Abstract
Obstructive sleep apnea (OSA), manifested by airway exposure to intermittent hypoxia (IH), is associated with excess reactive oxygen species (ROS) production in airways, airway inflammation, and hyperreactive airway diseases. The cause-effect relationship for these events remains unclear. We investigated the inflammatory role of ROS-sensitive AMP-activated protein kinase (AMPK) in IH-induced airway hypersensitivity mediated by lung vagal C fibers (LVCFs) in rats. Conscious rats were exposed to room air (RA) or IH with or without treatment with N-acetyl-L-cysteine (NAC, an antioxidant), Compound C (an AMPK inhibitor), ibuprofen (a cyclooxygenase inhibitor), or their vehicles. Immediately after exposure (24 h), we found that intravenous capsaicin, phenylbiguanide, or α,β-methylene-ATP evoked augmented LVCF-mediated apneic responses and LVCF afferent responses in rats subjected to IH exposure in comparison with those in RA rats. The potentiating effect of IH on LVCF responses decreased at 6 h after and vanished at 12 h after the termination of IH exposure. The potentiating effect of IH on LVCF-mediated apneic and LVCF afferent responses was significantly attenuated by treatment with NAC, compound C, or ibuprofen, but not by their vehicles. Further biochemical analysis revealed that rats exposed to IH displayed increased lung levels of lipid peroxidation (an index of oxidative stress), AMPK phosphorylation (an index of AMPK activation), and prostaglandin E2 (a cyclooxygenase metabolite), compared with those exposed to RA. IH-induced increase in lipid peroxidation was considerably suppressed by treatment with NAC but not by compound C or ibuprofen. IH-induced increase in AMPK phosphorylation was totally abolished by NAC or compound C but not by ibuprofen. IH-induced increase in prostaglandin E2 was considerably prevented by any of these three inhibitor treatments. The vehicles of these inhibitors exerted no significant effect on the three IH-induced responses. These results suggest that 24-h IH exposure sensitizes LVCFs, leading to an exaggerated reflex and afferent responses to chemical stimulants in rats. Moreover, this IH-induced LVCF sensitization is mediated through a cascade of inflammatory responses in the airways involving increases in ROS, AMPK activation, and cyclooxygenase metabolite release.
Highlights
Obstructive sleep apnea (OSA), manifested by airway exposure to intermittent hypoxia (IH), is associated with various types of hyperreactive airway diseases such as asthma, chronic cough, and bronchial hyperreactivity in humans (Lin and Lin, 1995; Ciftci et al, 2005; Sundar et al, 2010; Teodorescu et al, 2012)
The results of this study demonstrate that, immediately after exposure, rats treated with 24-h IH displayed augmented apneic responses to intravenous administration of three different lung vagal C-fibers (LVCFs) stimulants as compared with rats treated with 24-h room air (RA) exposure (Figures 1, 2)
The augmented apneic responses to these three stimulants were abolished by perivagal capsaicin treatment or vagotomy (Figures 1, 2), suggesting that these responses were reflex consequences mediated through LVCFs
Summary
Obstructive sleep apnea (OSA), manifested by airway exposure to intermittent hypoxia (IH), is associated with various types of hyperreactive airway diseases such as asthma, chronic cough, and bronchial hyperreactivity in humans (Lin and Lin, 1995; Ciftci et al, 2005; Sundar et al, 2010; Teodorescu et al, 2012). Patients with OSA display increased oxidative stress and inflammation in the airways (Carpagnano et al, 2008; Petrosyan et al, 2008; Fortuna et al, 2011; Karamanli et al, 2014) In these patients, repetitive periods of upper airway collapse result in cyclic periods of hypoxia/re-oxygenation (Lavie, 2003). We recently reported (Shen et al, 2012) that 10 episodes [each consisting of 30 s of hypoxia air exposure followed by 30 s of room air (RA) exposure] of acute IH in rats can induce LVCF-mediated airway hypersensitivity. An experimental model of IH that can induce a cascade of excess ROS, increased inflammatory mediators, and LVCF hypersensitivity is required for studying the cause-effect relationship and the underlying mechanism
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