In this observational study, we found significantly higher concentrations of circulating neutrophils in female than in male COPD patients with malnourishment. We could not identify any confounding factor explaining this difference, taking smoking, use of nicotine, and medication into account. The only variable identified other than gender related to neutrophil concentrations in the forward regression model was the concentration of MPO in serum. This is not surprising, because MPO might be produced by neutrophils.15
Users of inhaled steroids had marginally higher neutrophil concentrations than nonsteroid users, in line with previous studies.16
Notably, fewer female than male patients used inhaled steroids. Thus, the difference between users and nonusers of inhaled steroids cannot explain the gender difference in neutrophil concentrations in our study. Just like the use of inhaled steroids, the use of oral steroids will increase neutrophil concentrations. 17
The key results of our current study did not, however, change in any way if the three patients taking oral steroids were excluded. There were also other small gender differences concerning pharmacological therapy. Fewer females than males used β2
-adrenoceptor agonists. On the other hand, more female patients used anticholinergic drugs compared with male patients. The reason for these differences and their possible effects on neutrophil concentrations remains unclear. The finding of a considerably, but not significantly, higher concentration of circulation neutrophils in users of anticholinergic drugs compared with nonusers is somewhat surprising. Anticholinergic drugs are supposed to ameliorate neutrophilic inflammation.18
Our finding of significantly elevated neutrophil concentrations in female COPD patients must be interpreted with care, as this outcome was not the primary study variable of this investigation. However, in another, ongoing study of COPD patients (including patients with normal weight as well as malnourished patients) we found the same pattern (unpublished observations). The preliminary results of the referred, ongoing study thus support our current study.
Notably, we observed no clear difference in neutrophil concentrations for female and male control subjects. In line with this, clinically applied normal values for neutrophils do not differ for female and male subjects either. The comparison with the control group also indicates that the gender difference noted in the COPD patients is caused by increased neutrophil concentration in females rather then decreased concentrations in men.
We determined the concentrations of the neutrophil-mobilizing cytokines IL-6 and IL-8 to look for molecular correlates that could explain the increased neutrophil concentration in the female COPD patients included in our current study. Whereas the concentrations of both these cytokines tended to be higher among female patients, the difference compared with male patients did not reach statistical significance. Even though not conclusive, these findings are compatible with the archetype chemokine IL-8 and the neutrophil-activating cytokine IL-6, contributing to a gender difference in the concentration of circulating neutrophils, and it can be speculated that a better-powered study may prove this to be the case in the future.
Estrogens reduce the expression of adhesion molecules, leading to less extravasation of inflammatory cells.19
To study the hypothesis that the higher serum concentrations of neutrophils in female COPD patients were caused by low expression of adhesion molecules, which would reduce the capacity for extravascular migration, we studied ICAM-1, VCAM-1, and E-selectin. Hypothetically, a low expression of these molecules would lead to a larger fraction of neutrophils remaining in the circulation. However, we obtained no evidence supporting this hypothesis. On the contrary, the mean concentration of ICAM-1 and VCAM-1, respectively, was higher in female than in male patients, although not significantly so, suggesting more expression of these molecules at the cellular level, if anything. Furthermore, there was no correlation between the concentrations of inflammatory cells and circulating adhesion molecules.
The concentrations of circulating MPO and NE were determined to assess whether the increased concentrations of circulating neutrophils in female COPD patients were associated with an increased release of neutrophil-derived proinflammatory compounds. No evidence for this was found, however. There were no clear differences in MPO and NE concentrations between female and male COPD patients. The concentrations of MPO and NE did, however, display a very strong correlation to one another. That finding is compatible with a shared source at the cellular level. However, this source may not be the circulating neutrophil, as no correlation was found between MPO or NE, on the one hand, and the neutrophil concentration, on the other hand. We speculate that neutrophils residing in the lung tissue could be one possible source.
The concentrations of circulating CRP were considerably higher in female than in male patients with COPD and significantly higher in female patients than in female control subjects. Although the gender difference in subjects with COPD was not statistically significant, this is of concern. This is because, in elderly subjects, slightly elevated concentrations of CRP are reported as predictors of frailty and osteoporosis.20
Elevated CRP concentrations are also correlated to an increased risk of cardiovascular mortality.21
In the general elderly population in Sweden, there is no difference in CRP concentrations for female and male subjects.22