Responses to ozone (O3), an asthma trigger, are increased in obese (ob/ob) mice lacking the satiety hormone leptin. The long form of leptin receptor (Ob-Rb) is required for satiety; mice lacking this receptor (db/db mice) are also substantially obese. Here, wild-type (WT) and db/db mice were exposed to air or O3 (2 ppm) for 3 h. Airway responsiveness, measured by the forced oscillation technique, was greater in db/db than WT mice after air exposure. O3-induced increases in pulmonary resistance and airway responsiveness were also greater in db/db mice. BALF eotaxin, IL-6, KC, and MIP-2 increased 4 h after O3 exposure and subsided by 24 h, whereas protein and neutrophils continued to increase through 24 h. For each outcome, the effect of O3 was significantly greater in db/db than WT mice. Previously published results obtained in ob/ob mice were similar except for O3-induced neutrophils and MIP-2, which were not different from WT mice. O3 also induced pulmonary IL-1␤ and TNF-␣ mRNA expression in db/db but not ob/ob mice. Leptin was increased in serum of db/db mice, and pulmonary mRNA expression of short form of leptin receptor (Ob-Ra) was similar in db/db and WT mice. These data confirm obese mice have innate airway hyperresponsiveness and increased pulmonary responses to O3. Differences between ob/ob mice, which lack leptin, and db/db mice, which lack Ob-Rb but not Ob-Ra, suggest leptin, acting through Ob-Ra, can modify some pulmonary responses to O3. leptin; interleukin-1␤; airway responsiveness; macrophage inflammatory protein-2; neutrophil; ventilation EPIDEMIOLOGICAL DATA INDICATE that the prevalence of asthma is increased in the obese (21). Studies using objective measures of asthma, such as bronchodilator response, peak flow variability, or airway responsiveness, have confirmed this association (12,13,15,56). It is likely that obesity either causes or worsens asthma. Longitudinal studies indicate that obesity antedates asthma and that the relative risk of incident asthma increases with increasing body mass index (11,12,43). Furthermore, morbidly obese asthmatics studied after weight loss exhibit decreased severity and symptoms of asthma (1,24,53). Obesity may be particularly important for severe asthma since Ͼ75% of those visiting the emergency room for asthma are obese or overweight (56). In addition, ϳ70% of severe asthmatics are obese (2), and in women, asthma severity increases with body mass index (59).We have been investigating animal models that can be used to examine the mechanistic basis for the relationship between obesity and asthma. Ob/ob mice are genetically deficient in leptin, a satiety hormone, and Cpe fat mice are genetically deficient in carboxypeptidase E, an enzyme involved in processing of neuropeptides involved in satiety. Both ob/ob and Cpe fat mice are obese, and both types of mice exhibit innate airway hyperresponsiveness (AHR), a characteristic feature of asthma (36,46,50). In addition, in both ob/ob and Cpe fat mice, airway responses to ozone (O 3 ), a common asthma trigger, are au...

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.

These results demonstrate that obesity enhances OVA-induced changes in pulmonary resistance and serum IgE and that these changes are not the result of increased Th2 type airway inflammation.

Johnston RA, Theman TA, Lu FL, Terry RD, Williams ES, Shore SA. Diet-induced obesity causes innate airway hyperresponsiveness to methacholine and enhances ozone-induced pulmonary inflammation. J Appl Physiol 104: 1727-1735, 2008. First published March 6, 2008 doi:10.1152/japplphysiol.00075.2008.-We previously reported that genetically obese mice exhibit innate airway hyperresponsiveness (AHR) and enhanced ozone (O3)-induced pulmonary inflammation. Such genetic deficiencies in mice are rare in humans, and they may not be representative of human obesity. Thus the purpose of this study was to determine the pulmonary phenotype of mice with diet-induced obesity (DIO), which more closely mimics the cause of human obesity. Therefore, wild-type C57BL/6 mice were reared from the time of weaning until at least 30 wk of age on diets in which either 10 or 60% of the calories are derived from fat in the form of lard. Body mass was ϳ40% greater in mice fed 60 vs. 10% fat diets. Baseline airway responsiveness to intravenous methacholine, measured by forced oscillation, was greater in mice fed 60 vs. 10% fat diets. We also examined lung permeability and inflammation after exposure to room air or O3 (2 parts/million for 3 h), an asthma trigger. Four hours after the exposure ended, O3-induced increases in bronchoalveolar lavage fluid protein, interleukin-6, KC, macrophage inflammatory protein-2, interferon-␥-inducible protein-10, and eotaxin were greater in mice fed 60 vs. 10% fat diets. Innate AHR and augmented responses to O3 were not observed in mice raised from weaning until 20 -22 wk of age on a 60% fat diet. These results indicate that mice with DIO exhibit innate AHR and enhanced O3-induced pulmonary inflammation, similar to genetically obese mice. However, mice with DIO must remain obese for an extended period of time before this pulmonary phenotype is observed. bronchoalveolar lavage fluid; chemokine; leptin; lung elastance; resistance OBESITY IS AN IMPORTANT PUBLIC health problem that is associated with several respiratory diseases, including obesity-hypoventilation syndrome, obstructive sleep apnea, and asthma (14,15,53). Epidemiological studies indicate an increased incidence of asthma, wheezing, or airway hyperresponsiveness (AHR) in overweight or obese children, adolescents, and adults (14, 53). The relationship between obesity and asthma is likely to be a causal one, because longitudinal studies controlling for a number of potential confounders, including physical activity, indicate that the relative risk of incident asthma progressively increases with increasing body mass index and that obesity antedates asthma (6,7,18,41). Furthermore, morbidly obese asthmatic individuals examined after diet-or surgically induced weight loss report a decrease in both the severity and symptoms of asthma (38,42,56,57).Our laboratory has been utilizing murine models of obesity to explore the mechanistic basis for the relationship between obesity and asthma. Our laboratory has reported that obese mice exhibit innate AHR (29,30,37,48...

Autosomal dominant hypocalcemia (ADH) is an inherited form of hypoparathyroidism caused by activating mutations in the calcium-sensing receptor (CaR). Treatment with PTH(1-34) may be superior to conventional therapy but is contraindicated in children, and long-term effects on the skeleton are unknown. The patient is a 20-yr-old female with ADH treated with PTH continuously since 6 yr and 2 mo of age. A bone biopsy was obtained for histomorphometry and quantitative backscattered electron imaging (qBEI). Her data were compared with one age-, sex-, and length of hypoparathyroidism-matched control not on PTH and two sex-matched ADH controls before and after 1 yr of PTH. The patient's growth was normal. Hypercalciuria and hypermagnesuria persisted despite normal or subnormal serum calcium and magnesium levels. Nephrocalcinosis, without evidence of impaired renal function, developed by 19 yr of age. Cancellous bone volume was dramatically elevated in the patient and in ADH controls after 1 yr of PTH. BMD distribution (BMDD) by qBEI of the patient and ADH controls was strikingly shifted toward lower mineralization compared with the non-ADH control. Moreover, the ADH controls exhibited a further reduction in mineralization after 1 yr of PTH. These findings imply a role for CaR in bone matrix mineralization. There were no fractures or osteosarcoma. In conclusion, long-term PTH replacement in a child with ADH was not unsafe, increased bone mass without negatively impacting mineralization, and improved serum mineral control but did not prevent nephrocalcinosis. Additionally, this may be the first evidence of a role for CaR in human bone.