Diet-induced obesity causes innate airway hyperresponsiveness to methacholine and enhances ozone-induced pulmonary inflammation

Abstract

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...

Obesity Is Associated with Neutrophil Dysfunction and Attenuation of Murine Acute Lung Injury

“…Previous work has suggested that obesity may have an attenuating effect on hyperoxic and ozone-induced lung injury models, although in the case of ozone exposure findings are mixed and appear to vary with the acuity of exposure and possibly the timing of examination (22,32,33). These findings, in light of the early evidence that obesity may have a protective effect in human ALI/ARDS (7,34,35), suggest that a clinically relevant alteration in the acute pulmonary inflammatory response may be associated with weight gain.…”

Mechanisms of Asthma in Obesity. Pleiotropic Aspects of Obesity Produce Distinct Asthma Phenotypes

“…Obese mice fed a high-fat diet develop increased airway reactivity only after a certain age and weight: for example, 20-to 22-week-old C57BL/6 mice (average weight, 43 g) fed a high-fat diet did not have increased airway reactivity compared with mice fed a low-fat diet, whereas 30-to 38 week-old-mice (average weight 50 g) did (19). These results suggest that an interaction between aging and weight gain may contribute to the inherent airway reactivity of obesity, and more studies on this are needed in humans.…”

Obesity, Nutrition, and Asthma in Children

“…Largely through the work of Shore et al, molecular and physiologic characteristics of the murine model of obese asthma are currently being elucidated. 23,[26][27][28][29][30][31][32][33][34] However, assessing lung inflammation and lung responses among obese children remains challenging and limited by current technologies. Studies in children involving bronchodilator responsiveness, bronchoconstricting agonists (e.g., methacholine challenge), and airway inflammatory markers have yet to show the same consistent pattern of hyperresponsiveness that have been demonstrated in mice.…”