1 Department of Allergy and Immune Disorders, Murdoch Children's Research Institute, Melbourne, Victoria, Australia.
Am J Respir Cell Mol Biol. 2014 Jan;50(1):180-92. doi: 10.1165/rcmb.2013-0008OC.
It has been suggested that an inherent airway epithelial repair defect is the root cause of airway remodeling in asthma. However, the relationship between airway epithelial injury and repair, airway remodeling, and airway hyperresponsiveness (AHR) has not been directly examined. We investigated the contribution of epithelial damage and repair to the development of airway remodeling and AHR using a validated naphthalene (NA)-induced murine model of airway injury. In addition, we examined the endogenous versus exogenous role of the epithelial repair peptide trefoil factor 2 (TFF2) in disease pathogenesis. A single dose of NA (200 mg/kg in 10 ml/kg body weight corn oil [CO] vehicle, intraperitoneally) was administered to mice. Control mice were treated with CO (10 ml/kg body weight, intraperitoneally). At 12, 24, 48, and 72 hours after NA or CO injection, AHR and various measures of airway remodeling were examined by invasive plethysmography and morphometric analyses, respectively. TFF2-deficient mice and intranasal treatment were used to examine the role of the epithelial repair peptide. NA treatment induced denudation and apoptosis of airway epithelial cells, goblet cell metaplasia, elevated AHR, and increased levels of endogenous TFF2. Airway epithelial changes peaked at 12 hours after NA treatment, whereas airway remodeling changes were observed from 48 hours. TFF2 was protective against epithelial damage and induced remodeling and was found to mediate organ protection via a platelet-derived growth factor-associated mechanism. Our findings directly demonstrate the contribution of epithelial damage to airway remodeling and AHR and suggest that preventing airway epithelial damage and promoting epithelial repair may have therapeutic implications for asthma treatment.
有人认为，气道上皮固有修复缺陷是哮喘气道重塑的根本原因。然而，气道上皮损伤与修复、气道重塑和气道高反应性（AHR）之间的关系尚未被直接研究。我们使用已验证的萘（NA）诱导的气道损伤小鼠模型研究了上皮损伤和修复对气道重塑和 AHR 发展的贡献。此外，我们还研究了上皮修复肽三叶因子 2（TFF2）在疾病发病机制中的内源性和外源性作用。给予小鼠单次腹腔注射 200mg/kg 萘（溶于 10ml/kg 体重玉米油[CO]）。对照组小鼠接受 CO（10ml/kg 体重，腹腔内注射）。在 NA 或 CO 注射后 12、24、48 和 72 小时，通过侵入性测功法和形态计量分析分别检查 AHR 和各种气道重塑指标。使用 TFF2 缺陷小鼠和鼻内治疗来研究上皮修复肽的作用。NA 处理诱导气道上皮细胞脱落和凋亡、杯状细胞化生、AHR 升高和内源性 TFF2 水平升高。气道上皮变化在 NA 处理后 12 小时达到峰值，而气道重塑变化则在 48 小时观察到。TFF2 可防止上皮损伤并诱导重塑，并且通过血小板衍生生长因子相关机制介导器官保护。我们的研究结果直接证明了上皮损伤对气道重塑和 AHR 的贡献，并表明预防气道上皮损伤和促进上皮修复可能对哮喘治疗具有治疗意义。
