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

A. Jain, Riccardo Barrile, A. D. van der Meer, A. Mammoto, T. Mammoto, K. De Ceunynck, O. Aisiku, Monicah A. Otieno, Calvert S. Louden, Geraldine A. Hamilton, R. Flaumenhaft, Donald E. Ingber (Corresponding Author)

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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.

Original languageEnglish
Pages (from-to)332-340
Number of pages9
JournalClinical pharmacology & therapeutics
Volume103
Issue number2
DOIs
Publication statusPublished - 1 Feb 2018

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Thrombosis
Lung
Microfluidics
Endothelium
Therapeutics
Epithelium
PAR-1 Receptor
Microvessels
Endotoxins
Pharmaceutical Preparations
Toxicology
Lipopolysaccharides
Blood Platelets
Inflammation
Mortality

Keywords

  • UT-Hybrid-D

Cite this

Jain, A. ; Barrile, Riccardo ; van der Meer, A. D. ; Mammoto, A. ; Mammoto, T. ; De Ceunynck, K. ; Aisiku, O. ; Otieno, Monicah A. ; Louden, Calvert S. ; Hamilton, Geraldine A. ; Flaumenhaft, R. ; Ingber, Donald E. / Primary Human Lung Alveolus-on-a-chip Model of Intravascular Thrombosis for Assessment of Therapeutics. In: Clinical pharmacology & therapeutics. 2018 ; Vol. 103, No. 2. pp. 332-340.
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Jain, A, Barrile, R, van der Meer, AD, Mammoto, A, Mammoto, T, De Ceunynck, K, Aisiku, O, Otieno, MA, Louden, CS, Hamilton, GA, Flaumenhaft, R & Ingber, DE 2018, 'Primary Human Lung Alveolus-on-a-chip Model of Intravascular Thrombosis for Assessment of Therapeutics' Clinical pharmacology & therapeutics, vol. 103, no. 2, pp. 332-340. https://doi.org/10.1002/cpt.742

Primary Human Lung Alveolus-on-a-chip Model of Intravascular Thrombosis for Assessment of Therapeutics. / Jain, A.; Barrile, Riccardo; van der Meer, A. D.; Mammoto, A.; Mammoto, T.; De Ceunynck, K.; Aisiku, O.; Otieno, Monicah A.; Louden, Calvert S.; Hamilton, Geraldine A.; Flaumenhaft, R.; Ingber, Donald E. (Corresponding Author).

In: Clinical pharmacology & therapeutics, Vol. 103, No. 2, 01.02.2018, p. 332-340.

Research output: Contribution to journalArticleAcademicpeer-review

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AU - Jain, A.

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AU - van der Meer, A. D.

AU - Mammoto, A.

AU - Mammoto, T.

AU - De Ceunynck, K.

AU - Aisiku, O.

AU - Otieno, Monicah A.

AU - Louden, Calvert S.

AU - Hamilton, Geraldine A.

AU - Flaumenhaft, R.

AU - Ingber, Donald E.

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