To identify potential mechanisms involved in COPD-related co-morbidity, we considered the impact of gender and hypoxaemia on Adpl level and HMW form proportion. In our study, a gender difference in Adpl level was observed. Women exhibited a higher Adpl level compared with men. While this discrepancy was previously described (34,35), the mechanism underlying this divergence is still investigated. Testosterone level (36–39) and the different adipose tissue distribution in men and women were previously mentioned (40). For a given BMI, men exhibited higher lean mass, and women had a higher adiposity and Adpl level (40). In addition, muscle is well-known to be affected by COPD and in this context, muscle dysfunction was more intense in women than in men (41–43). This phenomenon could also contribute to increase Adpl level in women.
In addition to the gender difference in Adpl, we observed a gender divergence in TLC and RV, without any difference in BMI. These data suggested that, for a given FEV1, women had a more pronounced air trapping (increase of RV) or hyperinflation (increase of TLC) than men, while hyperinflation was quite limited in our study (mean TLC was 105%pv in women and 87%pv in men). These results 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 (44,45). Using the same method, Martinez et al. also found that emphysema was less extensive in women (46). However, the study group consisted in patients evaluated for lung volume reduction surgery. Therefore, emphysema was a predominant feature in the population studied, contrary to our population. Moreover, in Martinez et al. study, women had a greater FEV1 (%pv) than men, so we cannot exclude that the predominance of emphysema in men was associated to disease severity. This is consistent with the study of Hardin et al. (47) highlighting 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. Indeed, TLC %pv was not significantly higher in men (value of women tended to be higher). Moreover, inspiratory capacity (IC) to TLC ratio was even significantly smaller in women. 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.
In the present study, we also observed that the increased TLC %pv in women was associated with a reduced Adpl level. As pro-inflammatory cytokines were previously demonstrated to reduce Ad expression in adipocytes (48), it could be hypothesised that inflammatory state in these patients modulated 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 (49–51). The exact mechanism remains unclear. Rathod et al. showed that a divergent hormonal status could be involved in this regulation (50), whereas the study of Casimir et al. observed that some genes on X chromosome, involved in the inflammatory cascade, were overexpressed in women (49). 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 responses within the airway wall in women (52–54). 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.
The increase of TLC and RV %pv observed in women in our study was observed in other recent studies (43,55,56). Grabicki et al. observed that COPD women had more hyperinflation, air trapping and comorbidities, inducing a higher risk of mortality (55). In women, this increased air trapping also led to the development of hypercapnia (57). In Martinez’s study, women had a decreased IC/TLC ratio compared to men and was also more hypercapnic and hypoxemic, in spite of a higher mean FEV1 %pv. We also observed a significant difference between men and women for PaCO2. Moreover, in women, Adpl level was negatively associated with TLC and PaCO2, especially in hypoxic subgroup. Previous studies found a decreased Adpl level and a higher PaCO2 in mice with acute lung injury (58) or in patients with hypoventilation syndrome (59). However, a potential correlation between these parameters was not evaluated. Dimoulis et al. studied this association as well as the effect of non-invasive ventilation (NIV) on Adpl level in stable hypercapnic COPD (60). They observed that Adpl level was negatively correlated with bicarbonate level. In addition, NIV reduced PaCO2, increased PaO2, and Adpl level was also increased from the first month of intervention, without any change in BMI (61). In addition to physiological gender difference in Adpl level, our study suggested that functional alteration 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 HMW form level 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 (62). In this model, the only difference between the active and control group 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 (63,64). Further studies are therefore needed to better understand the impact of an increased HMW form level in hypoxemic women. No modulation of Adpl level or HMW form proportion were observed among hypoxemic and non-hypoxemic men, suggesting that Ad pathway 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 (65–67).
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 (≤55mmHg). However, patients in such condition received LTOT in order to reduce the risk of complications and mortality. It is therefore difficult to justify a washing period from oxygen therapy for those already on this treatment at the inclusion time. Treatment naïve patients should be selected and Ad pathway modulation could then be studied before and after LTOT in the same patient.