Lung Function In Smokers Research Articles

Association of genetic variations in the CSF2 and CSF3 genes with lung function in smoking-induced COPD

Granulocyte-macrophage colony-stimulating factor (CSF), also known as CSF2, and granulocyte CSF, also known as CSF3, are important survival and proliferation factors for neutrophils and macrophages. The objective of the present study was to determine whether single nucleotide polymorphisms (SNPs) of CSF2 and CSF3 are associated with lung function in smoking-induced chronic obstructive pulmonary disease. In total, five SNPs of CSF2 and CSF3 were studied in 587 non-Hispanic white subjects with the fastest (n = 281) or the slowest (n = 306) decline of lung function selected from among continuous smokers in the National Heart, Lung, and Blood Institute Lung Health Study (LHS). These SNPs were also studied in 1,074 non-Hispanic white subjects with the lowest (n = 536) or the highest (n = 538) baseline lung function at the beginning of the LHS. An increase in the number of CSF3 -1719T alleles was significantly associated with protection against low lung function (odds ratio 0.73, 95% confidence interval 0.56-0.95), and was still significant after adjustment for multiple comparisons. There was also a significant association of a CSF3 haplotype with baseline levels of forced expiratory volume in one second. No association was found for CSF2 SNPs and lung function, nor was there evidence of epistasis. In conclusion, genetic variation in colony-stimulating factor 3 is associated with cross-sectionally measured lung function in smokers.

Effect of ozone boluses on the lung function of smokers

During continuous exposure to ozone (O3), smokers have failed to experience the decrements in forced spirometric parameters that have been well‐established for comparable non‐smokers. We hypothesized that these differences in response are due to differences in the longitudinal distribution of O3 uptake. We measured the longitudinal distribution of O3 uptake using the bolus inhalation method but found no difference between populations of 29 non‐smokers (17M, 12F) and 30 smokers (19M, 11F, 4±4 pack‐years). We also measured FEV1 by spirometry and the normalized slope of the alveolar plateau (SN) by capnography. Smokers experienced a significant change in SN (8.1 ± 3.2%, p=0.02) and a small, but significant change in FEV1 (−1.3 ± 0.6%, p=0.03) after inhaling between 75 and 120 20‐mL O3 boluses with an average concentration of 1 ppm. Nonsmokers did not exhibit such responses. We conclude that during a transient exposure to O3, smokers may be differentially responsive to O3 in spite of the similarity of their O3 uptake distribution to that of non‐smokers.

Variation in the tumour necrosis factor gene is not associated with susceptibility to COPD

To the Editors: In a recent issue of the European Respiratory Journal , Tanaka et al. 1 studied polymorphisms in the tumour necrosis factor (TNF) and lymphotoxin A genes with respect to their effect on lung function of smokers, and failed to find any association with chronic obstructive pulmonary disease (COPD) phenotypes. Tanaka et al. 1 acknowledge that their work is not a true case–control study, but that it would be better described as an investigation of genetic contribution to disease severity. There have been several studies of variation in TNF with respect to susceptibility to COPD, although many of these have used relatively small sample sizes and are therefore underpowered, and so are likely to lead to results that cannot be replicated. As part of a European Union collaborative project, we have …

Tumour necrosis factor and lymphotoxin A polymorphisms: a relationship with COPD and its progression?: Table 1—

In this issue of the European Respiratory Journal , Tanaka et al. 1 present the results of their study on polymorphisms in tumour necrosis factor (TNF) and lymphotoxin A (LTA) in relation to lung function in smokers. They designed two nested case–control studies in the Lung Health Study, originally enrolling almost 6,000 smokers with mild-to-moderate chronic obstructive pulmonary disease (COPD). They conclude that there exist no significant associations between polymorphisms in TNF or LTA and lung function in COPD patients of Caucasian origin, contrary to previously reported studies in Asians. It is important to note that this study assesses the genetics of progression of COPD and that the study cannot make any inference from this population as to whether the genes under study are COPD susceptibility genes. To meet this aim, one needs a general population study in which smokers with and without accelerated lung function loss are compared. These findings are of importance, since they confirm and extend previously reported negative findings in Caucasians; among them is one of the authors’ own studies that included only two polymorphisms in the genes 2. In the present study, the authors analyse a sample that is sufficiently large to exclude potential negative findings due to small study populations, and thus lack of power. Indeed, one of the strengths of the study by Tanaka et al. 1 is the a priori power calculation, to ensure a sufficiently large sample to detect differences in distributions of polymorphisms between their COPD subgroups. Unfortunately, too many studies on genetics of COPD are still being performed in COPD patients derived from population samples investigators happen to have at …

Tumour necrosis factor and lymphotoxin A polymorphisms and lung function in smokers

Genetic variants in the tumour necrosis factor (TNF) gene have been investigated in chronic obstructive pulmonary disease (COPD). However, there are many instances of nonreplication of these associations due to insufficient power or other factors. In this study, a large number of subjects were examined to elucidate whether genetic variations of TNF and/or lymphotoxin A (LTA), which is clustered with TNF, are associated with variations in lung function among smokers. The present authors designed two nested case-control studies in the National Heart, Lung, and Blood Institute Lung Health Study (LHS), which enrolled 5,887 smokers. The first design included continuous smokers who had the fastest (n = 279) and the slowest (n = 304) decline of lung function during the 5-yr follow-up period, and the second included the subjects who had the lowest (n = 533) and the highest (n = 532) post-bronchodilator % predicted forced expiratory volume in one second at the start of the LHS. Within the TNF and LTA region, 10 tagging single-nucleotide polymorphisms were selected and genotyped. Unlike the previous associations between TNF-308 and COPD in Asians, the current study found no association between either of the two phenotypes and the LTA and TNF polymorphisms. In conclusion, these results support the findings of previous studies in late-onset chronic obstructive pulmonary disease in Caucasian populations.

Interferon gamma polymorphisms and their interaction with smoking are associated with lung function

Interactions between genetic and environmental determinants are likely to be important in the pathogenesis of chronic obstructive pulmonary disease. We hypothesized that interferon gamma (IFNG) single nucleotide polymorphisms (SNPs) and their interaction with smoking are associated with the rate of decline or level of lung function in smokers. We studied four SNPs in IFNG in 585 non-Hispanic whites (NHW) who had the fastest (n =280) or the slowest (n=305) decline of FEV(1)% predicted selected from among continuous smokers followed for 5 years in the NHLBI Lung Health Study. We also studied 1061 NHW with the lowest (n=530) or the highest (n=531) baseline lung function at the beginning of the LHS. Two SNPs were associated with baseline levels of lung function and the p values were 0.008 for +2197T/C in a dominant model and 0.002 for +5171A/G in a recessive model. However, after adjusting for confounding factors, only +5171A/G was still significant (p=0.001 for the recessive model). In addition, there was a significant genotype and smoking interaction with p=0.006 for the +5171A/G (GG vs.GA + AA) for the baseline lung function. When comparing individuals with GG versus individuals with AG + AA for low lung function, the adjusted odds ratios decreased significantly as pack-years increased. No association was found in the rate of decline study. There was an association between IFNG genotype and baseline of lung function and this association was modified by cigarette smoking.

Glutathione S-Transferase P1 and Lung Function in Patients With α1-Antitrypsin Deficiency and COPD

The glutathione S-transferase P1 (GSTP1) gene is involved in detoxification of electrophilic substances of tobacco smoke. A polymorphism at nucleotide 315 of this gene alters its enzymatic activity. We analyzed the association between the variability in the GSTP1 gene and impairment in lung function in smokers with and without alpha(1)-antitrypsin (AAT) deficiency and COPD. The study population consisted of 99 patients with smoking-related COPD and 69 patients with AAT deficiency; 198 healthy volunteers provided the frequency of the different polymorphisms in the general population. GSTP1 genotyping was performed by a real-time polymerase chain reaction amplification assay. The frequency (0.28) of the 105Val polymorphism was identical in COPD patients and the general population. However, the frequency was significantly increased (0.44) in patients with AAT deficiency (odds ratio [OR], 2.09; 95% confidence interval [CI], 1.17 to 3.72 compared to control subjects; and OR, 2.41; 95% CI, 1.27 to 4.59 compared to COPD). FEV(1) percentage of predicted was significantly impaired in AAT-deficient carriers of 105Val. This effect was not observed in COPD patients. These findings suggest that the frequency of the GSTP1 105Val polymorphism is increased in patients with AAT deficiency. Globally, GSTP1 genotypes, age, and tobacco smoking explained 41% of total FEV(1) percentage of predicted variability in patients with AAT deficiency. The modulatory role of GSTP1 in lung disease has only been observed in smokers lacking AAT.

Antioxidant gene polymorphisms and susceptibility to a rapid decline in lung function in smokers.

Oxidative stress is believed to play an important role in the pathogenesis of smoking-induced chronic obstructive pulmonary disease. We hypothesized that polymorphisms of antioxidant genes glutathione S-transferase M1 (GSTM1), GSTT1, GSTP1, and heme oxygenase-1 (HMOX1) would be associated with susceptibility to accelerated decline of lung function in smokers. We genotyped 621 subjects (299 rapid decliners [change in forced expiratory volume in 1 second (DeltaFEV(1)) = -152 +/- 2.5 ml/year] and 322 nondecliners [DeltaFEV(1) = +15 +/- 1.5 ml/year]) selected from among smokers followed for 5 years in the National Heart, Lung, and Blood Institute Lung Health Study. Because genotype frequencies were different between ethnic groups, we limited the association study to 594 whites (286 rapid decliners and 308 nondecliners). None of the genotypes studied had a statistically significant effect on decline of lung function when analyzed separately. There was an association between rapid decline of lung function and presence of all three GST polymorphisms (odds ratio [OR] = 2.83; p = 0.03). A combination of a family history of chronic obstructive pulmonary disease with GSTP1 105Ile/Ile genotype was also associated with rapid decline of lung function (OR = 2.20; p = 0.01). However, due to the multiple comparisons that were made, these associations may represent type 1 error. There was no association between HMOX1 (GT)n alleles and the rate of decline in lung function in smokers.

Association of IL-1β and IL-1 receptor antagonist haplotypes with rate of decline in lung function in smokers

BACKGROUNDThere is increasing evidence that the cytokine network is central to the immunopathology of inflammatory airway diseases. The interleukin 1 (IL-1) receptor antagonist (IL-1RN) is a naturally occurring anti-inflammatory agent...

Susceptibility genes for rapid decline of lung function in the lung health study.

The genes that contribute to the genetic susceptibility to chronic obstructive pulmonary disease (COPD) remain largely unknown. We hypothesized that widely divergent rates of decline in lung function in smokers would be a robust phenotype for detection of genes that contribute to COPD severity. We selected 283 rapid decliners (deltaFEV1 = -154 +/- 3 ml/yr) and 308 nondecliners (deltaFEV1 = +15 +/- 2 ml/yr) from among smokers followed for 5 yr in the NHLBI Lung Health Study. Rapid decline of FEV1 was associated with the MZ genotype of the alpha1-antitrypsin gene (odds ratio [OR] = 2.8, p = 0.03). This association was stronger for a combination of a family history of COPD with MZ (OR = 9.7, p = 0.03). These data suggest that the MZ genotype results in an increased rate of decline in lung function and interacts with other familial factors. Haplotype frequencies of the microsomal epoxide hydrolase (mEH) gene were significantly different between rapid decliners and nondecliners (p = 0.03). A combination of a family history of COPD with homozygosity for the His113/His139 mEH haplotype was also associated with rapid decline of lung function (OR = 4.9, p = 0.04). The alpha1-antitrypsin S and 3' polymorphisms, vitamin D-binding protein isoforms, and tumor necrosis factor (TNF-alpha G-308A and TNF-beta A252G) polymorphisms were not associated with rate of decline of lung function.

SMOKING AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE

Smoking is overwhelmingly the major cause of chronic bronchitis and emphysema worldwide. Additional risk factors for developing COPD are presented, along with the variables that govern cigarette smoke deposition in the lung. Major paradigms for the pathogenesis of COPD, including the protease-antiprotease and oxidant-antioxidant theories are described, and evidence for impaired reparative mechanisms in the causation of emphysema is noted. A description of the natural history of declining lung function in smokers and in the susceptible subset of smokers that ultimately develop smoking-induced COPD is accompanied by a discussion of the effects of smoking cessation on preservation of lung health. The disordered ventilation and gas-exchange physiology in the cigarette smoke-damaged lung is explained on the basis of the observed morphological changes.

Is there any relationship between plasma antioxidant capacity and lung function in smokers and in patients with chronic obstructive pulmonary disease?

BACKGROUNDIt has been suggested that oxidative stress is an important factor in the pathogenesis of chronic obstructive pulmonary disease (COPD). We have shown that an oxidant/antioxidant imbalance occurs in the...

Blood eosinophil and monocyte counts are related to smoking and lung function

The aim of this study was to investigate the predictive value of peripheral eosinophil and monocyte blood counts regarding lung function in smokers and non-smokers, and to investigate the influence of smoking on these cell counts. Forced expiratory volume in 1 s (FEV 1) measurements and blood samples were collected from 298 non-atopic smokers and 136 never-smokers. Blood samples were repeated in 160 smokers after cessation of smoking (quitters) and 30 continuing smokers, 2, 6, 12 and 26 weeks after smoking cessation. Monocyte ( P<0·05) but not eosinophil blood counts were higher in never-smokers compared to smokers. In never-smokers, blood eosinophil counts and monocyte counts correlated inversely ( P<0·05) and directly ( P<0·01), respectively, with standardized FEV 1 residuals (FEVR). In smokers, blood eosinophil ( P<0·05) and monocyte ( P<0·05) counts correlated directly with FEVR independent of smoking history. After smoking cessation, monocyte blood counts ( P<0·05) increased. Both eosinophil and monocyte blood counts showed a greater increase in quitters with decreased lung function ( P<0·05). Former heavy smokers had higher blood eosinophil ( P<0·05) but lower monocyte ( P<0·05) count increase than had former light smokers. These data suggest that smoking influences eosinophil and monocyte blood counts and that this is associated with a small negative effect on lung function. Eosinophil blood counts had an opposite relation to lung function in smokers and non-smokers. Further research should include investigations of relations between smoking and stimulatory factors for recruitment and activity of eosinophils and monocytes.

Is Screening for Chronic Obstructive Pulmonary Disease Justified?

Background.Many experts recommend spirometry to screen for chronic obstructive pulmonary disease (COPD) in asymptomatic patients; however, evidence for this recommendation has not been systematically reviewed. Methods.We examined whether screening spirometry meets standard criteria for effective screening. We performed structured searches of MEDLINE, followed by a selective search of the CITATION index, to locate randomized trials of interventions for asymptomatic patients with COPD. In regard to smoking cessation, we included all controlled trials of smoking cessation programs that used spirometry. We also included all studies that assessed the ability of spirometry to predict successful smoking cessation by comparing baseline lung function in smokers who subsequently quit versus those who did not. Results.With the exception of smoking cessation, all interventions for COPD have only been proven effective in symptomatic patients. Two studies found that multifaceted smoking cessation programs that included spirometry were efficacious. There was no effect in a third study that isolated the role of spirometry. Smokers with abnormal spirometric results are less likely than other smokers to quit over the ensuing year. Conclusions.There is no evidence that spirometry, as an isolated intervention, aids smoking cessation.

Pulmonary Function in Wood Workers Exposed to Formaldehyde: A Prospective Study

Employees exposed to formaldehyde in the woodworking industry (N = 47) and nonexposed control subjects (N = 20) were examined in 1980 by spirometry and the nitrogen washout technique. A transient impairment of lung function was noted over a work shift. Five years later, 21 subjects were still experiencing exposure to formaldehyde. A transient decrease in lung function was again found over a work shift, as evidenced by a reduction in forced mid-expiratory flow (FEF25-75) of 0.15 l/s and an increase in closing volume (CV%) of 3.0% in nonsmokers. Significant decreases in forced expired volume in 1 s as a percent of forced vital capacity (FEV1.0/FVC) and FEF25-75 were also noted over the 5 y in nonsmokers (0.4% and 0.2 l.s/y, respectively, after correction for normal aging). After 4 wk of no exposure (holidays), FEF25-75 and forced expired vital capacity (FVC, FEV1.0) returned to normal in the smoking group. Lung function in smokers improved less during the holiday. A dose-response relationship was found between exposure to formaldehyde and decrease in lung function. Thus, industrial exposure to formaldehyde causes transient lung function impairment over a work shift, with a cumulative effect over the years. The impairment, however, can be reversed with 4 wk of no exposure.

Sensitivity and Specificity of Early Diagnostic Tests of Lung Function in Smokers

What are the relative sensitivities and specificities of the "early" tests of lung dysfunction? We describe the findings from a study of virtually the entire population of a rural pollution-free community. Using abnormal spirometry as a marker of obstructive disease, we evaluated the two tests obtained from the single-breath nitrogen curve, closing volume (CV/VC) and the slope of the alveolar plateau (delta N2/L), as well as combinations of the two tests. While CV/VC is highly specific (92.3 percent in male and 94.0 percent in female subjects), it lacks sensitivity (36.8 percent in male and 13.3 percent in female subjects) and is abnormal in only 10.0 and 6.5 percent of male and female smokers, respectively, a percentage not dissimilar from the percentage with abnormal spirometry. However, delta N2/L, abnormal in 24.1 percent of male smokers and 28.8 percent of female smokers, rates reasonably well with regard to both sensitivity (63.2 percent in male and 66.7 percent in female subjects) and specificity (79.3 percent in male and 74.0 percent in female subjects). The group of smokers with abnormal delta N2/L did include fair numbers with abnormal spirometry (20.7 percent in male and 16.1 percent in female subjects). A combination of the two tests (abnormal in either delta N2/L and/or CV/VC) has good sensitivity (68.4 and 80.0 percent for male and female subjects, respectively) and specificity (74.3 and 69.0 percent for male and female subjects, respectively).

Blood Coagulation and Fibrinolysis in a Random Sample of 788 Men 54 Years Old

SummaryIn a population of 788 men 54 years of age plasma clotting times, factor II-VII-X activity, factor VIII, fibrinogen, fibrinolytic activity and plasminogen have been compared to anthropomorphic variables, blood lipids, blood sugar, blood pressure, heart rate, lung function and smoking.It was found by multiple regression analyses that fibrinogen, plasminogen and factor II-VII-X activity were correlated to serum cholesterol, and secondary to systolic blood pressure, heart rate and blood sugar.Independent of these correlations, fibrinogen, plasminogen and factor II-VII-X activity were also negatively correlated to FEV1 and VC which are measures of lung function.Smokers have a higher fibrinogen level than non smokers and this is not due to the decreased lung function in smokers. PTT (partial thromboplastin time) carried out in silicone tubes is correlated to serum cholesterol.There is a negative correlation between fibrinolytic activity and weight, subscapular and thorax skinfolds, chest and waist chcumference indicating that obese subjects have a low fibrinolytic activity. There is also a negative correlation between fibrinolytic activity and serum triglycerides but this is insignificant when the effect of obesity is taken into account.