Augmented responses to ozone in obese carboxypeptidase E-deficient mice.
We reported previously that mice obese as a result of leptin deficiency (ob/ob) have enhanced ozone (O3)-induced airway hyperresponsiveness (AHR) and inflammation compared with wild-type (C57BL/6) controls. To determine whether this increased response to O3 was independent of the modality of obesity, we examined O3-induced AHR and inflammation in Cpe(fat) mice. These mice are obese as a consequence of a mutation in the gene encoding carboxypeptidase E (Cpe), an enzyme important in processing prohormones and proneuropeptides involved in satiety and energy expenditure. Airway responsiveness to intravenous methacholine, measured by forced oscillation, was increased in Cpe(fat) vs. wild-type mice after air exposure. In addition, compared with air exposure, airway responsiveness was increased 24 h after O3 exposure (2 ppm for 3 h) in Cpe(fat) but not in wild-type mice. Compared with air-exposed controls, O3 exposure increased bronchoalveolar lavage fluid (BALF) protein, IL-6, KC, MIP-2, MCP-1, and soluble TNF receptors (sTNFR1 and sTNFR2) as well as BALF neutrophils. With the exception of sTNFR1 and sTNFR2, all of these outcome indicators were greater in Cpe(fat) vs. wild-type mice. Serum sTNFR1, sTNFR2, MCP-1, leptin, and blood leukocytes were elevated in Cpe(fat) compared with wild-type mice even in the absence of O3 exposure, similar to the chronic systemic inflammation observed in human obesity. These results indicate that increased O3-induced AHR and inflammation are consistent features of obese mice, regardless of the modality of obesity. These results also suggest that chronic systemic inflammation may enhance airway responses to O3 in obese mice.
Johnston
Richard A
RA
Physiology Program, Department of Environmental Health, Harvard School of Public Health, 665 Huntington Ave., Boston, MA 02115-6021, USA. rajohnst@hsph.harvard.edu
Theman
Todd A
TA
Shore
Stephanie A
SA
D000818:Animals; D015415:Biomarkers; D001835:Body Weight; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D043423:Carboxypeptidase H / Q000172:deficiency* / Q000235:genetics; D005260:Female; D017353:Gene Deletion; D015971:Gene Expression Regulation, Enzymologic; D007249:Inflammation / Q000097:blood / Q000139:chemically induced / Q000473:pathology; D008168:Lung / Q000187:drug effects / Q000502:physiology; D008171:Lung Diseases / Q000139:chemically induced / Q000235:genetics / Q000503:physiopathology; D008297:Male; D051379:Mice; D009765:Obesity / Q000503:physiopathology*; D009929:Organ Size; D010126:Ozone / Q000494:pharmacology*; D012119:Respiration
D015415:Biomarkers; D010126:Ozone; D043423:Carboxypeptidase H