Faculty Bibliography

Acute exposure to ozone (O3), an air pollutant, causes pulmonary inflammation, airway epithelial desquamation, and airway hyperresponsiveness (AHR). Pro-inflammatory cytokines, including interleukin (IL)-6 and ligands of chemokine (C-X-C motif) receptor 2 [keratinocyte chemoattractant (KC) and macrophage inflammatory protein (MIP)-2], tumor necrosis factor (TNF) receptor 1 and 2 (TNF), and type I IL-1 receptor (IL-1alpha and IL-1beta), promote these sequelae. Human resistin, a pleiotropic hormone and cytokine, induces expression of IL-1alpha, IL-1beta, IL-6, IL-8 (the human ortholog of murine KC and MIP-2), and TNF. Functional differences exist between human and murine resistin, yet given the aforementioned observations, we hypothesized that murine resistin promotes O3-induced lung pathology by inducing expression of the same inflammatory cytokines as human resistin. Consequently, we examined indices of O3-induced lung pathology in wild-type and resistin-deficient mice following acute exposure to either filtered room air or O3. In wild-type mice, O3 increased bronchoalveolar lavage fluid (BALF) resistin. Furthermore, O3 increased lung tissue or BALF IL-1alpha, IL-6, KC, TNF, macrophages, neutrophils, and epithelial cells in wild-type and resistin-deficient mice. With the exception of KC, which was significantly greater in resistin-deficient as compared to wild-type mice, no genotype-related differences in the other indices existed following O3 exposure. O3 caused AHR to acetyl-beta-methylcholine chloride (methacholine) in wild-type and resistin-deficient mice. However, genotype-related differences in airway responsiveness to methacholine were non-existent subsequent to O3 exposure. Taken together, these data demonstrate that murine resistin is increased in the lungs of wild-type mice following acute O3 exposure but does not promote O3-induced lung pathology.

Atopic, obese asthmatics exhibit airway obstruction with variable degrees of eosinophilic airway inflammation. We previously reported that mice obese as a result of a genetic deficiency in either leptin (ob/ob mice) or the long isoform of the leptin receptor (db/db mice) exhibit enhanced airway obstruction in the presence of decreased numbers of bronchoalveolar lavage fluid (BALF) eosinophils compared with lean, wild-type mice following antigen (ovalbumin; OVA) sensitization and challenge. To determine whether the genetic modality of obesity induction influences the development of OVA-induced airway obstruction and OVA-induced pulmonary inflammation, we examined indices of these sequelae in mice obese as a result of a genetic deficiency in carboxypeptidase E, an enzyme that processes prohormones and proneuropeptides involved in satiety and energy expenditure (Cpe(fat) mice). Accordingly, Cpe(fat) and lean, wild-type (C57BL/6) mice were sensitized to OVA and then challenged with either aerosolized PBS or OVA. Compared with genotype-matched, OVA-sensitized and PBS-challenged mice, OVA sensitization and challenge elicited airway obstruction and increased BALF eosinophils, macrophages, neutrophils, IL-4, IL-13, IL-18, and chemerin. However, OVA challenge enhanced airway obstruction and pulmonary inflammation in Cpe(fat) compared with wild-type mice. These results demonstrate that OVA sensitization and challenge enhance airway obstruction in obese mice regardless of the genetic basis of obesity, whereas the degree of OVA-induced pulmonary inflammation is dependent on the genetic modality of obesity induction. These results have important implications for animal models of asthma, as modeling the pulmonary phenotypes for subpopulations of atopic, obese asthmatics critically depends on selecting the appropriate mouse model.