Abstract
Ventilatory acclimatization to hypoxia is a time-dependent increase in ventilation and the hypoxic ventilatory response (HVR) that involves neural plasticity in both carotid body chemoreceptors and brainstem respiratory centers. The mechanisms of such plasticity are not completely understood but recent animal studies show it can be blocked by administering ibuprofen, a nonsteroidal anti-inflammatory drug, during chronic hypoxia. We tested the hypothesis that ibuprofen would also block the increase in HVR with chronic hypoxia in humans in 15 healthy men and women using a double-blind, placebo controlled, cross-over trial. The isocapnic HVR was measured with standard methods in subjects treated with ibuprofen (400mg every 8 hrs) or placebo for 48 hours at sea level and 48 hours at high altitude (3,800 m). Subjects returned to sea level for at least 30 days prior to repeating the protocol with the opposite treatment. Ibuprofen significantly decreased the HVR after acclimatization to high altitude compared to placebo but it did not affect ventilation or arterial O2 saturation breathing ambient air at high altitude. Hence, compensatory responses prevent hypoventilation with decreased isocapnic ventilatory O2-sensitivity from ibuprofen at this altitude. The effect of ibuprofen to decrease the HVR in humans provides the first experimental evidence that a signaling mechanism described for ventilatory acclimatization to hypoxia in animal models also occurs in people. This establishes a foundation for the future experiments to test the potential role of different mechanisms for neural plasticity and ventilatory acclimatization in humans with chronic hypoxemia from lung disease.
Highlights
The body’s first line of defense with decreased oxygen levels is the hypoxic ventilatory response (HVR), which is a reflex increase in breathing in response to low arterial partial pressure of oxygen (PO2) stimulating carotid body chemoreceptors [1]
ventilatory acclimatization to hypoxia (VAH) is generally thought to be advantageous because it can increase arterial O2 levels over time at a given altitude [1, 2]. This could be beneficial for patients with chronic hypoxemia from lung disease but it is is not clear if VAH occurs in such patients, or if individual variation in VAH contributes to differences in the progression of lung disease
Because the isocapnic HVR can vary in an individual over time [11, 12], we compared the effect of high altitude against a sea level measurement collected with each treatment
Summary
The body’s first line of defense with decreased oxygen levels is the hypoxic ventilatory response (HVR), which is a reflex increase in breathing in response to low arterial partial pressure of oxygen (PO2) stimulating carotid body (arterial) chemoreceptors [1]. There is a time-dependent increase in both ventilation and the ventilatory sensitivity to acute changes in O2 (i.e. the HVR), which collectively are termed “ventilatory acclimatization to PLOS ONE | DOI:10.1371/journal.pone.0146087. VAH is generally thought to be advantageous because it can increase arterial O2 levels over time at a given altitude [1, 2]. This could be beneficial for patients with chronic hypoxemia from lung disease but it is is not clear if VAH occurs in such patients, or if individual variation in VAH contributes to differences in the progression of lung disease. There is an interest in determining the mechanisms of VAH in humans
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