Detrimental Effect Of Cigarette Smoking Research Articles

Association between serum cotinine and muscle mass: results from NHANES 2011–2018

PurposeRecently, the detrimental effect of cigarette smoking on muscle metabolism has attracted much attention, but the relationship between cigarette smoking and muscle mass is poorly understood. Thus, this study investigated the association between exposure to cigarette smoke, defined based on serum cotinine, and muscle mass in the US population.MethodsWe utilized National Health and Nutrition Examination Survey (NHANES) data between 2011 and 2018 for analysis. Data on serum cotinine, muscle mass (quantified by appendicular skeletal muscle mass index, ASMI), and covariates were extracted and analyzed. Weighted multivariate linear regression analyses and smooth curve fittings were performed to investigate the association between serum cotinine and ASMI. Subgroup analyses were stratified by gender, race and smoking status. When nonlinearity was detected, the threshold effects were analyzed using a two-piecewise linear regression model.ResultsIn total, 8004 participants were included for analysis. The serum level of cotinine was negatively associated with ASMI in the fully adjusted model. Furthermore, comparing participants in the highest vs. the lowest tertile of serum cotinine, we found that ASMI decreased by 0.135 Kg/m2. In subgroup analysis stratified by gender and race, the association between serum cotinine and ASMI remained significant in all genders and races. In addition, the association remained significant among current and former smokers, but not among those who never smoked. Smooth curve fittings showed nonlinear relationships between serum cotinine and ASMI, with the inflection points identified at 356 ng/mL.ConclusionsOur study revealed that serum cotinine was negatively related to muscle mass. This finding improves our understanding of the deleterious effects of cigarette smoking on muscle mass and highlights the importance of smoking cessation for muscle health.

Effects of Combustible Cigarettes and Heated Tobacco Products on Systemic Inflammatory Response in Patients with Chronic Inflammatory Diseases.

Smoke derived from combustible cigarettes (CCs) contains numerous harmful chemicals that can impair the viability, proliferation, and activation of immune cells, affecting the progression of chronic inflammatory diseases. In order to avoid the detrimental effects of cigarette smoking, many CC users have replaced CCs with heated tobacco products (HTPs). Due to different methods of tobacco processing, CC-sourced smoke and HTP-derived aerosols contain different chemical constituents. With the exception of nicotine, HTP-sourced aerosols contain significantly lower amounts of harmful constituents than CC-derived smoke. Since HTP-dependent effects on immune-cell-driven inflammation are still unknown, herein we used flow cytometry analysis, intracellular staining, and an enzyme-linked immunosorbent assay to determine the impact of CCs and HTPs on systemic inflammatory response in patients suffering from ulcerative colitis (UC), diabetes mellitus (DM), and chronic obstructive pulmonary disease (COPD). Both CCs and HTPs significantly modulated cytokine production in circulating immune cells, affecting the systemic inflammatory response in COPD, DM, and UC patients. Compared to CCs, HTPs had weaker capacity to induce the synthesis of inflammatory cytokines (IFN-γ, IL-1β, IL-5, IL-6, IL-12, IL-23, IL-17, TNF-α), but more efficiently induced the production of immunosuppressive IL-10 and IL-35. Additionally, HTPs significantly enhanced the synthesis of pro-fibrotic TGF-β. The continuous use of CCs and HTPs aggravated immune-cell-driven systemic inflammation in COPD and DM patients, but not in UC patients, suggesting that the immunomodulatory effects of CC-derived smoke and HTP-sourced aerosols are disease-specific, and need to be determined for specific immune-cell-driven inflammatory diseases.

Smoke and Spike: Benzo[a]pyrene Enhances SARS-CoV-2 Infection by Boosting NR4A2-Induced ACE2 and TMPRSS2 Expression.

Cigarette smoke aggravates severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. However, the underlying mechanisms remain unclear. Here, they show that benzo[a]pyrene in cigarette smoke extract facilitates SARS-CoV-2 infection via upregulating angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2). Benzo[a]pyrene trans-activates the promoters of ACE2 and TMPRSS2 by upregulating nuclear receptor subfamily 4 A number 2 (NR4A2) and promoting its binding of NR4A2 to their promoters, which is independent of functional genetic polymorphisms in ACE2 and TMPRSS2. Benzo[a]pyrene increases the susceptibility of lung epithelial cells to SARS-CoV-2 pseudoviruses and facilitates the infection of authentic Omicron BA.5 in primary human alveolar type II cells, lung organoids, and lung and testis of hamsters. Increased expression of Nr4a2, Ace2, and Tmprss2, as well as decreased methylation of CpG islands at the Nr4a2 promoter are observed in aged mice compared to their younger counterparts. NR4A2 knockdown orinterferon-λ2/λ3 stimulationdownregulates the expression of NR4A2, ACE2, and TMPRSS2, thereby inhibiting the infection. In conclusion, benzo[a]pyrene enhances SARS-CoV-2 infection by boosting NR4A2-induced ACE2 and TMPRSS2 expression. This study elucidates the mechanisms underlying the detrimental effects of cigarette smoking on SARS-CoV-2 infection and provides prophylactic options for coronavirus disease 2019, particularly for the elderly population.

COVID-19 and smoking: Considerations after two years

COVID-19 and smoking: Considerations after two years

Synergistic Detrimental Effects of Cigarette Smoke, Alcohol, and SARS-CoV-2 in COPD Bronchial Epithelial Cells.

Lung conditions such as COPD, as well as risk factors such as alcohol misuse and cigarette smoking, can exacerbate COVID-19 disease severity. Synergistically, these risk factors can have a significant impact on immunity against pathogens. Here, we studied the effect of a short exposure to alcohol and/or cigarette smoke extract (CSE) in vitro on acute SARS-CoV-2 infection of ciliated human bronchial epithelial cells (HBECs) collected from healthy and COPD donors. We observed an increase in viral titer in CSE- or alcohol-treated COPD HBECs compared to untreated COPD HBECs. Furthermore, we treated healthy HBECs accompanied by enhanced lactate dehydrogenase activity, indicating exacerbated injury. Finally, IL-8 secretion was elevated due to the synergistic damage mediated by alcohol, CSE, and SARS-CoV-2 in COPD HBECs. Together, our data suggest that, with pre-existing COPD, short exposure to alcohol or CSE is sufficient to exacerbate SARS-CoV-2 infection and associated injury, impairing lung defences.

The effects of cigarette smoking and nicotine on the therapeutic potential of mesenchymal stem cells.

Due to their immunoregulatory properties and capacity for multi-lineage differentiation, mesenchymal stem cells (MSCs) have been used as new therapeutic agents in regenerative medicine. Numerous lifestyle habits and behavioral risk factors may modulate metabolic and cell growth signaling pathways in MSCs, affecting their phenotype and function. Accordingly, identification of these factors and minimization of their influence on viability and function of transplanted MSCs may greatly contribute to their better therapeutic efficacy. A large number of experimental and clinical studies have demonstrated the detrimental effects of cigarette smoke and nicotine on proliferation, homing, chondrogenic and osteogenic differentiation of MSCs. Cigarette smoke down-regulates expression of chemokine receptors and modulates activity of anti-oxidative enzymes in MSCs, while nicotine impairs synthesis of transcriptional factors that regulate the cell cycle, metabolism, migration, chondrogenesis and osteogenesis. In this review article, we summarize current knowledge about molecular mechanisms that are responsible for cigarette smoke and nicotine-dependent modulation of MSCs' therapeutic potential.

Early transcriptional responses of bronchial epithelial cells to whole cigarette smoke mirror those of in-vivo exposed human bronchial mucosa

BackgroundDespite the well-known detrimental effects of cigarette smoke (CS), little is known about the complex gene expression dynamics in the early stages after exposure. This study aims to investigate early transcriptomic responses following CS exposure of airway epithelial cells in culture and compare these to those found in human CS exposure studies.MethodsPrimary bronchial epithelial cells (PBEC) were differentiated at the air–liquid interface (ALI) and exposed to whole CS. Bulk RNA-sequencing was performed at 1 h, 4 h, and 24 h hereafter, followed by differential gene expression analysis. Results were additionally compared to data retrieved from human CS studies.ResultsALI-PBEC gene expression in response to CS was most significantly changed at 4 h after exposure. Early transcriptomic changes (1 h, 4 h post CS exposure) were related to oxidative stress, xenobiotic metabolism, higher expression of immediate early genes and pro-inflammatory pathways (i.e., Nrf2, AP-1, AhR). At 24 h, ferroptosis-associated genes were significantly increased, whereas PRKN, involved in removing dysfunctional mitochondria, was downregulated. Importantly, the transcriptome dynamics of the current study mirrored in-vivo human studies of acute CS exposure, chronic smokers, and inversely mirrored smoking cessation.ConclusionThese findings show that early after CS exposure xenobiotic metabolism and pro-inflammatory pathways were activated, followed by activation of the ferroptosis-related cell death pathway. Moreover, significant overlap between these transcriptomic responses in the in-vitro model and human in-vivo studies was found, with an early response of ciliated cells. These results provide validation for the use of ALI-PBEC cultures to study the human lung epithelial response to inhaled toxicants.

Cigarette Smoke Exposure, Pediatric Lung Disease, and COVID-19.

The detrimental effects of tobacco exposure on children’s health are well known. Nonetheless, the prevalence of secondhand or direct cigarette smoke exposure (CSE) in the pediatric population has not significantly decreased over time. On the contrary, the rapid incline in use of e-cigarettes among adolescents has evoked public health concerns since increasing cases of vaping-induced acute lung injury have highlighted the potential harm of these new “smoking” devices. Two pediatric populations are especially vulnerable to the detrimental effects of cigarette smoke. The first group is former premature infants whose risk is elevated both due to their prematurity as well as other risk factors such as oxygen and mechanical ventilation to which they are disproportionately exposed. The second group is children and adolescents with chronic respiratory diseases, in particular asthma and other wheezing disorders. Coronavirus disease 2019 (COVID-19) is a spectrum of diseases caused by infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that has spread worldwide over the last year. Here, respiratory symptoms ranging from mild to acute respiratory distress syndrome (ARDS) are at the forefront of COVID-19 cases among adults, and cigarette smoking is associated with worse outcomes in this population, and cigarette smoking is associated with worse outcomes in this population. Interestingly, SARS-CoV-2 infection affects children differently in regard to infection susceptibility, disease manifestations, and complications. Although children carry and transmit the virus, the likelihood of symptomatic infection is low, and the rates of hospitalization and death are even lower when compared to the adult population. However, multisystem inflammatory syndrome is recognized as a serious consequence of SARS-CoV-2 infection in the pediatric population. In addition, recent data demonstrate specific clinical patterns in children infected with SARS-CoV-2 who develop multisystem inflammatory syndrome vs. severe COVID-19. In this review, we highlight the pulmonary effects of CSE in vulnerable pediatric populations in the context of the ongoing SARS-CoV-2 pandemic.

Cigarette Smoking Increased Risk of Overall Mortality in Patients With Non-alcoholic Fatty Liver Disease: A Nationwide Population-Based Cohort Study.

Background: The evidence suggests a detrimental effect of cigarette smoking on the progression of chronic liver disease. However, the impact of cigarette smoking on mortality among patients with non-alcoholic fatty liver disease (NAFLD) remain unclear.Methods: We used the National Health Examination Survey data collected during 2008–2009 to link the National Death Index to follow-up respondent survival. Diagnosis of NAFLD was based on a lipid accumulation product in participants without significant alcohol use or other liver diseases.Results: During 64,116 person-years of follow-up, 928 of 7,529 participants with NAFLD died, and the cumulative all-cause mortality was 14.5 per 1,000 person-years. In a Cox regression model adjusted for age, body mass index, alcohol intake, exercise, comorbidities, lipid profiles, and handgrip strength, current smoking increased the risk of mortality by 109% (adjusted hazard ratio (aHR): 2.09, 95% confidence interval [CI]: 1.18–3.71) compared with never smoker status in women, but showed only a trend toward harm among men (aHR: 1.41, 95% CI: 0.96–2.08). After controlling for potential confounders, smoking ≥10 pack-years continued to show a significant harmful effect on all-cause mortality among women (aHR: 5.40, 95% CI: 2.19–13.4), but not in men. Among women who drink alcohol ≥10 grams per day, current smoking (aHR: 13.8, 95% CI: 1.66–145) and smoking ≥10 pack-years (aHR: 310, 95% CI: 78–1,296) also significantly increased risk of death.Conclusion: This nationwide population-based study highlight a detrimental effect of cigarette smoking on mortality, with a similar but more definite association in women than in men with NAFLD.

Effect of Cigarette Smoking on Functional Outcomes in Patients with Spontaneous Intracerebral Hemorrhage

Background: Nicotine may have neuroprotective effects on the injured brain through modulation of the cholinergic anti-inflammatory pathway. Aims: This study aimed to evaluate the relationship between cigarette smoking and outcomes in patients with spontaneous intracerebral hemorrhage (ICH). Methods: This was a retrospective review of consecutive ICH patients enrolled in the ICH Outcomes Project from 2009 to 2017. Patients with age ≥18 years and baseline modified Rankin Scale (mRS) score 0-2 were included. Smoking patterns were categorized as recent smoker (≤30 days prior to ICH) and not recent smoker (>30 days prior to ICH). Not recent smokers were further categorized into former smokers and nonsmokers. The primary outcome was good outcome (90-day mRS ≤ 2). Secondary outcomes were excellent outcome (90-day mRS 0-1), 90-day Barthel Index, and in-hospital and 90-day mortality. Results: The study cohort comprised 545 patients, including 60 recent smokers and 485 not recent smokers. Recent smokers had higher rates of good (35% versus 23%; odds ratio [OR] = 1.787, P = .047) and excellent (25% versus 13%; OR = 2.220, P = .015) outcomes compared to not recent smokers. These differences were not significant after baseline adjustments. Recent smokers had higher rates of good (36% versus 24%; OR = 1.732, P = .063) and excellent (25% versus 13%; OR = 2.203, P = .018) outcomes compared to nonsmokers. These differences were not significant after baseline adjustments. A 90-day Barthel Index, in-hospital, and 90-day mortality were comparable between recent and not recent smokers, recent and nonsmokers, and former and nonsmokers. Conclusions: Despite potential neuroprotective effects of nicotine found in cigarettes, these may be outweighed by the detrimental effects of cigarette smoking on health outcomes.

Protective effect of aerobic exercise on the vocal folds against cigarette smoke exposure.

Laryngeal pathologies due to cigarette smoking vary among individuals, whereas some smokers remain disease free. These differences can be explained by multiple factors among individuals. In this context, an animal study was designed to determine if there is any protective effect of aerobic exercise against the detrimental effects of cigarette smoke on laryngeal tissues. A total of 24 male Wistar albino rats were divided into three groups of eight animals each: control (no smoke exposure), smoking (smoke exposure), and exercise (smoke exposure and exercise) groups. Histopathological (light and electron microscopy) and immunohistochemical (GSTA1, CYP1A1, CYP2E1) evaluations of the vocal folds were performed at the end of experimental period. Exercise group revealed statistically significant decrease in edema (p = 0.03) and inflammatory cell infiltration (p = 0.02) compared to smoking group. In electron microscopic evaluation; cytoplasmic vacuoles were also present in exercise group, but were smaller than smoking group. Edema and swollen mitochondria were also less prominent in exercise group. Condensed chromatin material in the periphery of nucleus was observed only in few cells in exercise group, and observed in more cells in smoking group. GSTA1 expression was higher (p = 0.047) and CYP1A1 expression was lower (p = 0.01) in exercise group than smoking group. Our results indicate that aerobic exercise has a protective role on the larynx against the damaging effect of cigarette smoke. Smokers who exercise regularly may be at a lower risk of cigarette smoke-related laryngeal diseases, as compared with those who do not exercise.

Malay Glaucoma Eye Study: cigarette smoking and primary angle closure glaucoma

Introduction: The detrimental effects of cigarette smoking include impairment of optic nerve head perfusion and elevation of oxidative stress levels, which are believed to be part of the pathogenesis of glaucoma. However, there is no evidence on the effect of cigarette smoking as a risk for primary angle-closure glaucoma (PACG).
 Purpose: To determine the association between cigarette smoking and PACG in Malay patients.
 Study design: Case control study.
 Materials and methods: Two-hundred Malay PACG patients and 250 controls from three tertiary hospitals in Malaysia were involved in this study. PACG patients were diagnosed based on the World Glaucoma Association consensus. The smoking status was documented using validated questionnaire adopted from Singapore Malays Eye Study through face-to-face interview. Smoking status was divided into active smokers, ex-smokers, passive smokers, and non-smokers. The association of smoking and PACG was analysed with multiple logistic regression. Confounders such as age, gender, education status, and body mass index (BMI) were considered in the analysis.
 Results: There was female preponderance in PACG with 3:1 ratio. Active smokers (p = 0.656) and ex-smokers (0.073) were not significantly associated with PACG in Malays. Passive smoking significantly increased the risk of PACG by 6.8-fold (95% CI 2.49,18.67; p < 0.001). Number of cigarettes/day (p = 0.144) and duration of smoking (p = 0.176) were also not significantly associated with PACG (p = 0.144). No formal education, primary and secondary education level increased the risk of PACG (p < 0.001). Each unit increment of BMI increased the risk of PACG by 1.14-fold (95% CI 1.03, 1.27; p = 0.014). A year increased in age increased the risk by 1.05 times (95% CI 1.00, 1.09; p = 0.026).
 Conclusions: There is no significant association between active smoking and PACG. Passive smoking is a potential risk factor for PACG. The preponderance of women may contribute to this result. However, quantification of exposure to passive smoking is not possible in this study.

DNA repair as an emerging target for COPD-lung cancer overlap.

Cigarette smoking is the leading cause of lung cancer and chronic obstructive pulmonary disease (COPD). Many of the detrimental effects of cigarette smoke have been attributed to the development of DNA damage, either directly from chemicals contained in cigarette smoke or as a product of cigarette smoke-induced inflammation and oxidative stress. In this review, we discuss the environmental, epidemiological, and physiological links between COPD and lung cancer and the likely role of DNA damage and repair in COPD and lung cancer development. We explore alterations in DNA damage repair by DNA repair proteins and pathways. We discuss emerging data supporting a key role for the DNA repair protein, xeroderma pigmentosum group C (XPC), in cigarette smoke-induced COPD and early lung cancer development. Understanding the interplay between cigarette smoke, DNA damage repair, COPD, and lung cancer may lead to prognostic tools and new, potentially targetable, pathways for lung cancer prevention and treatment.

Friday, September 28, 2018 4:05 PM–5:05 PM abstracts: basic science of spinal fusion: 234. Phytochemicals combat the detrimental effects of cigarette smoke on osteogenic differentiation

BACKGROUND CONTEXT Cigarette smoking has been shown to inhibit bone healing and increase the risk of pseudarthrosis after spinal fusion. We previously reported that activation of the Aryl Hydrocarbon Receptor (Ahr) by dioxin, a prototype activator of the Ahr, inhibits bone regeneration and spine fusion in rat model. We also reported that the dioxin-mediated inhibition of osteogenic differentiation is mitigated by co-treatment with Ahr antagonists in vitro. PURPOSE Since dozens of dioxin-like Ahr ligands are present in cigarette smoke, we are investigating the downstream mechanisms of cigarette smoke action on osteogenic differentiation to identify potential therapeutic options to mitigate the effects of cigarette smoke on bone. METHODS Particulate phase extract (PPE) was prepared by passing CSE through a 0.1μm PTFE filter and eluting in the DMSO to yield a final concentration of 40mg/mL. Primary rat bone marrow stromal cells (BMSC) were purchased from Cell Biologics (Chicago, IL) and cultured under basal standard or osteogenic media. BMSC were subsequently exposed to either the vehicle control (DMSO) or dioxin or PPE. Some cells received co-treatment with Ahr antagonists, including: a-naphthoflavone (ANF, a synthetic antagonist); resveratrol (Res, a stilbenoid found in grapes and present in red wine), and 3,3’-diindolylmethane (DIM, a breakdown product of the indole-3-carbinol, which is present in cruciferous vegetables). EROD assays were used to evaluate Ahr-mediated CYP1 family induction, and ALP and mineralization assays were used to quantify effects on osteogenic differentiation. Cell proliferation assays and Wnt signaling assays were also performed. RESULTS PPE-treated cells showed increased activity of CYP1A subfamily proteins, demonstrating Ahr activation. PPE treatment inhibited ALP activity, an effect which was at least partially mitigated by co-treatment with each of the Ahr antagonists. A similar response was seen in and mineralization and cell proliferation assays. RNA expression studies showed that PPE down-regulated numerous pro-osteogenic genes, such as ALP, RunX2, OCN, and Phex, whereas co-treatment with Ahr antagonists prevented PPE-mediated inhibition of those RNA. Interestingly, PPE decreased the ratio of active:inactive β-Catenin, an effect which was recapitulated by treatment with dioxin (TCDD). CONCLUSIONS Cigarette smokers are a historically difficult patient population for spine surgeons to treat due to increased rates of pseudarthrosis and complications following spinal fusion procedures. Our results suggest that Ahr hyper-activation may play an important role in the adverse effects of cigarette smoke on bone healing—potentially by perturbation of canonical Wnt signaling—and that Ahr antagonists may be protective in combating cigarette smoke-mediated inhibition of bone regeneration and healing.

Roflumilast reverses CFTR-mediated ion transport dysfunction in cigarette smoke-exposed mice

BackgroundDysfunction in cystic fibrosis transmembrane conductance regulator (CFTR) can be elicited by cigarette smoke and is observed in patients with chronic bronchitis. We have previously demonstrated in human airway epithelial cell monolayers that roflumilast, a clinically approved phosphodiesterase 4 inhibitor that reduces the risk of exacerbations in chronic obstructive pulmonary disease patients with chronic bronchitis and a history of exacerbations, activates CFTR-dependent chloride secretion via a cAMP-mediated pathway, partially restores the detrimental effects of cigarette smoke on CFTR-mediated ion transport, and increases CFTR-dependent gastrointestinal fluid secretion in isolated murine intestine segments. Based on these findings, we hypothesized that roflumilast could improve CFTR-mediated chloride transport and induce secretory diarrhea in mice exhibiting cigarette smoke-induced CFTR dysfunction.MethodsA/J mice expressing wild type CFTR (+/+) were exposed to cigarette smoke or air with or without roflumilast and the effect of treatment on CFTR-dependent chloride transport was quantified using nasal potential difference (NPD) measurements in vivo and short-circuit current (Isc) analysis of trachea ex vivo. Stool specimen were collected and the wet/dry ratio measured to assess the effect of roflumilast on secretory diarrhea.ResultsAcute roflumilast treatment increased CFTR-dependent chloride transport in both smoke- and air-exposed mice (smoke, −2.0 ± 0.4 mV, 131.3 ± 29.3 μA/cm2, P < 0.01 and air, 3.9 ± 0.8 mV, 147.7 ± 38.0 μA/cm2, P < 0.01 vs. vehicle −0.3 ± 0.7 mV, 10.4 ± 7.0 μA/cm2). Oral administration of roflumilast over five weeks completely reversed the deleterious effects of cigarette smoke on CFTR function in smoke-exposed animals, in which CFTR-dependent chloride transport was 64% that of air controls (roflumilast, −15.22 ± 2.7 mV vs. air, −14.45 ± 1.4 mV, P < 0.05). Smoke exposure increased the wet/dry ratio of stool specimen to a level beyond which roflumilast had little additional effect.ConclusionsRoflumilast effectively rescues CFTR-mediated chloride transport in vivo, further implicating CFTR activation as a mechanism through which roflumilast benefits patients with bronchitis.

Electronic cigarette devices and oro-facial trauma (Literature review)

Detrimental effects of cigarette smoking have been well described and recognized globally. With recent advancement of technology, electronic cigarette has been introduced and gained its popularity and became a global trend, especially among young adults. However, the safety of the electronic devices remains debatable. This paper aimed to compile and review the reported cases of oro-facial trauma related to the usage of electronic cigarette devices. A literature search was conducted using PubMed/Medline in December 2016. The search terms used were a combination of “oral trauma”, “dental trauma”, “oral injury” and “electronic cigarette”. The search included all abstract published from the inception of the database until December 2016. that was written in English, case report, letter to editors, clinical and human studies were included for analysis. All selected abstract were searched for full articles. A total of 8 articles were included for review. All of the articles were published in 2016 with mostly case reports. The sample size of the studies ranged from 1 to 15 patients. Seven of the included articles are from United States of America and one from Mexico. Our review concluded that the use of electronic cigarette devices posed not only a safety concern but also that the devices were mostly unregulated. There should be a recognized authority body to regulate the safety and standard of the electronic devices.

Reduced expression of let-7f activates TGF-β/ALK5 pathway and leads to impaired ischaemia-induced neovascularization after cigarette smoke exposure.

This study sought to determine the potential role of microRNAs (miRNAs) in the detrimental effects of cigarette smoke on angiogenesis and neovascularization. Using large‐scale miRNA profiling and qRT‐PCR analyses, we identified let‐7f as a pro‐angiogenic miRNA which expression is significantly reduced in HUVECs treated with cigarette smoke extracts (CSE), and in the ischemic muscles of mice that are exposed to cigarette smoke (MES). In a mouse model of hindlimb ischaemia, intramuscular injection of let‐7f mimic restored ischaemia‐induced neovascularization in MES. Doppler flow ratios and capillary density in ischemic muscles were significantly improved in MES treated with let‐7f mimic. Clinically, this was associated with reduced ambulatory impairment and hindlimb ischaemic damage. Treatment with let‐7f mimic could also rescue pro‐angiogenic cell (PAC) number and function (attachment, proliferation, migration) in MES. ALK5 (TGF‐βR1), an important modulator of angiogenesis, is a target of let‐7f. Here we show that ALK5 is increased in HUVECs exposed to CSE and in the ischaemic muscles of MES. This is associated with a downstream activation of the anti‐angiogenic factors SMAD2/3 and PAI‐1. Importantly, treatment with let‐7f mimic reduces the expression of ALK5, SMAD2/3 and PAI‐1 both in vitro and in vivo. Moreover, let‐7f overexpression or ALK5 inhibition can rescue angiogenesis in HUVECs exposed to CSE. Cigarette smoke exposure is associated with reduced expression of let‐7f and activation of the anti‐angiogenic TGF‐β/ALK5 pathway. Overexpression of let‐7f using a miRNA mimic could constitute a novel therapeutic strategy to improve ischaemia‐induced neovascularization in pathological conditions.

Parametric Mediational g-Formula Approach to Mediation Analysis with Time-varying Exposures, Mediators, and Confounders

The assessment of direct and indirect effects with time-varying mediators and confounders is a common but challenging problem, and standard mediation analysis approaches are generally not applicable in this context. The mediational g-formula was recently proposed to address this problem, paired with a semiparametric estimation approach to evaluate longitudinal mediation effects empirically. In this article, we develop a parametric estimation approach to the mediational g-formula, including a feasible algorithm implemented in a freely available SAS macro. In the Framingham Heart Study data, we apply this method to estimate the interventional analogues of natural direct and indirect effects of smoking behaviors sustained over a 10-year period on blood pressure when considering weight change as a time-varying mediator. Compared with not smoking, smoking 20 cigarettes per day for 10 years was estimated to increase blood pressure by 1.2 mm Hg (95% CI: -0.7, 2.7). The direct effect was estimated to increase blood pressure by 1.5 mm Hg (95% CI: -0.3, 2.9), and the indirect effect was -0.3 mm Hg (95% CI: -0.5, -0.1), which is negative because smoking which is associated with lower weight is associated in turn with lower blood pressure. These results provide evidence that weight change in fact partially conceals the detrimental effects of cigarette smoking on blood pressure. Our study represents, to our knowledge, the first application of the parametric mediational g-formula in an epidemiologic cohort study (see video abstract at, http://links.lww.com/EDE/B159.).

Cigarette smoking and gastric cancer in the Stomach Cancer Pooling (StoP) Project.

Tobacco smoking is a known cause of gastric cancer, but several aspects of the association remain imprecisely quantified. We examined the relation between cigarette smoking and the risk of gastric cancer using a uniquely large dataset of 23 epidemiological studies within the 'Stomach cancer Pooling (StoP) Project', including 10 290 cases and 26 145 controls. We estimated summary odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) by pooling study-specific ORs using random-effects models. Compared with never smokers, the ORs were 1.20 (95% CI: 1.09-1.32) for ever, 1.12 (95% CI: 0.99-1.27) for former, and 1.25 (95% CI: 1.11-1.40) for current cigarette smokers. Among current smokers, the risk increased with number of cigarettes per day to reach an OR of 1.32 (95% CI: 1.10-1.58) for smokers of more than 20 cigarettes per day. The risk increased with duration of smoking, to reach an OR of 1.33 (95% CI: 1.14-1.54) for more than 40 years of smoking and decreased with increasing time since stopping cigarette smoking (P for trend<0.01) and became similar to that of never smokers 10 years after stopping. Risks were somewhat higher for cardia than noncardia gastric cancer. Risks were similar when considering only studies with information on Helicobacter pylori infection and comparing all cases to H. pylori+ controls only. This study provides the most precise estimate of the detrimental effect of cigarette smoking on the risk of gastric cancer on the basis of individual data, including the relationship with dose and duration, and the decrease in risk following stopping smoking.

Exposure to Cigarette Smoke Contributes to the Risk of Developing a Colorectal Adenoma, Doesn't It? Are Repeated Exposures to Such Smoke Dangerous?

See Article on Page 51-57 One cigarette contains over 600 ingredients, 4,000 chemicals, 50 cancer-causing agents and many poisonous toxins. In the early 1990s, Zahm et al. [1] of the National Cancer Institute, in a study that used flexible sigmoidoscopy to examine 185 nonsmokers, 229 ex-smokers, and 132 current smokers, reported respective risk ratios for developing adenomatous polyps of 1.0, 1.2, and 2.7. Standardized prevalence rates for polyps increased by smoking category (never smoked: 0.094, ex-smoker: 0.118, current smokers: 0.214). Both adenomatous and hyperplastic polyps showed an association with pack years among both current and ex-smokers. In a meta-analysis of 42 independent observational studies up to 2007 [2], the pooled risks estimated for current and former smokers and those who had always smokers in comparison with those who had never smoked were 2.14 (95% confidence interval [CI], 1.86–2.46), 1.47, and 1.82, respectively. The study provided strong evidence for the detrimental effect of cigarette smoking on the development of adenomatous polyps. Because the risk for developing an adenoma was greater, smoking may be important for both the formation and aggressiveness of adenomas. Anderson et al. [3] screened 600 patient who had high-definition wide-angle colonoscopes. Smoking was associated with having a flat adenoma of any size (adjusted odds ratio, 2.53). Figueiredo et al. [4] conducted a combined analysis of the occurrences of conventional adenomas and serrated polyps by using individual-level data from 2,915 patients participating in three colonoscopy-based clinical trials. Cigarette smoking had only a weak association with adenomas, but was associated with a significantly increased risk of developing serrated polyps, particularly in the left colorectum. The association between cigarette smoking and the risk of developing colorectal cancer in a large prospective cohort from the United States was reported in 2009 [5]. In that prospective study of 184,187 people, the incidence of colorectal cancer was significantly higher in current (hazard ratios [HR], 1.27) and former smokers (HR, 1.23) than it was in lifelong nonsmokers (Table 1). The relative risk was greatest among current smokers with at least 50 years of smoking (HR, 1.38; 95% CI, 1.04–1.84). Among former smokers, the risk of colorectal cancer decreased with greater time since cessation (P = 0.0003) and with earlier age at cessation (P = 0.0014). No association was seen among former smokers who had quit before the age of 40 years or had abstained for 31 years or more. Table 1 Hazard ratios for patients with colorectal cancer caused by cigarette smoking among current and former smokers compared with those who had never smoked (CPS-III nutrition cohort 1992–2005) Liu et al. [6] investigated the effects of exposure to cigarette smoke (CS) on inflammation-associated tumorigenesis in the balb/c mice. During exposure to smoke exposure, the mice were put into a ventilated smoking chamber (39.0 × 23.5 × 21.0 cm3) with 2% CS (v/v, smoke/air). The smoke/air concentration in the chamber was kept constant by the use of peristaltic pumps (Masterflex, Cole Parmer Instrument, Niles, IL, USA), which delivered smoke. Cigarette smoking significantly attenuated the apoptotic effect probably via the induction of antiapoptotic protein bcl-2. Vascular endothelial growth factor and angiogenesis in the colon were also increased in animals with colitis that had been exposed to CS. On the basis of the references mentioned above, the readers have to figure out carefully the purpose of this article, Association Between Exposure to Environmental Tobacco Smoke at the Workplace and Risk of Developing a Colorectal Adenoma: A Cross-Sectional Study, published in this issue [7]. In that research, patients in the nonadenoma group were compared with those in the colorectal adenoma group by using the variables of passive smoking. As a result of that comparison, the fully-adjusted odd ratio for developing a colorectal adenoma as a result of exposure to environmental tobacco smoke was 1.95 (95% CI, 1.08–2.44). The article is encouraging in that it provides evidence to support further study of the effects of environmental hazards on the risks for developing colorectal cancer in this country. Various approaches to one subject can be inspiring in many different ways.