Circulating biomarkers of airflow limitation across the life span.

BACKGROUND: Airflow limitation is a hallmark of chronic obstructive pulmonary disease, which can develop through different lung function trajectories across the life span. There is a need for longitudinal studies aimed at identifying circulating biomarkers of airflow limitation across different stages of life. OBJECTIVES: This study sought to identify a signature of serum proteins associated with airflow limitation and evaluate their relation to lung function longitudinally in adults and children. METHODS: This study used data from 3 adult cohorts (TESAOD [Tucson Epidemiological Study of Airway Obstructive Disease], SAPALDIA [Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in Adults], LSC [Lovelace Smoker Cohort]) and 1 birth cohort (TCRS [Tucson Children's Respiratory Study]) (N = 1940). In TESAOD, among 46 circulating proteins, we identified those associated with FEV1/forced vital capacity (FVC) percent (%) predicted levels and generated a score based on the sum of their z-scores. Cross-sectional analyses were used to test the score for association with concomitant lung function. Longitudinal analyses were used to test the score for association with subsequent lung function growth in childhood and decline in adult life. RESULTS: After false discovery rate adjustment, serum levels of 5 proteins (HP, carcinoembryonic antigen, ICAM1, CRP, TIMP1) were associated with percent predicted levels of FEV1/FVC and FEV1 in TESAOD. In cross-sectional multivariate analyses the 5-biomarker score was associated with FEV1 % predicted in all adult cohorts (meta-analyzed FEV1 decrease for 1-SD score increase: -2.9%; 95% CI: -3.9%, -1.9%; P = 2.4 × 10-16). In multivariate longitudinal analyses, the biomarker score at 6 years of age was inversely associated with FEV1 and FEV1/FVC levels attained by young adult life (P = .02 and .005, respectively). In adults, persistently high levels of the biomarker score were associated with subsequent accelerated decline of FEV1 and FEV1/FVC (P = .01 and .001). CONCLUSIONS: A signature of 5 circulating biomarkers of airflow limitation was associated with both impaired lung function growth in childhood and accelerated lung function decline in adult life, indicating that these proteins may be involved in multiple lung function trajectories leading to chronic obstructive pulmonary disease.

Cytomegalovirus serology in young to mid-adult life and decline of lung function.

INTRODUCTION: Cytomegalovirus (CMV) seropositivity has been recently linked to severity and progression of asthma, cystic fibrosis, and chronic obstructive pulmonary disease (COPD). To date, no longitudinal study has addressed the relation of CMV serology to levels and decline of lung function in the general adult population. METHODS: We evaluated 403 participants from the Tucson Epidemiological Study of Airway Obstructive Disease (TESAOD) who at enrollment were aged 28-55 years and completed lung function tests. During follow-up, the 403 participants completed on average 7.2 lung function tests per subject for a total of 2908 observations over a mean period of 14.7 years. We tested CMV serology in serum samples from enrollment and categorized participants into low, medium, and high CMV serology based on tertiles. The relation of CMV serology at enrollment to lung function levels and decline during follow-up was tested in multivariate random coefficients models. RESULTS: After full adjustment, participants in the highest CMV serology tertile had faster declines of forced expiratory volume in 1 s (FEV1 ) and FEV1 /forced vital capacity (FVC) compared with subjects in the lowest tertile (by -7.9 ml/year 95% confidence interval [-13.9 ml/year, -1.93 ml/year], and by -0.13%/year [-0.23%/year, -0.026%/year], respectively). These CMV effects were additive with those of cigarette smoking. No associations were found between CMV serology and FVC, indicating specific effects of CMV seropositivity on airflow limitation. CONCLUSION: High CMV serology in young to mid-adult life may be linked to increased COPD risk through an accelerated decline of lung function.

Club cell secretory protein and lung function in children with cystic fibrosis.

BACKGROUND: Club cell secretory protein (CC16) exerts anti-inflammatory functions in lung disease. We sought to determine the relation of serum CC16 deficits and genetic variants that control serum CC16 to lung function among children with cystic fibrosis (CF). METHODS: We used longitudinal data from CF children (EPIC Study) with no positive cultures for Pseudomonas aeruginosa prior to enrollment. Circulating levels of CC16 and an inflammatory score (generated from CRP, SAA, calprotectin, G-CSF) were compared between participants with the lowest and highest FEV1 levels in adolescence (LLF and HLF groups, respectively; N = 130-per-group). Single nucleotide variants (SNVs) in the SCGB1A1, EHF-APIP loci were tested for association with circulating CC16 and with decline of FEV1 and FEV1/FVC% predicted levels between ages 7-16 using mixed models. RESULTS: Compared with the HLF group, the LLF group had lower levels of CC16 (geometric means: 8.2 vs 6.5 ng/ml, respectively; p = 0.0002) and higher levels of the normalized inflammatory score (-0.21 vs 0.21, p = 0.0007). Participants in the lowest CC16 and highest inflammation tertile had the highest odds for having LLF (p<0.0001 for comparison with participants in the highest CC16 and lowest inflammation tertile). Among seven SNVs associated with circulating CC16, the top SNV rs3741240 was associated with decline of FEV1/FVC and, marginally, FEV1 (p = 0.003 and 0.025, respectively; N = 611 participants, 20,801 lung function observations). CONCLUSIONS: Serum CC16 deficits are strongly associated with severity of CF lung disease and their effects are additive with systemic inflammation. The rs3741240 A allele is associated with low circulating CC16 and, possibly, accelerated lung function decline in CF.

High cytomegalovirus serology and subsequent COPD-related mortality: a longitudinal study.

BACKGROUND: Positive serology for cytomegalovirus (CMV) has been associated with all-cause mortality risk but its role in COPD mortality is unknown. The objective of the present study was to assess the relationship between CMV serology and COPD mortality. METHODS: We analysed data from 806 participants in the Tucson Epidemiological Study of Airway Obstructive Disease who, at enrolment, were aged 28-70 years and had completed lung function tests. We tested CMV serology in sera from enrolment and defined "high CMV serology" as being in the highest tertile. Vital status, date and cause of death were assessed through death certificates and/or linkage with the National Death Index up to January 2017. The association of CMV serology with all-cause and cause-specific mortality risk was tested in Cox models adjusted for age, sex, level of education, body mass index, smoking status and pack-years. RESULTS: High CMV serology was marginally associated with all-cause mortality (p=0.071) but the effect was inversely dependent on age, with the association being much stronger among participants <55 years than among participants ≥55 years at enrolment (p-value for CMV-by-age interaction <0.001). Compared with low CMV serology, high CMV serology was associated with mortality from COPD among all subjects (adjusted hazard ratio (HR) 2.38, 95% CI 1.11-5.08; p=0.025) and particularly in subjects <55 years old at enrolment (HR 5.40, 95% CI 1.73-16.9; p=0.004). Consistent with these results, high CMV serology also predicted mortality risk among subjects who already had airflow limitation at enrolment (HR 2.10, 95% CI 1.20-3.68; p=0.009). CONCLUSIONS: We report a strong relationship between CMV serology and the risk of dying from COPD, and thus identify a novel risk factor for COPD mortality.

Persistent light to moderate alcohol intake and lung function: A longitudinal study.

Alcohol intake has been inconsistently associated with lung function levels in cross-sectional studies. The goal of our study was to determine whether longitudinally assessed light-to-moderate alcohol intake is associated with levels and decline of lung function. We examined data from 1333 adult participants in the population-based Tucson Epidemiological Study of Airway Obstructive Disease. Alcohol intake was assessed with four surveys between 1972 and 1992. Subjects who completed at least two surveys were classified into longitudinal drinking categories ("never", "inconsistent", or "persistent drinker"). Spirometric lung function was measured in up to 11 surveys between 1972 and 1992. Random coefficient models were used to test for differences in lung function by drinking categories. After adjustment for sex, age, height, education, BMI categories, smoking status, and pack-years, as compared to never-drinkers, persistent drinkers had higher FVC (coefficient: 157 mL, p < 0.001), but lower FEV1/FVC ratio (-2.3%, p < 0.001). Differences were due to a slower decline of FVC among persistent than among never-drinkers (p = 0.003), and these trends were present independent of smoking status. Inconsistent drinking showed similar, but weaker associations. After adjustment for potential confounders, light-to-moderate alcohol consumption was associated with a significantly decreased rate of FVC decline over adult life.

The relation of circulating YKL-40 to levels and decline of lung function in adult life.

BACKGROUND: YKL-40 is a chitinase-like protein that, in cross-sectional clinical studies, has been associated with severe asthma and COPD in smokers. AIM: To determine the longitudinal relation of circulating YKL-40 to levels and decline of lung function in the general population. METHODS: We used longitudinal data from up to 13 surveys from the population-based TESAOD study which was conducted in Tucson, Arizona between 1972 and 1996. In cross-sectional analyses, we also used data from 3 Spanish centers of the multicenter ECRHS study (ECRHS-Sp). Serum YKL-40 was measured at baseline in TESAOD and in survey 2 in ECRHS-Sp using ELISAs. Multivariate linear regression was used to test associations of serum YKL-40 to concomitant lung function. In TESAOD, random coefficients models were used to test associations of serum YKL-40 to subsequent decline of lung function. RESULTS: Data on YKL-40 and lung function were available from 1088 TESAOD and 854 ECRHS-Sp adult participants (59% and 51% females; respectively). In adjusted multivariate meta-analyses, being in the highest YKL-40 quartile was associated cross-sectionally with significant deficits in FEV1 and FVC %predicted. In adjusted longitudinal analyses, TESAOD participants in the top YKL-40 quartile had an FEV1 decline that was 5 ml/yr (p = 0.05) faster than subjects in the third quartile, 5 ml/yr (p = 0.02) faster than subjects in the second quartile, and 10 ml/yr (p < 0.001) faster than subjects in the lowest YKL-40 quartile. These longitudinal effects were particularly strong in smokers and absent in never smokers. After adjusting for covariates, as compared with the other three quartiles combined, the top YKL-40 quartile was associated with a 9 ml/yr (p = 0.001) faster FEV1 decline among smokers, while no significant effects were found among never smokers (2 ml/yr, p = 0.35). CONCLUSIONS: Circulating YKL-40 is associated with levels and decline of lung function in the general population and may be a biomarker of susceptibility to the long-term effects of cigarette smoking.

Combined effects of parental and active smoking on early lung function deficits: a prospective study from birth to age 26 years.

BACKGROUND: Cross-sectional reports have suggested that, among active smokers, previous exposure to parental smoking may increase susceptibility to development of chronic obstructive pulmonary disease. We assessed prospectively whether parental smoking enhances the effects of active smoking on early deficits of lung function in young adults. METHODS: We used data from the prospective birth cohort, the Tucson Children's Respiratory Study. Maternal and paternal smoking was assessed via questionnaires completed by the parents at the time of the participant's birth. Active smoking by participants was assessed via personal questionnaires completed at ages 16 (YR16), 22 and 26 years. Four groups were generated based on the combination of parental and active smoking. Lung function parameters, including forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ratio, were assessed by spirometry before and after inhalation of 180 µg of albuterol at YR11, YR16, YR22 and YR26. RESULTS: Complete data were available for 519 participants. Pre-bronchodilator FEV1/FVC values did not differ at YR11, YR16 or YR22 by parental or active smoking. However, at YR26 participants with exposure to parental and active smoking had pre-bronchodilator FEV1/FVC levels that were, on average, 2.8% (0.9% to 4.8%; p=0.003) lower than participants who were not exposed to parental or active smoking. In contrast, subjects who were only exposed to active smoking or only exposed to parental smoking did not differ from those who were not exposed to either. Between YR11 and YR26, participants with exposure to parental and active smoking had the steepest decline in sex, age and height adjusted residuals of FEV1/FVC, FEV1, forced expiratory flow between 25% and 75% of the FVC (FEF25-75) and FEF25-75/FVC (all p values between 0.03 and <0.001). CONCLUSIONS: Parental and active smoking act synergistically to affect early lung function deficits in young adulthood.

Acute exacerbations of COPD in the United States: inpatient burden and predictors of costs and mortality.

Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are a leading cause of hospitalizations in the United States and the major cost driver of COPD. This study determined the national inpatient burden of AECOPD and assessed the association of co-morbidities and hospital characteristics with inpatient costs and mortality. Discharge records from the Agency for Healthcare Research and Quality (AHRQ) Healthcare Cost and Utilization Project (HCUP) Nationwide Inpatient Sample for 2006 was utilized. Outcomes of costs and mortality were assessed for AECOPD hospitalizations in cases ≥40 years of age. Multivariate regression analyses using a generalized linear model framework were conducted to determine predictors of inpatient costs and mortality controlling for patient demographics, primary payer, co-morbidity index, length of stay, hospital region, mechanical ventilation, and admission period. Overall, 1,254,703 hospitalizations for AECOPD were observed with mean costs of $9545(±12,700) and total costs of $11.9 billion. In-hospital mortality was 4.3% (N = 53,748). Discharges averaged 70.6 (±11.9) years of age. The majority were female (52.8%) and of white race (83.6% of reported race). Several co-morbidities were significantly associated with both costs and mortality (p < 0.001): acute myocardial infarction; congestive heart failure; cerebrovascular disease; lung cancer; cardiac arrhythmias; pulmonary circulation disorders; and weight loss. Significantly higher costs (p < 0.001) were associated with large and urban hospitals. The importance of co-morbidities in AECOPD is indicated in their association with prognosis and inpatient costs. Future research should determine if better management of these conditions can favorably impact the COPD disease burden.

The European Respiratory Society spirometry tent: a unique form of screening for airway obstruction.

In order to raise public awareness of the importance of early detection of airway obstruction and to enable many people who had not been tested previously to have their lung function measured, the European Lung Foundation and the European Respiratory Society (ERS) organised a spirometry testing tent during the annual ERS Congresses in 2004-2009. Spirometry was performed during the ERS Congresses in volunteers; all participants answered a simple, brief questionnaire on their descriptive characteristics, smoking and asthma. Portable spirometers were freely provided by the manufacturer. Nurses and doctors from pulmonary departments of local hospitals/universities gave their service for free. Lower limit of normal (LLN) and Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria for diagnosing and grading airway obstruction were used. Of 12,448 participants in six congress cities, 10,395 (83.5%) performed acceptable spirometry (mean age 51.0 ± 18.4 yrs; 25.5% smokers; 5.5% asthmatic). Airway obstruction was present in 12.4% of investigated subjects according to LLN criteria and 20.3% according to GOLD criteria. Through multinomial logistic regression analysis, age, smoking habits and asthma were significant risk factors for airway obstruction. Relative risk ratio and 95% confidence interval for LLN stage I, for example, was 2.9 (2.0-4.1) for the youngest age (≤ 19 yrs), 1.9 (1.2-3.0) for the oldest age (≥ 80 yrs), 2.4 (2.0-2.9) for current smokers and 2.8 (2.2-3.6) for reported asthma diagnosis. In addition to being a useful advocacy tool, the spirometry tent represents an unusual occasion for early detection of airway obstruction in large numbers of city residents with an important public health perspective.

Identification of patients with sleep disordered breathing: comparing the four-variable screening tool, STOP, STOP-Bang, and Epworth Sleepiness Scales.

STUDY OBJECTIVE: The Epworth Sleepiness Scale (ESS) has been used to detect patients with potential sleep disordered breathing (SDB). Recently, a 4-Variable screening tool was proposed to identify patients with SDB, in addition to the STOP and STOP-Bang questionnaires. This study evaluated the abilities of the 4-Variable screening tool, STOP, STOP-Bang, and ESS questionnaires in identifying subjects at risk for SDB. METHODS: A total of 4,770 participants who completed polysomnograms in the baseline evaluation of the Sleep Heart Health Study (SHHS) were included. Subjects with RDIs ≥ 15 and ≥ 30 were considered to have moderate-to-severe or severe SDB, respectively. Variables were constructed to approximate those in the questionnaires. The risk of SDB was calculated by the 4-Variable screening tool according to Takegami et al. The STOP and STOP-Bang questionnaires were evaluated including variables for snoring, tiredness/sleepiness, observed apnea, blood pressure, body mass index, age, neck circumference, and gender. Sleepiness was evaluated using the ESS questionnaire and scores were dichotomized into < 11 and ≥ 11. RESULTS: The STOP-Bang questionnaire had higher sensitivity to predict moderate-to-severe (87.0%) and severe (70.4%) SDB, while the 4-Variable screening tool had higher specificity to predict moderate-to-severe and severe SDB (93.2% for both). CONCLUSIONS: In community populations such as the SHHS, high specificities may be more useful in excluding low-risk patients, while avoiding false positives. However, sleep clinicians may prefer to use screening tools with high sensitivities, like the STOP-Bang, in order to avoid missing cases that may lead to adverse health consequences and increased healthcare costs.

Role of neprilysin in airway inflammation induced by diesel exhaust emissions.

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.

Morbidity and mortality associated with the restrictive spirometric pattern: a longitudinal study.

BACKGROUND: Recent studies have suggested that a restrictive pattern assessed with a single spirometric test is associated with increased morbidity and mortality. This study was undertaken to determine demographic, clinical and mortality profiles of subjects with either a recurrent or an inconsistent restrictive spirometric pattern assessed prospectively. METHODS: Data from 2048 adult participants in the population-based TESAOD study were analysed. Normal (forced expiratory volume in 1 s/forced vital capacity (FEV(1)/FVC) ratio >or=70% and FVC >or=80% predicted), restrictive (FEV(1)/FVC >or=70% and FVC <80% predicted) and obstructive (FEV(1)/FVC <70%) patterns were assessed at the enrollment survey in 1972 and in 11 subsequent follow-up surveys up to 1996. Demographic and clinical characteristics were measured at enrollment and vital status and cause of death were assessed at January 2005. RESULTS: Overall, 12% of participants had a restrictive spirometric pattern at enrollment. They were less likely to be male, to smoke and to have asthma, and had lower IgE levels than subjects in the obstructive group. Among subjects with a restrictive pattern at enrollment, 38% developed an obstructive pattern during follow-up. The remaining 62% had either a recurrent (restrictive pattern >or=50% of follow-up surveys) or inconsistent (restrictive pattern <50% of follow-up surveys) longitudinal restrictive pattern. The recurrent and inconsistent restrictive groups had increased mortality risk for all-cause (adjusted HR 1.7 (95% CI 1.3 to 2.3) and 1.9 (95% CI 1.4 to 2.6), respectively), heart disease (2.0 (95% CI 1.3 to 3.1) and 2.7 (95% CI 1.7 to 4.3)), stroke (2.4 (95% CI 0.9 to 6.3) and 3.5 (95% CI 1.2 to 9.8)) and diabetes (8.0 (95% CI 2.9 to 21.8) and 6.0 (95% CI 1.9 to 19.2)). CONCLUSIONS: The restrictive spirometric pattern identifies a pulmonary condition that is distinguishable from obstructive lung disease and is associated with an increased risk of life-threatening comorbidities.

Pulmonary nocardiosis in cystic fibrosis.

BACKGROUND: The treatment of Nocardia species found in the sputum of cystic fibrosis patients is of unknown value. METHODS: We conducted a retrospective analysis of the impact of directed oral antibiotic therapy against Nocardia spp. isolated from the sputum of 17 cystic fibrosis patients over a 10-year period. Pulmonary Function Tests were used as the clinical indicator of the disease state and the data were analyzed by general linear mixed model statistics with univariate analysis. RESULTS: Pulmonary Function Test values of all patients studied showed no significant difference before, during, or after the antibiotic treatment period. Treatment groups did not differ from non-treatment groups. This held true for Forced Expiratory Volume over 1 s and Functional Vital Capacity analysis. In addition, individual patient analysis did not reveal any trends or outliers. CONCLUSIONS: Oral antibiotic therapy of cystic fibrosis patients colonized with Nocardia does not appear to affect clinical outcome. This suggests that deferring therapy may be an acceptable alternative and justifies conducting a future placebo controlled trial. In addition, this study model may be useful in analyzing the effect of therapy on other rare and difficult organisms, such as fungi and mycobacteria in the cystic fibrosis population.

The course of persistent airflow limitation in subjects with and without asthma.

RATIONALE: Most patients who develop persistent airflow limitation do so either as a manifestation of chronic obstructive pulmonary disease that is largely related to smoking or as a consequence of persistent asthma. We sought to compare the natural course of lung function associated with persistent airflow limitation in subjects with and without asthma from early to late adult life. METHODS: We studied 2552 participants aged 25 or more who had multiple questionnaire and lung function data from the long-term prospective population-based Tucson Epidemiological Study of Airway Obstructive Disease. Persistent airflow limitation was defined as FEV(1)/FVC ratio consistently < 70% in all completed surveys subsequent to the first survey with airflow limitation. Participants were divided into nine groups based on the combination of their physician-confirmed asthma status (never, onset < or = 25 years, or onset > 25 years) and the presence of airflow limitation during the study follow-up (never, inconsistent, or persistent). RESULTS: Among subjects with an asthma onset < or = 25 years, blood eosinophilia increased significantly the odds of developing persistent airflow limitation (adjusted ORs: 3.7, 1.4-9.5), whereas cigarette smoking was the strongest risk factor for persistent airflow limitation among non-asthmatics and among subjects with asthma onset after age 25 years. Among subjects with persistent airflow limitation, the natural course of lung function differed between subjects with asthma onset < or = 25 years and non-asthmatics, with the former having lower FEV(1) levels at age 25 (predicted value for a 175-cm tall male of 3400 versus 4090 ml, respectively; p<0.001) and the latter having greater FEV(1) loss between age 25 and 75 (1590 versus 2140 ml; p=0.003). CONCLUSION: In subjects who have asthma onset before 25 years of age and persistent airflow limitation in adult life, the bulk of the FEV(1) deficit is already established before age 25 years.

Effects of parental smoking on interferon gamma production in children.

OBJECTIVES: Environmental tobacco smoke is associated with several negative health outcomes in children, including an increased susceptibility to infections. One of the postulated mechanisms for these effects is the impairment of the immune system function and/or development. Yet, it remains unknown whether cumulative exposure to parental smoking is associated with altered immune responses in childhood and whether these effects are independent of in utero exposure to maternal smoking. In a population-based birth cohort, we sought to determine the relation of parental smoking, as assessed prospectively since pregnancy, to the child's interferon gamma and interleukin 4 production at 11 years of age. PATIENTS AND METHODS: We used data on 512 children and their parents from the Tucson Children's Respiratory Study cohort. Information on maternal and paternal smoking was collected prospectively by questionnaire, and pack-years for mother, father, and both parents combined were assessed prospectively between the prenatal period and year 11. At age 11 years, children's interferon gamma and interleukin 4 production from mitogen-stimulated peripheral blood mononuclear cells was measured. RESULTS: Children of parents who smoked between the prenatal period and year 11 were more likely to be in lower quartiles of interferon gamma production than children of nonsmoking parents. In addition, maternal, paternal, and parental pack-years showed significant inverse dose-response relationships with interferon gamma production in the child. These dose-response relationships with interferon gamma remained significant for both paternal and parental pack-years among children of mothers who did not smoke during pregnancy, suggesting the existence of specific postnatal effects of environmental tobacco smoke exposure. In contrast, no significant effects of parental smoking were found on interleukin 4 production. CONCLUSIONS: Interferon gamma responses of school-aged children are impacted by parental smoking.

Longitudinal decline of diffusing capacity of the lung for carbon monoxide in community subjects with the PiMZ alpha1-antitrypsin phenotype.

BACKGROUND: It is well known that homozygous deficiency of alpha(1)-antitrypsin, PiZZ, is associated with an increased risk of emphysema. However, studies evaluating associations between the heterozygous form PiMZ with emphysema and impaired lung function have provided conflicting results. STUDY OBJECTIVE: The goal of this study was to determine if the phenotype PiMZ is associated with an accelerated decline in diffusing capacity of the lung for carbon monoxide (Dlco). DESIGN AND METHODS: The Tucson Epidemiologic Study of Airway Obstructive Disease is a prospective, population-based cohort study initiated in 1972. Participants completed standardized questionnaires in up to 12 periodic surveys and Dlco assessments in up to 4 surveys. Random-effects models were used to determine the effects of alpha(1)-antitrypsin phenotypes on percentage of predicted (% predicted) Dlco levels among 1,075 subjects > or = 18 years old. RESULTS: % predicted Dlco declined more rapidly in subjects who smoked compared to nonsmoking subjects. Additionally, in smokers, the PiMZ phenotype was associated with borderline % predicted Dlco deficits at age 40 years (8.6%; p = 0.075) and significant % predicted Dlco deficits at age 60 years (15.2%; p = 0.001) and 80 years (21.9%; p = 0.003), as compared with the PiMM phenotype. CONCLUSIONS: Dlco may be a more sensitive indicator of the long-term effects of intermediate levels of alpha(1)-antitrypsin on lung function especially in subjects who smoke.

Neurogenic responses in rat lungs after nose-only exposure to diesel exhaust.

Using an in-line, real-time, in vivo exposure system, we investigated whether acute adverse effects of diesel exhaust (DE*) exposure involve neurogenic inflammation in the lungs via sensory nerve C fibers. A total of 168 female F344 rats (175 g, 8 weeks old) were randomly assigned to pretreatment with capsaicin or saline to deplete C-fiber neurotransmitters. In a 2 x 3 factorial design, groups of animals were then exposed nose-only to a low level of DE (LDE, 35.3 microg/m3), a high level of DE (HDE, 632.9 microg/m3), or side-stream cigarette smoke (CS, 0.4 mg/m3). Two control groups were exposed whole body to filtered air in the animal room (fRA) or unfiltered air in the diesel engine room (eRA), respectively. DE was taken directly from a heavy-duty Cummins N14 research engine operated at 75% throttle (California Air Resources Board [CARB] 8, mode 6). Exposure to DE or air was 4 hours/day, 5 days/week, for 3 weeks. Exposure to CS was for 4 hours/day for 7 days. Involvement of neurogenic inflammation in the response to DE or CS was assessed via comparison of plasma extravasation, a sensitive endpoint of neurogenic inflammation, between rats with and without capsaicin pretreatment. Lung injury was assessed via analysis of proinflammatory cytokines, respiratory permeability, and histopathology. Moreover, whether DE exposure affected the molecular mechanisms of neurogenic inflammation was analyzed through quantification of substance P (SP) and its primary neurokinin-1 (NK1) receptor at the gene and protein levels and through neutral endopeptidase (NEP) activity. DE and CS exposure induced dose-dependent plasma extravasation, which may play an important role in initiating the associated lung inflammation and injury. Exposure of rats to DE affected the SP signaling pathway as indicated by overexpression of the NK1 receptor or reduction of SP in the lung tissue. DE exposure consistently inactivated tissue NEP, a key factor that switches neurogenic inflammation from its physiological and protective functions to a role that increases and perpetuates lung injury. The roles of these overlapping neurokininergic mechanisms in the initiation of DE-associated lung injury are plausible, and these changes may contribute to DE-associated respiratory disorders. Capsaicin rats followed the same trends as those of saline animals when exposed to DE or CS: capsaicin rats did not have significantly different plasma extravasation in the airways or lung parenchyma compared to their corresponding controls. Histopathology evaluation likewise demonstrated the same degree of tissue changes, such as edema and alveolar macrophage collection, in capsaicin and saline rats after the same level of DE exposure. In summary, our data suggest that neurokininergic mechanisms may have been involved in DE-induced inflammatory conditions in rat lung but that C fibers did not appear to be involved under these exposure conditions. We believe that time-course or protein knockdown/knockout animal studies are required to characterize further the role of neurokininergic mechanisms in DE-induced lung injury.

Asthma as a risk factor for COPD in a longitudinal study.

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 time 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 [CI], 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.

Segregation analysis of bronchial hyperresponsiveness in a general population in north Italy.

Bronchial hyperresponsiveness (BHR) is an intermediate phenotype of asthma, with a heritability component of 30-67% and possible linkage to regions on chromosome arms 5q, 11q, and 20p. Familial correlation analysis and segregation analysis for BHR, using the FCOR and REGC programs of the S.A.G.E package, were performed to examine inheritance patterns of BHR in a general population of 1167 subjects in 550 families from the Po River Delta. BHR was assessed using the log(10) of the slope of the methacholine dose-response curve (log slope) for each subject who met inclusion criteria. Using multiple linear regression analysis, the log slope values were adjusted for age, age(2), sex, and height, and used in the familial correlation and segregation analyses. Father-offspring correlations are statistically significant, due specifically to high father-son correlations (r = 0.296, P < 0.001, adjusted values). Segregation analysis of BHR in the overall population, with and without a smoking covariate (number of packyears smoked), indicates an apparent absence of genetic transmission within families. However, in a segregation analysis of BHR in smoking families only, after adjusting for number of packyears smoked, the Mendelian transmission models could not be rejected. This may be evidence of a gene by smoking effect, and suggests that in families of smokers, a single locus gene may in part explain the inheritance of a compound phenotype (BHR x packyears).