A human disease model of drug toxicity-induced pulmonary edema in a lung-on-a-chip microdevice.
A human disease model of drug toxicity-induced pulmonary edema in a lung-on-a-chip microdevice.
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DOI：
10.1126/scitranslmed.3004249
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发表时间：
2012-11-07
影响因子：
17.1
通讯作者：
Ingber DE
中科院分区：
文献类型：
--
作者：
Huh D;Leslie DC;Matthews BD;Fraser JP;Jurek S;Hamilton GA;Thorneloe KS;McAlexander MA;Ingber DE
临床前药物开发研究目前依赖于昂贵且耗时的动物试验，因为现有的细胞培养模型无法重现人类复杂的器官水平疾病过程。在这里，我们提供了使用仿生微设备的原理证明，该仿生微设备重建器官水平的肺功能，以创建模拟肺水肿的人类疾病芯片模型。该微流体装置重建了人肺的肺泡-毛细血管界面，由通道组成，通道由经历空气和流体流动的人肺上皮和内皮细胞的紧密贴壁层排列，以及模拟正常呼吸运动的循环机械应变。在本研究中，该装置用于重现在相同时间范围内以相似剂量接受白细胞介素-2（IL-2）治疗的人类癌症患者中观察到的药物毒性诱导的肺水肿。使用这种芯片上疾病模型的研究表明，与生理呼吸运动相关的机械力在导致肺水肿的血管渗漏增加的发展中起着至关重要的作用，并且这种疾病的发展不需要循环免疫细胞。这些研究还鉴定了潜在的新疗法，包括血管生成素-1（Ang-1）和一种新的瞬时受体电位香草酸4（TRPV 4）离子通道抑制剂（GSK 2193874），这可能会在未来预防IL-2的这种危及生命的毒性。人体肺水肿的体外模型预测了之前在人体中观察到的药物毒性和功效。
Preclinical drug development studies currently rely on costly and time-consuming animal testing because existing cell culture models fail to recapitulate complex, organ-level, disease processes in humans. Here, we provide the proof-of-principle for using a biomimetic microdevice that reconstitutes organ-level lung functions to create a human disease model-on-a-chip that mimics pulmonary edema. The microfluidic device, which reconstitutes the alveolar-capillary interface of the human lung, consists of channels lined by closely apposed layers of human pulmonary epithelial and endothelial cells that experience air and fluid flow, as well as cyclic mechanical strain to mimic normal breathing motions. In the present study, this device was used to reproduce drug toxicity-induced pulmonary edema observed in human cancer patients treated with interleukin-2 (IL-2) at similar doses and over the same time frame. Studies using this on-chip disease model revealed that mechanical forces associated with physiological breathing motions play a crucial role in the development of increased vascular leakage that leads to pulmonary edema, and that circulating immune cells are not required for the development of this disease. These studies also led to identification of potential new therapeutics, including angiopoietin-1 (Ang-1) and a new transient receptor potential vanilloid 4 (TRPV4) ion channel inhibitor (GSK2193874), which might prevent this life-threatening toxicity of IL-2 in the future. An in vitro model of human pulmonary edema predicts drug toxicity and efficacy previously observed in humans.
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影响因子：
15.8
作者：
Parikh SM;Mammoto T;Schultz A;Yuan HT;Christiani D;Karumanchi SA;Sukhatme VP
通讯作者：
Sukhatme VP
影响因子：
6.1
作者：
Grosberg A;Alford PW;McCain ML;Parker KK
通讯作者：
Parker KK
影响因子：
19
作者：
Huh, Dongeun;Hamilton, Geraldine A.;Ingber, Donald E.
通讯作者：
Ingber, Donald E.
影响因子：
5
作者：
Hermanns, MI;Unger, RE;Kirkpatrick, CJ
通讯作者：
Kirkpatrick, CJ
DOI：
10.1073/pnas.0610868104
发表时间：
2007-11-27
影响因子：
11.1
作者：
Huh, Dongeun;Fujioka, Hideki;Takayama, Shuichi
通讯作者：
Takayama, Shuichi