The roles of inflammation and reactive oxygen species in the medulla during ventilatory acclimatization to hypoxia

Ventilatory acclimatization to hypoxia (VAH) is a time dependent increase in ventilation that develops after hypoxic exposures of hours to days. VAH consists of both a change in chemosensitivity to hypoxemia in the carotid body and a change in the central nervous system sensitivity to afferent carotid body signals (Nielsen et al., 1988; Dwinell &Powell, 1999). My dissertation tests the hypotheses that inflammation and reactive oxygen species (ROS) each plays an essential role in the respiratory control centers of the medulla during VAH. Inflammatory cytokines have recently been established as important in the increased O₂-sensitivity of the carotid body during VAH using ibuprofen to block this increased sensitivity (Liu et al., 2009). Using a similar experimental design to Liu et al. (2009), we examined the effect of systemic ibuprofen administration on the hypoxic ventilatory response and cytokine expression in the dorsal medulla, which contains respiratory control centers. Ibuprofen blocked VAH in rats breathing 10%O₂ and further analysis showed this result cannot be explained simply by the published effect of ibuprofen on the carotid body effect but it must involve the central nervous system as well. Measurements of cytokines in the dorsal medulla indicate that, inflammatory signals are increased with chronic hypoxia and this increase is blocked by ibuprofen, supporting our hypothesis of the signaling role inflammation plays in VAH. In a second set of experiments, we tested the hypothesis that ROS decrease in CNS respiratory centers with hypoxic exposure and these changes in ROS contribute to VAH in mice. To test this, we measured ROS in normoxia, acute hypoxia, chronic sustained hypoxia, and acute intermittent hypoxia under control conditions and under chronic anti-oxidant treatment. Results show a trend for decreased ROS in acute hypoxia and a return toward normoxic levels with chronic hypoxia. Chronic anti-oxidant treatment tended to decrease ROS more in n