This study aimed to develop an overlap syndrome rat model with intermittent hypoxia (IH) exposure as seen in obstructive sleep apnea, on a base of preexisting emphysema caused by 16 wk of smoke exposure to determine whether IH and emphysema existing simultaneously play overlapped roles on systematic/endothelial inflammation and endothelial damage.
METHODS:
Sixty male Wistar rats were divided into 4 groups of 15 each, labeled according to exposure conditions as control, IH, emphysema, and overlap groups. In these animals, electroencephalogram monitoring and preliminary experiments to obtain arterial blood gas values were performed. Serum concentrations of tumor necrosis factor (TNF)-α and interleukin (IL)-6, TNF-α and IL-6 concentrations in the culture medium, Ras homology A mRNA expression levels of endothelial cells from right common carotid artery, and ratio of carotid intima-media thickness of whole thickness of vascular wall expressed in percent (C-IMT) (%) values were evaluated. Subsequently, circulating endothelial progenitor cells (EPCs) within rat peripheral blood and bone marrow were measured with flow cytometry.
RESULTS:
The serum and endothelial concentrations of TNF-α and IL-6 and the levels of endothelial Ras homology A mRNA have statistically significant results described as overlap > emphysema > IH > control. The levels of EPCs in rat peripheral blood and bone marrow have statistically significant results described as overlap > IH > emphysema > control. C-IMT (%) values from right common carotid artery are the highest in the overlap group and the lowest in the control group. There is no statistical difference when comparing the IH and the emphysema groups.
CONCLUSIONS:
Regardless of whether IH and emphysema exposure are mechanistically synergistic, this overlap elicits a more severe systematic/endothelial inflammation and endothelial damage; meanwhile, a robust mobilization of EPCs is demonstrated, which is not to mean a robust adherent and repairing capability.
MarinJM, SorianoJB, CarrizoSJ, BoldovaA, CelliBR. Outcomes in patients with chronic obstructive pulmonary disease and obstructive sleep apnea: the overlap syndrome. Am J Respir Crit Care Med, 2010; 182(3):325–331.
2.
Greenberg-DotanS, ReuveniH, TalA, OksenbergA, CohenA, ShayaFT, et al. Increased prevalence of obstructive lung disease in patients with obstructive sleep apnea. Sleep Breath, 2014; 18(1):69–75.
3.
GangaHV, NairSU, PuppalaVK, MillerWL. Risk of new-onset atrial fibrillation in elderly patients with the overlap syndrome: a retrospective cohort study. J Geriatr Cardiol, 2013; 10(2):129–134.
4.
OwensRL, MalhotraA. Sleep-disordered breathing and COPD: the overlap syndrome. Respir Care, 2010; 55(10):1333–1344; discussion 1344-1346.
5.
FengJ, ChenBY, CuiLY. Carotid body-mediated changes of sympathetic nerve and their relationships with hypertension. Chin Med J (Engl), 2008; 121(17):1732–1735.
6.
FengJ, ChenBY, CuiLY, WangBL, LiuCX, ChenPF, et al. Inflammation status of rabbit carotid artery model endothelium during intermittent hypoxia exposure and its relationship with leptin. Sleep Breath, 2009; 13(3):277–283.
7.
FengJ, ChiangAA, WuQ, ChenBY, CuiLY, LiangDC, et al. Sleep-related hypoxemia aggravates systematic inflammation in emphysematous rats. Chin Med J (Engl), 2010; 123(17):2392–2399.
8.
FengJ, WangQS, ChiangA, ChenBY. The effects of sleep hypoxia on coagulant factors and hepatic inflammation in emphysematous rats. PLoS One, 2010; 5(10):e13201. doi: 10.1371/journal.pone.0013201.
9.
YangQ, WangY, FengJ, CaoJ, ChenB. Intermittent hypoxia from obstructive sleep apnea may cause neuronal impairment and dysfunction in central nervous system: the potential roles played by microglia. Neuropsychiatr Dis Treat, 2013; 9:1077–1086.
10.
McNicholasWT. Chronic obstructive pulmonary disease and obstructive sleep apnea: overlaps in pathophysiology, systemic inflammation, and cardiovascular disease. Am J Respir Crit Care Med, 2009; 180(8):692–700.
11.
BishopAL, HallA. Rho GTPases and their effector proteins. Biochem J, 2000; 348Pt 2:241–255.
12.
BergerS, AronsonD, LavieP, LavieL. Endothelial progenitor cells in acute myocardial infarction and sleep-disordered breathing. Am J Respir Crit Care Med, 2013; 187(1):90–98.
13.
FinkelsteinJ, ChaE, ScharfSM. Chronic obstructive pulmonary disease as an independent risk factor for cardiovascular morbidity. Int J Chron Obstruct Pulmon Dis, 2009; 4:337–349.
14.
IoachimescuOC, TeodorescuM. Integrating the overlap of obstructive lung disease and obstructive sleep apnoea: OLDOSA syndrome. Respirology, 2013; 18(3):421–431.
KilkennyC, BrowneW, CuthillIC, EmersonM, AltmanDG, NC3Rs Reporting Guidelines Working Group. Animal research: reporting in vivo experiments: the ARRIVE guidelines. J Gene Med, 2010; 12(7):561–563.
17.
NC3Rs Reporting Guidelines Working Group. Animal research: reporting in vivo experiments: the ARRIVE guidelines. Exp Physiol, 2010; 95(8):842–844.
18.
HornerRL, SanfordLD, AnnisD, PackAI, MorrisonAR. Serotonin at the laterodorsal tegmental nucleus suppresses rapid-eye-movement sleep in freely behaving rats. J Neurosci, 1997; 17(19):7541–7552.
19.
YangN, LiD, JiaoP, ChenB, YaoS, SangH, et al. The characteristics of endothelial progenitor cells derived from mononuclear cells of rat bone marrow in different culture conditions. Cytotechnology, 2011; 63(3):217–226.
20.
ZamarrónC, García PazV, MoreteE, del Campo MatíasF. Association of chronic obstructive pulmonary disease and obstructive sleep apnea consequences. Int J Chron Obstruct Pulmon Dis, 2008; 3(4):671–682.
21.
LiY, SchwabeRF, DeVries-SeimonT, YaoPM, Gerbod-GiannoneMC, TallAR, et al. Free cholesterol-loaded macrophages are an abundant source of tumor necrosis factor-alpha and interleukin-6: model of NF-kappaB- and map kinase-dependent inflammation in advanced atherosclerosis. J Biol Chem, 2005; 280(23):21763–21772.
22.
TamakiS, YamauchiM, FukuokaA, MakinodanK, KoyamaN, TomodaK, et al. Production of inflammatory mediators by monocytes in patients with obstructive sleep apnea syndrome. Intern Med, 2009; 48(15):1255–1262.
23.
RajeshM, MukhopadhyayP, BátkaiS, HaskóG, LiaudetL, HuffmanJW, et al. CB2-receptor stimulation attenuates TNF-alpha-induced human endothelial cell activation, transendothelial migration of monocytes, and monocyte-endothelial adhesion. Am J Physiol Heart Circ Physiol, 2007; 293(4):H2210–H2218.
24.
LacedoniaD, SalernoFG, SabatoR, CarpagnanoGE, AlianiM, PalladinoGP, BarbaroMP. Airway cell patterns in patients suffering from COPD and OSAS (overlap syndrome). Respir Med, 2011; 105(2):303–309.
25.
JoppaP, PetrasovaD, StancakB, TkacovaR. Systemic inflammation in patients with COPD and pulmonary hypertension. Chest, 2006; 130(2):326–333.
26.
YaoL, RomeroMJ, ToqueHA, YangG, CaldwellRB, CaldwellRW. The role of RhoA/Rho kinase pathway in endothelial dysfunction. J Cardiovasc Dis Res, 2010; 1(4):165–170.
27.
BeiY, Duong-QuyS, Hua-HuyT, DaoP, Le-DongNN, Dinh-XuanAT. Activation of RhoA/Rho-kinase pathway accounts for pulmonary endothelial dysfunction in patients with chronic obstructive pulmonary disease. Physiol Rep, 2013; 1(5):e00105. doi: 10.1002/phy2.105.
28.
HyvelinJM, HowellK, NicholA, CostelloCM, PrestonRJ, McLoughlinP. Inhibition of Rho-kinase attenuates hypoxia-induced angiogenesis in the pulmonary circulation. Circ Res, 2005; 97(2):185–191.
29.
CicconeMM, ScicchitanoP, MitacchioneG, ZitoA, GesualdoM, CaputoP, et al. Is there a correlation between OSAS duration/severity and carotid intima-media thickness?. Respir Med, 2012; 106(5):740–746.
30.
MarianiS, FioreD, BarbaroG, BascianiS, SaponaraM, D'ArcangeloE, et al. Association of epicardial fat thickness with the severity of obstructive sleep apnea in obese patients. Int J Cardiol, 2013; 167(5):2244–2249.
BergerS, LavieL. Endothelial progenitor cells in cardiovascular disease and hypoxia–potential implications to obstructive sleep apnea. Transl Res, 2011; 158(1):1–13.
35.
YunCH, JungKH, ChuK, KimSH, JiKH, ParkHK, et al. Increased circulating endothelial microparticles and carotid atherosclerosis in obstructive sleep apnea. J Clin Neurol, 2010; 6(2):89–98.
36.
KizawaT, NakamuraY, TakahashiS, SakuraiS, YamauchiK, InoueH. Pathogenic role of angiotensin II and oxidised LDL in obstructive sleep apnoea. Eur Respir J, 2009; 34(6):1390–1398.
37.
AlpsoyS, AkyuzA, MutluLC, OranM, AkkoyunDC, TopcuB, et al. Serum fetuin-A levels are associated with carotid intima media thickness in patients with normotensive chronic obstructive pulmonary disease. Cardiol J, 2014; 21(2):191–197.
38.
MatsuokaS, YamashiroT, DiazA, EstéparRS, RossJC, SilvermanEK, et al. The relationship between small pulmonary vascular alteration and aortic atherosclerosis in chronic obstructive pulmonary disease: quantitative CT analysis. Acad Radiol, 2011; 18(1):40–46.
39.
JonesCP, RankinSM. Bone marrow-derived stem cells and respiratory disease. Chest, 2011; 140(1):205–211.
40.
MurriM, García-DelgadoR, Alcázar-RamírezJ, Fernández-RamosA, AlcaideJ, CardonaF, TinahonesFJ. Effect of CPAP on oxidative stress and circulating progenitor cell levels in sleep patients with apnea-hypopnea syndrome. Respir Care, 2011; 56(11):1830–1836.
