A new target for caffeine in the developing lung: endoplasmic reticulum stress?

The utility of caffeine to manage apnea of prematurity is widely accepted, however, much controversy surrounds the potential for caffeine to drive post-natal lung maturation in settings of arrested lung development. Many studies have reported pathways relevant to lung injury and lung development are modulated by caffeine in vitro and in vivo, leading to the application of caffeine in experimental animal models of bronchopulmonary dysplasia (BPD). These studies have generated exciting, but at times confusing data. Particularly helpful in understanding the impact of caffeine would be to identify the target molecules or pathways in the developing lung that mediate the effects of caffeine. Here, we critically evaluate a recent report suggesting that endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) are targets of caffeine in a hyperoxia-based rat model of BPD. The authors documented ER stress and engagement of the UPR in the lungs of rats exposed to hyperoxia, where an axis of initiators, transducers, and effectors of the UPR was engaged. The concomitant administration of caffeine to affected rat pups dampened the activity of this axis, leading the authors to conclude that caffeine protects the developing rat lung from injurious stimuli by limiting ER stress and the UPR. The study highlights the need to now directly demonstrate that ER stress and the UPR, and not a plethora of other caffeine mediated physiological effects, are indeed the relevant targets of caffeine during arrested lung alveolarization.

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