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New therapies are needed to improve the mortality and morbidity of respiratory diseases, but few drug candidates for respiratory diseases are developed and only 3% drug candidates reach market (compared to 6-14% for other diseases). This breakdown in the respiratory drug development pipeline is due to a poor understanding of respiratory disease mechanisms and poor preclinical models for testing treatments. Organomimetic 3-D in vitro respiratory models may improve our understanding of respiratory disease pathogenesis, drug mechanism of action, and identify toxicity early in drug development. However, current assays were not designed for 3-D in vitro models or longitudinal studies. Here, we combine two label-free microscopy techniques to measure the time-dependent response to sodium cyanide in ex vivo mouse tracheae. Optical metabolic imaging (OMI) quantitatively assesses cellular metabolism without dyes by measuring the fluorescence of endogenous metabolic coenzymes NADH and FAD, and is sensitive to early cell injury and different pathways of drug toxicity. Optical coherence tomography (OCT) assesses the motility of cilia, an important cellular constituent in the respiratory system and for respiratory drug delivery. Our results support future development of this novel platform for respiratory drug development and basic science studies.