Numerous studies (Folinsbee and Hazucha, 1989
, Hazucha et al, 1989
, Hazucha et al., 2003
, Horvath et al, 1981
, Linn et al, 1986
, McDonnell et al, 1983
, McDonnell et al, 1993
, Passannante et al, 1998
, Rivera-Sanchez et al, 2004
, Weinmann et al, 1995
) have established that ozone exposure of healthy individuals results in acute, but reversible impairment of pulmonary function, modestly increased airway resistance (McDonnell et al, 1983
), and airways hyperreactivity (Seltzer et al, 1986
). The primary mechanism associated with the spirometric response to ozone exposure is a reflex nociceptive inhibition of inspiration (Hazucha et al, 1989
, Passannante et al, 1998
) that likely originates from bronchial C fibers. However, other mechanisms including inflammation and airway hyperresponsiveness likely play some role (Passannante et al, 1998
). A number of potential factors, including age, gender, race and antioxidant intake, have been evaluated as modifiers of responsiveness of humans to ozone (Hazucha et al., 2003
, McDonnell et al, 1993
). Recent data from mice (Rivera-Sanchez et al, 2004
, Shore et al, 2003
), suggest that obesity may also modulate the response to ozone. Genetically obese mice showed greater post-ozone airway hyperreactivity to methacholine and greater airway inflammation than wild type mice exposed under the same conditions (Shore et al, 2003
). Obese mice also had significant changes in airway and parenchymal mechanics in response to ozone while wild-type mice did not (Rivera-Sanchez et al, 2004
). We have found, for the first time in humans, that a respiratory response to ozone, in our study spirometry, may increase with greater adiposity, as measured by body mass index. It is notable that we observed this association in a population of predominantly normal weight individuals.
We found some suggestive evidence for a greater effect of BMI on ozone response in women. When we classified subjects according to standard classifications of body weight, among women the spirometric response to ozone increased across the three categories of underweight, normal weight and overweight. One factor that could explain the clearer signal in women is that the range of BMI was greater in our women (15.7-33.4 kg/m2
) than in the men (19.1-32.9 kg/m2
); none of the men would be classified as underweight (BMI < 18.5) (). We may therefore have had greater power to find an association among women than among men. However, even disregarding the five underweight women, we found a greater ozone response in the overweight and obese category (BMI > 25), compared with the normal weight group (BMI 18.5-24.9). This was seen for all parameters in both genders but attained statistical significance only for FVC in females. For FVC, this difference was significantly greater in women (P = 0.03). It is also possible that we observed a clearer relation between BMI and ozone response in women because BMI may be a better measure of adiposity in women than in men; for a given level of BMI, women have a higher percent body fat (Gallagher et al, 1996
). To the extent that the percent body fat may play a role in modulating ozone response, we would have better ability to observe an effect in women then men based on BMI alone as an index of adiposity. Clearly in future studies of the possible effects of obesity on ozone response, multiple measures of adiposity, including waist circumference and percent body fat, would be desirable. Further, it is possible that the associations that we observed would be stronger with better measures of obesity in both men and women.
The rationale for normalizing ventilation (Ve) to body size was based on the desire to exercise individuals at similar relative work efforts and metabolic requirements. This commonly used normalization in ozone exposure protocols also presumes that larger individuals (based on height) will have larger lung volumes as well (Knudsen et al, 1983) and therefore inhaled ozone dose will be normalized to an individual's lung volume. illustrates that within this group of subjects there was no significant effect of Ve on Δ FEV1, despite the fact that there was a very large range of Ve. The trend was actually for the decrement in FEV1 to decrease with increasing Ve in the women, i.e. opposite slope to that of BMI vs. Δ FEV1, . When we included Ve as a variable in the multiple regression of ozone-induced decrements, , it was not a significant predictor of these decrements, while BMI still predicted the ozone effects in women, indicating that the effect of BMI is independent of any variability in Ve. These data indicate that our normalization of Ve to body surface area (BSA), and the resulting intersubject variability in Ve during exposure, had no effect on the variation in lung function decrements induced by exposure to a relatively high ozone concentration. The reason that intersubject variation in Ve has no observable effect on ozone induced decrements in lung function under our exposure conditions (90 minutes at 0.42 ppm ozone) may be because most subjects were at or near their maximum acute responsiveness (i.e. the plateau of their dose response curve for spirometric decrements) (McDonnell et al, 1983
) and thus differences in dose by variable Ve had little or no further influence. On the other hand, we show that the intersubject variation in BMI slightly modified the intersubject variability in this maximum acute spirometric response.
The physiologic mechanisms responsible for the greater decline in spirometric volumes and flows after ozone exposure with increasing BMI are not clear. We considered the possibility that the decreased lung volumes with increased BMI may influence relative ozone dose to lung tissue. However, while it has been observed that the obese have lower lung volumes than normal weight individuals (King et al, 2005
) there was no significant relationship between BMI and baseline FVC (i.e. an index of lung volume) in our data (for all subjects or for females alone, e.g. r = 0.01 for females). Obese humans are also known to breathe with relatively smaller tidal volumes than normal weight individuals (Sampson and Grassino, 1983
), resulting in reduced stretching of lung tissue that might play a role in the increased responsiveness to ozone with BMI. However, in the subset of 127 (80M/47F) subjects with minute ventilation measurements, tidal volumes actually tended to increase with BMI, though not significantly [r = 0.13 in all subjects (P = 0.15) and r = 0.11 in females (P = 0.44)]. Finally, breathing frequency may also affect ozone dose to the lung by determining the residence time of ozone within the airways. But, again there was no relationship between BMI and breathing frequency among the subjects for whom ventilation data was recorded (r = 0.05, NS). Interestingly, spirometric responsiveness increased with higher breathing frequency during exercise in all subjects (r = − 0.24 for ΔFEV1 vs. frequency, P < 0.01), reflecting the fact that increased breathing frequency during exercise is another measure of increased ozone responsiveness (McDonnell et al, 1983
A number of circulating hormones and other inflammatory factors (e.g. leptin, adiponectin, and plasminogen activator inhibitor) derived from adipose tissue (Nawrocki et al, 2004
, Rajala and Scherer, 2003
) might affect airway function and responsiveness to ozone. These hormones/factors have been shown to affect airway hyper-responsiveness and inflammation in animal models, either as pro- or anti-inflammatory modulators (Savov et al, 2003
, Shore et al, 2003
, Shore et al, 2005
). If these adipocyte-derived factors play a role in the spirometric response we observed, then the fact that females have a considerably greater percent body fat for a given BMI than males (Gallagher et al, 1996
) may explain our ability to observe a more significant relationship among women. Future studies incorporating markers of inflammation from adipose tissue would help address mechanistic questions.
Ozone-induced spirometric decrements are vagally mediated through nociceptive sensory neurons (Beckett et al, 1985
, Passannante et al, 1998
). Thus, the question arises as to whether modulation of vagal responses might vary with BMI. For example, it may be that circulating catecholamines such as epinephrine can interfere with or inhibit these vagal reflexes. There is some evidence for this in the cardiovascular system where increased alpha-adrenergic agonists appear to interfere with the baroreceptor control of blood pressure and heart rate (Airaksinen et al, 2001
). Reims et al (2004)
recently reported that overweight men had lower plasma epinephrine levels. Unfortunately, there have been no studies designed to assess a possible role of sympathetic modulation on ozone-induced spirometric responses.
Our study has a number of important limitations. We did not have measures of systemic or airway inflammation, nor of airway hyperresponsiveness. However, in addition to greater increase in airway responsiveness and inflammation (Shore et al, 2003
), the obese mice also had greater changes in airway and parenchymal mechanics in response to ozone than wild-type mice (Rivera-Sanchez et al, 2004
). Also, we had only one measure of adiposity (BMI) and are lacking measures of central obesity that may be more relevant to the mouse models. Further, as these subjects were not selected with the study of BMI in mind, we had a paucity of obese individuals. While there was no exclusion based on subject weight, there may have been some recruitment bias based on a subject's ability to perform the treadmill exercise during the exposures.
A major strength of this study is that we were able to examine a measure of adiposity in relation to acute spirometric response to ozone in a substantial number of healthy individuals. We found, for the first time, that body mass index was positively related to greater acute spirometric response to controlled ozone exposure. Other studies have recently shown important particle deposition/responsiveness relationships with BMI, with few or no obese subjects in their analysis: e.g. 1) Bennett and Zeman (2004)
showed greater fine particle deposition in children with increasing BMI, rather than obesity, and 2) Alexis and Peden (2006)
showed greater responsiveness to inhaled endotoxin in asthmatics with increasing BMI, with no truly obese subjects in their population. Our findings add to this small body of data for variation in air pollution effects based on variation in BMI rather than frank obesity. Future studies with targeted selection of obese and lower weight subjects and additional adiposity and outcome measures would better elucidate the relationship between obesity and ozone response in humans.