Ibuprofen Blunts Ventilatory Acclimatization to Sustained Hypoxia in Humans

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.

The impact of inflammation on respiratory plasticity

“…CSH also increases the ‘CNS gain of the HVR’, which is an increase in ventilatory motor output (measured as integrated phrenic nerve activity or ventilation) for a given level of carotid body stimulation (Dwinell and Powell, 1999; Wilkinson et al, 2010) and this also must be decreased by ibuprofen during CSH to explain the results in rats (Popa et al, 2011). The importance of inflammatory signals for plasticity in VAH is also supported by significant decreases in the HVR of healthy human volunteers given ibuprofen during altitude acclimatization (Basaran et al, 2016), although the site of action cannot be determined in these studies. (see High Altitude below).…”

“…A recent double-blind, placebo controlled, cross-over trial found that the increase in isocapnic HVR observed with placebo in healthy volunteers over 48 hours at high altitude (3,800 m) was significantly less with ibuprofen treatment (Basaran et al, 2016). This is predictable from the animal studies showing decreased carotid body and ventilatory O 2 -sensitivity with ibuprofen during CSH (Liu et al, 2009; Popa et al, 2011).…”

“…Such differing results may be explained by changes in inflammatory and neurotrophic signaling during repetitive hypoxic episodes (Huxtable et al, 2015; Peters et al, 2015; Smith et al, 2013). Additionally, treatment with anti-inflammatories blunts ventilatory acclimatization to CSH in humans (Basaran et al, 2016), but during CIH does not inhibit hypoxic sensitization (Del Rio et al, 2012; Iturriaga et al, 2015), suggesting the role of inflammation in CSH and CIH are distinct. These results highlight the complexity of interactions between inflammatory stimuli and the respiratory system, but also the importance of further investigations to tease out the mechanistic intricacies.…”

Safety and Ergogenic Properties of Combined Aminophylline and Ambrisentan in Hypoxia

“…Subjects were confined in the Duke Early Phase Clinical Research Unit (DEPRU) throughout study procedures. Recruitment goals were to enroll 24 to complete at least 16 subjects, following a common design strategy for crossover safety studies . Primary outcome measures were safety and PK alterations.…”

Microcircuits in respiratory rhythm generation: commonalities with other rhythm generating networks and evolutionary perspectives

“…There is increasing awareness that central neuronal networks are hypoxia sensitive [43], which may critically depend on glial cells [85 • ,86]. Interestingly, the processes involved in the hypoxic response share common pathways with the inflammatory response [87,88]. In this context, not only astrocytes, but also microglia may play important roles, as demonstrated for the release of pro-inflammatory cytokines within the preBötC [87,89].…”