Parabiotic model for differentiating local and systemic effects of continuous and intermittent hypoxia

Abstract

Hypoxia can be damaging either because cells are directly sensitive to low oxygen pressure in their local microenvironment and/or because they are exposed to circulating factors systemically secreted in response to hypoxia. The conventional hypoxia model, breathing hypoxic air, does not allow one to distinguish between these local and systemic effects. Here we propose and validate a model for differentially applying local and systemic hypoxic challenges in an animal. We used parabiosis, two mice sharing circulation by surgical union through the skin, and tested the hypothesis that when one of the parabionts breathes room air and the other one is subjected to hypoxic air, both mice share systemic circulation but remain normoxic and hypoxic, respectively. We tested two common hypoxic paradigms in 10 parabiotic pairs: continuous hypoxia (10% O2) mimicking chronic lung diseases, and intermittent hypoxia (40 s, 21% O2; 20 s, 5% O2) simulating sleep apnea. Arterial oxygen saturation and oxygen partial pressure at muscle tissue were measured in both parabionts. Effective cross-circulation was assessed by intraperitoneally injecting a dye in one of the parabionts and measuring blood dye concentration in both animals after 2 h. The results confirmed the hypothesis that tissues of the parabiont under room air were perfused with normally oxygenated blood and, at the same time, were exposed to all of the systemic mediators secreted by the other parabiont actually subjected to hypoxia. In conclusion, combination of parabiosis and hypoxic/normoxic air breathing is a novel approach to investigate the effects of local and systemic hypoxia in respiratory diseases.

Intermittent Hypoxia Severity in Animal Models of Sleep Apnea

“…The major controversial point refers to one of the most commonly employed paradigms of intermittent hypoxia when applied to mice, and resulting in measured SaO 2 swings with nadir values in the range 50–70% (Jun et al, 2010 ; Reinke et al, 2011 ; Torres et al, 2014 , 2015 ; Lim et al, 2015 , 2016 ). Specifically, in a recent review focused on sleep apnea research in animals, it was stated that such intermittent hypoxia profiles may result in significantly more severe hypoxic events than those typically experienced by patients with OSA, in whom SaO 2 nadir ranges of 77–90% are usually documented (Lim et al, 2015 ), and that therefore extrapolation from murine models to human disease should be applied with caution (Chopra et al, 2016 ).…”

Intermittent Hypoxia Mimicking Sleep Apnea Increases Passive Stiffness of Myocardial Extracellular Matrix. A Multiscale Study

“…The current study was carried out using a widely accepted animal model of OSA that realistically mimics the episodic events of hypoxia-reoxygenation that characterize this highly prevalent medical condition. Indeed, the high frequency (60 events/h) and magnitude [arterial oxygen desaturation with nadir values of 60–70% ( Torres et al, 2015 )] of the IH events imposed to the mice, as well as the duration of daily exposures, were sufficient to warrant the designation of severe, but in no way unrealistic since they remarkably overlap and recapitulate the oxygenation patterns seen in patients with severe OSA ( Ruehland et al, 2009 ; Lloberes et al, 2011 ). Such an IH paradigm has been extensively employed to reproduce the different morbid consequences of OSA: cardiovascular ( Ramos et al, 2014 ), neurocognitive ( Gozal et al, 2017 ), metabolic ( Moreno-Indias et al, 2015 ), reproductive ( Torres et al, 2014 ), and malignancies ( Campillo et al, 2017 ).…”

Experimental Models to Study End-Organ Morbidity in Sleep Apnea: Lessons Learned and Future Directions

“…A fourth limitation of the IH model is that it does not allow us to determine whether the IH effects are caused because the cells in a tissue are directly sensitive to the low oxygen pressure in their local hypoxic microenvironment or because they are exposed to the influence of circulating factors systemically secreted in response to hypoxia. Interestingly, a parabiotic model can be useful for distinguishing between the effects of local and systemic hypoxia [78]. According to this setting, one of the parabionts is normally oxygenated while simultaneously exposed to the whole systemic response induced by intermittent hypoxia in his/her parabiont.…”