02565nas a2200421   4500000000100000000000100001008004100002260001500043653001200058653002500070653002200095653001600117653002400133653001000157653001100167653002400178653001800202653000900220653000900229653000900238653002300247653003900270653002300309653002000332100001600352700002100368700002500389700002000414700001700434700002600451700002300477700003000500700002100530245009900551490000600650520147300656022001402129       2012                            d  c2012-11-0710aAnimals10aBiological Transport10aBlood-Air Barrier10aCapillaries10aDisease Progression10aGases10aHumans10aIn Vitro Techniques10aInterleukin-210aLung10aMale10aMice10aMice, Inbred C57BL10aMicrofluidic Analytical Techniques10aModels, Biological10aPulmonary Edema1 aDongeun Huh1 aDaniel C. Leslie1 aBenjamin D. Matthews1 aJacob P. Fraser1 aSamuel Jurek1 aGeraldine A. Hamilton1 aKevin S. Thorneloe1 aMichael Allen McAlexander1 aDonald E. Ingber00aA human disease model of drug toxicity-induced pulmonary edema in a lung-on-a-chip microdevice0 v43 aPreclinical drug development studies currently rely on costly and time-consuming animal testing because existing cell culture models fail to recapitulate complex, organ-level disease processes in humans. We provide the proof of principle for using a biomimetic microdevice that reconstitutes organ-level lung functions to create a human disease model-on-a-chip that mimics pulmonary edema. The microfluidic device, which reconstitutes the alveolar-capillary interface of the human lung, consists of channels lined by closely apposed layers of human pulmonary epithelial and endothelial cells that experience air and fluid flow, as well as cyclic mechanical strain to mimic normal breathing motions. This device was used to reproduce drug toxicity-induced pulmonary edema observed in human cancer patients treated with interleukin-2 (IL-2) at similar doses and over the same time frame. Studies using this on-chip disease model revealed that mechanical forces associated with physiological breathing motions play a crucial role in the development of increased vascular leakage that leads to pulmonary edema, and that circulating immune cells are not required for the development of this disease. These studies also led to identification of potential new therapeutics, including angiopoietin-1 (Ang-1) and a new transient receptor potential vanilloid 4 (TRPV4) ion channel inhibitor (GSK2193874), which might prevent this life-threatening toxicity of IL-2 in the future.  a1946-6242