Hyperoxia, reactive oxygen species, and hyperventilation: oxygen sensitivity of brain stem neurons

Department of Anatomy and Physiology, Environmental and Hyperbaric Cell Biology Facility, Wright State University School of Medicine, College of Science and Mathematics, Dayton, Ohio 45435; and 1 Department of Military and Emergency Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814 Hyperoxia is a popular model of oxidative stress. However, hyperoxic gas mixtures are routinely used for chemical denervation of peripheral O 2 receptors in in vivo studies of respiratory control. The underlying assumption whenever using hyperoxia is that there are no direct effects of molecular O 2 and reactive O 2 species (ROS) on brain stem function. In addition, control superfusates used routinely for in vitro studies of neurons in brain slices are, in fact, hyperoxic. Again, the assumption is that there are no direct effects of O 2 and ROS on neuronal activity. Research contradicts this assumption by demonstrating that O 2 has central effects on the brain stem respiratory centers and several effects on neurons in respiratory control areas; these need to be considered whenever hyperoxia is used. This mini-review summarizes the long-recognized, but seldom acknowledged, paradox of respiratory control known as hyperoxic hyperventilation. Several proposed mechanisms are discussed, including the recent hypothesis that hyperoxic hyperventilation is initiated by increased production of ROS during hyperoxia, which directly stimulates central CO 2 chemoreceptors in the solitary complex. Hyperoxic hyperventilation may provide clues into the fundamental role of redox signaling and ROS in central control of breathing; moreover, oxidative stress may play a role in respiratory control dysfunction. The practical implications of brain stem O 2 and ROS sensitivity are also considered relative to the present uses of hyperoxia in respiratory control research in humans, animals, and brain stem tissues. Recommendations for future research are also proposed. brain stem respiratory centers; central chemoreceptors; oxidative stress; hyperoxic hyperventilation Address for reprint requests and other correspondence: J. B. Dean, Dept. of Anatomy and Physiology, 235C Bio. Sci. Bldg., 3640 Col. Glenn Hwy., Wright State Univ., Dayton, OH 45435 (E-mail: jay.dean{at}wright.edu ).