Augmented responses to ozone in obese carboxypeptidase E-deficient mice

Johnston, Richard A.; Theman, Todd A.; Shore, Stephanie A.

doi:10.1152/ajpregu.00306.2005

Cited by 80 publications

(154 citation statements)

References 63 publications

(88 reference statements)

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“…A similar result was found in the Normative Aging Study (9). Several experimental studies in mice have identified augmented responses to ozone in obese animals (26,27). A recent experimental study in mice found that adiponectin, which is deficient in the obese, protects against the inflammatory effects of ozone exposure (31).…”

Section: Discussionmentioning

confidence: 99%

Short-Term Exposure to Air Pollution and Lung Function in the Framingham Heart Study

Rice

Ljungman²,

Wilker³

et al. 2013

Am J Respir Crit Care Med

172

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Rationale: Short-term exposure to ambient air pollution has been associated with lower lung function. Few studies have examined whether these associations are detectable at relatively low levels of pollution within current U.S. Environmental Protection Agency (EPA) standards. Objectives: To examine exposure to ambient air pollutants within EPA standards and lung function in a large cohort study. Methods: We included 3,262 participants of the Framingham Offspring and Third Generation cohorts living within 40 km of the Harvard Supersite monitor in Boston, Massachusetts (5,358 examinations, 1995Massachusetts (5,358 examinations, -2011) who were not current smokers, with previousday pollutant levels in compliance with EPA standards. We compared lung function (FEV 1 and FVC) after previous-day exposure to particulate matter less than 2.5 mm in diameter (PM 2.5 ), nitrogen dioxide (NO 2 ), and ozone (O 3 ) in the "moderate" range of the EPA Air Quality Index to exposure in the "good" range. We also examined linear relationships between moving averages of pollutant concentrations 1, 2, 3, 5, and 7 days before spirometry and lung function. Measurements and Main Results: Exposure to pollutant concentrations in the "moderate" range of the EPA Air Quality Index was associated with a 20.1-ml lower FEV 1 for PM 2.5 (95% confidence interval [CI], 233.4, 26.9), a 30.6-ml lower FEV 1 for NO 2 (95% CI, 260.9, 20.2), and a 55.7-ml lower FEV 1 for O 3 (95% CI, 2100.7, 210.8) compared with the "good" range. The 1-and 2-day moving averages of PM 2.5 , NO 2 , and O 3 before testing were negatively associated with FEV 1 and FVC.Conclusions: Short-term exposure to PM 2.5 , NO 2 , and O 3 within current EPA standards was associated with lower lung function in this cohort of adults.Keywords: chronic obstructive pulmonary disease; asthma; air pollutants; U.S. Environmental Protection Agency A substantial body of evidence has shown that modest shortterm increases in ambient air pollution, especially PM 2.5 (particles with an aerodynamic diameter < 2.5 mm) and ground level ozone (O 3 ), but also nitrogen dioxide (NO 2 ), increase risk of hospitalization for chronic obstructive pulmonary disease (COPD) and respiratory mortality (1-4). Several studies have found that short-term (1-3 d) increases in PM 2.5 , NO 2 , and O 3 are associated with decreases in FEV 1 , FVC, and/or peak expiratory flow rate in healthy subjects (5-11) and in those with preexisting COPD or asthma (12)(13)(14)(15).Air quality has improved substantially since the 1980s and 1990s, when many epidemiologic investigations of lung function and air pollution were completed (16). To protect public health and in accordance with its mandate, the EPA has continued to review the latest evidence and reevaluate air quality standards. Recently, the EPA lowered the annual standard for PM 2.5 from 15 to 12 mg/m 3 and reduced the daily Air Quality Index (AQI) cut-off for "moderate" PM 2.5 from 15.4 to 12 mg/m 3 . It remains unclear whether acute effects of criteria air pollutants (inclu...

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Section: Discussionmentioning

confidence: 99%

Short-Term Exposure to Air Pollution and Lung Function in the Framingham Heart Study

Rice

Ljungman²,

Wilker³

et al. 2013

Am J Respir Crit Care Med

172

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“…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 augmented (36,50). Together, these results suggest that the effects of obesity on airway function are independent of the modality of obesity.…”

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confidence: 99%

“…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 augmented (36, 50).…”

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confidence: 99%

“…However, differences exist between ob/ob and Cpe fat mice with respect to their airway responses to O 3 . For example, O 3 -induced increases in bronchoalveolar lavage (BAL) neutrophils are greater in Cpe fat than in wild-type mice (36), whereas this is not the case in ob/ob mice even though certain BAL inflammatory cytokines and chemokines are elevated in ob/ob vs. wild-type mice (50). These differences may be related to the satiety hormone leptin, which is proinflammatory (32).…”

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confidence: 99%

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Increased pulmonary responses to acute ozone exposure in obese db/db mice

Lu¹,

Johnston²,

Flynt³

et al. 2006

American Journal of Physiology-Lung Cellular and Molecular Phys

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129

151

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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...

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“…Previous murine studies investigating the role of leptin in the pulmonary compartment during pneumococcal pneumonia (38), experimental tuberculosis (35), and ozone-induced airway hyperresponsiveness (39,40) suggested that the presence of leptin is likely required for effective balancing of the neutrophilic response in the pulmonary compartment induced by various triggers. One mechanism by which leptin may modulate trafficking of neutrophils in response to these triggers including CS is the induction of neutrophilic chemokines, such as CXCL1, by resident lung cells.…”

Section: Figurementioning

confidence: 99%

Leptin Modulates Innate and Adaptive Immune Cell Recruitment after Cigarette Smoke Exposure in Mice

Vernooy¹,

Bracke

Drummen³

et al. 2010

The Journal of Immunology

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Leptin, a pleiotropic type I cytokine, was recently demonstrated to be expressed by resident lung cells in chronic obstructive pulmonary disease patients and asymptomatic smokers. To elucidate the functional role of leptin in the onset of chronic obstructive pulmonary disease, we tested leptin-deficient ob/ob mice (C57BL/6), leptin receptor-deficient db/db mice (C57BKS), and littermates in a model of cigarette smoke (CS)-induced pulmonary inflammation. Wild-type (WT) C57BL/6 mice were exposed for 4 or 24 wk to control air or CS. Pulmonary leptin expression was analyzed by immunohistochemistry and real-time PCR. Pulmonary inflammation upon 4 wk CS exposure was evaluated in bronchoalveolar lavage fluid (BALF) and lung tissue of WT, ob/ob, and db/db mice. Immunohistochemical analysis revealed leptin expression in bronchial epithelial cells, pneumocytes, alveolar macrophages, and bronchial/vascular smooth muscle cells. The 4 and 24 wk CS exposure increased leptin expression in bronchial epithelial cells and pneumocytes versus air-exposed WT mice (p < 0.05). The 4 wk CS exposure resulted in increased accumulation of neutrophils, dendritic cells, macrophages, and lymphocytes in BALF and lung tissue of WT, ob/ob, and db/db mice. CS-exposed ob/ob and db/db mice showed in general higher numbers of neutrophils and lower numbers of CD4+, CD8+, and dendritic cells versus CS-exposed WT mice. Consistently, CXCL1 levels were enhanced in BALF of CS-exposed ob/ob and db/db mice versus WT mice (p < 0.05). Exogenous leptin administration completely restored the skewed inflammatory profile in ob/ob mice. These data reveal an important role of leptin in modulating innate and adaptive immunity after CS inhalation in mice.

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Augmented responses to ozone in obese carboxypeptidase E-deficient mice

Cited by 80 publications

References 63 publications

Short-Term Exposure to Air Pollution and Lung Function in the Framingham Heart Study

Short-Term Exposure to Air Pollution and Lung Function in the Framingham Heart Study

Increased pulmonary responses to acute ozone exposure in obese db/db mice

Leptin Modulates Innate and Adaptive Immune Cell Recruitment after Cigarette Smoke Exposure in Mice

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