Primary Human Lung Alveolus-on-a-chip Model of Intravascular Thrombosis for Assessment of Therapeutics

Clin Pharmacol Ther. 2018 Feb;103(2):332-340. doi: 10.1002/cpt.742. Epub 2017 Jul 14.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Video-Audio Media

MeSH terms

  • Blood-Air Barrier / drug effects*
  • Blood-Air Barrier / metabolism
  • Blood-Air Barrier / pathology
  • Cells, Cultured
  • Coculture Techniques
  • Drug Development / methods*
  • Drug Discovery / methods*
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism
  • Endothelial Cells / pathology
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism
  • Epithelial Cells / pathology
  • Evidence-Based Medicine / methods
  • Fibrinolytic Agents / pharmacology*
  • Humans
  • Lab-On-A-Chip Devices*
  • Microfluidic Analytical Techniques / instrumentation*
  • Microvessels / drug effects*
  • Microvessels / metabolism
  • Microvessels / pathology
  • Patient Safety
  • Pulmonary Alveoli / blood supply*
  • Risk Assessment
  • Signal Transduction / drug effects
  • Thrombosis / drug therapy*
  • Thrombosis / metabolism
  • Thrombosis / pathology
  • Translational Medical Research / methods

Substances

  • Fibrinolytic Agents