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In this study, we examined the role of neprilysin (NEP), a key membrane-bound endopeptidase, in the inflammatory response induced by diesel exhaust emissions (DEE) in the airways through a number of approaches: in vitro, animal, and controlled human exposure. Our specific aims were (1) to examine the role of NEP in inflammatory injury induced by diesel exhaust particles (DEP) using Nep-intact (wild-type) and Nep-null mice; (2) to examine which components of DEP are associated with NEP downregulation in vitro; (3) to determine the molecular impact of DEP exposure and decreased NEP expression on airway epithelial cells' gene expression in vitro, using a combination of RNA interference (RNAi) and microarray approaches; and (4) to evaluate the effects on NEP activity of human exposure to DEE. We report four main results: First, we found that exposure of normal mice to DEP consisting of standard reference material (SRM) 2975 via intratracheal installation can downregulate NEP expression in a concentration-dependent manner. The changes were accompanied by increases in the number of macrophages and epithelial cells, as well as proinflammatory cytokines, examined in bronchoalveolar lavage (BAL) fluid and cells. Nep-null mice displayed increased and/or additional inflammatory responses when compared with wild-type mice, especially in response to exposure to the higher dose of DEP that we used. These in vivo findings suggest that loss of NEP in mice could cause increased susceptibility to injury or exacerbate inflammatory responses after DEP exposure via release of specific cytokines from the lungs. Second, we found evidence, using in vitro studies, that downregulation of NEP by DEP in cultured human epithelial BEAS-2B cells was mostly attributable to DEP-adsorbed organic compounds, whereas the carbonaceous core and transition metal components of DEP had little or no effect on NEP messenger RNA (mRNA) expression. This NEP downregulation was not a specific response to DEP or its contents because the change also occurred after exposure to urban dust (SRM 1649a), which differs in physical and chemical composition from DEP. Third, we also collected the transcriptome profiles of the concentration-effects of SRM 2975 in cultured BEAS-2B cells through a 2 X 3 factorial design. DEP exposure upregulated 151 genes and downregulated 59 genes. Cells with decreased NEP expression (accomplished by transfecting an NEP-specific small interfering RNA [siRNA]) substantially altered the expression of genes (upregulating 17 and downregulating 14) associated with DNA/protein binding, calcium channel activities, and the cascade of intracellular signaling by cytokines. Data generated from the combined RNAi and microarray approaches revealed that there is a complex molecular cascade mediated by NEP in different subcellular compartments, possibly influencing the inflammatory response. Fourth, in a controlled human exposure study, we observed significant increases in soluble NEP in sputum after acute exposure to DEE, with an average net increase of 31%. We speculate that the change in NEP activity in sputum, if confirmed in larger epidemiologic investigations at ambient exposure levels to DEE, may provide a useful endpoint and promote insight into the mechanism of DEE-induced airway alterations.

Background: For several years, asthma and COPD have been regarded as distinct entities, with distinct clinical courses. However, despite distinctive physiologic features at the time of diagnosis, and different risk factors, the two diseases over lime may develop features that are quite similar. Study objective: To evaluate the association between physician-diagnosed asthma and the subsequent development of COPD in a cohort of 3,099 adult subjects from Tucson, AZ. Design and methods: A prospective observational study. Participants completed up to 12 standard respiratory questionnaires and 11 spirometry lung function measurements over a period of 20 years. Survival curves (with time to development of COPD as the dependent variable) were compared between subjects with asthma and subjects without asthma at the initial survey. Results: Subjects with active asthma (n = 192) had significantly higher hazard ratios than inactive (n = 156) or nonasthmatic subjects (n = 2751) for acquiring COPD. As compared with nonasthmatics, active asthmatics had a 10-times-higher risk for acquiring symptoms of chronic bronchitis (95% confidence interval LICIII, 4.94 to 20.25), 17-times-higher risk of receiving a diagnosis of emphysema (95% CI, 8.31 to 34.83), and 12.5-times-higher risk of fulfilling COPD criteria (95% CI, 6.84 to 22.84), even after adjusting for smoking history and other potential confounders. Conclusions: Physician-diagnosed asthma is significantly associated with an increased risk for CB, emphysema, and COPD. [ABSTRACT FROM AUTHOR]

Background: Recent studies have suggested a relationship between asthma and obesity. Despite these reports, the effect of being underweight or overweight as a risk factor for airway obstructive diseases (AODs) is not clear. Objectives: To determine whether a relation of body mass index (BMI) to asthma, chronic bronchitis (CB), or emphysema exists (analysis 1), and, if so, whether the association between obesity and asthma is modified by gender (analysis 2). Design: Nested case-control study from the longitudinal cohort of the Tucson Epidemiologic Study of Airways Obstructive Diseases. Patients: Analysis 1: physician-confirmed incident cases of asthma (n = 102), CB (n = 299), or emphysema (n = 72) who denied any prior AODs. Analysis 2: all 169 incident cases of asthma, regardless of any previous AODs, stratified by gender and by other potential effect modifiers. In both analyses, we selected only subjects at least 20 years old who had weight and height measured during the study. Measurements: BMI and other risk factors were assessed prior to the onset of the AOD (cases) or prior to the last completed survey (control subjects). Results: A diagnosis of emphysema was significantly associated with a BMI < 18.5 (odds ratio [OR], 2.97; 95% confidence interval [CI], 1.33 to 6.68, when compared to healthy control subjects). A BMI ≥ 28 increased the risk of receiving a diagnosis of asthma (OR, 2.10; 95% CI, 1.31 to 3.36) and CB (OR, 1.80; 95% CI, 1.32 to 2.46). About 30% of the patients with asthma and 25% of the patients with CB (vs 16% of the control subjects, p < 0.001) were preobese or obese, regardless whether BMI was assessed before the diagnosis or before the onset of respiratory symptoms. The relation of elevated BMI to asthma was significant only among women. Conclusions: Patients with emphysema are more likely to be underweight, and patients with CB are more likely to be obese. However, the temporal relationship between abnormal BMI and the onset of COPD is... [ABSTRACT FROM AUTHOR]

Study Objectives: To determine predictors of oxygen desaturation during submaximal exercise in patients with various lung diseases.Design and Setting: This retrospective case series used pulmonary function laboratory results from all patients referred to a major tertiary-care center.Patients and Measurements: All patients > or = 35 years old who underwent spirometry, diffusing capacity of the lung for carbon monoxide (DLCO), lung volumes, and pulse oximetry during 3-min submaximal step-test exercise during 1996 were included (4,545 men and 3,472 women). Logistic regression models, correcting for gender, age, and weight, determined the odds ratios (ORs) for oxygen desaturation of > or = 4% during exercise for each category of lung function abnormality (compared to those with entirely normal lung function).Results: Approximately 74% of the patients had airways obstruction, while only 5.6% had restriction of lung volumes. One third of those with obstruction had a low DLCO, compared to 56% with restriction, while 2.7% had a low DLCO without obstruction or restriction. The risk of oxygen desaturation during submaximal exercise was very high (OR, 34) in patients with restriction and low DLCO (as in interstitial lung disease) and in patients with obstruction and low DLCO (as in COPD; OR, 18), intermediate (OR, 9) in patients with only a low DLCO, and lowest in those with a normal DLCO (OR, 4 if restricted; OR, 2 if obstructed). A cut point of DLCO < 62% predicted resulted in 75% sensitivity and specificity for exercise desaturation. No untoward cardiac events occurred in any patients during or following the submaximal exercise tests.Conclusions: The risk of oxygen desaturation during submaximal exercise is very high in patients with a low DLCO. Submaximal exercise tests are safe, even in elderly patients with heart and lung diseases. [ABSTRACT FROM AUTHOR]