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Chronic hypoxaemia and gender status modulate adiponectin plasmatic level and its multimer proportion in severe COPD patients: new endotypic presentation?

Abstract

Background

Disease progression in COPD patient is associated to lung function decline, leading to a higher risk of hypoxaemia and associated comorbidities, notably cardiovascular diseases (CVD). Adiponectin (Ad) is an adipokine with cardio-protective properties. In COPD patients, conflicting results were previously reported regarding Ad plasmatic (Adpl) level, probably because COPD is a heterogeneous disease with multifactorial influence. Among these factors, gender and hypoxaemia could interact in a variety of ways with Ad pathway. Therefore, we postulated that these components could influence Adpl level and its multimers in COPD patients and contribute to the appearance of a distinct endotype associated to an altered CVD risk.

Methods

One hundred COPD patients were recruited: 61 were men and 39 were women. Patients who were not severely hypoxemic were allocated to non-hypoxemic group which included 46 patients: 27 men and 19 women. Hypoxemic group included 54 patients: 34 men and 20 women. For all patients, Adpl level and proportion of its different forms were measured. Differences between groups were evaluated by Rank-Sum tests. The relationship between these measures and BMI, blood gas analysis (PaO2, PaCO2), or lung function (FEV1, FEV1/FVC, TLCO, TLC, RV) were evaluated by Pearson correlation analysis.

Results

Despite similar age, BMI and obstruction severity, women had a higher TLC and RV (median: TLC = 105%; RV = 166%) than men (median: TLC = 87%; RV = 132%). Adpl level was higher in women (median = 11,152 ng/ml) than in men (median = 10,239 ng/ml) and was negatively associated with hyperinflation (R = − 0,43) and hypercapnia (R = − 0,42). The proportion of the most active forms of Ad (HMW) was increased in hypoxemic women (median = 10%) compared with non-hypoxemic women (median = 8%) but was not modulated in men.

Conclusion

COPD pathophysiology seemed to be different in hypoxemic women and was associated to Ad modulations. Hyperinflation and air-trapping in association with hypercapnia and hypoxaemia, could contribute to a modulation of Adpl level and of its HMW forms. These results suggest the development of a distinct endotypic presentation, based on gender.

Peer Review reports

Background

Chronic obstructive pulmonary disease (COPD) is a progressive disease associated with lung function decline and comorbidities such as cardiovascular diseases (CVD). By inducing secondary erythrocytosis, endothelial dysfunction, and pulmonary arterial hypertension, hypoxaemia in severe COPD patients was suggested to contribute to the increased CVD risk in these patients [1, 2]. The prevalence of the disease is increasing among women due to the higher smoking rate [3, 4]. Moreover, sex-differences were reported in the course of the disease. Women were described to exhibit a greater susceptibility to tobacco, faster annual decline of lung function and worse quality of life [3, 4]. This increased effect of tobacco smoke on women was suggested to be due to gender differences in airway structure [5,6,7], but inflammatory response to tobacco smoke was also suspected to differ at the level of the small airways [8] and to be at the origin of a more extensive airway remodelling [9]. The prevalence of co-morbidities also varies with gender in COPD patients and men were described to be more susceptible to CVD and diabetes mellitus [10].

Adiponectin (Ad), a 30 kDa protein mainly secreted by adipose tissue, was well described for its anti-inflammatory, anti-atherogenic and anti-diabetic effects [11]. The physiological plasmatic concentration of this adipokine is higher in women [12]. In circulating blood, Ad was detected in 3 different isoforms: low (LMW), medium (MMW), and high molecular weight forms (HMW). This latter form was described as the most active isoform: it was better correlated to insulin sensitivity and circulating glucose concentration [13, 14]. A reduced Ad plasmatic (Adpl) level was associated to multiple metabolic and CVD disorders [15]. In COPD patients, conflicting results regarding Adpl level were observed in previous studies [16,17,18] and could be explained by the heterogeneity of the disease. Several factors, such as exacerbation rate, BMI, disease severity and progression were associated to differences in Adpl level in COPD [16, 19,20,21,22]. In addition, exposure to chronic hypoxia was also shown to alter Ad expression in adipocytes in vitro, and in adipose tissue in vivo [23,24,25].

Adiponectin was previously proposed as a biomarker for COPD risk management, and its pathway was suggested as a potential therapeutic target [20, 26]. However, COPD is a complex and heterogeneous disease [27] that could interact in a variety of ways with Ad pathway [16, 19,20,21,22]. In this study, we therefore evaluated Adpl level and the proportion of HMW forms in COPD patients, with a special attention to gender and hypoxaemia effects. Potential relationships between these data and lung function were also evaluated.

Methods

Subjects

One hundred COPD patients were recruited from the outpatient clinic of a tertiary University Hospital from 2016 to 2018 and were referred for evaluation of need for oxygen therapy or for the adaptation of this treatment. COPD was diagnosed according to the ACCP/ATS/ERS guidelines [28] and severity of their airflow limitation was defined according to GOLD criteria, described in [29].

In this study, patients were divided into several groups according to gender and/or the severity of hypoxaemia. Among all patients of the study, 61 were men and 39 women. Concerning the hypoxaemia, patients were affected the hypoxemic group when they were severely hypoxemic patients (PaO2 ≤ 55 mmHg) or to the non-hypoxemic group when their PaO2 was above 55 mmHg, while breathing room air. This cut-off was based on ATS/ERS statement in which severe hypoxaemic COPD patients were defined as patients exhibiting a PaO2 ≤ 55 mmHg. Non-hypoxemic group included 46 patients (27 men and 19 women), whereas hypoxemic group included 54 patients (34 men and 20 women).

Patients with significant comorbidities such as malignancy, endocrine, liver, or gastrointestinal disorders, primitive cardiovascular abnormalities, or a recent surgery were excluded. All subjects were older than 40 years of age. This study was approved by the Erasme Hospital Ethics Committee and conducted in accordance with the Helsinki Declaration.

Patients’ data including age, gender and BMI were collected, and analyses were performed anonymously. Arterial blood samples were obtained at rest, with the patient in the sitting position, while breathing room air. Arterial oxygen (PaO2) and carbon dioxide (PaCO2) partial pressures were measured and recorded. Spirometry, lung volumes and single-breath determination of carbon monoxide uptake were then evaluated according to the ATS guidelines [30,31,32] (M.E.C PFT systems Body™ and Diff™, Belgium) and expressed as a percentage of the predicted value (%pv). FEV1 (forced expiratory volume in one second) and FVC (forced vital capacity), FEV1/FVC ratio, carbon monoxide transfer factor (TLCO), total lung capacity (TLC), and residual volume (RV) were recorded. As patients did not interrupt their medical treatment before medical appointment, these measures could be reasonably considered as post-bronchodilation data. TLC and RV have not been obtained from 2 non-hypoxemic women and 5 men because they were unable to perform plethysmography in a reproducible way.

Adiponectin plasmatic level measurement

Adpl level was measured according to the manufacturer’s instructions (DRP300: Human Total Adiponectin/Acrp30 Quantikine ELISA Kit, R&D Systems). Assay sensitivity was estimated at 0.891 ng/ml and assay range was between 3.9 and 250 ng/ml. Patient samples were diluted according to the manufacturer’s instructions in order to be within the predefined range.

Adiponectin oligomer distribution determined by Western blot

The relative amounts of LMW, MMW and HMW Admer were evaluated for each patient as previously described in Pierard et al. [33]. These amounts were determined using a non-denaturing PAGE-SDS followed by a Western blot [33]. Five microliter of plasma diluted to contain 5 μg/ml of Ad were loaded onto a 6% polyacrylamide gel in the presence of SDS [33]. For the Western blot, proteins were transferred to a nitrocellulose membrane (Millipore, Darmstadt, Germany) [33]. After blocking with 5% fat-free dry milk-TBS, the membranes were incubated with a rabbit polyclonal primary antibody directed against Ad (Ab85827, 1:1000, Abcam, Cambridge, UK) [33]. The membranes were then incubated with a horseradish peroxidase-labelled secondary antibody (1:5000, Sigma-Aldrich, St. Louis, MO, USA) [33]. The ECL™ Western Blotting Detection kit (GE Healthcare, Little Chalfont, UK) was used for the revelation step [33]. The immunoreactive bands were then submitted to a densitometric analysis using the Image J software to determine the proportion of LMW, MMW and HMW forms [33].

Statistical analysis

Sample size was estimated for a 4-group ANOVA study with a power of 0.8 and the significance level at 0.05. The expected difference in means was based on the difference in HMW% observed in mice [34] and the variation among experimental subjects was arbitrarily considered as twice as high as in this mouse study. The total sample size was rounded to 100 patients. A Rank-Sum test was used to evaluate differences between groups. In the tables, results were represented as median and 5th–95th percentiles. In the graphs, all data were represented as boxplots (5th–95th percentiles; dots are outliers). Pearson’s coefficient was used for correlation analyses. Pearson correlation coefficient (R) was calculated between every lung function parameter and Adpl level measured by ELISA or HMW form proportion determined by non-denaturant SDS-PAGE followed by a Western blot. All representative blots were included in supplementary material 1 and all data obtained to perform these correlations were included in supplementary material 2. Differences were considered statistically significant at a P value < 0.05. All statistical analyses were performed with Sigma Plot 11.0 Software (Systat Software, USA).

Results

Characteristics of subjects

One hundred COPD patients with moderate (16%), severe (43%) or very severe obstruction (41%) were included in this study. 61% of the cohort were male. 46% were not severely hypoxemic and allocated to the non-hypoxemic group (Table 1). On average, hypoxemic and non-hypoxemic patients exhibited the same age, BMI and disease severity based on FEV1 value. Both groups had a significant air trapping (increased RV). The alteration of TLCO was more severe in hypoxemic patients and these patients were more hypercapnic than non-hypoxemic counterparts. When the cohort was separated according to gender, no difference was observed for age, BMI, FEV1, PaCO2 or TLCO. However, we found an increased TLC and RV in women compared with men.

Table 1 Clinical characteristics of COPD subjects separated according to gender or hypoxaemia status. Median [25th – 75th percentiles]. * p < 0.05; **p < 0,001; Rank-Sum test

Effect of hypoxaemia on Adpl level and HMW forms

We did not observe any difference in Adpl level and in HMW form proportion between hypoxemic and non-hypoxemic patients (Fig. 1a-b, e). We found that Adpl level was negatively correlated with BMI in both groups but was not correlated with other parameters (Fig. 1c-d, Table 2). We detected a significant negative correlation between BMI and HMW form proportion in non-hypoxemic patients, but not in the hypoxemic group. Moreover, a negative correlation was observed between HMW forms and TLCO in non-hypoxemic patients. In the hypoxemic group, these parameters were positively correlated but without reaching a statistically significant level (p = 0.055).

Fig. 1
figure1

a-b Adpl level (a) and HMW form proportion (b) in non-hypoxemic and hypoxemic COPD patients. Adpl level was measured by ELISA and HMW form proportion was determined using a non-denaturing PAGE-SDS followed by a Western blot. Data were represented as boxplots (5th and 95th percentiles). Rank-Sum test: NS. c-d Correlation between lung function parameters and Adpl level (vertical) or HMW form proportion (horizontal), in non-hypoxemic (c) and hypoxemic (d) COPD patients. Pearson correlation coefficients (R) between every parameter and either Adpl level or HMW form proportion were calculated and represented as a point on the graph. The box in the graph represents the critical value for Pearson correlation coefficient to obtain a p < 0.05. Therefore, every point outside the box corresponds to a significant correlation. e Representative blots of Ad form proportions in hypoxemic and non-hypoxemic patients, determined by using non-denaturant PAGE-SDS followed by a Western blot. HMW forms correspond to the higher molecular weight bands. Admer/total Ad ratios were obtained after densitometric analysis

Table 2 Correlation between lung function parameters and Adpl level or HMW form proportion in non-hypoxemic and hypoxemic COPD patients. Adpl level was measured by ELISA and HMW form proportion was determined using a non-denaturing PAGE-SDS followed by a Western blot. Data were represented as Pearson correlation coefficient (p value)

Impact of gender difference on Adpl level and HMW forms

As gender differences in total and HMW Ad levels were previously observed in many studies [35, 36], we evaluated these parameters in men and women and correlated these values with lung function parameters. We found a higher Adpl level in women compared with men, while no difference between HMW form proportions was observed (Fig. 2a-b, e). As previously, in both groups, Adpl level was negatively correlated with BMI (Fig. 2c-d, Table 3). In women, we observed a significant negative correlation between Adpl level and TLC, as well as with PaCO2. These observations were in accordance with the decrease of Adpl level in hypercapnic women (PaCO2 > 45 mmHg) compared with normocapnic women (p < 0.05) (Fig. 3a). A reduced Adpl level was also observed in women characterized by hyperinflated lungs (TLC > 115%pv) (Fig. 3b). Concerning HMW form proportion, no gender difference and no correlation with BMI, arterial gas values, or lung parameters were detected.

Fig. 2
figure2

a-b Adpl level (a) and HMW form proportion (b) in men and women COPD patients. Adpl level was measured by ELISA and HMW form proportion was determined using a non-denaturing PAGE-SDS followed by a Western blot. Data were represented as boxplots (5th and 95th percentiles). * p < 0.05; Rank-Sum test. c-d Correlation between Adpl level (vertical), or HMW form proportion (horizontal) and lung function parameters in men (a) and women (b) COPD patients. Pearson correlation coefficients (R) between every parameter and either Adpl level or HMW form proportion were calculated and reported as a point on the graph. The box in the graph represents the critical value for Pearson correlation coefficient to obtain a p < 0.05. Therefore, every point outside the box corresponds to a significant correlation. e Representative blots of Ad form proportion in men and women, determined by using non-denaturant PAGE-SDS followed by a Western blot. HMW forms correspond to the higher molecular weight bands. Admer/total Ad ratios were obtained after densitometric analysis

Table 3 Correlation between lung function parameters and Adpl level or HMW form proportion in men and women COPD patients. Adpl level was measured by ELISA and HMW form proportion was determined using a non-denaturing PAGE-SDS followed by a Western blot. Data were represented as Pearson correlation coefficient (p value)
Fig. 3
figure3

Adpl level in women with or without hypercapnia (a) or lung hyperinflation (b). Adpl level was measured by ELISA. Data were represented as boxplots (5th and 95th percentiles). * p < 0.05; Rank-Sum test

Effect of combined gender difference and hypoxia on Adpl level and HMW forms

We did not observe any modification in total or HMW Ad level between hypoxemic and non-hypoxemic men (Fig. 4). In women, hypoxaemia did not modify total Adpl level but increased HMW form proportion. Indeed, as shown on representative blots (Fig. 4f), the higher bands, corresponding to HMW Ad forms, are more intense in hypoxemic women compared with non-hypoxemic women. As previously, whatever the gender, Adpl level was negatively correlated with BMI in hypoxemic and non-hypoxemic groups (Fig. 5, Table 4). A negative correlation between total Adpl level and TLC was statistically significant in non-hypoxemic women, and borderline in hypoxemic women (p = 0.07). Adpl level was also negatively correlated with PaCO2 in hypoxemic women. Regarding HMW forms, we observed a positive correlation between HMW proportion and RV in non-hypoxemic men (Fig. 5, Table 5). We also detected an opposite relationship between TLCO and HMW level in hypoxemic and non-hypoxemic men. While a positive correlation was observed in hypoxemic men, a negative correlation was detected in non-hypoxemic men. This relationship did not appear in women. Although, we observed that HMW level was negatively associated with RV in hypoxemic women.

Fig. 4
figure4

Adpl level (a-b) and HMW form proportion (c-d) in hypoxemic and non-hypoxemic men and women COPD patients. Adpl level was measured by ELISA and HMW form proportion was determined using a non-denaturing PAGE-SDS followed by a Western blot. Data were represented as boxplots (5th and 95th percentiles). * p < 0.05; Rank-Sum test. e-f Representative blots of Ad form proportion in non-hypoxemic and hypoxemic men (e) as well as in non-hypoxemic and hypoxemic women (f). HMW form proportion was determined by using non-denaturant PAGE-SDS followed by a Western blot and corresponds to the higher molecular weight bands. Admer/total Ad ratios were obtained after densitometric analysis

Fig. 5
figure5

Relationship between Adpl level, (vertical), HMW form proportion (horizontal) and lung function parameters in non-hypoxemic men (a), hypoxemic men (b), non-hypoxemic women (c) and hypoxemic women (d) COPD patients. Adpl level was measured by ELISA and HMW form proportion was determined using a non-denaturing PAGE-SDS followed by a Western blot. Pearson correlation coefficients (R) between every parameter and either Adpl level or HMW form proportion were calculated and were represented as a point on the graph. The box in the graph represents the critical value for Pearson correlation coefficient to obtain a p < 0.05. Therefore, every point outside the box corresponds to a significant correlation

Table 4 Correlation between lung function parameters and Adpl level in hypoxemic and non-hypoxemic men and women COPD patients. Adpl level was measured by ELISA and HMW form proportion was determined using a non-denaturing PAGE-SDS followed by a Western blot. Data were represented as Pearson correlation coefficient (p value)
Table 5 Correlation between lung function parameters and HMW form proportion in hypoxemic and non-hypoxemic men and women COPD patients. Adpl level was measured by ELISA and HMW form proportion was determined using a non-denaturing PAGE-SDS followed by a Western blot. Data were represented as Pearson correlation coefficient (p value)

Discussion

We postulated that gender and hypoxaemia could influence Adpl level as well as its multimers and therefore contribute to the appearance of a distinct endotype associated to an altered CVD risk. Our results showed a gender difference in Adpl level. Women exhibited a higher Adpl level compared with men. While this discrepancy was previously described [37, 38], the mechanism underlying this divergence is still investigated. Testosterone level [39,40,41,42] and the difference in adipose tissue distribution between men and women were previously mentioned [43]. Other mechanisms could also explain this gender variation in Adpl level in COPD patients. In our study, differences in men and women Adpl level were associated with divergent clinical characteristics, among which the increased TCL and RV %pv in women, reflecting hyperinflation and air-trapping respectively.

The increased TLC %pv was correlated with a reduced Adpl level. As pro-inflammatory cytokines were previously demonstrated to reduce Ad expression in adipocytes [44], it could be hypothesised that inflammatory state in these patients modulates Adpl level. Indeed, Rubinsztajn et al. observed that patients with hyperinflation had elevated inflammatory markers [21]. Another explanation supporting this hypothesis could be the gender difference in inflammatory processes [45,46,47]. The exact mechanism remains unclear. Rathod et al. showed that a divergent hormonal status could be involved in this regulation [46], whereas the study of Casimir et al. observed that some genes on X chromosome, involved in the inflammatory pathway, were overexpressed in women [45]. While this divergence in the inflammatory state was not previously described in COPD, this phenomenon is well known in patients with asthma, with a more pronounced inflammatory response within the airway wall in women [48,49,50]. Therefore, more studies are necessary for elucidating the potential role of inflammation in the association between Adpl level and TLC %pv in women with COPD.

Moreover, Adpl level in women was negatively associated with PaCO2, especially in the hypoxemic subgroup. These observations are consistent with previous studies that found a decreased Adpl level and a higher PaCO2 in mice with acute lung injury [51] or in patients with hypoventilation syndrome [52]. Moreover, Dimoulis et al. observed that Adpl level was negatively correlated with bicarbonate level [53]. They also found that, in stable hypercapnic COPD, non-invasive ventilation reduced PaCO2 and increased PaO2 and Adpl level from the first month of intervention, without any change in BMI [54]. Therefore, our study suggested that functional alterations such as hyperinflation, air trapping and impaired gas exchange also modulated Adpl level in COPD patients.

In addition to its potential modulation of Adpl level through its association with hypercapnia, hypoxaemia was associated to an increased level of HMW forms in women. Interestingly, these observations were in accordance with our previous study in which an increased HMW form proportion in a murine model of hypoxaemia was observed [34]. In this model, the only difference between the active and control groups was the exposure to hypoxia. However, we also observed that the increased HMW form proportion was associated to a decreased AdipoR protein level in different tissues [55, 56]. Further studies are therefore needed to better understand the impact of an increased level of HMW forms in hypoxemic women. No modulation of Adpl level or HMW form proportion were observed among hypoxemic and non-hypoxemic men, suggesting that Ad is modulated by different mechanisms in men and women. One explanation could be the presence of a gender-difference in the inflammatory response, as previously mentioned. Indeed, in different pathological contexts, previous studies reported that women were affected to a more extended level by a pro-inflammatory state but respond more vigorously [57,58,59].

Altogether, our results suggested that gender difference in Adpl level observed in our COPD patients could be explained by a divergent pathophysiology in men and women. Indeed, we observed a gender divergence in TLC and RV, without any difference in BMI. The increase of TLC and RV %pv observed in women in our study was also found in other recent studies [60,61,62]. These data suggested that, for a given FEV1, women had a more pronounced air trapping or hyperinflation than men, while hyperinflation was quite limited in our study (mean TLC was 105%pv in women and 87%pv in men). These observations are consistent with Grabicki et al. that showed that COPD women had more hyperinflation, air trapping and comorbidities, inducing a higher risk of mortality [61]. In addition, in women, this increased air trapping also led to the development of hypercapnia [63]. Our results also contrasted with previous studies in which men exhibited more emphysema than women. By using CT scan, previous studies observed that the percentage of low attenuation area was higher in men than in women [64,65,66]. However, the study of Hardin et al. [67] highlighted that gender difference in CT-determined emphysema is dependent on the severity of airway obstruction (GOLD classification). Despite of these considerations, it is interesting to note that the difference in radiological emphysema did not appear in functional hyperinflation in Martinez’s study. These results underlined the contrast between radiological evaluations in favour of more emphysema in men, and functional measures reflecting probably a higher air trapping in women. This study has some limitations. As we evaluated the effect of the hypoxaemia component in COPD patient, we separated our cohort according to the PaO2 (≤55 mmHg). However, patients in such severe condition received LTOT in order to reduce the risk of complications and mortality. It was therefore difficult to tolerate a washing period from oxygen therapy for those already on this treatment at the inclusion time. Treatment-naive patients should be selected and modulation of Adpl level and HMW form proportion could then be studied before and after LTOT in the same patient. In our study, the main confounding factors (age, BMI, gender) affecting Adpl level in COPD patients [68], were taken into consideration. However, we cannot exclude any influence of other concomitant factors such as medication, physical activity or cardio-vascular co-morbidities.

Conclusions

Altogether, these data suggested that men and women with severe hypoxaemia exhibited a different pathophysiology of COPD, which is linked to Ad modulation. Indeed, an increased Adpl level was observed in COPD women and was associated with a distinct pattern of functional alterations (for the same age, BMI or obstruction severity): women had more hyperinflation, air-trapping and hypercapnia, which, in association with hypoxaemia, could contribute to a modulation of Adpl level. These variations were accompanied with an increased level of HMW forms in hypoxemic women. All these results suggest the development of a distinct endotypic presentation, based on gender, with a more pronounced bronchiolar damages possibly associated with an inflammatory state, leading to an increased air-trapping. Consequently, a long-term study should be realized to evaluate if these modulations of total Adpl and HMW forms are associated with a better survival or with a lower risk of comorbidities.

Availability of data and materials

The datasets supporting the conclusion of this article are included within the article and its additional file.

Abbreviations

Ad:

Adiponectin

Adpl :

Ad plasmatic

COPD:

Chronic obstructive pulmonary disease

CVD:

Cardiovascular diseases

FEV1:

Forced expiratory volume in one second

FVC:

Forced vital capacity

HMW:

High molecular weight

IC:

Inspiratory capacity

LMW:

Low molecular weight

MMW:

Medium molecular weight

PaO2 :

Arterial oxygen partial pressure

PaCO2 :

Carbon dioxide partial pressure

R:

Pearson correlation coefficient

RV:

Residual volume

TLC:

Total lung capacity

TLco:

Carbon monoxide transfer factor

%pv:

Percentage of the predicted value

References

  1. 1.

    Kent BD, Mitchell PD, McNicholas WT. Hypoxemia in patients with COPD: cause, effects, and disease progression. Int J Chron Obstruct Pulmon Dis. 2011;6:199–208.

    PubMed  PubMed Central  Google Scholar 

  2. 2.

    Maclay JD, McAllister DA, Macnee W. Cardiovascular risk in chronic obstructive pulmonary disease. Respirology. 2007;12(5):634–41.

    PubMed  Article  PubMed Central  Google Scholar 

  3. 3.

    Kamil F, Pinzon I, Foreman MG. Sex and race factors in early-onset COPD. Curr Opin Pulm Med. 2013;19(2):140–4.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  4. 4.

    Han MK, Postma D, Mannino DM, Giardino ND, Buist S, Curtis JL, et al. Gender and chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2007;176(12):1179–84.

    PubMed  PubMed Central  Article  Google Scholar 

  5. 5.

    Raherison C, Biron E, Nocent-Ejnaini C, Taillé C, Tillie-Leblond I, Prudhomme A. Are there specific characteristics of COPD in women? Rev Mal Respir. 2010;27(6):611–24.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  6. 6.

    Kanner RE, Connett JE, Altose MD, Buist AS, Lee WW, Tashkin DP, et al. Gender difference in airway hyperresponsiveness in smokers with mild COPD. The lung health study. Am J Respir Crit Care Med. 1994;150(4):956–61.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  7. 7.

    Amaral AFS, Strachan DP, Burney PGJ, Jarvis DL. Female smokers are at greater risk of airflow obstruction than male smokers. UK biobank. Am J Respir Crit Care Med. 2017;195(9):1226–35.

    PubMed  Article  PubMed Central  Google Scholar 

  8. 8.

    Hogg JC, Chu F, Utokaparch S, Woods R, Elliott WM, Buzatu L, et al. The nature of small-airway obstruction in chronic obstructive pulmonary disease. N Engl J Med. 2004;350(26):2645–53.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  9. 9.

    Sayiner A, Hague C, Ajlan A, Leipsic J, Wierenga L, Krowchuk NM, et al. Bronchiolitis in young female smokers. Respir Med. 2013;107(5):732–8.

    PubMed  Article  PubMed Central  Google Scholar 

  10. 10.

    Sawalha S, Hedman L, Backman H, Stenfors N, Rönmark E, Lundbäck B, et al. The impact of comorbidities on mortality among men and women with COPD: report from the OLIN COPD study. Ther Adv Respir Dis. 2019;13:1753466619860058.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  11. 11.

    Kadowaki T, Yamauchi T, Kubota N, Hara K, Ueki K, Tobe K. Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome. J Clin Invest. 2006;116(7):1784–92.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  12. 12.

    Swarbrick MM, Havel PJ. Physiological, pharmacological, and nutritional regulation of circulating Adiponectin concentrations in humans. Metab Syndr Relat Disord. 2008;6(2):87–102.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  13. 13.

    Lara-Castro C, Luo N, Wallace P, Klein RL, Garvey WT. Adiponectin multimeric complexes and the metabolic syndrome trait cluster. Diabetes. 2006;55(1):249–59.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  14. 14.

    Yamauchi T, Kadowaki T. Adiponectin receptor as a key player in healthy longevity and obesity-related diseases. Cell Metab. 2013;17(2):185–96.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  15. 15.

    Ebrahimi-Mamaeghani M, Mohammadi S, Arefhosseini SR, Fallah P, Bazi Z. Adiponectin as a potential biomarker of vascular disease. Vasc Health Risk Manag. 2015;11:55–70.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Xie J, Yang X-Y, Shi J-D, Deng X-Q, Long W. A new inflammation marker of chronic obstructive pulmonary disease-adiponectin. World J Emerg Med. 2010;1(3):190–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Uzum AK, Aydin MM, Tutuncu Y, Omer B, Kiyan E, Alagol F. Serum ghrelin and adiponectin levels are increased but serum leptin level is unchanged in low weight chronic obstructive pulmonary disease patients. Eur J Intern Med. 2014;25(4):364–9.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  18. 18.

    Breyer M-K, Rutten EPA, Locantore NW, Watkins ML, Miller BE, Wouters EFM, et al. Dysregulated adipokine metabolism in chronic obstructive pulmonary disease. Eur J Clin Invest. 2012;42(9):983–91.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  19. 19.

    Bianco A, Nigro E, Monaco ML, Matera MG, Scudiero O, Mazzarella G, et al. The burden of obesity in asthma and COPD: role of adiponectin. Pulm Pharmacol Ther. 2017;43:20–5.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  20. 20.

    Jaswal S, Saini V, Kaur J, Gupta S, Kaur H, Garg K. Association of adiponectin with lung function impairment and disease severity in chronic obstructive pulmonary disease. Int J Appl Basic Med Res. 2018;8(1):14.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  21. 21.

    Rubinsztajn R, Przybyłowski T, Maskey-Warzęchowska M, Paplińska-Goryca M, Karwat K, Nejman-Gryz P, et al. Correlation between hyperinflation defined as an elevated RV/TLC ratio and body composition and cytokine profile in patients with chronic obstructive pulmonary disease. Pneumonol Alergol Pol. 2015;83(2):120–5.

    PubMed  Article  PubMed Central  Google Scholar 

  22. 22.

    Wert SE. Does adiponectin play a role in pulmonary emphysema? Am J Physiol Lung Cell Mol Physiol. 2008;294(6):L1032–4.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  23. 23.

    Guo Q, Jin S, Hu H, Zhou Y, Yan Y, Zong H, et al. Hypoxia in 3T3-L1 adipocytes suppresses adiponectin expression via the PERK and IRE1 unfolded protein response. Biochem Biophys Res Commun. 2017;493(1):346–51.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  24. 24.

    Ye J, Gao Z, Yin J, He Q. Hypoxia is a potential risk factor for chronic inflammation and adiponectin reduction in adipose tissue of Ob/Ob and dietary obese mice. Am J Physiol Endocrinol Metab. 2007;293(4):E1118–28.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  25. 25.

    Pan G, Su M, Ding W, Ding N, Huang H, Zhang X. Effects of chronic intermittent hypoxia on oxidative stress and inflammatory response and the interventional roles of adiponectin. Zhonghua Yi Xue Za Zhi. 2015;95(16):1218–21.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Sato K, Shibata Y, Abe S, Inoue S, Igarashi A, Yamauchi K, et al. Association between plasma adiponectin levels and decline in forced expiratory volume in 1 s in a general Japanese population: the Takahata study. Int J Med Sci. 2014;11(8):758–64.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  27. 27.

    Barrecheguren M, Miravitlles M. COPD heterogeneity: implications for management. Multidiscip Respir Med. 2016;11 [cited 2020 Jun 18]. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4794904/.

  28. 28.

    Qaseem A, Wilt TJ, Weinberger SE, Hanania NA, Criner G, van der Molen T, et al. Diagnosis and management of stable chronic obstructive pulmonary disease: a clinical practice guideline update from the American College of Physicians, American College of Chest Physicians, American Thoracic Society, and European Respiratory Society. Ann Intern Med. 2011;155(3):179–91.

    PubMed  Article  PubMed Central  Google Scholar 

  29. 29.

    Global Initiative for Chronic Obstructive Lung Disease. Gold Reports 2020. 2020 [cited 2020 Jun 19]. Available from: https://goldcopd.org/gold-reports/.

  30. 30.

    Macintyre N, Crapo RO, Viegi G, Johnson DC, van der Grinten CPM, Brusasco V, et al. Standardisation of the single-breath determination of carbon monoxide uptake in the lung. Eur Respir J. 2005;26(4):720–35.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  31. 31.

    Wanger J, Clausen JL, Coates A, Pedersen OF, Brusasco V, Burgos F, et al. Standardisation of the measurement of lung volumes. Eur Respir J. 2005;26(3):511–22.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  32. 32.

    Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, et al. Standardisation of spirometry. Eur Respir J. 2005;26(2):319–38.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  33. 33.

    Pierard M, Conotte S, Tassin A, Boutry S, Uzureau P, Boudjeltia KZ, et al. Interactions of exercise training and high-fat diet on adiponectin forms and muscle receptors in mice. Nutr Metab (Lond). 2016;13 [cited 2017 Jun 22]. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5094086/.

  34. 34.

    Pierard M, Tassin A, Conotte S, Zouaoui Boudjeltia K, Legrand A. Sustained intermittent hypoxemia induces Adiponectin oligomers redistribution and a tissue-specific modulation of Adiponectin receptor in mice. Front Physiol. 2019;10 [cited 2019 Feb 13]. Available from: https://www.frontiersin.org/articles/10.3389/fphys.2019.00068/full.

  35. 35.

    Song HJ, Oh S, Quan S, Ryu O-H, Jeong J-Y, Hong K-S, et al. Gender differences in adiponectin levels and body composition in older adults: Hallym aging study. BMC Geriatr. 2014;14:8.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  36. 36.

    Eglit T, Lember M, Ringmets I, Rajasalu T. Gender differences in serum high-molecular-weight adiponectin levels in metabolic syndrome. Eur J Endocrinol. 2013;168(3):385–91.

    CAS  PubMed  Article  Google Scholar 

  37. 37.

    Sun Y, Xun K, Wang C, Zhao H, Bi H, Chen X, et al. Adiponectin, an unlocking adipocytokine. Cardiovasc Ther. 2009;27(1):59–75.

    PubMed  Article  CAS  Google Scholar 

  38. 38.

    Breyer M-K, Rutten EPA, Vernooy JHJ, Spruit MA, Dentener MA, van der Kallen C, et al. Gender differences in the adipose secretome system in chronic obstructive pulmonary disease (COPD): a pivotal role of leptin. Respir Med. 2011;105(7):1046–53.

    PubMed  Article  Google Scholar 

  39. 39.

    Frederiksen L, Højlund K, Hougaard DM, Mosbech TH, Larsen R, Flyvbjerg A, et al. Testosterone therapy decreases subcutaneous fat and adiponectin in aging men. Eur J Endocrinol. 2012;166(3):469–76.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  40. 40.

    Horenburg S, Fischer-Posovszky P, Debatin K-M, Wabitsch M. Influence of sex hormones on adiponectin expression in human adipocytes. Horm Metab Res. 2008;40(11):779–86.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  41. 41.

    Nishizawa H, Shimomura I, Kishida K, Maeda N, Kuriyama H, Nagaretani H, et al. Androgens decrease plasma adiponectin, an insulin-sensitizing adipocyte-derived protein. Diabetes. 2002;51(9):2734–41.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  42. 42.

    Page ST, Herbst KL, Amory JK, Coviello AD, Anawalt BD, Matsumoto AM, et al. Testosterone administration suppresses adiponectin levels in men. J Androl. 2005;26(1):85–92.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43.

    Geer EB, Shen W. Gender differences in insulin resistance, body composition, and energy balance. Gend Med. 2009;6(Suppl 1):60–75.

    PubMed  PubMed Central  Article  Google Scholar 

  44. 44.

    Ouchi N, Walsh K. Adiponectin as an anti-inflammatory factor. Clin Chim Acta. 2007;380(1–2):24–30.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  45. 45.

    Casimir GJ, Heldenbergh F, Hanssens L, Mulier S, Heinrichs C, Lefevre N, et al. Gender differences and inflammation: an in vitro model of blood cells stimulation in prepubescent children. J Inflamm (Lond). 2010;7:28.

    Article  CAS  Google Scholar 

  46. 46.

    Rathod K, Kapil V, Velmurugan S, Khambata R, Siddique U, Khan S, et al. Sex differences in the inflammatory response and inflammation-induced vascular dysfunction. Lancet. 2017;389:S20.

    Article  Google Scholar 

  47. 47.

    Diodato MD, Knöferl MW, Schwacha MG, Bland KI, Chaudry IH. Gender differences in the inflammatory response and survival following haemorrhage and subsequent sepsis. Cytokine. 2001;14(3):162–9.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  48. 48.

    Zein JG, Erzurum SC. Asthma is different in women. Curr Allergy Asthma Rep. 2015;15(6):28.

    PubMed  PubMed Central  Article  Google Scholar 

  49. 49.

    Fuseini H, Newcomb DC. Mechanisms driving gender differences in asthma. Curr Allergy Asthma Rep. 2017;17(3):19.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  50. 50.

    Postma DS. Gender differences in asthma development and progression. Gend Med. 2007;4 Suppl B:S133–46.

    PubMed  Article  PubMed Central  Google Scholar 

  51. 51.

    Xu L, Bao H-G, Si Y-N, Han L, Zhang R, Cai M-M, et al. Effects of adiponectin on acute lung injury in cecal ligation and puncture-induced sepsis rats. J Surg Res. 2013;183(2):752–9.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  52. 52.

    Borel J, Roux-Lombard P, Tamisier R, Arnaud C, Monneret D, Arnol N, et al. Endothelial dysfunction and specific systemic inflammation in obesity hypoventilation syndrome. In: C20 endothelial dysfunction and beyond in sleep disordered breathing: American Thoracic Society; 2009. p. A3983. [cited 2018 Oct 3]. (American Thoracic Society International Conference Abstracts). Available from: https://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2009.179.1_MeetingAbstracts.A3983.

  53. 53.

    Dimoulis A, Pastaka C, Tsolaki V, Tsilioni I, Pournaras S, Liakos N, et al. Non-invasive ventilation (NIV) and homeostatic model assessment (HOMA) index in stable chronic obstructive pulmonary disease (COPD) patients with chronic Hypercapnic respiratory failure: a pilot study. COPD. 2015;12(4):427–34.

    PubMed  Article  PubMed Central  Google Scholar 

  54. 54.

    Ryo M, Nakamura T, Kihara S, Kumada M, Shibazaki S, Takahashi M, et al. Adiponectin as a biomarker of the metabolic syndrome. Circ J. 2004;68(11):975–81.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  55. 55.

    Van Berendoncks AM, Garnier A, Beckers P, Hoymans VY, Possemiers N, Fortin D, et al. Functional adiponectin resistance at the level of the skeletal muscle in mild to moderate chronic heart failure. Circ Heart Fail. 2010;3(2):185–94.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  56. 56.

    Li R, Xu M, Wang X, Wang Y, Lau WB, Yuan Y, et al. Reduced vascular responsiveness to adiponectin in hyperlipidemic rats--mechanisms and significance. J Mol Cell Cardiol. 2010;49(3):508–15.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  57. 57.

    Spitzer JA, Zhang P. Gender differences in neutrophil function and cytokine-induced neutrophil chemoattractant generation in endotoxic rats. Inflammation. 1996;20(5):485–98.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  58. 58.

    Casimir GJA, Duchateau J. Gender differences in inflammatory processes could explain poorer prognosis for males. J Clin Microbiol. 2011;49(1):478–9.

    PubMed  PubMed Central  Article  Google Scholar 

  59. 59.

    Onat A, Karadeniz Y, Tusun E, Yüksel H, Kaya A. Advances in understanding gender difference in cardiometabolic disease risk. Expert Rev Cardiovasc Ther. 2016;14(4):513–23.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  60. 60.

    Verhage TL, Heijdra Y, Molema J, Vercoulen J, Dekhuijzen R. Associations of muscle depletion with health status. Another gender difference in COPD? Clin Nutr. 2011;30(3):332–8.

    PubMed  Article  PubMed Central  Google Scholar 

  61. 61.

    Grabicki M, Kuźnar-Kamińska B, Rubinsztajn R, Brajer-Luftmann B, Kosacka M, Nowicka A, et al. COPD course and comorbidities: are there gender differences? Adv Exp Med Biol. 2019;1113:43–51.

  62. 62.

    Laviolette L, Lacasse Y, Doucet M, Lacasse M, Marquis K, Saey D, et al. Chronic obstructive pulmonary disease in women. Can Respir J. 2007;14(2):93–8.

    PubMed  PubMed Central  Article  Google Scholar 

  63. 63.

    Shade D, Cordova F, Lando Y, Travaline JM, Furukawa S, Kuzma AM, et al. Relationship between resting hypercapnia and physiologic parameters before and after lung volume reduction surgery in severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 1999;159(5 Pt 1):1405–11.

    PubMed  Article  PubMed Central  Google Scholar 

  64. 64.

    Camp PG, Coxson HO, Levy RD, Pillai SG, Anderson W, Vestbo J, et al. Sex differences in emphysema and airway disease in smokers. Chest. 2009;136(6):1480–8.

    PubMed  Article  PubMed Central  Google Scholar 

  65. 65.

    Dransfield MT, Washko GR, Foreman MG, Estepar RSJ, Reilly J, Bailey WC. Gender differences in the severity of CT emphysema in COPD. Chest. 2007;132(2):464–70.

    PubMed  Article  PubMed Central  Google Scholar 

  66. 66.

    Martinez FJ, Curtis JL, Sciurba F, Mumford J, Giardino ND, Weinmann G, et al. Sex differences in severe pulmonary emphysema. Am J Respir Crit Care Med. 2007;176(3):243–52.

    PubMed  PubMed Central  Article  Google Scholar 

  67. 67.

    Hardin M, Foreman M, Dransfield MT, Hansel N, Han MK, Cho MH, et al. Sex-specific features of emphysema among current and former smokers with COPD. Eur Respir J. 2016;47(1):104–12.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  68. 68.

    Lin Y-H, Jiang T-X, Hu S-X, Shi Y-H. Association between serum adiponectin concentrations and chronic obstructive pulmonary disease: a meta-analysis. Biosci Rep. 2020;40(3) [cited 2020 Apr 29]. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7069907/.

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Acknowledgements

We acknowledge V. Jenart and B. Blairon, for technical assistance.

Funding

FRMH (Fonds pour la Recherche Médicale dans le Hainaut) provided funding that helps us to perform Western blot and ELISA analyses. MP held PhD fellowships from the University of Mons.

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MP carried out the molecular studies, participated in the design of the study, drafted the manuscript and performed data recording, data analyses, and the statistical analyses. AT participated in the conception of the study and in its design and coordination. AT also supervised molecular studies, critically revised the manuscript and found sustaining funds for project. AL1 participated in study coordination, data recording and analysis. AL2 conceived of the study, and participated in its design and coordination, helped to draft the manuscript and to perform statistical analysis. All authors have read and approved the final manuscript.

Corresponding author

Correspondence to Alexandre Legrand.

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This study was approved by the Erasme Hospital Ethics Committee. All procedures were conducted in accordance with ACCP/ATS/ERS guidelines. All patients had previously given their written informed consent for this study.

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The authors declare that they have no conflict of interest regarding the publication of this paper. Each author meets the criteria for authorship and assumes the corresponding responsibility.

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Pierard, M., Tassin, A., Legrand, A. et al. Chronic hypoxaemia and gender status modulate adiponectin plasmatic level and its multimer proportion in severe COPD patients: new endotypic presentation?. BMC Pulm Med 20, 255 (2020). https://doi.org/10.1186/s12890-020-01288-3

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Keywords

  • COPD
  • Gender difference
  • Hypoxaemia
  • Hypoxia
  • Adiponectin
  • Multimers