Sleep-related hypoxemia aggravates systematic inflammation in emphysematous rats

Sleep disturbance is common in patients with emphysema. This study aimed to develop a novel model of sleep-related hypoxemia (SRH) in emphysema (SRHIE) with rats, and to explore the inflammatory status of SRHIE in lung, liver, pancreas, carotid artery and whole blood.

Seventy-five male Wistar rats were assigned to 5 groups with 15 per group according to the exposure conditions. The protocols varied with the degree of hypoxia exposure and severity of pre-existing emphysema caused by cigarette smoke exposure: (1) SRH control (SRHCtrl) group, sham smoke exposure (smoke exposure, exposed to smoke of 15 cigarettes twice everyday, 16 weeks) and SRH exposure (12.5% O2, 3 hours, SRH exposure, divide total hypoxia time (1.5 hours or 3 hours) into 4 periods evenly (22.5 minutes or 45 minutes) and distribute these hypoxia periods evenly into physiological sleep time of rats identified by electroencephalogram, week 9 to week 16); (2) Emphysema control (ECtrl) group, smoke exposure and sham SRH exposure (21% O2, 3 hours); (3) Short SRH in emphysema (SRHShort) group, smoke exposure and short SRH exposure (12.5% O2, 1.5 hours); (4) Mild SRH in emphysema (SRHMild) group, smoke exposure and mild SRH exposure (15% O2, 3 hours); (5) Standard SRH in emphysema (SRHStand) group, smoke exposure and SRH exposure (12.5% O2, 3 hours). ECtrl, SRHShort, SRHMild and SRHStand groups were groups with emphysematous rats. Two days before the end of exposure, 5 rats in each group were randomly selected for arterial blood gas analysis. In the rest 10 rats in each group, we obtained blood samples and bronchoalveolar lavage fluid (BALF) for routine tests. We also obtained tissue blocks of lung, liver, pancreas, and right carotid artery for pathologic scoring and measurements of liver oxidative stress (measuring hepatic oxidative stress enzymes, superoxide dismutase (SOD) activity, catalase (CAT) activity and malondialdehyde (MDA) concentration).

Emphysematous groups had higher mean linear intercept (MLI) and mean alveolar number (MAN) values than SRHCtrl group. MLI values in SRHStand group were the highest (all P < 0.05). O2Sat in SRHStand rats when SRH exposure was (83.45 ± 1.76)%. Histological scores of lung, liver, pancreas and right carotid artery were higher in emphysematous groups than SRHCtrl group, and SRHStand group were the highest (all P < 0.05) (SOD and CAT values were lower and MDA values were higher in groups with emphysema than without and in SRHStand group than in ECtrl group (all P < 0.05)). MDA values were the highest in SRHStand group (all P < 0.05). Total cellular score in BALF and White blood cell (WBC) in whole blood were the highest in SRHStand group (all P < 0.05). Lymphocyte ratios were the highest in SRHStand group both in BALF and blood (all P < 0.05). Red blood cell (RBC) and hemoglobin in emphysematous groups were higher than that in SRHCtrl group, and SRHStand group were higher than ECtrl group (all P < 0.05).

With a proper novo model of SRHIE with Wistar rats, we have demonstrated SRH may aggravate the degree of emphysematous changes, polycythemia, oxidative stress and systematic inflammation. SRH and emphysema may have a synergistic action in causing systematic damages, and lymphocyte may be playing a central role in this process. Longer duration and more severe extent of SRHIE exposure also seem to result in more serious systematic damages. The mechanisms of all these concerned processes remain to be studied.