Abstract
Obstructive sleep apnea is mainly characterized by intermittent hypoxia (IH), which is associated with hyperreactive airway diseases and lung inflammation. Sensitization of lung vagal C fibers (LVCFs) induced by inflammatory mediators may play a central role in the pathogenesis of airway hypersensitivity. In females, estrogen interferes with inflammatory signaling pathways that may modulate airway hyperreactivity. In this study, we investigated the effects of IH on the reflex and afferent responses of LVCFs to chemical stimulants and lung inflammation in adult female rats, as well as the role of estrogen in these responses. Intact and ovariectomized (OVX) female rats were exposed to room air (RA) or IH for 14 consecutive days. On day 15, IH enhanced apneic responses to right atrial injection of chemical stimulants of LVCFs (e.g., capsaicin, phenylbiguanide, and α,β-methylene-ATP) in intact anesthetized females. Rats subjected to OVX prior to IH exposure exhibited an augmented apneic response to the same dose of stimulants compared with rats subjected to other treatments. Apneic responses to the stimulants were completely abrogated by bilateral vagotomy or perivagal capsaicin treatment, which blocked the neural conduction of LVCFs. Electrophysiological experiments revealed that in IH-exposed rats, OVX potentiated the excitability of LVCFs to stimulants. Moreover, LVCF hypersensitivity in rats subjected to OVX prior to IH exposure was accompanied by enhanced lung inflammation, which was reflected by elevated inflammatory cell infiltration in bronchoalveolar lavage fluid, lung lipid peroxidation, and protein expression of inflammatory cytokines. Supplementation with 17β-estradiol (E2) at a low concentration (30 μg/ml) but not at high concentrations (50 and 150 μg/ml) prevented the augmenting effects of OVX on LVCF sensitivity and lung inflammation caused by IH. These results suggest that ovarian hormones prevent the enhancement of LVCF sensitivity and lung inflammation by IH in female rats, which are related to the effect of low-dose estrogen.
Highlights
Airway exposure to long-term intermittent hypoxia (IH) may contribute to several obstructive sleep apnea (OSA)-related hyperreactive airway diseases such as asthma (Teodorescu et al, 2012), chronic cough (Chan et al, 2015), and bronchial hyperreactivity (Sariman et al, 2011)
This study aimed to investigate whether 14 days of exposure to IH enhances the reflex and afferent responses of lung vagal C fibers (LVCFs) to chemical stimulants in female rats; whether OVX-augmented LVCF sensitivity induced by IH is associated with lung inflammation; and whether the supplementation of physiological E2 concentrations influences LVCF hypersensitivity and lung inflammation in OVX rats exposed to IH
This study demonstrates that compared with room air (RA) exposure, 14 days of IH exposure slightly increased LVCF-mediated apneic responses and LVCF fiber responses to intravenous injection of capsaicin, phenylbiguanide, and α,β-methylene-ATP in intact anesthetized female rats
Summary
Airway exposure to long-term intermittent hypoxia (IH) may contribute to several obstructive sleep apnea (OSA)-related hyperreactive airway diseases such as asthma (Teodorescu et al, 2012), chronic cough (Chan et al, 2015), and bronchial hyperreactivity (Sariman et al, 2011). Previous studies have reported that increased airway levels of inflammation and oxidative stress were found in patients with OSA (Aihara et al, 2013; Tichanon et al, 2016) and IH-exposed animals (Yang et al, 2016a,b). Estrogen is a critical contributor to gender effects on OSA-associated cardiovascular consequences (Kapsimalis and Kryger, 2002; Lan et al, 2017), its role in the development of OSA-related hyperreactive airway diseases in females remains unclear
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