TY - JOUR
KW - Blood-Air Barrier
KW - Cells, Cultured
KW - Coculture Techniques
KW - Drug development
KW - Drug Discovery
KW - Endothelial Cells
KW - Epithelial Cells
KW - Evidence-Based Medicine
KW - Fibrinolytic Agents
KW - Humans
KW - Lab-On-A-Chip Devices
KW - Microfluidic Analytical Techniques
KW - Microvessels
KW - Patient Safety
KW - Pulmonary Alveoli
KW - Risk Assessment
KW - Signal Transduction
KW - Thrombosis
KW - Translational Research, Biomedical
AU - A. Jain
AU - R. Barrile
AU - A. D. van der Meer
AU - A. Mammoto
AU - T. Mammoto
AU - K. De Ceunynck
AU - O. Aisiku
AU - M. A. Otieno
AU - C. S. Louden
AU - G. A. Hamilton
AU - R. Flaumenhaft
AU - D. E. Ingber
AB - Pulmonary thrombosis is a significant cause of patient mortality; however, there are no effective in vitro models of thrombi formation in human lung microvessels that could also assess therapeutics and toxicology of antithrombotic drugs. Here, we show that a microfluidic lung alveolus-on-a-chip lined by human primary alveolar epithelium interfaced with endothelium and cultured under flowing whole blood can be used to perform quantitative analysis of organ-level contributions to inflammation-induced thrombosis. This microfluidic chip recapitulates in vivo responses, including platelet-endothelial dynamics and revealed that lipopolysaccharide (LPS) endotoxin indirectly stimulates intravascular thrombosis by activating the alveolar epithelium, rather than acting directly on endothelium. This model is also used to analyze inhibition of endothelial activation and thrombosis due to a protease activated receptor-1 (PAR-1) antagonist, demonstrating its ability to dissect complex responses and identify antithrombotic therapeutics. Thus, this methodology offers a new approach to study human pathophysiology of pulmonary thrombosis and advance drug development.
BT - Clinical Pharmacology and Therapeutics
DA - 2018-02
DO - 10.1002/cpt.742
IS - 2
LA - eng
N2 - Pulmonary thrombosis is a significant cause of patient mortality; however, there are no effective in vitro models of thrombi formation in human lung microvessels that could also assess therapeutics and toxicology of antithrombotic drugs. Here, we show that a microfluidic lung alveolus-on-a-chip lined by human primary alveolar epithelium interfaced with endothelium and cultured under flowing whole blood can be used to perform quantitative analysis of organ-level contributions to inflammation-induced thrombosis. This microfluidic chip recapitulates in vivo responses, including platelet-endothelial dynamics and revealed that lipopolysaccharide (LPS) endotoxin indirectly stimulates intravascular thrombosis by activating the alveolar epithelium, rather than acting directly on endothelium. This model is also used to analyze inhibition of endothelial activation and thrombosis due to a protease activated receptor-1 (PAR-1) antagonist, demonstrating its ability to dissect complex responses and identify antithrombotic therapeutics. Thus, this methodology offers a new approach to study human pathophysiology of pulmonary thrombosis and advance drug development.
PY - 2018
SP - 332
EP - 340
T2 - Clinical Pharmacology and Therapeutics
TI - Primary Human Lung Alveolus-on-a-chip Model of Intravascular Thrombosis for Assessment of Therapeutics
VL - 103
SN - 1532-6535
ER -