Human Mesenchymal Stem Cells Resolve Airway Inflammation, Hyperreactivity, and Histopathology in a Mouse Model of Occupational Asthma
Human Mesenchymal Stem Cells Resolve Airway Inflammation, Hyperreactivity, and Histopathology in a Mouse Model of Occupational Asthma
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DOI：
10.1089/scd.2013.0616
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发表时间：
2014-10-01
影响因子：
4
通讯作者：
Aran, Josep M.
中科院分区：
文献类型：
--
作者：
Martinez-Gonzalez, Itziar;Cruz, Maria-Jesus;Aran, Josep M.
职业性哮喘（OA）的特征是过敏性气道炎症和高反应性，导致进行性气道重塑和肺功能下降。在临床实践中，OA的管理仍不理想。因此，建立有效的治疗方法可能会克服疾病的自然史。我们评估了人脂肪组织来源的间充质干细胞（hASC）的能力，无论是未经修饰的或工程化分泌IL-33诱饵受体sST 2，以减轻炎症和呼吸系统症状，在先前验证的小鼠模型OA过硫酸铵（AP）。在皮肤AP致敏和鼻内激发方案后24小时，动物静脉内接受1 × 106个细胞（hASC或过表达sST 2的hASC）或盐水，并在治疗后1、3和6天进行分析。输注的hASC在到达AP损伤的哮喘肺部后诱导了抗炎和恢复程序，导致中性粒细胞炎症和总IgE产生早期减少，保留了肺泡结构，几乎不存在淋巴浆细胞浸润，细支气管周围区域的平滑肌增生/肥大可忽略不计，以及基线气道高反应性（AHR）乙酰甲胆碱。局部sST 2过表达几乎没有增加未修饰的hASC所显示的实质性功效。因此，hASC可能代表一种可行的多作用治疗剂，能够通过解决OA典型的炎症、组织重塑和支气管高反应性来充分响应AP损伤的肺环境。
Occupational asthma (OA) is characterized by allergic airway inflammation and hyperresponsiveness, leading to progressive airway remodeling and a concomitant decline in lung function. The management of OA remains suboptimal in clinical practice. Thus, establishing effective therapies might overcome the natural history of the disease. We evaluated the ability of human adipose-tissue-derived mesenchymal stem cells (hASCs), either unmodified or engineered to secrete the IL-33 decoy receptor sST2, to attenuate the inflammatory and respiratory symptoms in a previously validated mouse model of OA to ammonium persulfate (AP). Twenty-four hours after a dermal AP sensitization and intranasal challenge regimen, the animals received intravenously 1 x 10(6) cells (either hASCs or hASCs overexpressing sST2) or saline and were analyzed at 1, 3, and 6 days after treatment. The infused hASCs induced an anti-inflammatory and restorative program upon reaching the AP-injured, asthmatic lungs, leading to early reduction of neutrophilic inflammation and total IgE production, preserved alveolar architecture with nearly absent lymphoplasmacytic infiltrates, negligible smooth muscle hyperplasia/hypertrophy in the peribronchiolar areas, and baseline airway hyperreactivity (AHR) to methacholine. Local sST2 overexpression barely increased the substantial efficacy displayed by unmodified hASCs. Thus, hASCs may represent a viable multiaction therapeutic capable to adequately respond to the AP-injured lung environment by resolving inflammation, tissue remodeling, and bronchial hyperresponsiveness typical of OA.