Department of Pediatrics, University of Wisconsin, Madison, WI, United States.
Department of Medicine, University of Wisconsin, Madison, WI, United States.
Cytotherapy. 2016 Apr;18(4):536-45. doi: 10.1016/j.jcyt.2016.01.010.
In the field of cellular therapy, potential cell entrapment in the lungs following intravenous administration in a compromised or injured pulmonary system is an important concern that requires further investigation. We developed a rat model of inflammatory and fibrotic lung disease to mimic the human clinical condition of obliterative bronchiolitis (OB) and evaluate the safety of intravenous infusion of mesenchymal stromal cells (MSCs). This model was used to obtain appropriate safety information and functional characterization to support the translation of an ex vivo-generated cellular product into human clinical trials. To overcome spontaneous recovery and size limitations associated with current animal models, we used a novel multiple dose bleomycin strategy to induce lasting lung injury in rats.
Intratracheal instillation of bleomycin was administered to rats on multiple days. MSCs were intravenously infused 7 days apart. Detailed pulmonary function tests including forced expiratory volume, total lung capacity, and invasive hemodynamic measurements were conducted to define the representative disease model and monitor cardiopulmonary hemodynamic consequences of the cell infusion. Post-euthanasia assessments included a thorough evaluation of lung morphology and histopathology.
The double dose bleomycin instillation regimen resulted in severe and irreversible lung injury and fibrosis. Cardiopulmonary physiological monitoring reveled that no adverse events could be attributed to the cell infusion process.
Although our study did not show the infusion of MSCs to result in an improvement in lung function or rescue of damaged tissue this study does confirm the safety of MSC infusion into damaged lungs.
在细胞治疗领域，静脉给药后潜在的细胞在受损或受伤的肺部中被捕获是一个重要的关注点，需要进一步研究。我们开发了一种炎症和纤维化肺部疾病的大鼠模型，以模拟人类闭塞性细支气管炎（OB）的临床情况，并评估间质基质细胞（MSCs）静脉输注的安全性。该模型用于获得适当的安全性信息和功能特征，以支持体外生成的细胞产品转化为人类临床试验。为了克服与当前动物模型相关的自发恢复和尺寸限制，我们使用了一种新的多次剂量博来霉素策略来诱导大鼠持久的肺损伤。
在多天内通过气管内滴注博来霉素向大鼠给药。MSCs 在 7 天内静脉输注。进行详细的肺功能测试，包括用力呼气量、总肺活量和侵入性血流动力学测量，以定义代表性疾病模型并监测细胞输注对心肺血流动力学的影响。安乐死后评估包括对肺形态和组织病理学的全面评估。
双剂量博来霉素滴注方案导致严重且不可逆转的肺损伤和纤维化。心肺生理监测表明，细胞输注过程没有不良反应。
尽管我们的研究并未显示 MSC 输注可改善肺功能或挽救受损组织，但该研究确实证实了 MSC 输注到受损肺部的安全性。
