用于评估抗炎药物反应的肺泡炎症可拉伸人肺芯片模型

IF 6.1 2区 医学 Q1 ENGINEERING, BIOMEDICAL Bioengineering & Translational Medicine Pub Date : 2024-09-05 DOI:10.1002/btm2.10715
Clémentine Richter, Lorenz Latta, Daria Harig, Patrick Carius, Janick D. Stucki, Nina Hobi, Andreas Hugi, Paul Schumacher, Tobias Krebs, Alexander Gamrekeli, Felix Stöckle, Klaus Urbschat, Galia Montalvo, Franziska Lautenschläger, Brigitta Loretz, Alberto Hidalgo, Nicole Schneider‐Daum, Claus‐Michael Lehr
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引用次数: 0

摘要

本研究描述了一种复杂的人体体外模型,用于评估抗炎药物在肺泡中的反应,该模型可能有助于减少药物开发临床前阶段的动物试验。该模型基于人肺泡上皮细胞系 Arlo 与 THP-1 细胞系分化出的巨噬细胞共同培养,创造了一个生理生物微环境。为了模拟气血屏障的三维结构和动态扩张与松弛,它们生长在可拉伸的微生理肺芯片上。为了验证体外模型,我们制定了三种不同的方案,以证明糖皮质激素在不同促炎刺激后减少某些炎症指标的临床公认抗炎效果:(1)细菌LPS(脂多糖)引起的炎症,模拟LPS诱导的急性肺损伤,最好用细胞因子IL-6释放来测量;(2)LPS在ALI(空气-液体界面)引起的炎症,研究气溶胶抗炎治疗,用趋化因子IL-8释放来测量;(3) 结合使用人类炎症细胞因子 TNFα 和 IFNγ 引起的炎症,以模拟导致上皮屏障破坏的临界细胞因子风暴,从而测量上皮屏障的最终削弱或保护情况。在所有情况下,巨噬细胞的存在似乎对肺泡上皮的炎症变化至关重要。LPS 诱导的炎症变化与拉伸条件无关。仿呼吸力学的动态拉伸对于体外模拟 TNFα/IFNγ 诱导炎症时上皮屏障破坏的临床相关结果至关重要。
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A stretchable human lung‐on‐chip model of alveolar inflammation for evaluating anti‐inflammatory drug response
This study describes a complex human in vitro model for evaluating anti‐inflammatory drug response in the alveoli that may contribute to the reduction of animal testing in the pre‐clinical stage of drug development. The model is based on the human alveolar epithelial cell line Arlo co‐cultured with macrophages differentiated from the THP‐1 cell line, creating a physiological biological microenvironment. To mimic the three‐dimensional architecture and dynamic expansion and relaxation of the air‐blood‐barrier, they are grown on a stretchable microphysiological lung‐on‐chip. For validating the in vitro model, three different protocols have been developed to demonstrate the clinically established anti‐inflammatory effect of glucocorticoids to reduce certain inflammatory markers after different pro‐inflammatory stimuli: (1) an inflammation caused by bacterial LPS (lipopolysaccharides) to simulate an LPS‐induced acute lung injury measured best with cytokine IL‐6 release; (2) an inflammation caused by LPS at ALI (air‐liquid interface) to investigate aerosolized anti‐inflammatory treatment, measured with chemokine IL‐8 release; and (3) an inflammation with a combination of human inflammatory cytokines TNFα and IFNγ to simulate a critical cytokine storm leading to epithelial barrier disruption, where the eventual weakening or protection of the epithelial barrier can be measured. In all cases, the presence of macrophages appeared to be crucial to mediating inflammatory changes in the alveolar epithelium. LPS induction led to inflammatory changes independently of stretch conditions. Dynamic stretch, emulating breathing‐like mechanics, was essential for in vitro modeling of the clinically relevant outcome of epithelial barrier disruption upon TNFα/IFNγ‐induced inflammation.
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来源期刊
Bioengineering & Translational Medicine
Bioengineering & Translational Medicine Pharmacology, Toxicology and Pharmaceutics-Pharmaceutical Science
CiteScore
8.40
自引率
4.10%
发文量
150
审稿时长
12 weeks
期刊介绍: Bioengineering & Translational Medicine, an official, peer-reviewed online open-access journal of the American Institute of Chemical Engineers (AIChE) and the Society for Biological Engineering (SBE), focuses on how chemical and biological engineering approaches drive innovative technologies and solutions that impact clinical practice and commercial healthcare products.
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