The current study was performed with the aim of exploring the relationship between BMI and AHR in a large cohort of male and female adults with suspected asthma. Overall, the proportion of hyperresponsive subjects did not differ with body weight in the population tested. Similarly, the level of AHR was equally distributed among the body weight groups. However, an interesting bi-modal behaviour emerged in females with moderate degree of AHR: a “protective” effect of body weight in the underweight condition and a “detrimental” effect of body weight in the obese state, thus describing an imaginary inverted U-shape curve of the relationship between BMI and PD20. These findings suggest that the influence of the adipose tissue on airway function should be further investigated in the moderate hyperresponsive female phenotype.
Our results are in line with some studies
] that did not find any difference in PD20
values in obese and normal-weight asthmatics, and differ from those observed in the study of Schachter et al.
], who found an increase in AHR in underweight subjects, although no plausible explanations were provided. Our results in the underweight subgroup are conflicting. In fact, in underweight females with moderate AHR, a significant positive correlation was found between BMI and PD20
which allowed us to infer that increasing weight might reduce the degree of AHR in these subjects. Therefore, the underweight condition in females seems to be a risk factor for AHR even though the logistic regression model did not confirm such a risk. On the contrary, the underweight condition in males seems to be a protective factor for AHR, probably due to hormonal differences.
In addition, our study showed that BMI (adjusted for age, pulmonary function, smoking and seasons) was an AHR risk factor in females but not in males. In fact, the obese status in females was an important AHR risk factor only when subjects with moderate levels of AHR were considered. Like other investigators, we could not find the expected relationship between BMI and PD20
in subjects with severe AHR,
]. In fact, they found that obesity in asthmatic patients is negatively correlated to the intensity of AHR and not to asthma severity. This could be explained by the fact that in most severe stages, AHR is mainly characterized by a non-reversible component, probably associated with airway structural changes.
The observed different behaviours between sexes can already be found in literature. In fact, other studies showed differences between sexes with regard to the influence of BMI on AHR
], with a more pronounced association in females
]. It is plausible that sexual hormones, and in particular estrogens, may play a role in modulating the relationship between BMI and asthma. In obesity, the production of estrogens is generally increased and is associated with early menarche in women and delay in the onset of puberty in men. Some authors demonstrated that the prevalence of asthma, the association between BMI and the severity of the disease were greater in women with early menarche
]. Furthermore, estrogens and progesterone may modify the inflammatory response to favour a Th2 response
]. In this respect, β-estradiol enhances eosinophil adhesion to human mucosal microvascular endothelial cells and induces degranulation (unlike the testosterone effect), whereas progesterone increases bronchial eosinophilia and enhances bronchial responsiveness
]. Another explanation may lie in the different abdominal fat distribution in males and females. In the latter, there is a greater subcutaneous fat distribution, whereas in males a higher visceral adipose tissue is observed. Interestingly, the subcutaneous abdominal fat appears to increase the risk of hyperresponsiveness, whereas visceral abdominal fat is not associated with AHR
]. Furthermore, gynoid fat mass was associated with higher degrees of hyperrresponsiveness after an hypertonic saline challenge test in females
]. Likely, the higher leptin production from subcutaneous fat rather than visceral fat, with greater values in females compared with males, may be the cause of a more serious status of asthma in obese women
]. Leptin may activate or increase the airway inflammation in asthmatics
]; in fact, a relationship between circulating leptin levels and risk of asthma development was observed in females
]. Recently, an increase in neutrophilic airways inflammation in obese female asthmatics was documented in a study
]. Another study showed that a gynoid fat mass is associated with a lower concentration of airway eosinophils in females
]. Therefore, the different influence of BMI on AHR could be due to a different inflammatory pattern induced by obesity in males and females. Likely, a higher production of leptin from subcutaneous adipose tissue, which is typical of females, promotes T-helper type 1 cell differentiation and increases activation of neutrophils via tumour necrosis factor α
The alternative explanation for our findings could be a pure mechanical factor, as demonstrated by the influence of the reduction in the FEV1
/FVC ratio for unit of BMI increase (obstructive pattern). An excess soft tissue weight compressing the thoracic cage, a fatty infiltration of chest wall and an increase in pulmonary blood volume, might contribute to determine a reduction in lung volumes for a mechanical effect especially in females
]. This is associated with an impairment in the lung inflation-induced airway distensibility and a reduction in airway peripheral diameter, which, over time, alter smooth muscle function thus increasing both airway obstruction and consequently AHR
]. In our study, the FEV1
increase was a protective factor for AHR in both sexes, therefore suggesting that a reduction of lung function may favour AHR. It is likely that the already smaller calibre of airways in females may be influenced by BMI-induced obstruction in a more pronounced fashion than in males. This is supported by other studies who also observed a greater effect of adipose tissue on females’ lung function compared with males’
Another interesting result of this study, as already pointed out, is the different relationship between BMI and AHR at various levels of AHR (mild, moderate and severe) in females. The absence of any associations between BMI and mild AHR is certainly due to the fact that a great proportion of subjects belonging to this group did not result asthmatics. In fact, high values of PD20
, in case of suspected asthma (as in our patients), make an asthma diagnosis less probable
]. It is difficult to explain why BMI and AHR are associated only in moderate hyperresponsive females and not in severe AHR. The factors that contribute to AHR may be divided into two categories: persistent and variable
]. The airway structural changes (i.e. sub-endothelial and sub-basement membrane thickening, smooth muscle hypertrophy, matrix deposition, and altered vascular components - due to the chronic and long standing airway inflammation) represent persistent alterations
]. On the other hand, the variable AHR component is believed to relate to inflammatory airway events, which may vary and be influenced by numerous environmental events (ie, allergens, respiratory infections and treatment)
]. It is logical to hypothesize that these two components are interrelated. Obesity is a chronic inflammatory state
] and may have a variable component role in the bronchial hyperreactivity mechanism. In fact, neutrophilic airways inflammation is increased by obesity and fatty acids in asthma
]. Similarly, weight loss, through bariatric surgery, produces significant reductions in exhaled nitric oxide concentrations in obese asthmatic patients
]. Proinflammatory molecules, expressed by adipose tissue such as leptin, TNF-α, IL-6, TGF- β1, adiponectin and C-reactive protein, increase in obese subjects
], especially in females (above all C-reactive protein and leptin)
]. These obesity factors may interfere with persistent AHR mechanisms and they may be greater in severe than in moderate AHR. In fact, the exhaled nitric oxide level increases significantly with the increasing of the AHR level in asthmatics
]. Patients with intermittent asthma also showed airway inflammation but to a lower extent than those with persistent asthma
]. Therefore, the supposed additional effects of inflammatory components, due to obesity (variable component), may have a lower impact in subjects with severe AHR because they have already a basal high level of asthma induced-inflammation (persistent component). On the other hand, basal airway inflammation may be less extensive in subjects with moderate AHR and therefore the variable inflammatory effect of weight may be greater, thus influencing AHR. In other words, systemic inflammation (BMI-induced) might influence airways inflammation only in asthma mild forms, whereas this influence might be trivial in more severe asthmatics. The fact that we could not find any relationships between BMI and pulmonary function in females with severe AHR strengthens our hypothesis.
Obesity may influence AHR in females with moderate hyperresponsiveness through a greater bronchial obstruction (reduced FEV1
/FVC for unit of BMI increase). Reduction in FEV1
/FVC was also found both in obese children
] and adults
], but not confirmed by Scott et al.
]. This low level of FEV1
/FVC may be a consequence of a systemic inflammation induced by adipose tissues or simply the mechanical effect of weight. When AHR becomes severe, the relationship between BMI and pulmonary function disappears so that we may hypothesize that the factors responsible for AHR may be only due to airway inflammation but probably not to systemic BMI induced inflammation and probably not to mechanical induced obstruction either.