恶唑乙酸甲酯（ISO-1），在OVA小鼠模型中与气道重塑过程相关的病理学方面，我们发现，1显著减轻了由OVA治疗引起的所有症状。此外，用MIF拮抗剂ISO-1治疗OVA致敏小鼠，肺组织中β 1 mRNA水平和支气管肺泡灌洗液上清液中β 1蛋白水平我们认为，ISO-1治疗组可显著抑制哮喘小鼠模型中与变应原诱导的肺部炎症和纤维化相关的炎症反应。本研究结果提示MIF在慢性哮喘的发病机制中可能起作用，并提示MIF可能是气道重塑的重要治疗靶点。(C)2010年费恩斯坦医学研究所，www.feinsteininstitute.org
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-beta 1 (TGF-beta 1) 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-hydroxyphenyl)-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-beta 1 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. (C) 2010 The Feinstein Institute for Medical Research, www.feinsteininstitute.org