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INVITED EDITORIAL
Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut
AT THE TIME OF BIRTH, peripheral chemoreceptors are relatively insensitive to hypoxia and begin maturing to normal hypoxia sensitivity over the first postnatal days to weeks. The signal that initiates this maturation process is unresolved but appears to be related to the increase in the partial pressure of arterial oxygen (PaO2), which takes place at the time of birth. Birthing into a low-oxygen atmosphere and clinical syndromes such as congenital heart disease that limit the postnatal increase in PaO2 result in a prolonged, impaired chemoreceptor response to hypoxia when measured at ages that should show a potent sensitivity to hypoxia (3). This impairment is often maintained despite a correction to normal levels of oxygen (6). Similarly, but likely through a different mechanism, postnatal exposure to high levels of oxygen results in impaired chemoreceptor function (2), which is maintained through adulthood, despite a return to normal oxygen levels (1).
The work reported in the Journal of Applied Physiology by Pawar et al. (7) adds some important new insights into how environmental oxygen exposure may alter chemoreceptor maturation and function. On the basis of their work and the work of others, it was known that chronic intermittent hypoxia (CIH: 5% oxygen x 9 episodes/h x 8 h/day) applied to mature animals resulted in two changes: 1) an enhancement of the chemoreceptor response to acute hypoxia (Fig. 1, line 2), and 2) a functional change such that an episode of CIH will induce a prolonged enhancement of baseline chemoreceptor activity (Fig. 1, line 4) (8). This was termed long-term facilitation (LTF) and may be a significant contributor to sympathetic activation (and hypertension) associated with sleep apnea syndromes.
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With a risk of anthropomorphizing, the newborn response allows Nature to fine-tune the chemoreceptor response in proportion to the incidence of CIH events. Unlike in the adult, the tuned state is maintained for a prolonged period following the tuning and is not associated with induction of LTF, which is associated with chronic sympathetic stimulation. Given this, these results suggest that there is a potential for clinicians to mold the respiratory control system so as to ameliorate future pathological conditions. For instance, a major risk factor for suffering a fatal asthmatic attack is a low ventilatory sensitivity to hypoxia (5), and a low sensitivity to hypoxia is associated with failure to arouse during desaturations during sleep. In both cases, patients would likely improve if subjected to treatment that evokes the same developmental pathway as does CIH in the newborn animal.
Development of a clinical intervention would benefit from a mechanistic understanding of how CIH alters carotid body hypoxia sensitivity, particularly in the newborn. CIH in the newborn enhances carotid body cell proliferation (7), which may, potentially, enhance the hypoxia-induced excitatory signal to the nerve endings. In contrast, no change in carotid body morphology is observed following CIH in the adult. From previous work, the sensitization and LTF observed in the adult could be suppressed by treatment with a superoxide dismutase mimetic, suggesting that reactive oxygen species (ROS) generation is an important component (8). The source of ROS may be the electron transport chain because CIH induced a downregulation of complex I but not complex III (8). Whether similar gene changes are observed in the newborn is unknown, but since LTF is not observed in the newborn, it seems likely that different pathways are affected.
A natural extension of the present work would be to understand how the cellular elements within the carotid body are altered by CIH exposure in the newborn period. Work in other laboratories has demonstrated developmental increases in the expression of leak K+ (9) channels and BK-type K+ channels (4), both of which are oxygen sensitive. The oxygen-sensitive channels are purported to link hypoxia with membrane depolarization, activation of voltage-dependent calcium channels, increased intracellular calcium, and enhanced release of an excitatory transmitter. Each of these elements may potentially be enhanced by CIH in the newborn, but this is yet to be resolved.
At present, this story is in the early stage of unfolding, and its elucidation may reveal how the respiratory system may be molded by environmental interventions in the postnatal period. Not only may this prove useful for ameliorating several clinical conditions, but it may prove insightful in understanding of the mechanistic basis for oxygen transduction in the carotid body.
FOOTNOTES
Address for reprint requests and other correspondence: D. F. Donnelly, Dept. of Pediatrics, Yale Univ. School of Medicine, New Haven, CT 06520 (e-mail: david.donnelly{at}yale.edu)
REFERENCES
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