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. 2023 Jul 19;24(1):189.
doi: 10.1186/s12931-023-02493-4.

Chronic intermittent hypoxia increases airway hyperresponsiveness during house dust mites exposures in rats

Mihaela Teodorescu  1   2   3 , Ruolin Song  4 , Jacqueline A Brinkman  4 , Ronald L Sorkness  5
Affiliations

Chronic intermittent hypoxia increases airway hyperresponsiveness during house dust mites exposures in rats

Mihaela Teodorescu et al. Respir Res. .

Abstract

Introduction: Accumulating clinical evidence links Obstructive Sleep Apnea (OSA) with worse outcomes of asthma, but impact on airway function remains sparsely studied. We tested effects of Chronic Intermittent Hypoxia (CIH) - a hallmark of OSA - on airway hyperresponsiveness (AHR), in a rat model of chronic allergen-induced inflammation.

Methods: Brown Norway rats were exposed to six weeks of CIH or normoxia (NORM) concurrent with weekly house dust mites (HDM) or saline (SAL) challenges. At endpoint, we assessed responses to seven Methacholine (Mch) doses (0, 4, 8, 16, 32, 64, 128 mg/mL) on a FlexiVent system (Scireq). Maximal (or plateau) responses (reactivity) for total respiratory system Resistance (Rrs) and Elastance (Ers), Newtonian airway resistance (RN, a measure of central airways function) and tissue damping (G, a measure of distal airways function) were plotted.

Results: HDM/CIH-treated animals demonstrated the highest reactivity to Mch in Rrs and Ers compared to all other groups (HDM/NORM, SAL/CIH and SAL/NORM p < 0.05 for all comparisons, for doses 5-7 for Rrs, and for doses 4-7 for Ers). The enhanced Rrs response was due to an increase in G (doses 4-7, p < 0.05 for comparisons to all other groups), whereas RN was not affected by CIH.

Conclusions: In rats chronically challenged with HDM, concurrent CIH exposure induces AHR primarily in the distal airways, which affects the respiratory system frequency-dependent elastic properties.

Keywords: Airway hyperresponsiveness; Allergic airway inflammation; Asthma; Intermittent hypoxia; Lower airway; Methacholine chloride/pharmacology; Obstructive; Rats; Sleep apnea.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
CIH exposure did not substantially alter baseline pulmonary function. Baseline lung physiology was tested on day 44, two days after last HDM or SAL challenge, using the FlexiVent. (A) total respiratory system resistance (Rrs); (B) total respiratory system elastance (Ers); (C) Newtonian resistance (RN, index of central airways resistance), and; (D) tissue damping (G, index of distal, peripheral airway resistance). N = 10–12 rats/group; Bars: mean ± SEM; Accolades: general or group effect of HDM (2-way ANOVA and Holm-Sidak post-hoc tests for group comparisons)
Fig. 2
Fig. 2
CIH increased Methacholine reactivity expressed primarily in the distal airway. The maximal responses (reactivity) for respiratory system resistance (Rrs) (A) and elastance (Ers) (B), Newtonian resistance (RN) (C) and tissue damping (G) (D) recorded across Methacholine concentrations of 0, 4, 8, 16, 32, 64 and 128 mg/mL. HDM/CIH group significantly different vs.: *SAL/NORM, †SAL/CIH and ‡HDM/NORM (all p < 0.05); HDM/CIH group trends relative to §SAL/CIH and #HDM/NORM (p = 0.056 for each comparison); (2-way [RM] ANOVA and Holm-Sidak post-hoc tests for group comparisons). Data presented as mean ± SEM. N = 10–12 rats/group
Fig. 3
Fig. 3
Serum HDM-specific IgE level was significantly increased in HDM-challenged animals. At the endpoint (day 44), blood was collected and HDM-IgE level assayed in serum by ELISA. An overall effect of HDM was found, of greatest magnitude among CIH-exposed animals. General effects of CIH and HDM p-values shown; Accolades: group effect of CIH p-values shown (2-way ANOVA and Holm-Sidak post-hoc tests for group comparisons). Data presented as mean ± SEM; N = 8–10 rats/ group
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