Onset of obesity in carboxypeptidase E-deficient mice and effect on airway responsiveness and pulmonary responses to ozone

Johnston RA, Zhu M, Hernandez CB, Williams ES, Shore SA. Onset of obesity in carboxypeptidase E-deficient mice and effect on airway responsiveness and pulmonary responses to ozone. J Appl Physiol 108: 1812-1819, 2010. First published March 18, 2010; doi:10.1152/japplphysiol. 00784.2009.-When compared with lean, wild-type mice, obese Cpe(fat) mice, 14 wk of age and older, manifest innate airway hyperresponsiveness (AHR) to intravenous methacholine and enhanced pulmonary inflammation following acute exposure to ozone (O-3). The purpose of this study was to examine the onset of these augmented pulmonary responses during the onset of obesity. Thus airway responsiveness and O-3-induced pulmonary inflammation and injury were examined in 7- and 10-wk-old Cpe(fat) and age-matched, wild-type, C57BL/6 mice. Compared with age-matched controls, 7- and 10-wk-old Cpe(fat) mice were approximately 25 and 61% heavier, respectively. Airway responsiveness to intravenous methacholine was assessed via forced oscillation in unexposed Cpe(fat) and wild-type mice. The 10- but not 7-wk-old Cpe(fat) mice exhibited innate AHR. O-3 exposure (2 ppm for 3 h) increased markers of pulmonary inflammation and injury in the bronchoalveolar lavage fluid of all mice. However, most markers were greater in Cpe(fat) vs. wild-type mice, regardless of age. Serum levels of leptin, a satiety hormone and proinflammatory cytokine, were increased in Cpe(fat) vs. wild-type mice of both age groups, but the serum levels of other systemic inflammatory markers were greater only in 10- wk-old Cpe(fat) vs. wild-type mice. These results demonstrate that a 25% increase in body weight is sufficient to augment pulmonary responses to O-3, but innate AHR is not manifest until the mice become much heavier. These results suggest that the mechanistic bases for these responses are different and may develop according to the nature and degree of the chronic systemic inflammation that is present.