Abstract
Obstructive sleep apnea (OSA), manifested by exposure to chronic intermittent hypoxia (CIH) and excess production of reactive oxygen species (ROS) in the airways, is associated with hyperreactive airway diseases. ROS, particularly when created by NADPH oxidase, are known to sensitize lung vagal C fibers (LVCFs), which may contribute to airway hypersensitivity pathogenesis. We investigated whether CIH augments the reflex and afferent responses of LVCFs to chemical stimulants and the roles of ROS and NADPH oxidase in such airway hypersensitivity. Rats were exposed to room air (RA) or CIH with/without daily treatment with MnTMPyP (a superoxide anion scavenger), apocynin (an NADPH oxidase inhibitor), or vehicle. At 16 h after their last exposure, intravenous capsaicin, adenosine, or α,β-methylene-ATP evoked an augmented apneic response in anesthetized rats with 14-days CIH exposure, compared to anesthetized rats with 14-days RA exposure. The augmented apneic responses to these LVCF stimulants were abolished by bilateral vagotomy or perivagal capsaicin treatment, which block LVCFs neural conduction and were significantly suppressed by treatment with MnTMPyP or apocynin, but not vehicle. Electrophysiological studies revealed that 14-days CIH exposure potentiated the responses of LVCFs to these stimulants. This effect was inhibited by treatment with MnTMPyP or apocynin treatment and was not seen in rats who received 7-days of CIH exposure. Biochemical analysis indicated that 14-days CIH exposure increased both lung lipid peroxidation, which is indicative of oxidative stress, and expression of the p47phox subunit in the membrane fraction of lung tissue, which is an index of NADPH oxidase activation. The former was prevented by treatment with either MnTMPyP or apocynin, while the later was prevented by treatment with apocynin only. These results suggest that 14-days CIH exposure sensitizes LVCFs in rats, leading to an exaggerated reflex and afferent responses to stimulants and that this sensitization is mediated via ROS generated by NADPH oxidase.
Highlights
Obstructive sleep apnea (OSA), manifested by airway exposure to chronic intermittent hypoxia (CIH), is associated with various hyperreactive airway diseases of humans including asthma (Teodorescu et al, 2012), chronic cough (Sundar et al, 2010), and bronchial hyperreactivity (Lin and Lin, 1995)
The baseline lung vagal C fibers (LVCFs) activities of the rats exposed to 7- or 14-days CIH without daily drug treatment were not significantly different from that of the rats exposed to 14-days room air (RA) without daily drug treatment (Table 2)
The results of this study demonstrate that, 16 h after the last exposure, rats treated with 14-days CIH exposure displayed augmented apneic responses to an intravenous injection of three different LVCF stimulants as compared to rats treated with 14-days RA exposure (Figures 1, 2)
Summary
Obstructive sleep apnea (OSA), manifested by airway exposure to chronic intermittent hypoxia (CIH), is associated with various hyperreactive airway diseases of humans including asthma (Teodorescu et al, 2012), chronic cough (Sundar et al, 2010), and bronchial hyperreactivity (Lin and Lin, 1995). These patients display increased oxidative stress due to an excess production of reactive oxygen species (ROS) (Alonso-Fernandez et al, 2009; Hopps and Caimi, 2015). While oxidative stress is implicated in the pathogenesis of several OSA-related diseases such as cardiovascular (Hopps and Caimi, 2015), neurodegenerative (Zhang and Veasey, 2012), and metabolic complications (Mesarwi et al, 2015), its role in the development of OSA-associated hyperreactive airway diseases is still not known
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