title: Human intermittent hypoxia-induced respiratory plasticity is not caused by inflammation.
abstract: Ventilatory instability, reflected by enhanced acute hypoxic (AHVR) and hypercapnic (AHCVR) ventilatory responses is a fundamental component of obstructive sleep apnoea (OSA) pathogenesis. Intermittent hypoxia-induced inflammation is postulated to promote AHVR enhancement in OSA, although the role of inflammation in intermittent hypoxia-induced respiratory changes in humans has not been examined. Thus, this study assessed the role of inflammation in intermittent hypoxia-induced respiratory plasticity in healthy humans.In a double-blind, placebo-controlled, randomised crossover study design, 12 males were exposed to 6 h of intermittent hypoxia on three occasions. Prior to intermittent hypoxia exposures, participants ingested (for 4  days) either placebo or the nonsteroidal anti-inflammatory drugs indomethacin (nonselective cyclooxygenase (COX) inhibitor) and celecoxib (selective COX-2 inhibitor). Pre- and post-intermittent hypoxia resting ventilation, AHVR, AHCVR and serum concentration of the pro-inflammatory cytokine tumour necrosis factor (TNF)-α were assessed.Pre-intermittent hypoxia resting ventilation, AHVR, AHCVR and TNF-α concentrations were similar across all three conditions (p≥0.093). Intermittent hypoxia increased resting ventilation and the AHVR similarly across all conditions (p=0.827), while the AHCVR was increased (p=0.003) and TNF-α was decreased (p=0.006) with only selective COX-2 inhibition.These findings indicate that inflammation does not contribute to human intermittent hypoxia-induced respiratory plasticity. Moreover, selective COX-2 inhibition augmented the AHCVR following intermittent hypoxia exposure, suggesting that selective COX-2 inhibition could exacerbate OSA severity by increasing ventilatory instability.
authors.affiliation: Dept of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Beaudin
authors.affiliation: Dept of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
authors.forename: Xavier
authors.initials: X
authors.lastname: Waltz
authors.affiliation: Dept of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
authors.forename: Matiram
authors.initials: M
authors.lastname: Pun
authors.affiliation: Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada Faculty of Veterinary Medicine, University of Calgary, Calgary, AB, Canada.
authors.forename: Katherine E
authors.initials: KE
authors.lastname: Wynne-Edwards
authors.affiliation: Dept of Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada Libin Cardiovascular Institute of Alberta, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
authors.forename: Sofia B
authors.initials: SB
authors.lastname: Ahmed
authors.affiliation: Libin Cardiovascular Institute of Alberta, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada Dept of Cardiac Science, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
authors.forename: Todd J
authors.initials: TJ
authors.lastname: Anderson
authors.affiliation: Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada Dept of Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada Sleep Centre, Foothills Medical Centre, Calgary, AB, Canada.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Hanly
authors.affiliation: Dept of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada Libin Cardiovascular Institute of Alberta, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada Dept of Clinical Neurosciences, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada Faculty of Kinesiology, University of Calgary, Calgary, AB, Canada poulin@ucalgary.ca.
authors.forename: Marc J
authors.initials: MJ
authors.lastname: Poulin
mesh_terms: D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D000068579:Celecoxib / Q000627:therapeutic use; D018592:Cross-Over Studies; D004311:Double-Blind Method; D064368:Healthy Volunteers; D006801:Humans; D006935:Hypercapnia / Q000503:physiopathology*; D000860:Hypoxia / Q000503:physiopathology*; D007213:Indomethacin / Q000627:therapeutic use; D007249:Inflammation / Q000503:physiopathology*; D053583:Interleukin-1beta / Q000378:metabolism; D008297:Male; D020181:Sleep Apnea, Obstructive / Q000503:physiopathology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; C508585:IL1B protein, human; D053583:Interleukin-1beta; C439524:TNF protein, human; D014409:Tumor Necrosis Factor-alpha; D000068579:Celecoxib; D007213:Indomethacin