Prospective study of e-cigarette use and respiratory symptoms in adolescents and young adults.

RATIONALE: Electronic cigarette (e-cigarette) aerosol contains volatile aldehydes, including flavourings and oxidant metals with known pulmonary toxicity. OBJECTIVES: To evaluate the associations of e-cigarette use with symptoms of wheeze, bronchitic symptoms and shortness of breath (SOB) across 4 years of prospective data. METHODS: Participants completed questionnaires on respiratory symptoms and past 30-day e-cigarette, cigarette and cannabis use in 2014 (wave 1; N=2094; mean age 17.3 years, SD=0.6 years). Follow-up information was collected in 2015 (wave 2; n=1609), 2017 (wave 3; n=1502) and 2018 (wave 4; n=1637) using online surveys. Mixed-effects logistic regression models evaluated associations of e-cigarette use with respiratory symptoms. MEASUREMENTS AND MAIN RESULTS: Participants were mostly Hispanic white (51.8%) and evenly representative by sex (49.6% female; 50.4% male). Compared with never e-cigarette users, past 30-day e-cigarette users reported increased odds of wheeze (OR 1.81; 95% CI 1.28, 2.56), bronchitic symptoms (OR 2.06; 95% CI 1.58, 2.69) and SOB (OR 1.78; 95% CI 1.23, 2.57), adjusting for study wave, age, sex, race, lifetime asthma diagnosis and parental education. Effect estimates were attenuated (wheeze (OR 1.41; 95% CI 0.99, 2.01), bronchitic symptoms (OR 1.55; 95% CI 1.18, 2.05), SOB (OR 1.48; 95% CI 1.01, 2.18)), after adjusting additionally for current cigarette use, cannabis use and secondhand exposure to e-cigarettes/cigarettes/cannabis. CONCLUSIONS: E-cigarette use in young adults was associated with respiratory symptoms, independent of combustible cannabis and cigarette exposures.

Immediate smoking cessation support during lung cancer screening: long-term outcomes from two randomised controlled trials.

BACKGROUND: Immediate smoking cessation interventions delivered alongside targeted lung health checks (TLHCs) to screen for lung cancer increase self-reported abstinence at 3 months. The impact on longer term, objectively confirmed quit rates remains to be established. METHODS: We followed up participants from two clinical trials in people aged 55-75 years who smoked and took part in a TLHC. These randomised participants in the TLHC by day of attendance to either usual care (UC) (signposting to smoking cessation services) or an offer of immediate smoking cessation support including pharmacotherapy. In the QuLIT1 trial, this was delivered face to face and in QuLIT2, it was delivered remotely. Follow-up was conducted 12 months after the TLHC by telephone interview with subsequent biochemical verification of smoking cessation using exhaled CO. RESULTS: 430 people were enrolled initially (115 in QuLIT1 and 315 in QuLIT2), with 4 deaths before 12 months leaving 426 (62.1±5.27 years old and 48% women) participants for analysis. At 12 months, those randomised to attend on smoking cessation support intervention days had higher quit rates compared with UC adjusted for age, gender, deprivation, and which trial they had been in; self-reported 7-day point prevalence (20.0% vs 12.8%; adjusted OR (AOR)=1.78; 95% CI 1.04 to 2.89) and CO-verified quits (12.1% vs 4.7%; AOR=2.97; 95% CI 1.38 to 6.90). Those in the intervention arm were also more likely to report having made a quit attempt (30.2% vs UC 18.5%; AOR 1.90; 95% CI 1.15 to 3.15). CONCLUSION: Providing immediate smoking cessation support alongside TLHC increases long term, biochemically confirmed smoking abstinence. TRIAL REGISTRATION NUMBER: ISRCTN12455871.

Appraising the causal role of smoking in idiopathic pulmonary fibrosis: a Mendelian randomization study.

Smoking has been considered a risk factor for idiopathic pulmonary fibrosis (IPF) in observational studies. To assess whether smoking plays a causal role in IPF, we performed a Mendelian randomization study using genetic association data of 10 382 cases with IPF and 968 080 controls. We found that genetic predisposition to smoking initiation (based on 378 variants) and lifetime smoking (based on 126 variants) were associated with a higher risk of IPF. Our study suggests a potential causal effect of smoking on increasing IPF risk from a genetic perspective.

Epigenome-wide association study of lung cancer among never smokers in two prospective cohorts in Shanghai, China.

BACKGROUND: The aetiology of lung cancer among individuals who never smoked remains elusive, despite 15% of lung cancer cases in men and 53% in women worldwide being unrelated to smoking. Epigenetic alterations, particularly DNA methylation (DNAm) changes, have emerged as potential drivers. Yet, few prospective epigenome-wide association studies (EWAS), primarily focusing on peripheral blood DNAm with limited representation of never smokers, have been conducted. METHODS: We conducted a nested case-control study of 80 never-smoking incident lung cancer cases and 83 never-smoking controls within the Shanghai Women's Health Study and Shanghai Men's Health Study. DNAm was measured in prediagnostic oral rinse samples using Illumina MethylationEPIC array. Initially, we conducted an EWAS to identify differentially methylated positions (DMPs) associated with lung cancer in the discovery sample of 101 subjects. The top 50 DMPs were further evaluated in a replication sample of 62 subjects, and results were pooled using fixed-effect meta-analysis. RESULTS: Our study identified three DMPs significantly associated with lung cancer at the epigenome-wide significance level of p<8.22×10-8. These DMPs were identified as cg09198866 (MYH9; TXN2), cg01411366 (SLC9A10) and cg12787323. Furthermore, examination of the top 1000 DMPs indicated significant enrichment in epithelial regulatory regions and their involvement in small GTPase-mediated signal transduction pathways. Additionally, GrimAge acceleration was identified as a risk factor for lung cancer (OR=1.19 per year; 95% CI 1.06 to 1.34). CONCLUSIONS: While replication in a larger sample size is necessary, our findings suggest that DNAm patterns in prediagnostic oral rinse samples could provide novel insights into the underlying mechanisms of lung cancer in never smokers.

Environmental pollutants exposure-derived extracellular vesicles: crucial players in respiratory disorders.

BACKGROUND: Individual exposure to environmental pollutants, as one of the most influential drivers of respiratory disorders, has received considerable attention due to its preventability and controllability. Considering that the extracellular vesicle (EV) was an emerging intercellular communication medium, recent studies have highlighted the crucial role of environmental pollutants derived EVs (EPE-EVs) in respiratory disorders. METHODS: PubMed and Web of Science were searched from January 2018 to December 2023 for publications with key words of environmental pollutants, respiratory disorders and EVs. RESULTS: Environmental pollutants could disrupt airway intercellular communication by indirectly stimulating airway barrier cells to secrete endogenous EVs, or directly transmitting exogenous EVs, mainly by biological pollutants. Mechanistically, EPE-EVs transferred specific contents to modulate biological functions of recipient cells, to induce respiratory inflammation and impair tissue and immune function, which consequently contributed to the development of respiratory diseases, such as asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, pulmonary hypertension, lung cancer and infectious lung diseases. Clinically, EVs could emerged as promising biomarkers and biological agents for respiratory diseases attributed by their specificity, convenience, sensibility and stability. CONCLUSIONS: Further studies of EPE-EVs are helpful to understand the aetiology and pathology of respiratory diseases, and facilitate the precision respiratory medicine in risk screening, early diagnosis, clinical management and biotherapy.

Early menopause and hormone therapy as determinants for lung health outcomes: a secondary analysis using the PLCO trial.

RATIONALE: Early natural menopause (early-M; <45 years of age) increases the risk of lung morbidities and mortalities in smokers. However, it is largely unknown whether early-M due to surgery demonstrates similar effects and whether menopausal hormone therapy (MHT) is protective against lung diseases. OBJECTIVES: To assess the associations of early-M and MHT with lung morbidities and mortalities using the prospective Prostate, Lung, Colorectal and Ovarian (PLCO) trial. METHODS: We estimated the risk among 69 706 postmenopausal women in the PLCO trial, stratified by menopausal types and smoking status. RESULTS: Early-M was associated with an increased risk of most lung disease and mortality outcomes in ever smokers with the highest risk seen for respiratory mortality (HR 1.98, 95% CI 1.34 to 2.92) in those with bilateral oophorectomy (BO). Early-M was positively associated with chronic bronchitis, and all-cause, non-cancer and respiratory mortality in never smokers with natural menopause or BO, with the highest risk seen for BO- respiratory mortality (HR 1.91, 95% CI 1.16 to 3.12). Ever MHT was associated with reduced all-cause, non-cancer and cardiovascular mortality across menopause types regardless of smoking status and was additionally associated with reduced risk of non-ovarian cancer, lung cancer (LC) and respiratory mortality in ever smokers. Among smokers, ever MHT use was associated with a reduction in HR for all-cause, non-cancer and cardiovascular mortality in a duration-dependent manner. CONCLUSIONS: Smokers with early-M should be targeted for smoking cessation and LC screening regardless of menopause types. MHT users had a lower likelihood of dying from LC and respiratory diseases in ever smokers.

Nationwide indoor smoking ban and impact on smoking behaviour and lung function: a two-population natural experiment.

INTRODUCTION: Many countries have implemented indoor smoking bans over the past two decades. Although smoking bans have been shown to reduce cardiovascular outcomes, little is known about their impact on respiratory health. This study investigated the impact of a nationwide indoor smoking ban on smoking behaviour and lung function. METHODS: We used repeated cross-sectional data from two large cohorts of the general population comprising 31 807 Swiss and 62 093 Danish adults. We compared associations between smoking ban and smoking prevalence and prebronchodilator lung function trends in Denmark (indoor smoking ban introduced in 2007) and Switzerland (indoor smoking ban introduced in 2010) from 2005 to 2010 using a quasi-experimental study design. We performed difference-in-difference analyses with linear regression models adjusted for age, sex, weight and height. RESULTS: Denmark had a stronger decrease in active smokers compared with Switzerland. Also, forced expiratory volume in the first second was higher in Danish adults than in Swiss adults: 26 mL (95% CI 2.4 to 49) 1 year, 88 mL (65 to 112) 2 years, and 74 mL (51 to 98) 3 years after smoking ban implementation. Correspondingly, forced vital capacity was higher in Danish adults compared with Swiss adults (80 mL (50 to 109) after 1 year and 126 mL (97 to 155) after two and 3 years). Improvements were observed in both never-smokers and ever-smokers, most pronounced in ever-smokers. CONCLUSIONS: Nationwide indoor smoking ban is associated with less smoking and improved lung function in the general population. Implementing an indoor smoking ban can improve lung function by influencing smoking behaviour and reducing secondhand smoke.

CT pectoralis muscle area is associated with DXA lean mass and correlates with emphysema progression in a tobacco-exposed cohort.

INTRODUCTION: Muscle loss is an important extrapulmonary manifestation of COPD. Dual energy X-ray absorptiometry (DXA) is the method of choice for body composition measurement but is not widely used for muscle mass evaluation. The pectoralis muscle area (PMA) is quantifiable by CT and predicts cross-sectional COPD-related morbidity. There are no studies that compare PMA with DXA measures or that evaluate longitudinal relationships between PMA and lung disease progression. METHODS: Participants from our longitudinal tobacco-exposed cohort had baseline and 6-year chest CT (n=259) and DXA (n=164) data. Emphysema was quantified by CT density histogram parenchymal scoring using the 15th percentile technique. Fat-free mass index (FFMI) and appendicular skeletal mass index (ASMI) were calculated from DXA measurements. Linear regression model relationships were reported using standardised coefficient (ß) with 95% CI. RESULTS: PMA was more strongly associated with DXA measures than with body mass index (BMI) in both cross-sectional (FFMI: ß=0.76 (95% CI 0.65 to 0.86), p<0.001; ASMI: ß=0.76 (95% CI 0.66 to 0.86), p<0.001; BMI: ß=0.36 (95% CI 0.25 to 0.47), p<0.001) and longitudinal (ΔFFMI: ß=0.43 (95% CI 0.28 to 0.57), p<0.001; ΔASMI: ß=0.42 (95% CI 0.27 to 0.57), p<0.001; ΔBMI: ß=0.34 (95% CI 0.22 to 0.46), p<0.001) models. Six-year change in PMA was associated with 6-year change in emphysema (ß=0.39 (95% CI 0.23 to 0.56), p<0.001) but not with 6-year change in airflow obstruction. CONCLUSIONS: PMA is an accessible measure of muscle mass and may serve as a useful clinical surrogate for assessing skeletal muscle loss in smokers. Decreased PMA correlated with emphysema progression but not lung function decline, suggesting a difference in the pathophysiology driving emphysema, airflow obstruction and comorbidity risk.

Cigarette smoking is a secondary cause of folliculin loss.

BACKGROUND: Birt-Hogg-Dubé syndrome (BHD) is a clinical syndrome manifesting with cystic lung disease and pneumothorax. Features of BHD result from the loss-of-function mutations of the folliculin (FLCN) gene. Chronic obstructive pulmonary disease (COPD), characterised by an irreversible airflow limitation, is primarily caused by cigarette smoking. OBJECTIVE: Given that COPD often shares structural features with BHD, we investigated the link between COPD, cigarette smoke (CS) exposure and FLCN expression. METHODS: We measured the expression of FLCN in human COPD lungs and CS-exposed mouse lungs, as well as in CS extract (CSE)-exposed immortalised human airway epithelial cells by immunoblotting. RESULTS: We found that the lung FLCN protein levels in smokers with COPD and CS exposure mice exhibit a marked decrease compared with smokers without COPD and room air exposure mice, respectively. We confirmed CS induced degradation of FLCN in immortalised human bronchial epithelial Beas-2B cells via ubiquitin proteasome system. Further, siRNA targeting FLCN enhanced CSE-induced cytotoxicity. By contrast, FLCN overexpression protected cells from CSE-induced cytotoxicity. We found that FBXO23, the ubiquitin E3 ligase subunit, specifically binds to and targets FLCN for degradation. Inhibition of ATM (ataxia-telangiectasia mutated) attenuated CSE induced FLCN degradation, suggesting a role of ATM in FLCN proteolysis. We further confirmed that the mutant of major FLCN phosphorylation site serine 62A is resistant to CSE-induced degradation and cytotoxicity. CONCLUSIONS: Our study demonstrates that CS exposure is a secondary cause of FLCN deficiency due to the enhanced proteolysis, which promoted airway epithelial cell death.

Faster lung function decline in people living with HIV despite adequate treatment: a longitudinal matched cohort study.

INTRODUCTION: Chronic lung disease is common among people living with HIV (PLWH). We hypothesised that PLWH receiving antiretroviral therapy (ART) have faster lung function decline than matched controls. METHODS: We performed a prospective matched cohort study by including ART-treated PLWH from the Copenhagen Co-morbidity in HIV Infection Study (n=705) and the INSIGHT Strategic Timing of Antiretroviral Treatment Pulmonary Substudy (n=425) and frequency matched population controls from the Copenhagen General Population Study (n=2895) in a 1:3 ratio. Eligible participants were ≥25 years old and had two spirometry tests separated by at least 2 years of follow-up. Forced expiratory volume in 1 s (FEV1) decline (mL/year) was compared between PLWH and controls using a linear mixed model adjusted for age, sex, ethnicity and smoking status. Effect modification by smoking was investigated in subgroup analyses. RESULTS: The majority of PLWH were virally suppressed (96.1%). The adjusted mean annual decline in FEV1 was faster in PLWH than in controls with 36.4 (95% CI 33.7 to 39.1) vs 27.9 (95% CI 26.9 to 28.8) mL/year, yielding a difference of 8.5 (95% CI 5.6 to 11.4) mL/year. The association between HIV and FEV1 decline was modified by smoking, with the largest difference in current smokers (difference: 16.8 (95% CI 10.5 to 23.0) mL/year) and the smallest difference in never-smokers (difference: 5.0 (95% CI 0.7 to 9.3) mL/year). FEV1 decline >40 mL/year was more prevalent in PLWH (adjusted OR: 1.98 (95% CI 1.67 to 2.34)). CONCLUSION: Well-treated PLWH have faster lung function decline than controls and smoking seems to modify this association, suggesting that smoking may lead to more rapid lung function decline in PLWH than in controls.

Secondhand nicotine vaping at home and respiratory symptoms in young adults.

RATIONALE: Despite high prevalence of e-cigarette use (vaping), little is currently known regarding the health effects of secondhand nicotine vape exposure. OBJECTIVE: To investigate whether exposure to secondhand nicotine vape exposure is associated with adverse respiratory health symptoms among young adults. METHOD: We investigated the effect of secondhand nicotine vape exposure on annually reported wheeze, bronchitic symptoms and shortness of breath in the prospective Southern California Children Health Study cohort. Data were collected from study participants (n=2097) with repeated annual surveys from 2014 (average age: 17.3 years) to 2019 (average age: 21.9). We used mixed effect logistic regression to evaluate the association between secondhand nicotine vape and respiratory symptoms after controlling for relevant confounders. RESULTS: Prevalence of secondhand nicotine vape increased from 11.7% to 15.6% during the study period in this population. Prevalence of wheeze, bronchitic symptoms and shortness of breath ranged from 12.3% to 14.9%, 19.4% to 26.0% and 16.5% to 18.1%, respectively, during the study period. Associations of secondhand nicotine vape exposure with bronchitic symptoms (OR 1.40, 95% CI 1.06 to 1.84) and shortness of breath (OR 1.53, 95% CI 1.06 to 2.21) were observed after controlling for vaping, active and passive exposure to tobacco or cannabis, and demographic characteristics (age, gender, race/ethnicity and parental education). Stronger associations were observed when analysis was restricted to participants who were neither smokers nor vapers. There were no associations with wheezing after adjustment for confounders. CONCLUSION: Secondhand nicotine vape exposure was associated with increased risk of bronchitic symptoms and shortness of breath among young adults.

Different responses of the oral, nasal and lung microbiomes to cigarette smoke.

To examine the role of smoking on the bacterial community composition of the upper and the lower respiratory tract, a monocentric, controlled prospective study was performed, including healthy smokers, ex-smokers and never-smokers. Smokers were further grouped according to their smoking history. Bacterial diversity was analysed using a molecular barcoding approach based on directly extracted DNA. Our study shows for the first time distinct bacterial response patterns in the upper and lower respiratory tract to cigarette smoking leading to a higher abundance of opportunistic pathogens. The clinical significance of these dysbioses for health needs to be further explored.

Assessment of formal tobacco treatment and smoking cessation in dual users of cigarettes and e-cigarettes.

BACKGROUND: The utility of electronic cigarettes ('e-cigarettes') as a smoking cessation adjunct remains unclear. Similarly, it is unclear if formal tobacco treatment (pharmacotherapy and/or behavioural support) augments smoking cessation in individuals who use both cigarettes and e-cigarettes. METHODS: We performed a longitudinal cohort study of adult outpatients evaluated in our tertiary care medical centre (6/2018-6/2020). E-cigarette use, smoking status and formal tobacco treatment (deterrent pharmacotherapy and/or behavioural support) were assessed in 6-month blocks (eg, cohort 1 (C1)=6/2018-12/2018, C2=1/2019-6/2019 and so on) using our electronic health record. We assessed the relationship between e-cigarette use (either with or without formal tobacco treatment) and point prevalence of smoking cessation at 6 and 12 months. RESULTS: 111 823 unique patients were included in the study. The prevalence of dual use of cigarettes and e-cigarettes increased significantly over the study period (C1=0.8%; C2=1.1%; C3=1.8%; C4=2.3%; p<0.001). The prevalence of smoking cessation at 12 months was higher among e-cigarette users (20.8%) compared with non-users (16.8%) (risk difference, 4.0% (95% CI 2.5% to 5.5%); adjusted relative risk (aRR) 1.354, 95% CI 1.252 to 1.464, p<0.0001). Further, among dual users of cigarettes and e-cigarettes, the prevalence of smoking cessation at 12 months was higher among individuals who received tobacco treatment (29.1%) compared with individuals who did not receive tobacco treatment (19.6%) (risk difference, 9.5% (95% CI, 4.6% to 14.4%); aRR 1.238, 95% CI 1.071 to 1.432, p=0.004). INTERPRETATION: These results suggest that dual users of cigarettes and e-cigarettes benefit from formal tobacco treatment. Clinicians should consider offering formal tobacco treatment to such patients, though future trials are needed.

Effects of tobacco smoking on recurrent hospitalisation with pneumonia: a population-based cohort study.

The incidence of and risk factors for recurrent hospitalisation for pneumonia were investigated using data from Hospital Episode Statistics, linked to a UK primary care database. Within 90 days and 1 year of follow-up, 1733 (3.1%) and 5064 (9.0%), developed recurrent pneumonia respectively. Smoking status at the time of hospitalisation with index pneumonia was associated with the risk of readmission with recurrent pneumonia within a year of discharge: current versus never smokers: adjusted subhazard ratio (sHR) 1.42, 95% CI 1.32 to 1.53, p<0.001, and ex smokers versus never smokers: adjusted sHR 1.24, 95% CI 1.15 to 1.34, p<0.001. Other independent risk factors associated with recurrent pneumonia were age, gender, deprivation and underlying comorbidities.

Tobacco industry ownership of pharmaceutical companies: an international survey of people with respiratory disease.

The 2021 purchase of the respiratory pharmaceutical company Vectura by Phillip Morris International has been criticised by the public health and medical community, as a conflict of interest, with little input to date, from the patient community or the public. To address this gap, the COPD Foundation, along with global partners, surveyed 1196 people with chronic respiratory disease. 70% were bothered by a tobacco company making an inhaler to treat lung conditions and 48% reported that they would want to switch inhalers if they knew that a tobacco company made or sold their inhaler devices. Patients care about who makes the therapies used to treat their diseases.

Effect of quitting smoking on health outcomes during treatment for tuberculosis: secondary analysis of the TB & Tobacco Trial.

BACKGROUND: Despite treatment, patients with tuberculosis (TB) who smoke have poorer outcomes compared with non-smokers. It is unknown, however, if quitting smoking during the 6 months of TB treatment improves TB outcomes. METHODS: The TB & Tobacco Trial was a double-blind, placebo-controlled randomised trial of cytisine for smoking cessation in 2472 patients with pulmonary TB in Bangladesh and Pakistan. In a secondary analysis, we investigated the hypothesis that smoking cessation improves health outcomes in patients during the TB treatment course. The outcomes included an eight-point TB clinical score, sputum conversion rates, chest X-ray grades, quality of life (EQ-5D-5L), TB cure plus treatment completion rates and relapse rates. These were compared between those who stopped smoking and those who did not, using regression analysis. RESULTS: We analysed the data of 2273 (92%) trial participants. Overall, 25% (577/2273) of participants stopped smoking. Compared with non-quitters, those who quit had better TB cure plus treatment completion rates (91% vs 80%, p<0.001) and lower TB relapse rates (6% vs 14%, p<0.001). Among quitters, a higher sputum conversion rate at week 9 (91% vs 87%, p=0.036), lower mean TB clinical scores (-0.20 points, 95% CI -0.31 to -0.08, p=0.001) and slightly better quality of life (mean EQ-5D-5L 0.86 vs 0.85, p=0.015) at 6 months were also observed. These differences, except quality of life, remained statistically significant after adjusting for baseline values, trial arm and TB treatment adherence rates. CONCLUSION: Patients with TB who stop smoking may have better outcomes than those who don't. Health professionals should support patients in stopping smoking.

Impact of smoking on the development of idiopathic pulmonary fibrosis: results from a nationwide population-based cohort study.

BACKGROUND: Smoking has been considered an important risk factor for idiopathic pulmonary fibrosis (IPF) incidence. However, there are no population-based large-scale studies demonstrating the effects of smoking on the development of IPF. We aimed to evaluate the effect of smoking on IPF development using a nationwide population-based cohort. METHODS: Using the Korean National Health Information Database, we enrolled individuals who had participated in the health check-up service between 2009 and 2012. Participants having a prior diagnosis of IPF were excluded. The history of smoking status and quantity was collected by a questionnaire. We identified all cases of incident IPF through 2016 on the basis of ICD-10 codes for IPF and medical claims. Cox proportional hazards models were used to calculate the adjusted HR (aHR) of the development of IPF. RESULTS: A total of 25 113 individuals (0.11%) with incident IPF were identified out of 23 242 836 participants registered in the database. The risk of IPF was significantly higher in current and former smokers than in never smokers, with an aHR of 1.66 (95% CI 1.61 to 1.72) and 1.42 (95% CI 1.37 to 1.48), respectively. Current smokers had a higher risk of IPF than former smokers (aHR 1.17, 95% CI 1.13 to 1.21). The risk of IPF development increased as the smoking intensity and duration increased. CONCLUSION: Smoking significantly increased the risk of IPF development. Current smokers had a higher risk of IPF than former smokers. A dose-response relationship was observed between smoking and the development of IPF.

Cigarette smoke exposure and alveolar macrophages: mechanisms for lung disease.

Cigarette smoking is the leading cause of preventable death worldwide. It causes chronic lung disease and predisposes individuals to acute lung injury and pulmonary infection. Alveolar macrophages are sentinel cells strategically positioned in the interface between the airway lumen and the alveolar spaces. These are the most abundant immune cells and are the first line of defence against inhaled particulates and pathogens. Recently, there has been a better understanding about the ontogeny, phenotype and function of alveolar macrophages and their role, not only in phagocytosis, but also in initiating and resolving immune response. Many of the functions of the alveolar macrophage have been shown to be dysregulated following exposure to cigarette smoke. While the mechanisms for these changes remain poorly understood, they are important in the understanding of cigarette smoking-induced lung disease. We review the mechanisms by which smoking influences alveolar macrophage: (1) recruitment, (2) phenotype, (3) immune function (bacterial killing, phagocytosis, proteinase/anti-proteinase release and reactive oxygen species production) and (4) homeostasis (surfactant/lipid processing, iron homeostasis and efferocytosis). Further understanding of the mechanisms of cigarette smoking on alveolar macrophages and other lung monocyte/macrophage populations may allow novel ways of restoring cellular function in those patients who have stopped smoking in order to reduce the risk of subsequent infection or further lung injury.

The association of smoking cessation with mortality from pneumonia among middle-aged and elderly community residents: The Japan Collaborative Cohort (JACC) study.

Several studies have shown that smoking is a significant risk factor for pneumonia, but it is uncertain to what extent smoking cessation reduces the risk. This study aimed to investigate whether and to what extent smoking cessation is associated with reduced risk of mortality from pneumonia in a Japanese, prospective, community-based cohort. We examined 94,972 individuals (mean age, 57 years; women, 57%) who provided valid responses to a lifestyle questionnaire including questions about smoking. We used years of smoking cessation at baseline to divide former smokers into 5 groups: 0-1 year, 2-4 years, 5-9 years, 10-14 years, and 15 years or more. The endpoint was the underlying cause of death from pneumonia. During the median 19-year follow-up of 94,972 study participants, 1806 died from pneumonia. Multivariable hazard ratios (95% confidence intervals) compared with the current smokers were 1.02 (0.72-1.45) for 0-1 year of smoking cessation at baseline, 0.92 (0.70-1.22) for 2-4 years, 0.95 (0.74-1.21) for 5-9 years, 0.71 (0.53-0.96) for 10-14 years, 0.63 (0.48-0.83) for 15 years or more, and 0.50 (0.36-0.70) for never-smokers. Although smoking increases the risk of pneumonia mortality, the present study showed that the risk of pneumonia mortality decreased with years of smoking cessation, eventually improving to levels similar to those of non-smokers for 10 years or more. Continued smoking cessation may be effective in preventing pneumonia deaths.

Interaction between Genetic Risk Scores for reduced pulmonary function and smoking, asthma and endotoxin.

RATIONALE: Genome-wide association studies (GWASs) have identified numerous loci associated with lower pulmonary function. Pulmonary function is strongly related to smoking and has also been associated with asthma and dust endotoxin. At the individual SNP level, genome-wide analyses of pulmonary function have not identified appreciable evidence for gene by environment interactions. Genetic Risk Scores (GRSs) may enhance power to identify gene-environment interactions, but studies are few. METHODS: We analysed 2844 individuals of European ancestry with 1000 Genomes imputed GWAS data from a case-control study of adult asthma nested within a US agricultural cohort. Pulmonary function traits were FEV1, FVC and FEV1/FVC. Using data from a recent large meta-analysis of GWAS, we constructed a weighted GRS for each trait by combining the top (p value<5×10-9) genetic variants, after clumping based on distance (±250 kb) and linkage disequilibrium (r2=0.5). We used linear regression, adjusting for relevant covariates, to estimate associations of each trait with its GRS and to assess interactions. RESULTS: Each trait was highly significantly associated with its GRS (all three p values<8.9×10-8). The inverse association of the GRS with FEV1/FVC was stronger for current smokers (pinteraction=0.017) or former smokers (pinteraction=0.064) when compared with never smokers and among asthmatics compared with non-asthmatics (pinteraction=0.053). No significant interactions were observed between any GRS and house dust endotoxin. CONCLUSIONS: Evaluation of interactions using GRSs supports a greater impact of increased genetic susceptibility on reduced pulmonary function in the presence of smoking or asthma.