The level of lipopolysaccharide-binding protein is elevated in adult patients with obstructive sleep apnea

The level of lipopolysaccharide-binding protein is elevated in adult patients with obstructive... Background: lipopolysaccharide-binding protein (LBP) has been to be a surrogate marker of inflammation in OSA. This study aimed to test the hypothesis that the concentration of LBP is elevated in adult patients with obstructive sleep apnea (OSA). Methods: A total of 90 patients were enrolled into the study, 50 subjects were divided into OSA groups and 40 in healthy control according to PSG examination. Subsequently, patients with apnea-hypopnea index (AHI) ≧ 5, were divided into different subgroups according to blood pressure, gender, body mass index (BMI) and AHI. Venous blood samples were collected for detection after polysomnography. The serum levels of LBP and proinflammatory cytokines (interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α) were tested by ELISA. Results: The present study demonstrated that the serum levels of both LBP and proinflammatory cytokines were elevated in OSA patients. A stratified analysis conducted to analyze differences among subgroups indicated that OSA patients with a higher AHI or BMI had an increased level of LBP and proinflammatory cytokines (all p < 0.05). Furthermore, a significant correlations were observed between LBP and inflammation and AHI. Multivariate regression analysis also demonstrated that AHI, LSaO2 and BMI had impact on the concentration of LBP. Conclusion: The research showed that the serum level of LBP and proinflammatory cytokines were elevated in adult patients with OSA, and an association with severity of disease and BMI were established. Furthermore, sleep apnea and BMI had effect on the concentration of LBP. Keywords: Obstructive sleep apnea, Lipopolysaccharide-binding protein, Inflammation, Serum Background derangements is through the systemic inflammatory cas- Obstructive sleep apnea (OSA) is described as repeated cade [2–4]. In the past several years, it has become appar- collapse of the upper airways during sleep, leading to ent that the increasing level of inflammation are strongly repeated cycle of hypoxemia-reoxygenation and sleep associated with OSA [5]. A meta-analysis including 1985 disruption. Risk factors for OSA, including obesity and OSA patients and conducted by Xie et al. indicated that aging, are on the rise in the public; therefore, the preva- proinflammatory factors, such as interleukin (IL)-6, IL-8, lence of OSA is increasing worldwide, and is estimated and tumor necrosis factor (TNF)-α, are increased in pa- to affect up to 17% of middle-aged men and 9% of tients with OSA, which is partially reversed after continu- middle-aged women [1]. ous positive airway pressure intervention [6]. However, The putative mechanism by which OSA has been linked the potential molecular mechanisms how to initiate the to numerous pathologic conditions including stroke, inflammation are not fully understood in OSA patients. cardiovascular disease, hypertension, and metabolic Lipopolysaccharide-binding protein (LBP) is an acute-phase reactant predominantly derived from the liver, adipose and intestinal epithelial cells. LBP binds * Correspondence: zjyyhqd@163.com lipopolysaccharide (LPS) through recognition of lipid A Yinfeng Kong and Zhijun Li contributed equally to this work. and initiates its response by forming a complex with Department of Respiratory Medicine in Zhejiang Hospital, 12 Lingyin Road, Xihu District, Hangzhou 310013, Zhejiang Province, China © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Kong et al. BMC Pulmonary Medicine (2018) 18:90 Page 2 of 8 myeloid differentiation factor 2 leading to activation of All subjects provided their informed written consent. both MyD88-dependent and non-MyD88-dependent The study was conducted according to the World Med- downstream signaling pathways causing subsequent ical Association Declaration of Helsinki in 1975, as re- inflammatory responses, such as the release of various vised in 1983, and was approved by the Ethic Committee biomediators including IL-6, TNF-α, and IL-1β [7]. of Zhejiang Hospital. Therefore, LBP usually as a biomarker of system inflam- mation, intestinal barrier and microbe translocation in Polysomnography deferent study [8–11]. All participants received overnight polysomnography Metabolic endotoxemia has been shown to be the (PSG) according to standardized criteria [15]. The primary contributor to the pathogenesis of chronic results of PSG were reviewed by two sleep specialists low-grade inflammation, characterized by increased (Juan Liu & Liang Gu). Apnea was defined as continu- plasma LBP levels, which are believed to originate from ous cessation of airflow for > 10 s. Hypopnea was changes in gut microbiota and increasing of intestinal defined as a ≥ 30% reduction in airflow for > 10 s with permeability [10]. Altered gut microbiota composition oxygen desaturation of ≥4%. Apnea-hypopnea index are key factors affecting gut barrier integrity. The gut (AHI) was calculated as the sum of apneas and hypop- microbiota, which serves as reservoir for bacterial LPS, neas per hour during overnight. A respiratory event was could be altered by OSA and subsequently trigger scored as an obstructive apnea or hypopnea if chest and inflammation. At present, several studies reported that abdominal respiratory movement was identified and the chronic intermittent hypoxia of OSA has a signifi- oronasal airflow ceased, or there is an associated thora- cant impact on the overall microbial community coabdominal paradox that occurs during the hypopnea structure of mice, indicating that the homeostatic rela- with snoring. Microarousal index (MAI) was defined tionships between host and gut microbiota could be according to the American Academy of Sleep Medicine compromised in OSA patients [12, 13]. Moreno-Indias Scoring Manual [16]. The oxygen desaturation index et al. study indicated that fecal microbiota composition (ODI) was defined as ≥4% oxygen desaturation per hour and diversity were altered as a result of intermittent during sleep. Patients with OSA were divided into the hypoxia realistically mimicking OSA [12]. Therefore, it is mild group (AHI: 5–15 events/h), moderate group (AHI: rational to deduce that the concentration of LBP is 15–30 events/h), and severe group (AHI > 30 events/h) elevated in OSA patients. At present, one study from [17]. Subjects with sleepy and snore who accepted PSG Kheirandish-Gozal et al. reported that children with examination, with an AHI < 5 events/h were included in OSA exhibited increased LBP levels [14]. However, only the study as healthy controls. The exclusion criteria of children were recruited into the Kheirandish-Gozal et al. subjects were as follows: (1) chronic hypoxia caused by research. There is indeed a paucity of published litera- asthma, chronic obstructive pulmonary disease, intersti- ture on the association between LBP levels and adult tial lung disease and other respiratory disorders. (2) Par- patients with OSA. ticipants with a history of drug or alcohol abuse, or Based on previous studies, we conducted the study to taking drugs to regulate intestinal flora. (3) cardiovascu- test the hypothesis that the serum level of LBP is elevated lar, endocrine, and other disorders that could lead to in adult patients with OSA, and the correlations with pro- hypoxemia. (4) Diseases which may lead to the release of inflammatory factors and AHI were also evaluated. proinflammatory factors, such as connective tissue disease, cancer, and inflammatory bowel disease. (5) Methods required gastrointestinal surgical procedures or had re- Study population ceived antibiotic therapy in the preceding 8 weeks were A total of 50 patients with OSA (mild [n = 10], moderate also excluded. [n = 15], and severe OSA [n = 25]) and 40 healthy controls were consecutively recruited in the study. The Blood collection and analysis patients were examined at sleep laboratory of the re- Peripheral blood, drawn from each subject on the morn- spiratory department of Zhejiang Hospital from January ing after PSG, was centrifuged at 3000 rpm for 15 min, 2016 to June 2016. Body weight and height were mea- and serum was stored at − 70 °C for analysis. Concentra- sured, and body mass index (BMI) was calculated as tions of serum LBP, IL-1β, IL-6, TNF-ɑ were measured weight (kg)/height (m), and overweight was defined as using commercially available ELISA kits (R&D Sys- BMI ≥ 25 kg/m . Blood pressure was recorded using a tems, Minneapolis, MN, USA) in duplicate according mercury sphygmomanometer, and elevated blood pres- to the manufacturer’s instruction. An automatic sure was defined as systolic blood pressure (SBP) ≧ 140 biochemical analyzer (UniCel DxC 800 Synchron, mmHg and/or diastolic blood pressure (DBP) ≧ 90 Beckman Coulter, Inc., Brea, CA, USA) was used to mmHg or taking antihypertensive drug. test the serum level of lipids. Kong et al. BMC Pulmonary Medicine (2018) 18:90 Page 3 of 8 Statistical analysis Table 1 Clinical characteristics of the OSA and control group Continuous variables are expressed as the mean ± stand- Variables Patients Controls p value ard deviation. Comparisons were performed using t test Gender 0.317 or χ tests depending on data differences among groups. Male 34 31 Spearman’s correlation analysis were conducted to Female 16 9 examine potential associations between LBP and proin- Age (years) 54.34 ± 14.38 50.42 ± 8.35 0.112 flammatory factors. A multivariate regression analysis BMI(kg/m ) 26.86 ± 3.12 22.26 ± 3.54 0.000 was also performed to evaluate the role of confounding factors on LBP. Statistical significance was determined Normal weight 11(22.00%) 27(67.50%) by a level of 0.05 on two-sided tests. All statistical ana- Overweight 39(78.00%) 13(32.50%) lysis was performed using the SPSS Statistics 19.0.0 SBP(mmHg) 133.60 ± 16.37 120.19 ± 17.11 0.000 (IBM Corporation, Somers, NY, USA). DBP(mmHg) 81.16 ± 14.45 74.05 ± 10.72 0.005 Respiratory events Results Obstructive 241.76 ± 106.12 17.49 ± 7.18 < 0.001 General clinical characteristics of the study participants The basic clinical characteristics of the subjects are Central 1.32 ± 0.59 0.94 ± 0.37 0.551 detailed in Table 1. The mean age of patients with OSA AHI 37.34 ± 19.02 3.31 ± 1.09 < 0.001 was 54.34 ± 14.38 years, compared with 50.42 ± 8.35 LSaO2 75.29 ± 11.83 95.95 ± 4.65 < 0.001 years in the control group. There are significant differ- mSaO2 93.01 ± 4.18 96.35 ± 3.87 < 0.001 ences were observed between cases and controls group ODI 41.83 ± 25.9 3.56 ± 1.12 < 0.001 in terms of BMI, blood pressure (SBP and DBP), the MAI 22.61 ± 15.12 4.27 ± 2.16 < 0.001 serum concentration of triglyceride (TG), and PSG parameters (all p < 0.05). NREM1(%) 23.21 ± 12.79 15.9 ± 13.04 0.031 NREM21(%) 52.73 ± 12.31 48.1 ± 16.21 0.335 The comparison of LBP and proinflammatory factors NREM31(%) 14.51 ± 9.95 20.23 ± 8.72 0.045 between patients and controls REM(%) 10.23 ± 5.31 16.74 ± 7.36 0.012 There were significant differences in the serum level of TG 2.96 ± 2.53 1.71 ± 1.07 0.004 LBP (36.05 ± 7.35 vs 32.11 ± 5.94, p = 0.01) and inflamma- TC 4.98 ± 1.10 4.71 ± 0.91 0.189 tory factors (IL-1β, 27.15 ± 5.91 vs 21.17 ± 1.70, p =0.000; IL-6, 61.59 ± 9.76 vs 54.46 ± 9.43, p =0.005; TNF-ɑ HDL 1.04 ± 0.23 1.23 ± 0.26 0.000 327.34 ± 46.81 vs 307.95 ± 27.15, p = 0.020) between cases LDL 2.98 ± 1.10 3.02 ± 0.89 0.847 and control group. LBP 36.05 ± 7.35 32.11 ± 5.94 0.010 To further analyze differences among subgroups, a IL-1β 27.15 ± 5.91 21.17 ± 1.70 0.000 stratified analysis was performed according to blood IL-6 61.59 ± 9.76 54.46 ± 9.43 0.001 pressure, gender, BMI and severity of disease (AHI). The TNF-ɑ 327.34 ± 46.81 307.95 ± 27.15 0.027 results demonstrated that a significant differences were AHI Apnea-hypopnea index, BMI Body mass index, SBP Systolic blood pressure, found between normal weight and overweight patients DBP Diastolic blood pressure, LSaO2 Lowest saturation oxygen, mSaO2 Mean with OSA, which suggested that OSA patients with a saturation oxygen, ODI Oxygen desaturation index, MAI Microarousal index, TG higher BMI had a higher serum level of LBP and proin- triglyceride, TC Total cholesterol, LDL Low-density lipoprotein, HDL High-density lipoprotein flammatory factors (all p < 0.05). However, no differ- ences were identified in other subgroups based on blood pressure and gender (p > 0.05) (Table 2). Alterna- (r = 0.490, p = 0.001), and AHI (r = 0.371, p = 0.001). In tively, a marked differences were determined in the addition, a multivariate regression analysis were per- mild vs moderate, mild vs severe, moderate vs severe formed to determine the role of possible confounding groups (all p < 0.05), except for IL-1β in the mild vs factor to the concentration of LBP. The result of analysis moderate group (t = − 1.837, p = 0.091) (Table 3). showed that AHI, LSaO2 and BMI had a significant impact on the LBP (all p < 0.05), which suggested that The correlations between LBP and proinflammatory sleep apnea and obesity have effect on the levels of factors and severity of disease serum LBP. However, other variables were not identified Based on aforementioned findings, The correlations be- (p > 0.05) (Table 4). tween LBP and proinflammatory cytokines and severity of diseases were also evaluated. As evident in Fig. 1, sig- Discussion nificant correlations were found between LBP and IL-1β This is the first study to investigate OSA has an impact (r = 0.464, p = 0.003), IL-6 (r = 0.586, p = 0.000), TNF-ɑ on the concentration of LBP in adults. The results Kong et al. BMC Pulmonary Medicine (2018) 18:90 Page 4 of 8 Table 2 Comparison of various index in OSA subgroups according to blood pressure, gender and BMI Variables HBP vs Normal BP p value Male vs Female p value Normal weight vs Overweight p value HBP(21) Normal BP(29) Male(34) Female(16) Normal weight(14) Overweight(36) Age(years) 49.76 ± 13.28 56.46 ± 14.55 0.083 55.76 ± 12.76 52.13 ± 9.41 0.912 58.36 ± 18.68 52.78 ± 12.29 0.315 BMI(kg/m ) 28.30 ± 3.32 25.09 ± 2.83 0.022 27.28 ± 2.79 25.44 ± 3.12 0.531 24.42 ± 1.17 27.56 ± 2.60 0.017 SBP(mmHg)150.06 ± 7.61 123.61 ± 11.33 0.000 135.12 ± 15.61 131.50 ± 17.14 0.362 126.15 ± 14.31 136.63 ± 16.38 0.051 DBP(mmHg) 92.71 ± 13.12 74.14 ± 10.15 0.000 83.08 ± 14.23 78.42 ± 9.12 0.112 75.85 ± 11.83 83.31 ± 15.02 0.117 AHI 34.43 ± 17.72 40.19 ± 20.51 0.322 40.35 ± 16.63 29.61 ± 23.02 0.073 33.87 ± 16.52 38.69 ± 19.96 0.426 LSaO2(%) 77.17 ± 10.71 71.83 ± 13.75 0.160 72.87 ± 12.24 75.85 ± 7.77 0.132 75.83 ± 11.09 75.12 ± 12.22 0.859 mSaO2(%) 92.96 ± 5.37 93.67 ± 2.30 0.684 92.73 ± 4.78 94.11 ± 1.54 0.315 93.74 ± 2.67 92.89 ± 4.59 0.546 ODI 36.58 ± 23.77 48.89 ± 27.72 0.126 47.75 ± 24.49 25.91 ± 23.50 0.008 36.71 ± 22.46 43.54 ± 27.03 0.435 MAI 20.13 ± 13.27 26.33 ± 17.25 0.180 24.49 ± 16.22 17.44 ± 10.45 0.170 20.25 ± 13.07 23.56 ± 15.97 0.512 LBP 36.25 ± 8.71 35.72 ± 4.52 0.805 35.78 ± 7.73 37.14 ± 5.93 0.645 26.75 ± 3.50 37.38 ± 6.79 0.002 IL-1β 26.89 ± 6.27 27.58 ± 5.44 0.728 27.81 ± 5.93 24.52 ± 5.36 0.161 20.90 ± 2.03 28.04 ± 5.75 0.010 IL-6 61.69 ± 10.62 61.46 ± 8.47 0.944 61.52 ± 10.22 61.90 ± 8.24 0.924 46.41 ± 5.50 63.78 ± 8.18 0.000 TNF-α 325.11 ± 49.82 331.06 ± 42.73 0.703 329.95 ± 49.06 316.88 ± 37.36 0.487 252.99 ± 18.74 337.96 ± 39.29 0.000 AHI Apnea-hypopnea index, BMI Body mass index, SBP Systolic blood pressure, DBP Diastolic blood pressure, LSaO Lowest saturation oxygen, mSaO Mean saturation oxygen, ODI Oxygen desaturation index, MAI 2 2 Microarousal index Kong et al. BMC Pulmonary Medicine (2018) 18:90 Page 5 of 8 Table 3 Comparison of various index in subgroups according to severity of disease Variables OSA Mild vs Moderate Mild vs Severe Moderate vs Severe Mild(10) Moderate(15) Severe(25) t p value t p value t p value Age(years) 59.60 ± 15.13 56.73 ± 15.93 52.27 ± 13.54 0.352 0.729 1.104 0.277 −0.983 0.331 BMI(kg/m ) 27.04 ± 2.58 26.81 ± 3.80 27.28 ± 3.16 0.120 0.906 −0.164 0.871 0.436 0.665 SBP(mmHg) 140.40 ± 13.05 130.31 ± 16.79 133.93 ± 16.82 1.204 0.246 0.812 0.423 0.638 0.528 DBP(mmHg) 85.20 ± 9.61 79.85 ± 15.63 81.04 ± 14.63 0.686 0.502 0.597 0.555 0.236 0.815 AHI 10.14 ± 2.95 22.88 ± 3.93 49.11 ± 14.96 −6.066 0.000 −12.848 0.000 −8.999 0.000 LSaO2 87.20 ± 1.30 79.53 ± 9.13 70.90 ± 12.00 3.159 0.006 6.958 0.000 2.429 0.020 mSaO2 94.80 ± 1.48 93.88 ± 2.27 92.38 ± 5.10 0.840 0.412 1.040 0.307 1.077 0.288 ODI 11.94 ± 5.37 26.41 ± 18.78 55.44 ± 22.17 −1.672 0.112 −9.008 0.000 −4.305 0.000 MAI 14.56 ± 2.87 16.45 ± 8.12 27.06 ± 17.40 −0.501 0.623 −3.484 0.002 −2.627 0.012 LBP 25.81 ± 7.16 33.55 ± 3.50 38.29 ± 7.40 −2.743 0.018 − 2.771 0.010 − 2.642 0.012 IL-1β 20.10 ± 1.47 24.35 ± 3.83 29.15 ± 5.91 −1.837 0.091 −2.604 0.015 −2.475 0.018 IL-6 46.20 ± 6.09 58.34 ± 7.09 64.76 ± 9.05 −2.686 0.020 −3.434 0.002 − 2090 0.044 TNF-α 274.64 ± 4.91 308.75 ± 42.48 341.28 ± 44.80 −2.601 0.025 −2.534 0.017 −2.048 0.048 AHI Apnea-hypopnea index, BMI Body mass index, SBP Systolic blood pressure, DBP Diastolic blood pressure, LSaO Lowest saturation oxygen, mSaO Mean 2 2 saturation oxygen, ODI Oxygen desaturation index, MAI Microarousal index demonstrated that the serum level of LBP and inflamma- Significant correlations were also determined between tion were higher in OSA patients, compared with LBP and AHI and proinflammatory factors, which was is healthy subjects, and subgroups analysis indicated that in line with the previous study. Another study of OSA patients with a higher BMI and AHI had a higher Moreno-Indias et al. demonstrated that the LPS concen- serum level of LBP and proinflammatory factors. Add- tration was elevated at the end of intermittent hypoxia itionally, the correlational analysis showed that serum in mouse model, and a significant association was found LBP levels were positively correlated with inflammation between gut bacterial dysbiosis and the increases in and AHI. A multivariate regression analysis indicated plasma LPS levels [20]. In a recent study conducted by that sleep apnea and BMI had a significant impact on Table 4 The effect of confounding factor on concentation of the concentration of LBP. LBP in OSA patients To the best of our knowledge, OSA has an impact on Variables β 95% CI p value the intestinal barrier function and gut microflora. A study conducted by Moreno-Indias et al. suggested that AHI 14.430 (5.152, 29.078) 0.026 composition and diversity of intestinal microflora are ODI −0.139 (−0.397, 0.119) 0.276 altered caused by intermittent hypoxia [12]. The trans- MAI 0.074 (−0.135, 0.282) 0.472 location or change of commensal microbiota across the LSaO2 10.125 (3.917, 25.071) 0.035 intestinal barrier can result in a persistent state of low mSaO2 −0.256 (− 0.929, 0.416) 0.438 grade immune activation or inflammation. LBP is Age 0.115 (−0.150, 0.379) 0.379 located upstream of IL-1β, IL-6, and TNF-α expression, and initiates the recognition of bacterial LPS exposure BMI 8.245 (1.154, 18.386) 0.041 and amplifies the host immune response which, if con- SBP −0.214 (− 0.470, 0.042) 0.097 tinued long-term, results in adverse sequelae to the host. DBP 0.345 (−0.008, 0.698) 0.055 Therefore, LBP has been suggested to serve as a surro- TG 1.378 (−0.964, 3.719) 0.236 gate marker of chronic inflammatory status in several TC −5.532 (−12.988, 1.924) 0.138 disorders, such as obesity, diabetes, hypertension and HDL −4.509 (−20.564, 11.546) 0.567 other chronic inflammation diseases [18, 19]. Kim et al. study indicated that LBP levels were positively associated LDL 5.397 (−2.166, 12.960) 0.153 with BMI, SDP, total cholesterol, low density IL-1β 0.373 (−0.730, 1.476) 0.492 lipoprotein-cholesterol, fasting glucose and insulin, and IL-6 −0.079 (−0.363, 0.204) 0.569 insulin resistance [18]. TNF-α −0.006 (−0.076, 0.064) 0.859 The present study showed that the levels of LBP and AHI Apnea-hypopnea index, BMI Body mass index, SBP Systolic blood pressure, inflammation are increased in adult OSA patients and DBP Diastolic blood pressure, LSaO Lowest saturation oxygen, mSaO Mean 2 2 are positively associated with the severity of disease. saturation oxygen, ODI Oxygen desaturation index, MAI Microarousal index Kong et al. BMC Pulmonary Medicine (2018) 18:90 Page 6 of 8 Fig. 1 The scotterplots of the correlation of LBP vs IL-1β, IL-6, TNF-α and AHI Kheirandish-Gozal et al. [14], they assessed the LBP demonstrated that the concentration of LBP and level of plasma levels of 219 child patients with OSA, and found inflammation had only a positive association with BMI that systemic low-level endotoxemia and elevation of in OSA patients, and no relation with hypertension. As LBP was established in children with OSA, associated we known, obesity is one of the strongest risk factors for with measures of OSA severity. However, only chil- OSA, which imposes mechanical loads on the upper air- dren with OSA were included to analyze in the way, resulting in flow limitation and apnea, with > 50% study. Another research conducted by Sakura et al. of OSA diagnoses attributable to being overweight [21]. also domenstrated that serum LBP levels were Kheirandish-Gozal et al. also indicated that a significant positively correlated with inflammation [19]. Taken increases was identified in LBP levels in children with together, we can deduce that chronic intermittent obesity or OSA, and the highest LBP levels was observed hypoxia of OSA may lead to elevation of systemic when both conditions are present [14]. Additionally, a LBP levels with resultant inflammation by causing study came from Kim et al. showed that circulating disorder of intestinal microflora. plasma LBP levels were significantly increased in As previously described, several researches reported overweight/obese participants compared with those in that LBP levels and proinflammation factors had posi- normal weight participants [18]. The same results drew tively associated with BMI and hypertension [18]. from another study conducted by Gonzalez-Quintela et Although a remarkable differences were obsevered be- al. [22]. Therefore, the current evidence supported that tween cases and controls in term of BMI and blood that sleep apnea and other factors such as obesity may pressure. However, the result of present study disrupt intestinal barrier function or gut microbiota, and Kong et al. BMC Pulmonary Medicine (2018) 18:90 Page 7 of 8 casue to increased the serum LPS concentration with re- detection and prepare tables, QDH conceived and participated in the study design. All authors read and approved the final manuscript. sultant systemic inflammation. In interpreting the results of the research, there are Ethics approval and consent to participate some methodological limitations requiring comment. The study was conducted according to the World Medical Association Declaration of Helsinki in 1975, as revised in 1983, and was approved by the First, disruption of gut microflora plays an important Ethic Committee of Zhejiang Hospital. All subjects provided their informed role in low-grade inflammation, we should therefore written consent. detect changes of gut microflora in future studies to ex- Competing interests plain the underlying mechanism of increased of LBP and The authors declare that they have no competing interests. inflammatory factors caused by OSA. Second, the study was not a clinical randomized controlled trial, and only Publisher’sNote the serum level of LBP and proinflammatory factors Springer Nature remains neutral with regard to jurisdictional claims in were evaluated in patients with OSA. It would be published maps and institutional affiliations. important to test if we can detect the changes in LBP Received: 9 August 2017 Accepted: 9 May 2018 and proinflammatory factors levels before and after intervention. Third, the sample size of the study was References relatively small, with only 50 OSA patients included. 1. Peppard PE, Young T, Barnet JH, Palta M, Hagen EW, Hla KM. Increased These limitations could have affected the power of the prevalence of sleep-disordered breathing in adults. Am J Epidemiol. 2011; conclusions. In the future, we intend to conduct an ana- 177(9):1006–14. 2. Wu H, Yuan X, Wang L, Sun J, Liu J, Wei Y. The relationship between lysis of a larger sample size and a randomized controlled obstructive sleep apnea hypopnea syndrome and inflammatory markers trial, which will include these risk factors. and quality of life in subjects with acute coronary syndrome. Respir Care. 2016;61(9):1207–16. 3. Ifergane G, Ovanyan A, Toledano R, Goldbart A, Abu-Salame I, Tal A, Stavsky Conclusions M, Novack V. Obstructive sleep apnea in acute sroke: a role for stroke The present study shown that higher LBP levels and in- inflammation. Stroke. 2016;47(5):1207–12. 4. Kim J, Yoon DW, Lee SK, Lee S, Choi KM, Robert TJ, Shin C. Concurrent flammation are detected in the presence of obesity and presence of inflammation and obstructive sleep apnea exacerbates the risk in the presence of sleep-disordered breathing in a of metabolic syndrome: A KoGES 6-year follow-up study. Medicine severity-dependent fashion. Furthermore, higher serum (Baltimore). 2017;96(7):e4488. 5. Vicente E, Marin JM, Carrizo SJ, Osuna CS, González R, Marin-Oto M, Forner LBP levels were positively correlated with AHI, and sleep M, Vicente P, Cubero P, Gil AV, et al. Upper airway and systemic apnea and BMI had effect on the concention of LBP. Im- inflammation in obstructive sleep apnoea. Eur Respir J. 2016;48(4):1108–17. proved understanding the mechanism underlying these 6. Xie X, Pan L, Ren D, Du C, Guo Y. Effects of continuous positive airway pressure therapy on systemic inflammation in obstructive sleep apnea: A associations may offer not only opportunities for detec- meta-analysis. Sleep Med. 2013;14(11):1139–50. tion of OSA patients at risk of comorbidities, but may 7. Tobias PS, Soldau K, Ulevitch RJ. Identification of a lipid A binding site in also enable delineation of therapeutic interventions, such the acute phase reactant lipopolysaccharide binding protein. J Biol Chem. 1989;264(18):10867–71. as regulation of intestinal flora through probiotics, for 8. Forsyth CB, Shannon KM, Kordower JH, Voigt RM, Shaikh M, Jaglin JA, Estes example, to reduce end-organ damage caused by OSA. JD, Dodiya HB, Keshavarzian A. Increased intestinal permeability correlates with sigmoid mucosa alpha-synuclein staining and endotoxin exposure Abbreviations markers in early Parkinson's disease. PLoS One. 2011;6(12):e28032. AHI: Apnea-hypopnea index; BMI: Body mass index; DBP: Diastolic blood 9. Sun L, Yu Z, Ye X, Zou S, Li H, Yu D, Wu H, Chen Y, Dore J, Clément K, et al. pressure; HDL: High-density lipoprotein; IL: Interleukin; A marker of endotoxemia is associated with obesity and related metabolic LBP: Lipopolysaccharide-binding protein; LDL: Low-density lipoprotein; disorders in apparently healthy Chinese. Diabetes Care. 2010;33(9):1925–32. LPS: Lipopolysaccharide; LSaO2: Lowest saturation oxygen; MAI: Microarousal 10. Cani PD, Bibiloni R, Knauf C, Waget A, Neyrinck AM, Delzenne NM, Burcelin index; mSaO2: Mean saturation oxygen; ODI: Oxygen desaturation index; R. Changes in gut microbiota control metabolic endotoxemia-induced SBP: Systolic blood pressure; TC: Total cholesterol; TG: Triglyceride; inflammation in high-fat-diet-induced obesity and diabetes in mice. TNF: Tumor necrosis factor Diabetes. 2008;57(6):1470–81. 11. Giloteaux L, Goodrich JK, Walters WA, Levine SM, Ley RE, Hanson MR. Reduced diversity and altered composition of the gut microbiome in Funding individuals with myalgic encephalomyelitis/chronic fatigue syndrome. The Medical and Health Science and Technology Plan of Zhejiang Province Microbiome. 2016;4(1):30. (2014KYA001) and TCM Science and Technology Plan of Zhejiang Province 12. Moreno-Indias I, Torres M, Montserrat JM, Sanchez-Alcoholado L, Cardona F, (2015ZB002) provided financial support in the form of researcher funding. Tinahones FJ, Gozal D, Poroyko VA, Navajas D, Queipo-Ortuño MI, et al. The sponsor had no role in the design or conduct of this research. Intermittent hypoxia alters gut microbiota diversity in a mouse model of sleep apnoea. Eur Respir J. 2015;45(4):1055–65. Availability of data and materials 13. Durgan DJ, Ganesh BP, Cope JL, Ajami NJ, Phillips SC, Petrosino JF, Hollister The dataset of this article are stored in sleep laboratory of the respiratory EB, Bryan RM Jr. Role of the gut microbiome in obstructive sleep apnea– department of Zhejiang Hospital and can be made available upon request induced hypertension. Hypertension. 2016;67(2):469–74. by contacting corresponding author. 14. Kheirandish-Gozal L, Peris E, Wang Y, Tamae Kakazu M, Khalyfa A, Carreras A, Gozal D. Lipopolysaccharide-binding protein plasma levels in children: Authors’ contributions effects of obstructive sleep apnea and obesity. J Clin Endocrinol Metab. YFK and ZJL planned the experimental design and drafted the manuscript, 2014;99(2):656–63. LG and JL helped PSG examination and analyze data, HYW and TYT collected 15. Berry RB, Budhiraja R, Gottlieb DJ, Gozal D, Iber C, Kapur VK, Marcus CL, Mehra the samples and prepared revision of manuscript, TZ contributed to perform R, Parthasarathy S, Quan SF, et al. Rule for scoring respiratory events in sleep: Kong et al. BMC Pulmonary Medicine (2018) 18:90 Page 8 of 8 update of the 2007 AASM Manual for the scoring of sleep and sssociated events. Deliberations of the sleep apnea definitions task force of the American academy of sleep medicine. J Clin Sleep Med. 2012;8(5):597–619. 16. EEG arousals. Scoring rules and examples: a preliminary report from the sleep disorders atlas task force of the American Sleep Disorders Association. Sleep. 1992;15(2):173–84. 17. Sleep-related breathing disorders in adults: recommendations for syndrome definition and measurement techniques in clinical research. The Report of an American Academy of Sleep Medicine Task Force. Sleep. 1999;22(5):667–89. 18. Kim KE, Cho YS, Baek KS, Li L, Baek KH, Kim JH, Kim HS, Sheen YH. Lipopolysaccharide-binding protein plasma levels as a biomarker of obesity- related insulin resistance in adolescents. Korean J Pediatr. 2016;59(5):231–8. 19. Sakura T, Morioka T, Shioi A, Kakutani Y, Miki Y, Yamazaki Y, Motoyama K, Mori K, Fukumoto S, Shoji T, et al. Lipopolysaccharide-binding protein is associated with arterial stiffness in patients with type 2 diabetes: a cross- sectional study. Cardiovasc Diabetol. 2017;16(1):62. 20. Moreno-Indias I, Torres M, Sanchez-Alcoholado L, Cardona F, Almendros I, Gozal D, Montserrat JM, Queipo-Ortuño MI, Farré R. Normoxic recovery mimicking treatment of sleep apnea does not reverse intermittent hypoxia- induced bacterial dysbiosis and low-grade endotoxemia in mice. Sleep. 2016;39(10):1891–7. 21. Young T, Peppard PE, Taheri S. Excess weight and sleep-disordered breathing. J Appl Physiol. 2005;99(4):1592–9. 22. Gonzalez-Quintela A, Alonso M, Campos J, Vizcaino L, Loidi L, Gude F. Determinants of serum concentrations of lipopolysaccharide-binding protein (LBP) in the adult population: the role of obesity. PLoS One. 2013; 8(1):e54600. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png BMC Pulmonary Medicine Springer Journals

The level of lipopolysaccharide-binding protein is elevated in adult patients with obstructive sleep apnea

Free
8 pages

Loading next page...
 
/lp/springer_journal/the-level-of-lipopolysaccharide-binding-protein-is-elevated-in-adult-8EcCyXjbVe
Publisher
Springer Journals
Copyright
Copyright © 2018 by The Author(s).
Subject
Medicine & Public Health; Pneumology/Respiratory System; Internal Medicine; Intensive / Critical Care Medicine
eISSN
1471-2466
D.O.I.
10.1186/s12890-018-0647-z
Publisher site
See Article on Publisher Site

Abstract

Background: lipopolysaccharide-binding protein (LBP) has been to be a surrogate marker of inflammation in OSA. This study aimed to test the hypothesis that the concentration of LBP is elevated in adult patients with obstructive sleep apnea (OSA). Methods: A total of 90 patients were enrolled into the study, 50 subjects were divided into OSA groups and 40 in healthy control according to PSG examination. Subsequently, patients with apnea-hypopnea index (AHI) ≧ 5, were divided into different subgroups according to blood pressure, gender, body mass index (BMI) and AHI. Venous blood samples were collected for detection after polysomnography. The serum levels of LBP and proinflammatory cytokines (interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α) were tested by ELISA. Results: The present study demonstrated that the serum levels of both LBP and proinflammatory cytokines were elevated in OSA patients. A stratified analysis conducted to analyze differences among subgroups indicated that OSA patients with a higher AHI or BMI had an increased level of LBP and proinflammatory cytokines (all p < 0.05). Furthermore, a significant correlations were observed between LBP and inflammation and AHI. Multivariate regression analysis also demonstrated that AHI, LSaO2 and BMI had impact on the concentration of LBP. Conclusion: The research showed that the serum level of LBP and proinflammatory cytokines were elevated in adult patients with OSA, and an association with severity of disease and BMI were established. Furthermore, sleep apnea and BMI had effect on the concentration of LBP. Keywords: Obstructive sleep apnea, Lipopolysaccharide-binding protein, Inflammation, Serum Background derangements is through the systemic inflammatory cas- Obstructive sleep apnea (OSA) is described as repeated cade [2–4]. In the past several years, it has become appar- collapse of the upper airways during sleep, leading to ent that the increasing level of inflammation are strongly repeated cycle of hypoxemia-reoxygenation and sleep associated with OSA [5]. A meta-analysis including 1985 disruption. Risk factors for OSA, including obesity and OSA patients and conducted by Xie et al. indicated that aging, are on the rise in the public; therefore, the preva- proinflammatory factors, such as interleukin (IL)-6, IL-8, lence of OSA is increasing worldwide, and is estimated and tumor necrosis factor (TNF)-α, are increased in pa- to affect up to 17% of middle-aged men and 9% of tients with OSA, which is partially reversed after continu- middle-aged women [1]. ous positive airway pressure intervention [6]. However, The putative mechanism by which OSA has been linked the potential molecular mechanisms how to initiate the to numerous pathologic conditions including stroke, inflammation are not fully understood in OSA patients. cardiovascular disease, hypertension, and metabolic Lipopolysaccharide-binding protein (LBP) is an acute-phase reactant predominantly derived from the liver, adipose and intestinal epithelial cells. LBP binds * Correspondence: zjyyhqd@163.com lipopolysaccharide (LPS) through recognition of lipid A Yinfeng Kong and Zhijun Li contributed equally to this work. and initiates its response by forming a complex with Department of Respiratory Medicine in Zhejiang Hospital, 12 Lingyin Road, Xihu District, Hangzhou 310013, Zhejiang Province, China © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Kong et al. BMC Pulmonary Medicine (2018) 18:90 Page 2 of 8 myeloid differentiation factor 2 leading to activation of All subjects provided their informed written consent. both MyD88-dependent and non-MyD88-dependent The study was conducted according to the World Med- downstream signaling pathways causing subsequent ical Association Declaration of Helsinki in 1975, as re- inflammatory responses, such as the release of various vised in 1983, and was approved by the Ethic Committee biomediators including IL-6, TNF-α, and IL-1β [7]. of Zhejiang Hospital. Therefore, LBP usually as a biomarker of system inflam- mation, intestinal barrier and microbe translocation in Polysomnography deferent study [8–11]. All participants received overnight polysomnography Metabolic endotoxemia has been shown to be the (PSG) according to standardized criteria [15]. The primary contributor to the pathogenesis of chronic results of PSG were reviewed by two sleep specialists low-grade inflammation, characterized by increased (Juan Liu & Liang Gu). Apnea was defined as continu- plasma LBP levels, which are believed to originate from ous cessation of airflow for > 10 s. Hypopnea was changes in gut microbiota and increasing of intestinal defined as a ≥ 30% reduction in airflow for > 10 s with permeability [10]. Altered gut microbiota composition oxygen desaturation of ≥4%. Apnea-hypopnea index are key factors affecting gut barrier integrity. The gut (AHI) was calculated as the sum of apneas and hypop- microbiota, which serves as reservoir for bacterial LPS, neas per hour during overnight. A respiratory event was could be altered by OSA and subsequently trigger scored as an obstructive apnea or hypopnea if chest and inflammation. At present, several studies reported that abdominal respiratory movement was identified and the chronic intermittent hypoxia of OSA has a signifi- oronasal airflow ceased, or there is an associated thora- cant impact on the overall microbial community coabdominal paradox that occurs during the hypopnea structure of mice, indicating that the homeostatic rela- with snoring. Microarousal index (MAI) was defined tionships between host and gut microbiota could be according to the American Academy of Sleep Medicine compromised in OSA patients [12, 13]. Moreno-Indias Scoring Manual [16]. The oxygen desaturation index et al. study indicated that fecal microbiota composition (ODI) was defined as ≥4% oxygen desaturation per hour and diversity were altered as a result of intermittent during sleep. Patients with OSA were divided into the hypoxia realistically mimicking OSA [12]. Therefore, it is mild group (AHI: 5–15 events/h), moderate group (AHI: rational to deduce that the concentration of LBP is 15–30 events/h), and severe group (AHI > 30 events/h) elevated in OSA patients. At present, one study from [17]. Subjects with sleepy and snore who accepted PSG Kheirandish-Gozal et al. reported that children with examination, with an AHI < 5 events/h were included in OSA exhibited increased LBP levels [14]. However, only the study as healthy controls. The exclusion criteria of children were recruited into the Kheirandish-Gozal et al. subjects were as follows: (1) chronic hypoxia caused by research. There is indeed a paucity of published litera- asthma, chronic obstructive pulmonary disease, intersti- ture on the association between LBP levels and adult tial lung disease and other respiratory disorders. (2) Par- patients with OSA. ticipants with a history of drug or alcohol abuse, or Based on previous studies, we conducted the study to taking drugs to regulate intestinal flora. (3) cardiovascu- test the hypothesis that the serum level of LBP is elevated lar, endocrine, and other disorders that could lead to in adult patients with OSA, and the correlations with pro- hypoxemia. (4) Diseases which may lead to the release of inflammatory factors and AHI were also evaluated. proinflammatory factors, such as connective tissue disease, cancer, and inflammatory bowel disease. (5) Methods required gastrointestinal surgical procedures or had re- Study population ceived antibiotic therapy in the preceding 8 weeks were A total of 50 patients with OSA (mild [n = 10], moderate also excluded. [n = 15], and severe OSA [n = 25]) and 40 healthy controls were consecutively recruited in the study. The Blood collection and analysis patients were examined at sleep laboratory of the re- Peripheral blood, drawn from each subject on the morn- spiratory department of Zhejiang Hospital from January ing after PSG, was centrifuged at 3000 rpm for 15 min, 2016 to June 2016. Body weight and height were mea- and serum was stored at − 70 °C for analysis. Concentra- sured, and body mass index (BMI) was calculated as tions of serum LBP, IL-1β, IL-6, TNF-ɑ were measured weight (kg)/height (m), and overweight was defined as using commercially available ELISA kits (R&D Sys- BMI ≥ 25 kg/m . Blood pressure was recorded using a tems, Minneapolis, MN, USA) in duplicate according mercury sphygmomanometer, and elevated blood pres- to the manufacturer’s instruction. An automatic sure was defined as systolic blood pressure (SBP) ≧ 140 biochemical analyzer (UniCel DxC 800 Synchron, mmHg and/or diastolic blood pressure (DBP) ≧ 90 Beckman Coulter, Inc., Brea, CA, USA) was used to mmHg or taking antihypertensive drug. test the serum level of lipids. Kong et al. BMC Pulmonary Medicine (2018) 18:90 Page 3 of 8 Statistical analysis Table 1 Clinical characteristics of the OSA and control group Continuous variables are expressed as the mean ± stand- Variables Patients Controls p value ard deviation. Comparisons were performed using t test Gender 0.317 or χ tests depending on data differences among groups. Male 34 31 Spearman’s correlation analysis were conducted to Female 16 9 examine potential associations between LBP and proin- Age (years) 54.34 ± 14.38 50.42 ± 8.35 0.112 flammatory factors. A multivariate regression analysis BMI(kg/m ) 26.86 ± 3.12 22.26 ± 3.54 0.000 was also performed to evaluate the role of confounding factors on LBP. Statistical significance was determined Normal weight 11(22.00%) 27(67.50%) by a level of 0.05 on two-sided tests. All statistical ana- Overweight 39(78.00%) 13(32.50%) lysis was performed using the SPSS Statistics 19.0.0 SBP(mmHg) 133.60 ± 16.37 120.19 ± 17.11 0.000 (IBM Corporation, Somers, NY, USA). DBP(mmHg) 81.16 ± 14.45 74.05 ± 10.72 0.005 Respiratory events Results Obstructive 241.76 ± 106.12 17.49 ± 7.18 < 0.001 General clinical characteristics of the study participants The basic clinical characteristics of the subjects are Central 1.32 ± 0.59 0.94 ± 0.37 0.551 detailed in Table 1. The mean age of patients with OSA AHI 37.34 ± 19.02 3.31 ± 1.09 < 0.001 was 54.34 ± 14.38 years, compared with 50.42 ± 8.35 LSaO2 75.29 ± 11.83 95.95 ± 4.65 < 0.001 years in the control group. There are significant differ- mSaO2 93.01 ± 4.18 96.35 ± 3.87 < 0.001 ences were observed between cases and controls group ODI 41.83 ± 25.9 3.56 ± 1.12 < 0.001 in terms of BMI, blood pressure (SBP and DBP), the MAI 22.61 ± 15.12 4.27 ± 2.16 < 0.001 serum concentration of triglyceride (TG), and PSG parameters (all p < 0.05). NREM1(%) 23.21 ± 12.79 15.9 ± 13.04 0.031 NREM21(%) 52.73 ± 12.31 48.1 ± 16.21 0.335 The comparison of LBP and proinflammatory factors NREM31(%) 14.51 ± 9.95 20.23 ± 8.72 0.045 between patients and controls REM(%) 10.23 ± 5.31 16.74 ± 7.36 0.012 There were significant differences in the serum level of TG 2.96 ± 2.53 1.71 ± 1.07 0.004 LBP (36.05 ± 7.35 vs 32.11 ± 5.94, p = 0.01) and inflamma- TC 4.98 ± 1.10 4.71 ± 0.91 0.189 tory factors (IL-1β, 27.15 ± 5.91 vs 21.17 ± 1.70, p =0.000; IL-6, 61.59 ± 9.76 vs 54.46 ± 9.43, p =0.005; TNF-ɑ HDL 1.04 ± 0.23 1.23 ± 0.26 0.000 327.34 ± 46.81 vs 307.95 ± 27.15, p = 0.020) between cases LDL 2.98 ± 1.10 3.02 ± 0.89 0.847 and control group. LBP 36.05 ± 7.35 32.11 ± 5.94 0.010 To further analyze differences among subgroups, a IL-1β 27.15 ± 5.91 21.17 ± 1.70 0.000 stratified analysis was performed according to blood IL-6 61.59 ± 9.76 54.46 ± 9.43 0.001 pressure, gender, BMI and severity of disease (AHI). The TNF-ɑ 327.34 ± 46.81 307.95 ± 27.15 0.027 results demonstrated that a significant differences were AHI Apnea-hypopnea index, BMI Body mass index, SBP Systolic blood pressure, found between normal weight and overweight patients DBP Diastolic blood pressure, LSaO2 Lowest saturation oxygen, mSaO2 Mean with OSA, which suggested that OSA patients with a saturation oxygen, ODI Oxygen desaturation index, MAI Microarousal index, TG higher BMI had a higher serum level of LBP and proin- triglyceride, TC Total cholesterol, LDL Low-density lipoprotein, HDL High-density lipoprotein flammatory factors (all p < 0.05). However, no differ- ences were identified in other subgroups based on blood pressure and gender (p > 0.05) (Table 2). Alterna- (r = 0.490, p = 0.001), and AHI (r = 0.371, p = 0.001). In tively, a marked differences were determined in the addition, a multivariate regression analysis were per- mild vs moderate, mild vs severe, moderate vs severe formed to determine the role of possible confounding groups (all p < 0.05), except for IL-1β in the mild vs factor to the concentration of LBP. The result of analysis moderate group (t = − 1.837, p = 0.091) (Table 3). showed that AHI, LSaO2 and BMI had a significant impact on the LBP (all p < 0.05), which suggested that The correlations between LBP and proinflammatory sleep apnea and obesity have effect on the levels of factors and severity of disease serum LBP. However, other variables were not identified Based on aforementioned findings, The correlations be- (p > 0.05) (Table 4). tween LBP and proinflammatory cytokines and severity of diseases were also evaluated. As evident in Fig. 1, sig- Discussion nificant correlations were found between LBP and IL-1β This is the first study to investigate OSA has an impact (r = 0.464, p = 0.003), IL-6 (r = 0.586, p = 0.000), TNF-ɑ on the concentration of LBP in adults. The results Kong et al. BMC Pulmonary Medicine (2018) 18:90 Page 4 of 8 Table 2 Comparison of various index in OSA subgroups according to blood pressure, gender and BMI Variables HBP vs Normal BP p value Male vs Female p value Normal weight vs Overweight p value HBP(21) Normal BP(29) Male(34) Female(16) Normal weight(14) Overweight(36) Age(years) 49.76 ± 13.28 56.46 ± 14.55 0.083 55.76 ± 12.76 52.13 ± 9.41 0.912 58.36 ± 18.68 52.78 ± 12.29 0.315 BMI(kg/m ) 28.30 ± 3.32 25.09 ± 2.83 0.022 27.28 ± 2.79 25.44 ± 3.12 0.531 24.42 ± 1.17 27.56 ± 2.60 0.017 SBP(mmHg)150.06 ± 7.61 123.61 ± 11.33 0.000 135.12 ± 15.61 131.50 ± 17.14 0.362 126.15 ± 14.31 136.63 ± 16.38 0.051 DBP(mmHg) 92.71 ± 13.12 74.14 ± 10.15 0.000 83.08 ± 14.23 78.42 ± 9.12 0.112 75.85 ± 11.83 83.31 ± 15.02 0.117 AHI 34.43 ± 17.72 40.19 ± 20.51 0.322 40.35 ± 16.63 29.61 ± 23.02 0.073 33.87 ± 16.52 38.69 ± 19.96 0.426 LSaO2(%) 77.17 ± 10.71 71.83 ± 13.75 0.160 72.87 ± 12.24 75.85 ± 7.77 0.132 75.83 ± 11.09 75.12 ± 12.22 0.859 mSaO2(%) 92.96 ± 5.37 93.67 ± 2.30 0.684 92.73 ± 4.78 94.11 ± 1.54 0.315 93.74 ± 2.67 92.89 ± 4.59 0.546 ODI 36.58 ± 23.77 48.89 ± 27.72 0.126 47.75 ± 24.49 25.91 ± 23.50 0.008 36.71 ± 22.46 43.54 ± 27.03 0.435 MAI 20.13 ± 13.27 26.33 ± 17.25 0.180 24.49 ± 16.22 17.44 ± 10.45 0.170 20.25 ± 13.07 23.56 ± 15.97 0.512 LBP 36.25 ± 8.71 35.72 ± 4.52 0.805 35.78 ± 7.73 37.14 ± 5.93 0.645 26.75 ± 3.50 37.38 ± 6.79 0.002 IL-1β 26.89 ± 6.27 27.58 ± 5.44 0.728 27.81 ± 5.93 24.52 ± 5.36 0.161 20.90 ± 2.03 28.04 ± 5.75 0.010 IL-6 61.69 ± 10.62 61.46 ± 8.47 0.944 61.52 ± 10.22 61.90 ± 8.24 0.924 46.41 ± 5.50 63.78 ± 8.18 0.000 TNF-α 325.11 ± 49.82 331.06 ± 42.73 0.703 329.95 ± 49.06 316.88 ± 37.36 0.487 252.99 ± 18.74 337.96 ± 39.29 0.000 AHI Apnea-hypopnea index, BMI Body mass index, SBP Systolic blood pressure, DBP Diastolic blood pressure, LSaO Lowest saturation oxygen, mSaO Mean saturation oxygen, ODI Oxygen desaturation index, MAI 2 2 Microarousal index Kong et al. BMC Pulmonary Medicine (2018) 18:90 Page 5 of 8 Table 3 Comparison of various index in subgroups according to severity of disease Variables OSA Mild vs Moderate Mild vs Severe Moderate vs Severe Mild(10) Moderate(15) Severe(25) t p value t p value t p value Age(years) 59.60 ± 15.13 56.73 ± 15.93 52.27 ± 13.54 0.352 0.729 1.104 0.277 −0.983 0.331 BMI(kg/m ) 27.04 ± 2.58 26.81 ± 3.80 27.28 ± 3.16 0.120 0.906 −0.164 0.871 0.436 0.665 SBP(mmHg) 140.40 ± 13.05 130.31 ± 16.79 133.93 ± 16.82 1.204 0.246 0.812 0.423 0.638 0.528 DBP(mmHg) 85.20 ± 9.61 79.85 ± 15.63 81.04 ± 14.63 0.686 0.502 0.597 0.555 0.236 0.815 AHI 10.14 ± 2.95 22.88 ± 3.93 49.11 ± 14.96 −6.066 0.000 −12.848 0.000 −8.999 0.000 LSaO2 87.20 ± 1.30 79.53 ± 9.13 70.90 ± 12.00 3.159 0.006 6.958 0.000 2.429 0.020 mSaO2 94.80 ± 1.48 93.88 ± 2.27 92.38 ± 5.10 0.840 0.412 1.040 0.307 1.077 0.288 ODI 11.94 ± 5.37 26.41 ± 18.78 55.44 ± 22.17 −1.672 0.112 −9.008 0.000 −4.305 0.000 MAI 14.56 ± 2.87 16.45 ± 8.12 27.06 ± 17.40 −0.501 0.623 −3.484 0.002 −2.627 0.012 LBP 25.81 ± 7.16 33.55 ± 3.50 38.29 ± 7.40 −2.743 0.018 − 2.771 0.010 − 2.642 0.012 IL-1β 20.10 ± 1.47 24.35 ± 3.83 29.15 ± 5.91 −1.837 0.091 −2.604 0.015 −2.475 0.018 IL-6 46.20 ± 6.09 58.34 ± 7.09 64.76 ± 9.05 −2.686 0.020 −3.434 0.002 − 2090 0.044 TNF-α 274.64 ± 4.91 308.75 ± 42.48 341.28 ± 44.80 −2.601 0.025 −2.534 0.017 −2.048 0.048 AHI Apnea-hypopnea index, BMI Body mass index, SBP Systolic blood pressure, DBP Diastolic blood pressure, LSaO Lowest saturation oxygen, mSaO Mean 2 2 saturation oxygen, ODI Oxygen desaturation index, MAI Microarousal index demonstrated that the serum level of LBP and inflamma- Significant correlations were also determined between tion were higher in OSA patients, compared with LBP and AHI and proinflammatory factors, which was is healthy subjects, and subgroups analysis indicated that in line with the previous study. Another study of OSA patients with a higher BMI and AHI had a higher Moreno-Indias et al. demonstrated that the LPS concen- serum level of LBP and proinflammatory factors. Add- tration was elevated at the end of intermittent hypoxia itionally, the correlational analysis showed that serum in mouse model, and a significant association was found LBP levels were positively correlated with inflammation between gut bacterial dysbiosis and the increases in and AHI. A multivariate regression analysis indicated plasma LPS levels [20]. In a recent study conducted by that sleep apnea and BMI had a significant impact on Table 4 The effect of confounding factor on concentation of the concentration of LBP. LBP in OSA patients To the best of our knowledge, OSA has an impact on Variables β 95% CI p value the intestinal barrier function and gut microflora. A study conducted by Moreno-Indias et al. suggested that AHI 14.430 (5.152, 29.078) 0.026 composition and diversity of intestinal microflora are ODI −0.139 (−0.397, 0.119) 0.276 altered caused by intermittent hypoxia [12]. The trans- MAI 0.074 (−0.135, 0.282) 0.472 location or change of commensal microbiota across the LSaO2 10.125 (3.917, 25.071) 0.035 intestinal barrier can result in a persistent state of low mSaO2 −0.256 (− 0.929, 0.416) 0.438 grade immune activation or inflammation. LBP is Age 0.115 (−0.150, 0.379) 0.379 located upstream of IL-1β, IL-6, and TNF-α expression, and initiates the recognition of bacterial LPS exposure BMI 8.245 (1.154, 18.386) 0.041 and amplifies the host immune response which, if con- SBP −0.214 (− 0.470, 0.042) 0.097 tinued long-term, results in adverse sequelae to the host. DBP 0.345 (−0.008, 0.698) 0.055 Therefore, LBP has been suggested to serve as a surro- TG 1.378 (−0.964, 3.719) 0.236 gate marker of chronic inflammatory status in several TC −5.532 (−12.988, 1.924) 0.138 disorders, such as obesity, diabetes, hypertension and HDL −4.509 (−20.564, 11.546) 0.567 other chronic inflammation diseases [18, 19]. Kim et al. study indicated that LBP levels were positively associated LDL 5.397 (−2.166, 12.960) 0.153 with BMI, SDP, total cholesterol, low density IL-1β 0.373 (−0.730, 1.476) 0.492 lipoprotein-cholesterol, fasting glucose and insulin, and IL-6 −0.079 (−0.363, 0.204) 0.569 insulin resistance [18]. TNF-α −0.006 (−0.076, 0.064) 0.859 The present study showed that the levels of LBP and AHI Apnea-hypopnea index, BMI Body mass index, SBP Systolic blood pressure, inflammation are increased in adult OSA patients and DBP Diastolic blood pressure, LSaO Lowest saturation oxygen, mSaO Mean 2 2 are positively associated with the severity of disease. saturation oxygen, ODI Oxygen desaturation index, MAI Microarousal index Kong et al. BMC Pulmonary Medicine (2018) 18:90 Page 6 of 8 Fig. 1 The scotterplots of the correlation of LBP vs IL-1β, IL-6, TNF-α and AHI Kheirandish-Gozal et al. [14], they assessed the LBP demonstrated that the concentration of LBP and level of plasma levels of 219 child patients with OSA, and found inflammation had only a positive association with BMI that systemic low-level endotoxemia and elevation of in OSA patients, and no relation with hypertension. As LBP was established in children with OSA, associated we known, obesity is one of the strongest risk factors for with measures of OSA severity. However, only chil- OSA, which imposes mechanical loads on the upper air- dren with OSA were included to analyze in the way, resulting in flow limitation and apnea, with > 50% study. Another research conducted by Sakura et al. of OSA diagnoses attributable to being overweight [21]. also domenstrated that serum LBP levels were Kheirandish-Gozal et al. also indicated that a significant positively correlated with inflammation [19]. Taken increases was identified in LBP levels in children with together, we can deduce that chronic intermittent obesity or OSA, and the highest LBP levels was observed hypoxia of OSA may lead to elevation of systemic when both conditions are present [14]. Additionally, a LBP levels with resultant inflammation by causing study came from Kim et al. showed that circulating disorder of intestinal microflora. plasma LBP levels were significantly increased in As previously described, several researches reported overweight/obese participants compared with those in that LBP levels and proinflammation factors had posi- normal weight participants [18]. The same results drew tively associated with BMI and hypertension [18]. from another study conducted by Gonzalez-Quintela et Although a remarkable differences were obsevered be- al. [22]. Therefore, the current evidence supported that tween cases and controls in term of BMI and blood that sleep apnea and other factors such as obesity may pressure. However, the result of present study disrupt intestinal barrier function or gut microbiota, and Kong et al. BMC Pulmonary Medicine (2018) 18:90 Page 7 of 8 casue to increased the serum LPS concentration with re- detection and prepare tables, QDH conceived and participated in the study design. All authors read and approved the final manuscript. sultant systemic inflammation. In interpreting the results of the research, there are Ethics approval and consent to participate some methodological limitations requiring comment. The study was conducted according to the World Medical Association Declaration of Helsinki in 1975, as revised in 1983, and was approved by the First, disruption of gut microflora plays an important Ethic Committee of Zhejiang Hospital. All subjects provided their informed role in low-grade inflammation, we should therefore written consent. detect changes of gut microflora in future studies to ex- Competing interests plain the underlying mechanism of increased of LBP and The authors declare that they have no competing interests. inflammatory factors caused by OSA. Second, the study was not a clinical randomized controlled trial, and only Publisher’sNote the serum level of LBP and proinflammatory factors Springer Nature remains neutral with regard to jurisdictional claims in were evaluated in patients with OSA. It would be published maps and institutional affiliations. important to test if we can detect the changes in LBP Received: 9 August 2017 Accepted: 9 May 2018 and proinflammatory factors levels before and after intervention. Third, the sample size of the study was References relatively small, with only 50 OSA patients included. 1. Peppard PE, Young T, Barnet JH, Palta M, Hagen EW, Hla KM. Increased These limitations could have affected the power of the prevalence of sleep-disordered breathing in adults. Am J Epidemiol. 2011; conclusions. In the future, we intend to conduct an ana- 177(9):1006–14. 2. Wu H, Yuan X, Wang L, Sun J, Liu J, Wei Y. The relationship between lysis of a larger sample size and a randomized controlled obstructive sleep apnea hypopnea syndrome and inflammatory markers trial, which will include these risk factors. and quality of life in subjects with acute coronary syndrome. Respir Care. 2016;61(9):1207–16. 3. Ifergane G, Ovanyan A, Toledano R, Goldbart A, Abu-Salame I, Tal A, Stavsky Conclusions M, Novack V. Obstructive sleep apnea in acute sroke: a role for stroke The present study shown that higher LBP levels and in- inflammation. Stroke. 2016;47(5):1207–12. 4. Kim J, Yoon DW, Lee SK, Lee S, Choi KM, Robert TJ, Shin C. Concurrent flammation are detected in the presence of obesity and presence of inflammation and obstructive sleep apnea exacerbates the risk in the presence of sleep-disordered breathing in a of metabolic syndrome: A KoGES 6-year follow-up study. Medicine severity-dependent fashion. Furthermore, higher serum (Baltimore). 2017;96(7):e4488. 5. Vicente E, Marin JM, Carrizo SJ, Osuna CS, González R, Marin-Oto M, Forner LBP levels were positively correlated with AHI, and sleep M, Vicente P, Cubero P, Gil AV, et al. Upper airway and systemic apnea and BMI had effect on the concention of LBP. Im- inflammation in obstructive sleep apnoea. Eur Respir J. 2016;48(4):1108–17. proved understanding the mechanism underlying these 6. Xie X, Pan L, Ren D, Du C, Guo Y. Effects of continuous positive airway pressure therapy on systemic inflammation in obstructive sleep apnea: A associations may offer not only opportunities for detec- meta-analysis. Sleep Med. 2013;14(11):1139–50. tion of OSA patients at risk of comorbidities, but may 7. Tobias PS, Soldau K, Ulevitch RJ. Identification of a lipid A binding site in also enable delineation of therapeutic interventions, such the acute phase reactant lipopolysaccharide binding protein. J Biol Chem. 1989;264(18):10867–71. as regulation of intestinal flora through probiotics, for 8. Forsyth CB, Shannon KM, Kordower JH, Voigt RM, Shaikh M, Jaglin JA, Estes example, to reduce end-organ damage caused by OSA. JD, Dodiya HB, Keshavarzian A. Increased intestinal permeability correlates with sigmoid mucosa alpha-synuclein staining and endotoxin exposure Abbreviations markers in early Parkinson's disease. PLoS One. 2011;6(12):e28032. AHI: Apnea-hypopnea index; BMI: Body mass index; DBP: Diastolic blood 9. Sun L, Yu Z, Ye X, Zou S, Li H, Yu D, Wu H, Chen Y, Dore J, Clément K, et al. pressure; HDL: High-density lipoprotein; IL: Interleukin; A marker of endotoxemia is associated with obesity and related metabolic LBP: Lipopolysaccharide-binding protein; LDL: Low-density lipoprotein; disorders in apparently healthy Chinese. Diabetes Care. 2010;33(9):1925–32. LPS: Lipopolysaccharide; LSaO2: Lowest saturation oxygen; MAI: Microarousal 10. Cani PD, Bibiloni R, Knauf C, Waget A, Neyrinck AM, Delzenne NM, Burcelin index; mSaO2: Mean saturation oxygen; ODI: Oxygen desaturation index; R. Changes in gut microbiota control metabolic endotoxemia-induced SBP: Systolic blood pressure; TC: Total cholesterol; TG: Triglyceride; inflammation in high-fat-diet-induced obesity and diabetes in mice. TNF: Tumor necrosis factor Diabetes. 2008;57(6):1470–81. 11. Giloteaux L, Goodrich JK, Walters WA, Levine SM, Ley RE, Hanson MR. Reduced diversity and altered composition of the gut microbiome in Funding individuals with myalgic encephalomyelitis/chronic fatigue syndrome. The Medical and Health Science and Technology Plan of Zhejiang Province Microbiome. 2016;4(1):30. (2014KYA001) and TCM Science and Technology Plan of Zhejiang Province 12. Moreno-Indias I, Torres M, Montserrat JM, Sanchez-Alcoholado L, Cardona F, (2015ZB002) provided financial support in the form of researcher funding. Tinahones FJ, Gozal D, Poroyko VA, Navajas D, Queipo-Ortuño MI, et al. The sponsor had no role in the design or conduct of this research. Intermittent hypoxia alters gut microbiota diversity in a mouse model of sleep apnoea. Eur Respir J. 2015;45(4):1055–65. Availability of data and materials 13. Durgan DJ, Ganesh BP, Cope JL, Ajami NJ, Phillips SC, Petrosino JF, Hollister The dataset of this article are stored in sleep laboratory of the respiratory EB, Bryan RM Jr. Role of the gut microbiome in obstructive sleep apnea– department of Zhejiang Hospital and can be made available upon request induced hypertension. Hypertension. 2016;67(2):469–74. by contacting corresponding author. 14. Kheirandish-Gozal L, Peris E, Wang Y, Tamae Kakazu M, Khalyfa A, Carreras A, Gozal D. Lipopolysaccharide-binding protein plasma levels in children: Authors’ contributions effects of obstructive sleep apnea and obesity. J Clin Endocrinol Metab. YFK and ZJL planned the experimental design and drafted the manuscript, 2014;99(2):656–63. LG and JL helped PSG examination and analyze data, HYW and TYT collected 15. Berry RB, Budhiraja R, Gottlieb DJ, Gozal D, Iber C, Kapur VK, Marcus CL, Mehra the samples and prepared revision of manuscript, TZ contributed to perform R, Parthasarathy S, Quan SF, et al. Rule for scoring respiratory events in sleep: Kong et al. BMC Pulmonary Medicine (2018) 18:90 Page 8 of 8 update of the 2007 AASM Manual for the scoring of sleep and sssociated events. Deliberations of the sleep apnea definitions task force of the American academy of sleep medicine. J Clin Sleep Med. 2012;8(5):597–619. 16. EEG arousals. Scoring rules and examples: a preliminary report from the sleep disorders atlas task force of the American Sleep Disorders Association. Sleep. 1992;15(2):173–84. 17. Sleep-related breathing disorders in adults: recommendations for syndrome definition and measurement techniques in clinical research. The Report of an American Academy of Sleep Medicine Task Force. Sleep. 1999;22(5):667–89. 18. Kim KE, Cho YS, Baek KS, Li L, Baek KH, Kim JH, Kim HS, Sheen YH. Lipopolysaccharide-binding protein plasma levels as a biomarker of obesity- related insulin resistance in adolescents. Korean J Pediatr. 2016;59(5):231–8. 19. Sakura T, Morioka T, Shioi A, Kakutani Y, Miki Y, Yamazaki Y, Motoyama K, Mori K, Fukumoto S, Shoji T, et al. Lipopolysaccharide-binding protein is associated with arterial stiffness in patients with type 2 diabetes: a cross- sectional study. Cardiovasc Diabetol. 2017;16(1):62. 20. Moreno-Indias I, Torres M, Sanchez-Alcoholado L, Cardona F, Almendros I, Gozal D, Montserrat JM, Queipo-Ortuño MI, Farré R. Normoxic recovery mimicking treatment of sleep apnea does not reverse intermittent hypoxia- induced bacterial dysbiosis and low-grade endotoxemia in mice. Sleep. 2016;39(10):1891–7. 21. Young T, Peppard PE, Taheri S. Excess weight and sleep-disordered breathing. J Appl Physiol. 2005;99(4):1592–9. 22. Gonzalez-Quintela A, Alonso M, Campos J, Vizcaino L, Loidi L, Gude F. Determinants of serum concentrations of lipopolysaccharide-binding protein (LBP) in the adult population: the role of obesity. PLoS One. 2013; 8(1):e54600.

Journal

BMC Pulmonary MedicineSpringer Journals

Published: May 29, 2018

References

You’re reading a free preview. Subscribe to read the entire article.


DeepDyve is your
personal research library

It’s your single place to instantly
discover and read the research
that matters to you.

Enjoy affordable access to
over 18 million articles from more than
15,000 peer-reviewed journals.

All for just $49/month

Explore the DeepDyve Library

Search

Query the DeepDyve database, plus search all of PubMed and Google Scholar seamlessly

Organize

Save any article or search result from DeepDyve, PubMed, and Google Scholar... all in one place.

Access

Get unlimited, online access to over 18 million full-text articles from more than 15,000 scientific journals.

Your journals are on DeepDyve

Read from thousands of the leading scholarly journals from SpringerNature, Elsevier, Wiley-Blackwell, Oxford University Press and more.

All the latest content is available, no embargo periods.

See the journals in your area

DeepDyve

Freelancer

DeepDyve

Pro

Price

FREE

$49/month
$360/year

Save searches from
Google Scholar,
PubMed

Create lists to
organize your research

Export lists, citations

Read DeepDyve articles

Abstract access only

Unlimited access to over
18 million full-text articles

Print

20 pages / month

PDF Discount

20% off