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‐
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 (Ad
pl) level was associated to multiple metabolic and CVD disorders [
15]. In COPD patients, conflicting results regarding Ad
pl level were observed in previous studies [
16‐
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 Ad
pl level in COPD [
16,
19‐
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‐
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‐
22]. In this study, we therefore evaluated Ad
pl 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.
Discussion
We postulated that gender and hypoxaemia could influence Ad
pl 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 Ad
pl level. Women exhibited a higher Ad
pl level compared with men. While this discrepancy was previously described [
37,
38], the mechanism underlying this divergence is still investigated. Testosterone level [
39‐
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 Ad
pl level in COPD patients. In our study, differences in men and women Ad
pl 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 Ad
pl 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 Ad
pl 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‐
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‐
50]. Therefore, more studies are necessary for elucidating the potential role of inflammation in the association between Ad
pl level and TLC %pv in women with COPD.
Moreover, Ad
pl level in women was negatively associated with
PaCO
2, especially in the hypoxemic subgroup. These observations are consistent with previous studies that found a decreased Ad
pl level and a higher
PaCO
2 in mice with acute lung injury [
51] or in patients with hypoventilation syndrome [
52]. Moreover, Dimoulis et al. observed that Ad
pl level was negatively correlated with bicarbonate level [
53]. They also found that, in stable hypercapnic COPD, non-invasive ventilation reduced
PaCO
2 and increased
PaO
2 and Ad
pl 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 Ad
pl level in COPD patients.
In addition to its potential modulation of Ad
pl 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 Ad
pl 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‐
59].
Altogether, our results suggested that gender difference in Ad
pl 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‐
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‐
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
PaO
2 (≤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 Ad
pl 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 Ad
pl 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.
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