Departments of Respiratory Diseases and ShenZhen Third People Hospital, Guangdong, China.
Mol Med. 2010 Sep-Oct;16(9-10):400-8. doi: 10.2119/molmed.2009.00128. Epub 2010 May 14.
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.
气道重塑是哮喘患者持续炎症反应导致气道结构改变的过程，导致疾病严重程度增加。减少这种持续炎症的药物在管理哮喘发作中起着至关重要的作用。用卵清蛋白（OVA）经腹腔注射致敏然后经吸入挑战的小鼠会发展出广泛的嗜酸性粒细胞炎症反应、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，类似于人类哮喘中观察到的病理学。我们使用 OVA 致敏/挑战的小鼠作为慢性过敏性气道炎症伴亚上皮纤维化（即哮喘）的小鼠模型。在这种 OVA 小鼠模型中，巨噬细胞移动抑制因子（MIF）的 mRNA 和蛋白表达上调，这与人类哮喘急性炎症发病机制中观察到的反应相似。我们假设 MIF 诱导转化生长因子-β1（TGF-β1）的合成，这在哮喘和气道重塑中起着重要作用。为了探讨 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）对与气道重塑过程相关的病理的影响在 OVA 小鼠模型中。我们发现，ISO-1 的给药显著减轻了 OVA 处理引起的所有症状。此外，用 MIF 拮抗剂 ISO-1 治疗 OVA 致敏的小鼠可显著降低肺组织中 TGF-β1 mRNA 水平及其支气管肺泡灌洗液上清液中的蛋白水平。我们认为 ISO-1 治疗组中 MIF 的抑制导致我们的小鼠哮喘（OVA）模型中观察到的与过敏原诱导的肺炎症和纤维化相关的炎症反应显著抑制。我们的结果表明 MIF 可能在慢性哮喘的发病机制中起作用，并表明 MIF 可能是气道重塑的重要治疗靶点。
