Animal models of asthma: reprise or reboot?

Animal models of disease represent the pinnacle of hierarchical research efforts to validate targets and compounds for therapeutic intervention. Yet models of asthma, particularly in the mouse, which, for practical reasons, has become the sine qua non of asthma research, have been a bone of contention for decades. With barely a nod to their limitations and an extensive history of translational failures, they continue to be used for target identification and to justify the clinical evaluation of new compounds. Recent improvements - including sensitization directly to the airways; use of more relevant allergens; development of a chronic rather than short-term condition; utilization of techniques to measure lung function beyond uninterpretable measures of airway hyperresponsiveness - are laudable but cannot bridge the chasm between the models and the myriad complexities of the human disorder and multiple asthma endophenotypes. While further model developments are necessary, including recognition of key environmental factors beyond allergens, the judicious integration with newer ex vivo and in vitro techniques, including human precision-cut lung slices, reprograming of patient-derived induced pluripotent stem cells and fibroblasts to epithelial and smooth muscle cells, and use of other clinical samples to create a more holistic depiction of activities, might improve their translational success.