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Correspondence |

Normoxic Recovery Reverses Intermittent Hypoxia-Induced Systemic and Vascular Inflammation FREE TO VIEW

Claire Arnaud, PharmD, PhD; Pauline Béguin, PhD; Patrick Lévy, MD, PhD; Jean-Louis Pépin, MD, PhD
Author and Funding Information

FINANCIAL/NONFINANCIAL DISCLOSURES: None declared.

aUniversité Grenoble Alpes, Grenoble, France

bINSERM U1042, Grenoble, France

cCHU de Grenoble, Grenoble, France

CORRESPONDENCE TO: Claire Arnaud, PharmD, PhD, BP170, Grenoble 38042, France


Copyright 2016, American College of Chest Physicians. All Rights Reserved.


Chest. 2016;150(2):471-473. doi:10.1016/j.chest.2016.05.031
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Published online

Castro-Grattoni et al should be congratulated for their article published in CHEST (June 2016) demonstrating in a mouse model of sleep apnea (OSA) that intermittent hypoxia (IH)-induced cardiovascular remodeling is reversed after removal of IH exposure (mimicking OSA treatment by CPAP). We would like to contribute to this important topic by providing additional data and comments.

First, in the study by Castro-Grattoni et al, animals were exposed to a 6-week IH exposure, followed by 6 weeks of normoxia. We previously demonstrated that only 14 days of IH are enough to induce the same vascular remodeling, with increased intima-media thickness, elastin fiber network disorganization, and mucoid deposition. Therefore, more than the duration of IH exposure, we believe that the kinetics of hypoxia/reoxygenation cycles, as well as the severity of hypoxia, represents the main triggers explaining IH-induced deleterious effects.

Second, the authors mentioned that aortic wall remodeling is “the result of multiple interactions between intermediary mechanisms, including oxidative stress, systemic and tissue inflammation,” but they do not investigate the impact of IH removal on these parameters. In previous studies, we indeed demonstrated that inflammation plays a major role in IH-induced vascular remodeling and atherosclerosis.,,,,, IH-induced inflammation has been evidenced by increased splenocyte migration capacities, expression of chemokines, and increased leukocyte rolling at the systemic level and by an elevated expression of the proinflammatory transcription factor nuclear factor κB (NF-kB), chemokine expression, and increased infiltration of lymphocytes in the arterial wall (ie, aorta) (Fig 1). In accordance with the study of Castro-Grattoni et al, we have also observed a beneficial effect of IH exposure cessation on these inflammatory markers. After only a few days of return to a normoxic situation, proliferative capacities of splenocytes, splenic chemokine expression, and aortic expression of NF-κB were indeed normalized (Fig 1).

Figure Jump LinkFigure 1 A-C, Splenic chemokine mRNA expressions (A), splenocyte proliferative capacities in response to increasing doses of concanavalin A (Con-A) (B), and aortic NF-κB protein expression (C). All these experiments were realized on tissues from mice exposed to either 14 days of intermittent hypoxia (IH) or normoxia (N) and 14 days of IH or N, followed by 7 days of normoxic recovery (n = 5-10 per group; *P < .05 vs N). GADPH = glyceraldehyde 3-phosphate dehydrogenase; MCP-1 = monocyte chemotactic protein-1; MIP-1 = macrophage inflammatory protein-1; p50NFκB = p50 subunit of nuclear factor kappa B; RANTES = regulated on activation, normal T cell expressed and secreted.Grahic Jump Location

These experiments in rodents are reflecting the effects of relatively short exposure to IH before irreversible lesions of the vasculature. Taken together, the study of Castro-Grattoni et al and our additional results strongly support the high interest in early diagnosis and alleviation of IH in patients with OSA to limit cardiovascular complications.

References

Castro-Grattoni A.L. .Alvarez R. .Torres M. .et al Intermittent hypoxia-induced cardiovascular remodeling is reversed by normoxia in a mouse model of sleep apnea. Chest. 2016;149:1400-1408 [PubMed]journal. [CrossRef] [PubMed]
 
Arnaud C. .Beguin P.C. .Lantuejoul S. .et al The inflammatory preatherosclerotic remodeling induced by intermittent hypoxia is attenuated by RANTES/CCL5 inhibition. Am J Respir Crit Care Med. 2011;184:724-731 [PubMed]journal. [CrossRef] [PubMed]
 
Gras E. .Belaidi E. .Briancon-Marjollet A. .et al Endothelin-1 mediates intermittent hypoxia-induced inflammatory vascular remodeling through HIF-1 activation. J Appl Physiol (1985). 2016;120:437-443 [PubMed]journal. [CrossRef] [PubMed]
 
Poulain L. .Richard V. .Levy P. .et al Toll-like receptor-4 mediated inflammation is involved in the cardiometabolic alterations induced by intermittent hypoxia. Mediators Inflamm. 2015;2015:620258- [PubMed]journal. [PubMed]
 
Arnaud C. .Poulain L. .Levy P. .et al Inflammation contributes to the atherogenic role of intermittent hypoxia in apolipoprotein-E knock out mice. Atherosclerosis. 2011;219:425-431 [PubMed]journal. [CrossRef] [PubMed]
 
Gautier-Veyret E. .Arnaud C. .Back M. .et al Intermittent hypoxia-activated cyclooxygenase pathway: role in atherosclerosis. Eur Respir J. 2013;42:404-413 [PubMed]journal. [CrossRef] [PubMed]
 
Poulain L. .Thomas A. .Rieusset J. .et al Visceral white fat remodelling contributes to intermittent hypoxia-induced atherogenesis. Eur Respir J. 2014;43:513-522 [PubMed]journal. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1 A-C, Splenic chemokine mRNA expressions (A), splenocyte proliferative capacities in response to increasing doses of concanavalin A (Con-A) (B), and aortic NF-κB protein expression (C). All these experiments were realized on tissues from mice exposed to either 14 days of intermittent hypoxia (IH) or normoxia (N) and 14 days of IH or N, followed by 7 days of normoxic recovery (n = 5-10 per group; *P < .05 vs N). GADPH = glyceraldehyde 3-phosphate dehydrogenase; MCP-1 = monocyte chemotactic protein-1; MIP-1 = macrophage inflammatory protein-1; p50NFκB = p50 subunit of nuclear factor kappa B; RANTES = regulated on activation, normal T cell expressed and secreted.Grahic Jump Location

Tables

References

Castro-Grattoni A.L. .Alvarez R. .Torres M. .et al Intermittent hypoxia-induced cardiovascular remodeling is reversed by normoxia in a mouse model of sleep apnea. Chest. 2016;149:1400-1408 [PubMed]journal. [CrossRef] [PubMed]
 
Arnaud C. .Beguin P.C. .Lantuejoul S. .et al The inflammatory preatherosclerotic remodeling induced by intermittent hypoxia is attenuated by RANTES/CCL5 inhibition. Am J Respir Crit Care Med. 2011;184:724-731 [PubMed]journal. [CrossRef] [PubMed]
 
Gras E. .Belaidi E. .Briancon-Marjollet A. .et al Endothelin-1 mediates intermittent hypoxia-induced inflammatory vascular remodeling through HIF-1 activation. J Appl Physiol (1985). 2016;120:437-443 [PubMed]journal. [CrossRef] [PubMed]
 
Poulain L. .Richard V. .Levy P. .et al Toll-like receptor-4 mediated inflammation is involved in the cardiometabolic alterations induced by intermittent hypoxia. Mediators Inflamm. 2015;2015:620258- [PubMed]journal. [PubMed]
 
Arnaud C. .Poulain L. .Levy P. .et al Inflammation contributes to the atherogenic role of intermittent hypoxia in apolipoprotein-E knock out mice. Atherosclerosis. 2011;219:425-431 [PubMed]journal. [CrossRef] [PubMed]
 
Gautier-Veyret E. .Arnaud C. .Back M. .et al Intermittent hypoxia-activated cyclooxygenase pathway: role in atherosclerosis. Eur Respir J. 2013;42:404-413 [PubMed]journal. [CrossRef] [PubMed]
 
Poulain L. .Thomas A. .Rieusset J. .et al Visceral white fat remodelling contributes to intermittent hypoxia-induced atherogenesis. Eur Respir J. 2014;43:513-522 [PubMed]journal. [CrossRef] [PubMed]
 
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