NADPH Oxidase-Derived ROS Induced by Chronic Intermittent Hypoxia Mediates Hypersensitivity of Lung Vagal C Fibers in Rats

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.

Acute intermittent hypoxia with concurrent hypercapnia evokes P2X and TRPV1 receptor‐dependent sensory long‐term facilitation in naïve carotid bodies

“…Previously, we demonstrated that transient receptor potential vanilloid type 1 (TRPV1) receptors in CB chemosensory afferents are largely responsible for the anandamide and exquisite heat sensitivity of the CB (Roy et al 2012). Because TRPV1 plays an important role in neuronal plasticity in the hippocampus and several sensory systems, and because, in some of these systems, ATP activation of P2X receptor leads to TRPV1 phosphorylation, we hypothesized that TRPV1 receptors contribute to CB sensory LTF (Bhave et al 2003;Marsch et al 2007;Li et al 2008;Hasegawa et al 2009;Shen et al 2012;Lin et al 2013;Saloman et al 2013;Ruan et al 2014;Yang et al 2016).…”

Inflammatory Role of ROS-Sensitive AMP-Activated Protein Kinase in the Hypersensitivity of Lung Vagal C Fibers Induced by Intermittent Hypoxia in Rats

“…Not surprisingly, excess ROS plays an important role in the IH-induced sensitization of LVCFs. Similar contributions are also found in the development of LVCF hypersensitivity induced by acute IH (Shen et al, 2012 ) or 14-day chronic IH (Yang et al, 2016 ), as well as the development of several other cardiorespiratory responses induced by IH (Nisbet et al, 2009 ; Edge et al, 2012 ; Schulz et al, 2014 ). IH produces cyclic periods of hypoxia/re-oxygenation, which seems to promote ROS production in the airways (Prabhakar, 2001 ).…”

“…The method of general preparations has been described in detail previously (Yang et al, 2016 ). Briefly, at termination of 24 h IH exposure, rats were anesthetized.…”

“…The method of western blot analysis has been described in detail previously (Yang et al, 2016 ). Briefly, fresh lung tissues were immediately obtained at 15 min after exposure to RA or IH.…”

Effects of lunar dust simulant on cardiac function and fibrosis in rats

“…In the ROS-based oxygen sensing model, NOX-derived ROS is known to sensitize the lung vagal fibers and is considered to be a major signaling molecule in the chronic hypoxia model. 22 LDS leads to a significant increase in NOX4 levels and redox imbalance. These results indicate that LDS exposure can cause imbalances in the sympathetic and parasympathetic nervous systems.…”