Smoking-associated Lung Research Articles

Differential involvement of gp130 signalling pathways in modulating tobacco carcinogen-induced lung tumourigenesis.

Interleukin (IL)-6 family cytokines signal exclusively via the gp130 coreceptor, and are implicated in smoking-associated lung cancer, the most lethal cancer worldwide. However, the role of gp130 signalling pathways in transducing the carcinogenic effects of tobacco-related compounds is ill-defined. Here, we report that lung tumourigenesis induced by the potent tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (Nicotine-derived Nitrosamine Ketone; NNK) is suppressed in gp130(F/F) knock-in mice characterized by the contrasting gp130-dependant hypoactivation of extracellular signal-regulated kinase mitogen-activated protein kinase (ERK MAPK) and phosphatidylinositol 3-kinase/Akt, and hyperactivation of signal transducer and activator of transcription (STAT)3 signalling cascades. Specifically, in response to NNK, the absolute number and size of lung lesions in gp130(F/F) mice were significantly reduced compared with gp130(+/+) littermate controls, and associated with lower cellular proliferation without any alteration to the level of apoptosis in gp130(F/F) lung tumours. At the molecular level, reduced activation of ERK MAPK, but not Akt, was observed in lung tumours of gp130(F/F) mice, and corresponded with impaired expression of several tumour suppressor genes (for example, Trp53, Tsc2). Notably, STAT3 was not activated in the lungs of gp130(+/+) mice by NNK, and genetic normalization of STAT3 activation in gp130(F/F):Stat3(-/+) mice had no effect on NNK-induced tumourigenesis. The expression of tumour suppressor genes was reduced in tumours from current versus never-smoking lung cancer patients, and in vitro pharmacological inhibition of ERK MAPK signalling in human lung cancer cells abrogated NNK-induced downmodulation of tumour suppressor gene expression. Among IL-6 cytokine family members, IL-6 gene expression was specifically upregulated by NNK in vitro and in vivo, and inversely correlated with tumour suppressor gene expression. Collectively, our data reveal that a key molecular mechanism by which NNK promotes tumour cell proliferation during tobacco carcinogen-induced lung carcinogenesis is via upregulation of IL-6 and the preferential usage of gp130-dependant ERK MAPK signalling to downmodulate tumour suppressor gene expression.

Impact of Neuro-Psychological Factors on Smoking-Associated Lung Cancer

Smoking has been extensively documented as a risk factor for all histological types of lung cancer and tobacco-specific nitrosamines and polycyclic aromatic hydrocarbons reproducibly cause lung cancer in laboratory rodents. However, the most common lung cancer, non-small cell lung cancer (NSCLC), frequently develops in never smokers and is particularly common in women and African Americans, suggesting that factors unrelated to smoking significantly impact this cancer. Recent experimental investigations in vitro and in animal models have shown that chronic psychological stress and the associated hyperactive signaling of stress neurotransmitters via β-adrenergic receptors significantly promote the growth and metastatic potential of NSCLC. These responses were caused by modulation in the expression and sensitization state of nicotinic acetylcholine receptors (nAChRs) that regulate the production of stress neurotransmitters and the inhibitory neurotransmitter γ-aminobutyric acid (GABA). Similar changes in nAChR-mediated neurotransmitter production were identified as the cause of NSCLC stimulation in vitro and in xenograft models by chronic nicotine. Collectively, these data suggest that hyperactivity of the sympathetic branch of the autonomic nervous system caused by chronic psychological stress or chronic exposure to nicotinic agonists in cigarette smoke significantly contribute to the development and progression of NSCLC. A recent clinical study that reported improved survival outcomes with the incidental use of β-blockers among patients with NSCLC supports this interpretation.

A regression model for risk difference estimation in population-based case-control studies clarifies gender differences in lung cancer risk of smokers and never smokers.

BackgroundAdditive risk models are necessary for understanding the joint effects of exposures on individual and population disease risk. Yet technical challenges have limited the consideration of additive risk models in case–control studies.MethodsUsing a flexible risk regression model that allows additive and multiplicative components to estimate absolute risks and risk differences, we report a new analysis of data from the population-based case–control Environment And Genetics in Lung cancer Etiology study, conducted in Northern Italy between 2002–2005. The analysis provides estimates of the gender-specific absolute risk (cumulative risk) for non-smoking- and smoking-associated lung cancer, adjusted for demographic, occupational, and smoking history variables.ResultsIn the multiple-variable lexpit regression, the adjusted 3-year absolute risk of lung cancer in never smokers was 4.6 per 100,000 persons higher in women than men. However, the absolute increase in 3-year risk of lung cancer for every 10 additional pack-years smoked was less for women than men, 13.6 versus 52.9 per 100,000 persons.ConclusionsIn a Northern Italian population, the absolute risk of lung cancer among never smokers is higher in women than men but among smokers is lower in women than men. Lexpit regression is a novel approach to additive-multiplicative risk modeling that can contribute to clearer interpretation of population-based case–control studies.

Epigenomic analysis of lung adenocarcinoma reveals novel DNA methylation patterns associated with smoking

The importance of epigenetic regulation has been increasingly recognized in the development of cancer. In this study, we investigated the impact of smoking, a major risk factor of lung cancer, on DNA methylation by comparing the genome-wide DNA methylation patterns between lung adenocarcinoma samples from six smokers and six nonsmokers. We identified that smoking-induced DNA methylations were enriched in the calcium signaling and neuroactive ligand receptor signaling pathways, which are closely related to smoking-induced lung cancers. Interestingly, we discovered that two genes in the mitogen-activated protein kinase signaling pathway (RPS6KA3 and ARAF) were hypomethylated in smokers but not in nonsmokers. In addition, we found that the smoking-induced lung cancer-specific DNA methylations were mostly enriched in nuclear activities, including regulation of gene expression and chromatin remodeling. Moreover, the smoking-induced hypermethylation could only be seen in lung adenocarcinoma tissue but not in adjacent normal lung tissue. We also used differentially methylated DNA loci to construct a diagnostic model to distinguish smoking-associated lung cancer from nonsmoking lung cancer with a sensitivity of 88.9% and specificity of 83.2%. Our results provided novel evidence to support that smoking can cause dramatic changes in the DNA methylation landscape of lung cancer, suggesting that epigenetic regulation of specific oncogenic signaling pathways plays an important role in the development of lung cancer.

Smoking-Induced CXCL14 Expression in the Human Airway Epithelium Links Chronic Obstructive Pulmonary Disease to Lung Cancer

CXCL14, a recently described epithelial cytokine, plays putative multiple roles in inflammation and carcinogenesis. In the context that chronic obstructive pulmonary disease (COPD) and lung cancer are both smoking-related disorders associated with airway epithelial disorder and inflammation, we hypothesized that the airway epithelium responds to cigarette smoking with altered CXCL14 gene expression, contributing to the disease-relevant phenotype. Using genome-wide microarrays with subsequent immunohistochemical analysis, the data demonstrate that the expression of CXCL14 is up-regulated in the airway epithelium of healthy smokers and further increased in COPD smokers, especially within hyperplastic/metaplastic lesions, in association with multiple genes relevant to epithelial structural integrity and cancer. In vitro experiments revealed that the expression of CXCL14 is induced in the differentiated airway epithelium by cigarette smoke extract, and that epidermal growth factor mediates CXCL14 up-regulation in the airway epithelium through its effects on the basal stem/progenitor cell population. Analyses of two independent lung cancer cohorts revealed a dramatic up-regulation of CXCL14 expression in adenocarcinoma and squamous-cell carcinoma. High expression of the COPD-associated CXCL14-correlating cluster of genes was linked in lung adenocarcinoma with poor survival. These data suggest that the smoking-induced expression of CXCL14 in the airway epithelium represents a novel potential molecular link between smoking-associated airway epithelial injury, COPD, and lung cancer.

Abstract 4013: The positive role of TPγ in the induction of COX-2, TxA2 and cell growth by NNK in human lung cancer cells

Abstract Many studies have shown that 4-Methylnitrosamino-1-3-pyridyl-1-butanone (NNK), the most potent carcinogen present in tobacco smoke, can induce lung tumor growth. We previously demonstrated that the activation of extracellular regulated protein kinases (ERK) and cAMP response element-binding protein (CREB) is responsible for the pro-survival and proliferative effects of thromboxane A2 (TxA2) and its receptor (TP) in the human lung cancer cells stimulated with NNK (reported in oncogene journal). In current study, we further determined the role of cyclooxygenase(COX)-2/TxA2/TP pathway in lung cancer cell growth mediated by NNK. TP exists as two isoforms, ≤ and β, in human beings. Western blotting showed that TPα, but not TPα, was widely expressed in a series of human lung cells. NCI-H23 and CRL-2066, which express both TPγ and TPα, were selected as models in this study. COX-2 inhibitor NS398 could significantly reduce NNK-stimulated TxA2 synthesis. Moreover, NS398 and BM567, an agent combining TxA2 synthase inhibition and TP antagonism, had the similar effects to reverse NNK-induced activation of ERK and CREB and the increase in cell growth. Furthermore, the administration of TxA2 mimetic U46619 could almost reconstituted NNK-induced ERK and CREB activation in the presence of COX-2-siRNA. Collectively, these findings suggest that in lung cancer cells stimulated with NNK, TxA2 is mainly derived from COX-2 and acts as a key mediator for tumor-promoting effects of COX-2. Interestingly, TP antagonist SQ29548 could inhibit NNK-induced COX-2 protein expression and TxA2 production, indicating that TP is able to modulate NNK-induced COX-2 expression and activity, thereby constituting an auto-amplification mechanism of TxA2 synthesis in lung cancer cells stimulated with NNK. We further examined which TP isoform contributes to the NNK effects. We observed that the protein expression of TPα, but not TPα, was time-dependently increased by NNK. Moreover, the activation of ERK and CREB and the production of COX-2 and TxA2 by NNK were potentiated in cells transfected with pcDNA3-TPγ as compared with cells transfected with control vector or pcDNA3-TPα, and such effects could be reversed by SQ29548. However, in cells transfected with pcDNA3-TPα, the COX-2, TxA2, phospho-ERK and phospho-CREB levels were similar to that seen in the cells transfected with control vector, and neither NNK nor SQ29548 had any additional effects when compared to the control cells. Taken together, these data strongly suggest that TPγ rather than TPγ is, at least in part, responsible for the induction of COX-2, TxA2 and cell growth by NNK in lung cancer cells. Our study implies that targeting TxA2 and its receptor TPγ may represent a promising strategy for prevention of smoking-associated lung cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4013. doi:1538-7445.AM2012-4013

Angiotensin receptor blockade attenuates cigarette smoke–induced lung injury and rescues lung architecture in mice

Chronic obstructive pulmonary disease (COPD) is a prevalent smoking-related disease for which no disease-altering therapies currently exist. As dysregulated TGF-β signaling associates with lung pathology in patients with COPD and in animal models of lung injury induced by chronic exposure to cigarette smoke (CS), we postulated that inhibiting TGF-β signaling would protect against CS-induced lung injury. We first confirmed that TGF-β signaling was induced in the lungs of mice chronically exposed to CS as well as in COPD patient samples. Importantly, key pathological features of smoking-associated lung disease in patients, e.g., alveolar injury with overt emphysema and airway epithelial hyperplasia with fibrosis, accompanied CS-induced alveolar cell apoptosis caused by enhanced TGF-β signaling in CS-exposed mice. Systemic administration of a TGF-β-specific neutralizing antibody normalized TGF-β signaling and alveolar cell death, conferring improved lung architecture and lung mechanics in CS-exposed mice. Use of losartan, an angiotensin receptor type 1 blocker used widely in the clinic and known to antagonize TGF-β signaling, also improved oxidative stress, inflammation, metalloprotease activation and elastin remodeling. These data support our hypothesis that inhibition of TGF-β signaling through angiotensin receptor blockade can attenuate CS-induced lung injury in an established murine model. More importantly, our findings provide a preclinical platform for the development of other TGF-β-targeted therapies for patients with COPD.

Hope for smoking-associated lung cancer?

Squamous cell carcinoma, a subtype of non-small cell lung cancer (NSCLC), is strongly associated with smoking, and the prognosis for patients with this disease is dire. Traditional chemotherapeutic approaches are not very effective, and although exciting molecular targets, such as mutated epidermal growth factor receptor (EGFR) and EML4–ALK fusion proteins have been identified in NSCLC, they occur mostly in non-smokers with NSCLC of the adenocarcinoma subtype. Now, reporting in Science Translational Medicine, Jonathan Weiss and colleagues show that fibroblast growth factor receptor 1 (FGFR1) is a promising new molecular target for the treatment of smoking-associated lung cancer.

A Therapeutic Target for Smoking-Associated Lung Cancer

A report in this issue of Science Translational Medicine reveals that amplification of the FGFR1 gene-which encodes fibroblast growth factor receptor 1-is a major oncogenic aberration in squamous cell lung cancer. This genetic variation may represent the first relatively high-frequency therapeutic target of smoking-associated lung cancer.

Is Overweight or Obese Status an Independent Prognostic Factor in Various Solid Organ Cancers?

While obesity has been found to be a risk factor for several types of cancer, its use as a prognostic tool is unclear. The authors have reviewed literature interrogating the link between overweight status and obesity and cancer prognosis for five distinct solid organ malignancies: colon, breast, ovarian, lung, and renal. There appears to be a positive correlation between overnutrition and poor prognosis in breast and colon cancer. Similarly, there may well be a survival advantage for overweight or obese patients with newly diagnosed renal cell carcinoma and smoking-associated lung cancer. The relationship between ovarian cancer and obesity is less clear, as is the relationship between lung cancer in never/scant-smokers and obesity.

4-Methylnitrosamino-1-3-pyridyl-1-butanone (NNK) promotes lung cancer cell survival by stimulating thromboxane A2 and its receptor

The role of thromboxane A(2) (TxA(2)) in smoking-associated lung cancer is poorly understood. This study was conducted to study the role of TxA(2) in smoking carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-promoted cell survival and growth in human lung cancer cells. We found that NNK increased TxA(2) synthase (TxAS) expression and thromboxane B(2) (TxB(2)) generation in cultured lung cancer cells, the result of which was supported by the increased level of TxAS in lung cancer tissues of smokers. Both TxAS-specific inhibitor furegrelate and TxA(2) receptor antagonist SQ29548 completely blocked NNK-mediated cell survival and growth via inducting apoptosis. TxA(2) receptor agonist U46619 reconstituted a near-full survival and growth response to NNK when TxAS was inhibited, affirming the role of TxA(2) receptor in NNK-mediated cell survival and growth. Suppression of cyclic adenosine monophosphate response element binding protein (CREB) activity by its small interference RNA blocked the effect of NNK. Phosphatidylinositol 3-kinase (PI3K)/Akt and extracellular signal-regulated kinase (ERK) also had a positive role. Altogether, our results have revealed that NNK stimulates TxA(2) synthesis and activates its receptor in lung cancer cells. The increased TxA(2) may then activate CREB through PI3K/Akt and extracellular ERK pathways, thereby contributing to the NNK-promoted survival and growth of lung cancer cells.

Cigarette smoking, cadmium exposure, and zinc intake on obstructive lung disorder.

Background and objectiveThis study examined whether zinc intake was associated with lower risk of smoking-induced obstructive lung disorder through interplay with cadmium, one of major toxicants in cigarette smoke.MethodsData were obtained from a sample of 6,726 subjects aged 40+ from the Third National Health and Nutrition Examination Survey. The forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) were measured using spirometry. Gender-, ethnicity-, and age-specific equations were used to calculate the lower limit of normal (LLN) to define obstructive lung disorder as: observed FEV1/FVC ratio and FEV1 below respective LLN. Zinc intake was assessed by questionnaire. Logistic regression analysis was applied to investigate the associations of interest.ResultsThe analyses showed that an increased prevalence of obstructive lung disorder was observed among individuals with low zinc intake regardless of smoking status. The adjusted odds of lung disorder are approximately 1.9 times greater for subjects in the lowest zinc-intake tertile than those in the highest tertile (odds ratio = 1.89, 95% confidence interval = 1.22-2.93). The effect of smoking on lung function decreased considerably after adjusting for urinary cadmium. Protective association between the zinc-to-cadmium ratio (log-transformed) and respiratory risk suggests that zinc may play a role in smoking-associated lung disorder by modifying the influence of cadmium.ConclusionsWhile zinc intake is associated with lower risk of obstructive lung disorder, the role of smoking cession and/or prevention are likely to be more important given their far greater effect on respiratory risk. Future research is warranted to explore the mechanisms by which zinc could modify smoking-associated lung disease.

Smoking-Associated Interstitial Lung Diseases

Smoking-Associated Interstitial Lung Diseases

Nicotine Metabolism in Three Ethnic/Racial Groups with Different Risks of Lung Cancer

Previously, we documented that smoking-associated lung cancer risk is greater in Hawaiians and lower in Japanese compared with Whites. Nicotine metabolism by cytochrome P450 2A6 (CYP2A6) varies across ethnicity/race and is hypothesized to affect smoking behavior. We investigated whether higher CYP2A6 activity results in the smoker extracting more nicotine (adjusting for cigarettes per day) and being exposed to higher levels of tobacco-specific nitrosamine [4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)] and pyrene, a representative polycyclic aromatic hydrocarbon. We conducted a cross-sectional study of 585 smokers among the three main ethnic/racial groups in Hawaii and examined whether differences in CYP2A6 activity correlate with the ethnic/racial differences in lung cancer risk. We assessed CYP2A6 activity by nicotine metabolite ratio (total trans-3-hydroxycotinine/total cotinine) and caffeine metabolite ratio (1,7-dimethyl uric acid/1,7-dimethylxanthine) in 12 h urine. We also measured urinary nicotine equivalents (sum of nicotine, cotinine, and trans-3-hydroxycotinine and their respective glucuronides), a marker of nicotine dose, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and its glucuronide, markers of NNK exposure, and 1-hydroxypyrene, a marker of pyrene exposure. The nicotine metabolite ratio was higher in Whites than in Japanese and intermediate in Hawaiians (P values < 0.05). Cigarettes per day-adjusted nicotine equivalents were lower in Japanese compared with Hawaiians or Whites (P = 0.005 and P < 0.0001, respectively) and greater in men than women (P < 0.0001). Nicotine equivalents and total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol increased with CYP2A6 activity, indicating that smokers with greater nicotine metabolism smoke more extensively and have a higher internal NNK dose. The particularly low nicotine metabolism of Japanese smokers may contribute to their previously described decreased lung cancer risk.

Induction of centrosome amplification and chromosome instability in p53‐deficient lung cancer cells exposed to benzo[a]pyrene diol epoxide (B[a]PDE)

Benzo[a]pyrene diol epoxide (B[a]PDE), the ultimate carcinogenic metabolite of benzo[a] pyrene, has been implicated in the mutagenesis of the p53 gene involved in smoking-associated lung cancer. To further understand the role of B[a]PDE in lung tumour progression, we investigated its effect on the numerical integrity of centrosomes and chromosome stability in lung cancer cells lacking p53. Exposure of p53-deficient H1299 lung cancer cells to B[a]PDE resulted in S-phase arrest, leading to abnormal centrosome amplification. Analysis of H1299 cells stably expressing fluorescence-tagged centrin (a known centriolar marker) revealed that the centrosome amplification was primarily attributable to excessive centrosome duplication rather than to centriole splitting. Forced expression of POLK DNA polymerase, which has the ability to bypass B[a]PDE-guanine lesions in an error-free manner, suppressed the B[a]PDE-induced centrosome amplification. Fluorescence in situ hybridization analyses with probes specific for chromosomes 2, 3, and 16 revealed that B[a]PDE exposure also led to chromosome instability, which was likely to have resulted from centrosome amplification. We extended these findings to primary lung carcinomas containing non-functional p53, and found a strong association between centrosome amplification and a high level of B[a]PDE-DNA accumulation. Therefore B[a]PDE contributes to neoplasia by inducing centrosome amplification and consequent chromosome destabilization as well as its mutagenic activity.

Nongenomic β Estrogen Receptors Enhance β1 Adrenergic Signaling Induced by the Nicotine-Derived Carcinogen 4-(Methylnitrosamino)-1-(3-Pyridyl)-1-Butanone in Human Small Airway Epithelial Cells

Women are at higher risk for the development of lung adenocarcinoma than men; however, the mechanisms responsible for this are poorly understood. In lung adenocarcinoma cells, the estrogen receptor beta (ERbeta) is the predominating form. We found that 17beta-estradiol enhanced proliferation of the putative cells of origin of lung adenocarcinoma, small airway epithelial cells (HPLD1), in response to the nicotine-derived nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Reverse-phase protein microarrays combined with Western blotting revealed that NNK induced phosphorylation of ERbeta, an effect that involved stimulation of the adrenergic receptors beta1 (beta1AR). In transiently transfected cells, beta1AR coprecipitated with ERbeta, which increased with NNK treatment. ERbeta enhanced NNK-induced cyclic AMP accumulation as well as Galphai-mediated mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) 1/2 activation. Coexpression of beta1AR and ERbeta activated NNK-mediated ERK1/2 cooperatively. ERbeta gene knockdown, as well as coexpression of the dominant negative Ras and Raf, reduced stimulation of ERK1/2 by NNK. Whereas NNK phosphorylated Akt at Thr(308) and Ser(473), ERbeta had no effect on this activity. Luciferase reporter assays showed that, in response to NNK, ERbeta stimulated transcription of serum responsive element (SRE) but had a very small effect on the activity of estrogen responsive element (ERE). Together, the phosphorylation of ERbeta, the dependence on Galphai proteins, the activation of ERK1/2, and the preferential targeting of SRE over the classic ERE pathway support a role for nongenomic ERbeta in the development of smoking-associated lung cancer. This novel cooperation between beta1AR and ERbeta signaling may contribute to the prominence of lung adenocarcinoma in women.

Lung Cancer Incidence in Never Smokers

Lung cancer is a leading cause of cancer death worldwide. Although smoking remains the predominant cause of lung cancer, lung cancer in never smokers is an increasingly prominent public health issue. However, data on this topic, particularly lung cancer incidence rates in never smokers, are limited. We reviewed the existing literature on lung cancer incidence and mortality rates among never smokers and present new data regarding rates in never smokers from the following large, prospective cohorts: Nurses' Health Study; Health Professionals Follow-Up Study; California Teachers Study; Multiethnic Cohort Study; Swedish Lung Cancer Register in the Uppsala/Orebro region; and First National Health and Nutrition Examination Survey Epidemiologic Follow-Up Study. Truncated age-adjusted incidence rates of lung cancer among never smokers age 40 to 79 years in these six cohorts ranged from 14.4 to 20.8 per 100,000 person-years in women and 4.8 to 13.7 per 100,000 person-years in men, supporting earlier observations that women are more likely than men to have non-smoking-associated lung cancer. The distinct biology of lung cancer in never smokers is apparent in differential responses to epidermal growth factor receptor inhibitors and an increased prevalence of adenocarcinoma histology in never smokers. Lung cancer in never smokers is an important public health issue, and further exploration of its incidence patterns, etiology, and biology is needed.

Modifier Role of Nrf2 in Cigarette Smoke-induced Emphysema

Background: CCAAT/enhancer binding proteins (C/EBPs) are key regulators of cell differentiation and linked processes such as proliferation, apoptosis, and gene expression in several organs. C/EBPs are also central for inflammatory responses and infectious defenses, but so far little is known of their role in lung diseases. Chronic bronchitis and chronic obstructive pulmonary disease (COPD) are common smoking-associated lung diseases involving the airway epithelium. Methods: Gel shifts were used to study C/EBP transcription factor activity in airway epithelial cells obtained by bronchial brush biopsy in four groups: healthy never-smokers (n 10), asymptomatic smokers (n 7), and smokers with chronic bronchitis and recurrent infectious exacerbations without (n 23) and with (n 13) COPD. Results: C/EBP-binding activity was increased 4.6-fold in airway epithelial cells of healthy smokers compared with never-smokers. In contrast, C/EBP-binding activity was not increased in the epithelium of smokers with chronic bronchitis or COPD. C/EBP was the dominant C/EBP in the airway epithelium in all groups. Conclusions: We hypothesize that this lack of increase in C/EBP-activity renders the epithelium incompetent of efficient regeneration and more sensitive to infection, suggesting a previously unknown role for C/EBPs in the pathogenesis of chronic bronchitis and COPD. In addition, decreased C/EBP-activity in chronic bronchitis and COPD could contribute to the glucocorticoid resistance of these diseases.

Decreased CCAAT/Enhancer Binding Protein (C/EBP)Transcription Factor Activity in Chronic Bronchitis and Chronic Obstructive Pulmonary Disease

Background: CCAAT/enhancer binding proteins (C/EBPs) are key regulators of cell differentiation and linked processes such as proliferation, apoptosis, and gene expression in several organs. C/EBPs are also central for inflammatory responses and infectious defenses, but so far little is known of their role in lung diseases. Chronic bronchitis and chronic obstructive pulmonary disease (COPD) are common smoking-associated lung diseases involving the airway epithelium. Methods: Gel shifts were used to study C/EBP transcription factor activity in airway epithelial cells obtained by bronchial brush biopsy in four groups: healthy never-smokers (n 10), asymptomatic smokers (n 7), and smokers with chronic bronchitis and recurrent infectious exacerbations without (n 23) and with (n 13) COPD. Results: C/EBP-binding activity was increased 4.6-fold in airway epithelial cells of healthy smokers compared with never-smokers. In contrast, C/EBP-binding activity was not increased in the epithelium of smokers with chronic bronchitis or COPD. C/EBP was the dominant C/EBP in the airway epithelium in all groups. Conclusions: We hypothesize that this lack of increase in C/EBP -activity renders the epithelium incompetent of efficient regeneration and more sensitive to infection, suggesting a previously unknown role for C/EBPs in the pathogenesis of chronic bronchitis and COPD. In addition, decreased C/EBP-activity in chronic bronchitis and COPD could contribute to the glucocorticoid resistance of these diseases.

Smoking and Deaths between 40 and 70 Years of Age in Women and Men

The vast scientific literature on smoking and health contains few large studies with direct estimates of long-term mortality by smoking habits. Data have been lacking, particularly for women. To study smoking and deaths and causes of death in women and men of middle age (40 to 70 years of age). Population-based cohort study. Norway (the Norwegian Counties Study). 24,505 women and 25,034 men who were born between 1925 and 1941. Initial information on smoking habits was collected between 1974 and 1978. Smoking status was also assessed about 5 years and 10 years after the first examination. Death during 1974 to 2000 was studied by using death certificate information. During follow-up, 2333 women and 4680 men died in middle age. Among women and men, 9% and 14% of never smokers, respectively, and 26% and 41% of continuing heavy smokers (> or =20 cigarettes per day), respectively, died in middle age. Years of life lost among heavy smokers between 40 and 70 years of age were 1.4 years in women and 2.7 years in men, compared with never smokers. Rates of smoking-associated lung cancer were similar in women and men, while lower cardiovascular mortality rates in women explained most of the difference in smoking-associated all-cause mortality between men and women. Data on changes in smoking habits after the baseline examination were not available for all participants and for the last 15 years of follow-up. Mortality levels in middle age may not apply to non-Norwegian populations. Continuing smoking strongly increased and smoking cessation decreased the risk for death between 40 and 70 years of age for both women and men. Despite similar rates for lung cancer death, women who smoked had lower mortality rates in middle age than men with similar smoking histories due to fewer cardiovascular deaths in women.