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Metabolic Syndrome

Augmented responses to ozone in obese carboxypeptidase E-deficient mice

Physiology Program, Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts

Submitted 29 April 2005 ; accepted in final form 7 July 2005

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.

airway hyperresponsiveness; leptin; monocyte chemotactic protein-1; neutrophil; airway resistance

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