Ibuprofen blocks time-dependent increases in hypoxic ventilation in rats

Abstract

Recently, inflammatory processes have been shown to increase O₂-sensitivity of the carotid body during chronic sustained hypoxia [Liu, X., He, L., Stensaas, L., Dinger, B., Fidone, S., 2009. Adaptation to chronic hypoxia involves immune cell invasion and increased expression of inflammatory cytokines in rat carotid body. Am. J. Physiol. Lung Cell Mol. Physiol. 296, L158–L166]. We hypothesized that blocking inflammation with ibuprofen would reduce ventilatory acclimatization to hypoxia by blocking such increases in carotid body O₂ sensitivity. We tested this in conscious rats treated with ibuprofen (4 mg/kg IP daily) or saline during acclimatization to hypoxia ($P_{{\text{I}}_{{\text{O}}_2}}=70\text{Torr}$ for 7 days). Ibuprofen blocked the increase in hypoxic ventilation observed in chronically hypoxic rats treated with saline; ibuprofen had no effects on ventilation in normoxic control rats. Ibuprofen blocked increases in inflammatory cytokines (IL-1β, IL-6) in the brainstem with chronic hypoxia. The data supports our hypothesis and further analysis indicates that ibuprofen also blocks inflammatory processes in the central nervous system contributing to ventilatory acclimatization to hypoxia. Possible mechanisms linking inflammatory and hypoxic signaling are reviewed.

Introduction

Ventilatory acclimatization to hypoxia is a time-dependent increase in ventilation during chronic sustained hypoxia (Powell et al., 1998). Several laboratories have demonstrated that this involves increased O₂-sensitivity of carotid body chemoreceptors resulting in increased afferent input to ventilatory chemoreflexes for a given arterial $P_{{\text{O}}_2}$ after chronic hypoxia (reviewed by Powell, 2007). Additionally, we have shown time-dependent changes in the central nervous system (CNS) processing of carotid body chemoreceptor input resulting in a greater respiratory motor output for a given afferent input (Dwinell and Powell, 1999). Plasticity in the carotid body-ventilatory chemoreflex with chronic hypoxia involves changes in neurotransmitters and ion channels in the carotid bodies and CNS (reviewed by Powell, 2007), and changes in gene expression controlled by Hypoxia Inducible Factor 1, HIF-1 (Kline et al., 2002, Powell and Fu, 2008).

Recently, inflammatory processes have been shown to be important for the increased O₂-sensitivity of carotid bodies with chronic sustained hypoxia (Liu et al., 2009). Using an in vitro rat carotid body preparation, these investigators showed that chronic sustained hypoxia increases the frequency of action potentials recorded in the carotid sinus nerve when $P_{{\text{O}}_2}$ is lowered in a solution superfusing the carotid body. They also found increased mRNA expression for inflammatory cytokines in carotid bodies from chronically hypoxic rats. The increased cytokine expression, as well as the increased carotid body neural response to acute hypoxia, was blocked by ibuprofen and dexamethasone treatment during the chronic hypoxia.

To test the physiological significance of these inflammatory signals for plasticity in chronically hypoxic carotid bodies, we studied the effects of a nonsteroidal anti-inflammatory drug, ibuprofen, on ventilatory acclimatization to hypoxia in conscious rats. Also, we measured the effects of chronic hypoxia and ibuprofen on cytokine expression in the CNS. Ibuprofen decreased ventilatory acclimatization to hypoxia and cytokine gene expression in the CNS, providing evidence that inflammatory signaling in the CNS contributes to ventilatory acclimatization to hypoxia.