02510nas a2200505   4500000000100000000000100001008004100002260001200043653002200055653002000077653002500097653002100122653001900143653002200162653002100184653002800205653002400233653001100257653002600268653003900294653001700333653001900350653002200369653002000391653002400411653001500435653003900450100001200489700001500501700002300516700001500539700001500554700001900569700001400588700001700602700001700619700001900636700001900655700001700674245010700691300001200798490000800810520117200818022001401990       2018                            d  c2018-0210aBlood-Air Barrier10aCells, Cultured10aCoculture Techniques10aDrug development10aDrug Discovery10aEndothelial Cells10aEpithelial Cells10aEvidence-Based Medicine10aFibrinolytic Agents10aHumans10aLab-On-A-Chip Devices10aMicrofluidic Analytical Techniques10aMicrovessels10aPatient Safety10aPulmonary Alveoli10aRisk Assessment10aSignal Transduction10aThrombosis10aTranslational Research, Biomedical1 aA. Jain1 aR. Barrile1 aA. D. van der Meer1 aA. Mammoto1 aT. Mammoto1 aK. De Ceunynck1 aO. Aisiku1 aM. A. Otieno1 aC. S. Louden1 aG. A. Hamilton1 aR. Flaumenhaft1 aD. E. Ingber00aPrimary Human Lung Alveolus-on-a-chip Model of Intravascular Thrombosis for Assessment of Therapeutics  a332-3400 v1033 aPulmonary 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.  a1532-6535