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Setting: Smoking is reported to be associated with tuberculosis (TB), but its effect on sputum smear conversion remains a matter for discussion., Objective: To assess the effects of smoking and smoking cessation on treatment outcomes in patients newly diagnosed with TB in Iran., Design: Newly diagnosed smear-positive TB patients were included in the study. All smokers participated in a smoking cessation programme. Sputum smear status was evaluated at the end of month 2, 5 and 6 of treatment, and smoking status was evaluated at the end of month 2. Differences in smear conversion rates were compared between the three groups, i.e., non-smokers, smokers and quitters., Results: A total of 183 smokers and 151 non-smokers were included. When smoking cessation was assessed after 2 months, 42.6% (78/183) of the smokers were found to have quit. The cure rate at the end of 6 months, precisely compatible with the conversion rate, was significantly higher among non-smokers (P = 0.004) and quitters at 2 months (P = 0.049) than among persisting smokers (83.4%, 80.8% and 67.6%, respectively)., Conclusion: Cure rates in patients newly diagnosed with pulmonary TB were higher in non-smokers and quitters at 2 months than in smokers. Smoking cessation advice should be included in TB control programmes.

Background: Tuberculosis (TB) and tobacco use are two major alarming global health issues that tend to be co-prevalent in many developing countries and various surveys have provided evidence on their entangled associations. Accordingly, it is strongly suggested that smoking cessation be incorporated in TB control programs. Therefore, we aimed to evaluate the effectiveness of two smoking cessation methods among newly-diagnosed pulmonary TB patients., Methods: A total of 210 newly-diagnosed pulmonary TB patients from Tehran, Iran with smoking habits were included in this randomized clinical trial during 2012-2013. Patients were assigned to three groups of control (just TB medical treatment), brief advice (TB medical treatment plus individualized counseling sessions of quitting behavioral therapy) and combined intervention (TB medical treatment plus individualized counseling sessions of quitting behavioral therapy plus medical treatment with slow release bupropion). Patients' abstinence was followed at six time point during six months. Data were analyzed by SPSS v.22 using Generalized Estimating Equations (GEE) model., Results: Abstinance rate at the end of six months were 71.7 % for combined intervention group, 33.9 % for brief advice group and 9.8 % for the control group (p < 0.001). Combined intervention group and brief advice group respectively had 35 times (p < 0.001, OR = 35.26, 95 % CI = 13.77-90.32) and 7 times (p < 0.001, OR = 7.14, 95 % CI = 2.72-18.72) more odds of not being an active smoker at each time point, compared to the control group., Conclusion: Considering the prevalence and importance of TB and the substantial influence of these preventive measures on controlling tobacco use, application of such programs is recommended., Trial Registration: The survey was registered in the Iranian registry of clinical trials website (irct.ir) in August 31, 2013 with IRCT ID: IRCT2013062613783N1 .

Tuberculosis (TB) and tobacco use are two major alarming global health issues posing immense threats to human populations. Mycobacterium tuberculosis (MTB) by activation of macrophages could induce the sequences of cells activation and releases of inflammatory cytokines such as CXCL-8, Il-12 and TNF-α which in turn induces the immune system network. However no information is available on other activity of cells by MTB and smoking. In the current study we aimed to investigate the serum levels TNF-a, CXCL-8 and phagocytosis capacity in tuberculosis patients with and without smoking. 103 subjects entered the study including 61 new diagnosed pulmonary TB patients (23 smokers and 38 nonsmokers) and 42 control healthy subjects. The phagocytosis of fluorescein isothiocyanate dextran (FITC-dextran) in blood monocytes/macrophages through flowcytometry was assessed. Serum levels of TNF-a and CXCL-8 were analyzed by ELISA methods. A lower percentage of cells from TB patients who smoked [50.29% (43.4-57.2), p<0.01] took up FITC-dextran after 2h compared to non-smoking TB subjects [71.62% (69.2-74.1)] and healthy cases [97.45% (95.9-99.1). Phagocytic capacity was inversely correlated with cigarette smoking as measured by pack years (r=-0.73, p<0.001). The serum levels of TNF-a and CXCL-8 were significantly higher in the TB patients who smoked compared to the TB non-smoker group (p<0.001, p<0.01 respectively). Blood monocytes/macrophages from TB patients have reduced phagocytic capacity which is further reduced in TB patients who smoke. Smoking enhanced serum levels of TNF-a and CXCL-8 suggesting a greater imbalance between the proinflammatory and anti-inflammatory factors in these patients.

Background: The association between pulmonary tuberculosis (PTB) and tobacco smoke has been verified by most studies on the subject; figures from different countries for the prevalence of smoking among PTB patients vary., Objective: To assess the prevalence of and factors associated with smoking among TB patients in Iran., Design: In this cross-sectional study, subjects were included on a first-come, first-served basis from among newly diagnosed PTB patients using a multistage cluster sampling method during 2012-2014. Data were collected during face-to-face interviews and a questionnaire was used to gather information on smoking habits., Results: Of 1127 newly diagnosed PTB patients included in the study (mean age 50.0 ± 19.8 years), 228 (20.2%) were daily smokers, 20 (1.8%) were occasional smokers and 93 (8.9%) had quit before diagnosis. Simultaneous drug use (P < 0.001, OR 75.21), increasing age (P = 0.001), being single (P < 0.001, OR 16.95), being an Iranian national (P < 0.001, OR 6.26) and living in a rural area (P < 0.001, OR 5.85) were found to be independent risk factors for smoking in study patients., Conclusion: The prevalence of smoking among PTB patients in Iran is relatively high. It is therefore necessary to include smoking cessation interventions in the National TB Programme.

The recruitment and activation of inflammatory cells into the respiratory system is considered a crucial feature in the pathophysiology of chronic obstructive pulmonary disease (COPD). Because dendritic cells (DCs) have a pivotal role in the onset and regulation of immune responses, we investigated the effect of modulating DC subsets on airway inflammation by acute cigarette smoke (CS) exposure. CS-exposed mice (5 days) were treated with fms-like tyrosine kinase 3 ligand (Flt3L) and 120g8 antibody to increase total DC numbers and deplete plasmacytoid DCs (pDCs), respectively. Flt3L treatment decreased the number of inflammatory cells in the bronchoalveolar lavage (BALF) of the smoke-exposed mice and increased these in lung tissue. DC modulation reduced IL-17 and increased IL-10 levels, which may be responsible for the suppression of the BALF cells. Furthermore, depletion of pDCs led to increased infiltration of alveolar macrophages while restricting the presence of CD103(+) DCs. This study suggests that DC subsets may differentially and compartment-dependent influence the inflammation induced by CS. pDC may play a role in preventing the pathogenesis of CS by inhibiting the alveolar macrophage migration to lung and increasing CD103(+) DCs at inflammatory sites to avoid extensive lung tissue damage., (Copyright © 2016 the American Physiological Society.)

Background: Dendritic cells (DCs) as professional antigen presenting cells (APCs) play a critical role in the regulation of host immune responses. DCs evolve from immature, antigen-capturing cells, to mature antigen-presenting cells. The relative contribution of DCs to cigarette smoke-induced inflammation is not well documented. In the current study, we investigated a modulatory effect of cigarette smoke extract (CSE) on differentiation, maturation and function of DCs., Methods: Primary murine DCs were grown from bone marrow cells with GM-CSF. Development of DC was analyzed by expression of CD11c, MHCII, CD86, CD40 and CD83 using flow cytometry. Murine DC's and human L428 cells were co-cultured with CSE for various periods of time. Functional activity was analyzed by measuring FITC-dextran uptake, cytokine production and the ability to stimulate T cell activation in a mixed lymphocyte reaction., Results: Our results show that short-term CSE stimulation (~24 h) influence the maturation status of newly differentiated and immature DCs towards more mature cells as revealed by upregulation of MHCII, CD83, CD86, CD40, reduction in antigen up-take capacity and enhanced secretion of pro-inflammatory (IL-12, IL-6 and TNF-α) cytokines. Interestingly, long-term CSE exposure, time- and concentration-dependently, suppressed the development of functional DCs. This suppression was demonstrated by a decline in CD11c/MHCII, CD83, CD86 and CD40 expression, the production of cytokines and ability to stimulate T lymphocytes. Moreover, CSE significantly suppressed the endocytosis function of mouse DCs which was not due to diminished DC viability. Similar to mouse DCs, long-term co-culturing of the human L428 DC cell line with CSE time-dependently suppressed the expression of CD54., Conclusions: The present study provides evidence that CSE modulates DC-mediated immune responses via affecting both the function and maturation of DCs. The suppressive effects of cigarette smoke on DC function might lead to impaired immune responses to various infections.

Chronic Obstructive Pulmonary Disease (COPD) is an important lung and airway disease which affects the lives of around 200 million people worldwide. The pathological hallmark of COPD is emphysema and bronchiolitis and is based on the inflammatory response of the innate and adaptive immune system to the inhalation of toxic particles and gases. The inflamed airways of COPD patients contain several inflammatory cells including neutrophils, macrophages, T lymphocytes, and dendritic cells (DC). The potential role of DCs as mediators of inflammation in the airways of smokers and COPD patients is poorly understood. The current study investigated the role of DC subsets in an animal model of cigarette smoke-induced lung emphysema through the expansion or depletion of DC subsets. Expansion of both myeloid DC (mDC) and plasmacytoid DC (pDC) by Flt3L treatment induced a decline in macrophage numbers and increased the levels of fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF) in the bronchoalveolar lavage (BAL) fluid of smoke-exposed animals. The increase in the mean linear intercept (Lm) following Flt3L treatment was decreased by pDC depletion. In conclusion, pharmacological modulation of DC subsets may have an effect on the development of airway responses and emphysema as indicated by the decline in macrophage numbers and the increase in FGF and VEGF levels in the bronchoalveolar lavage fluid. Moreover, the depletion of pDCs decreased the Lm which might suggest a role for pDC in the pathogenesis of lung emphysema., (Crown Copyright © 2013 Published by Elsevier B.V. All rights reserved.)

Background: Lung cancer is the leading cause of cancer-related death worldwide, and half of all incident lung cancers are believed to occur in the developing countries, including Iran., Objective: We investigated the association of opium with the risk of lung cancer in a case-control study., Methods: We enrolled 242 cases and 484 matched controls in this study. A questionnaire was developed, containing questions on basic demographic characteristics, as well as lifelong history of smoking cigarettes, exposure to passive smoking, opium use and alcohol consumption. For smoking cigarettes and opium and also oral opium intake frequency, duration and cumulative use were categorized into three groups: no use, low use and high use. Conditional logistic regression was used to calculate the odds ratios (ORs) and 95% confidence intervals (CIs)., Results: Multivariate analysis in men showed that after adjusting for the effect of ethnicity, education and pack years of smoking cigarettes, smoking opium remained as a significant independent risk factor with an OR of 3.1 (95% CI 1.2-8.1). In addition, concomitant heavy smoking of cigarettes and opium dramatically increased the risk of lung cancer to an OR of 35.0 (95% CI 11.4-107.9)., Conclusion: This study demonstrated that smoking opium is associated with a high risk of lung cancer as an independent risk factor., (Copyright © 2012 S. Karger AG, Basel.)

Chronic obstructive pulmonary disease (COPD) is a multicomponent disease characterized by emphysema and/or chronic bronchitis. COPD is mostly associated with cigarette smoking. Cigarette smoke contains over 4,700 chemical compounds, including free radicals and LPS (a Toll-Like Receptor 4 agonist) at concentrations which may contribute to the pathogenesis of diseases like COPD. We have previously shown that short-term exposure to cigarette smoke medium (CSM) can stimulate several inflammatory cells via TLR4 and that CSM reduces the degranulation of bone-marrow-derived mast cells (BMMCs). In the current study, the effect of CSM on mast cells maturation and function was investigated. Coculturing of BMMC with CSM during the development of bone marrow progenitor cells suppressed the granularity and the surface expression of c-kit and Fc ε RI receptors. Stimulation with IgE/antigen resulted in decreased degranulation and release of Th1 and Th2 cytokines. The effects of CSM exposure could not be mimicked by the addition of LPS to the culture medium. In conclusion, this study shows that CSM may affect mast cell development and subsequent response to allergic activation in a TLR4-independent manner.

Background: Cigarette smoking induces inflammatory responses in all smokers and is the major risk factor for lung disease such as chronic obstructive pulmonary disease (COPD). In this progressive disease, chronic inflammation in the lung contributes to lung tissue destruction leading to the formation of chemotactic collagen fragments such as N-acetylated Proline-Glycine-Proline (N-ac-PGP). The generation of this tripeptide is mediated by a multistep pathway involving matrix metalloproteases (MMPs) 8 and 9 and prolyl endopeptidase (PE). Here we investigated whether cigarette smoke extract (CSE) stimulates human PMNs to breakdown whole matrix collagen leading to the generation of the chemotactic collagen fragment N-ac-PGP., Methodology/principal Findings: Incubating PMNs with CSE led to the release of chemo-attractant CXCL8 and proteases MMP8 and MMP9. PMNs constitutively expressed PE activity as well as PE protein. Incubating CSE-primed PMNs with collagen resulted in collagen breakdown and in N-ac-PGP generation. Incubation of PMNs with the tripeptide N-ac-PGP resulted in the release of CXCL8, MMP8 and MMP9. Moreover, we tested whether PMNs from COPD patients are different from PMNs from healthy donors. Here we show that the intracellular basal PE activity of PMNs from COPD patients increased 25-fold compared to PMNs from healthy donors. Immunohistological staining of human lung tissue for PE showed that besides neutrophils, macrophages and epithelial cells express PE., Conclusions: This study indicates that neutrophils activated by cigarette smoke extract can breakdown collagen into N-ac-PGP and that this collagen fragment itself can activate neutrophils, which may lead in vivo to a self-propagating cycle of neutrophil infiltration, chronic inflammation and lung emphysema. MMP-, PE- or PGP-inhibitors can serve as an attractive therapeutic target and may open new avenues towards effective treatment of COPD.

Chronic obstructive pulmonary disease (COPD) is a multicomponent disease characterized by emphysema and/or chronic bronchitis. The aim of this study was to investigate the effect of cigarette smoke exposure on mast cells and mast cell function in vitro and in vivo in order to get further insight in the role of mast cells in the pathogenesis of emphysema. Cigarette smoke conditioned medium (CSM) induced the expression of mast cell tryptase (MMCP-6) in primary cultured mast cells. This tryptase expression was caused by the CSM-stimulated production of TGF-β in culture and neutralization of TGF-β suppressed the CSM-induced expression of tryptase in mast cells. An increase in mast cell tryptase expression was also found in an experimental model for emphysema. Exposure of mice to cigarette smoke increased the number of mast cells in the airways and the expression of mast cell tryptase. In accordance with the in vitro findings, TGF-β in bronchoalveolar lavage fluid of smoke-exposed animals was significantly increased. Our study indicates that mast cells may be a source of TGF-β production after cigarette smoke exposure and that in turn TGF-β may change the tryptase expression in mast cells., (2012 Elsevier B.V. All rights reserved.)

COPD is a chronic airway disease associated with inflammation and cigarette smoking. Airway epithelial cells are the first cells exposed to cigarette smoke (CS) and can release CXCL-8 and IL-1β. These cytokines are involved in acute and chronic inflammatory processes in COPD. The aim of this study was to investigate whether toll-like receptors (TLRs) located in/on epithelial cells were involved in cigarette smoke-induced cytokine production. Here we demonstrate that CS induces the release of CXCL-8 and IL-1β from human bronchial epithelial cells (HBE-14o). CS-induced CXCL-8 production was inhibited by an antibody against TLR4 and by inhibitory ODN suggesting the involvement of TLR4 and TLR9. In addition, exposure of HBE-14o cells to TLR4 or TLR9 ligands resulted in the release of CXCL-8 and IL1β. TLR4 and also TLR9 were present on the cell surface and the expression of both receptors decreased after CS exposure. The molecular mechanism of the CS-induced CXCL-8 production by the epithelial cells was further investigated. It was found that P2X7 receptors and reactive oxygen species were involved. Interestingly, the inflammasome activator monosodium urate crystals (MSU) induced the release of CXCL-8 and IL-1β and the caspase-1 inhibitor Z-VADDCB suppressed the CS-induced release of CXCL-8. In addition, CS, CpGODN, lipopolysaccharide and MSU all increased the expression of caspase-1 and IL-1β. In conclusion, our results demonstrate that CS releases CXCL-8 from HBE-14o cells via TLR4 and TLR9 and inflammasome activation. Therefore, inflammasome signaling in airway epithelial cells may play an important role in pathogenesis of diseases like COPD., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Chronic obstructive pulmonary disease (COPD) is characterized by chronic airway inflammation. Cigarette smoke has been considered a major player in the pathogenesis of COPD. The inflamed airways of COPD patients contain several inflammatory cells. Vitamin A metabolites have been implicated in the repair of lung damage. Exposure to cigarette smoke has been shown to depress levels of retinol in lungs of rats. The purpose of this study was to investigate if a low, but not deficient, vitamin A status potentiated susceptibility to the development of cigarette smoke-induced lung emphysema in mice. Mice were bred that were the offspring's of 3 generations of mice that were fed a purified diet containing low levels of vitamin A and exposed to cigarette smoke for 3 months, every weekday. Then, levels of 9-cis, 13-cis, and all-trans retinoic acid, retinol and retinyl palmitate were measured in plasma, liver and right lung lobe. The left lung lobe was used to assess mean linear intercept (Lm), as a measure of smoke-induced lung damage. Average feed intakes were not different between treatment groups. We show that both retinol and retinyl palmitate levels were dramatically decreased in the storage organs of mice on the low vitamin A diet (retinol 2-fold in both lung and liver, and retinyl palmitate 5- fold in lung) which shows that the depletion was successful. However, this treatment did not result in the development of lung emphysema. However, smoke exposure led to a significant increase in Lm in mice with a low vitamin A status compared to the room air-breathing controls. Lung levels of acid retinoids were similar in all mice, irrespective of diet or smoke exposure. Concluding, a low vitamin A status increases the susceptibility to the development of cigarette smoke-induced lung emphysema, possibly because of decreased anti-oxidant capacity in the lungs due to locally reduced retinol and retinyl palmitate levels. These observations indicate that human populations with a low vitamin A status and a high prevalence of smoking may be at increased risk of developing lung emphysema.

Chronic obstructive pulmonary disease (COPD) is a major health problem and cigarette smoke is the main risk factor for the development of COPD. The characteristic changes in airway morphology, inflammatory cell infiltration and mediator expression in COPD may result from direct effects of cigarette smoke on airway cells. Toll-like receptors (TLRs) are key elements in pathogen recognition by the host immune system. Although TLRs have been intensely studied in innate immunity and infection, their critical role in noninfectious challenges has only recently emerged. Here we investigate whether cigarette smoke induces TLR9 signalling in human neutrophils. Human neutrophils were isolated from buffy coat and exposed to cigarette smoke extract. The production of CXC chemokine ligand (CXCL)8 was measured as a functional readout and the role of TLR9 signalling was investigated. Cigarette smoke extract induced CXCL8 release via TLR9 activation in neutrophils, which was confirmed in TLR9 stably transfected human embryonic kidney 293 cells. Moreover, cigarette smoke extract upregulated the expression of TLR9 and the upregulated expression was suppressed by N-acetylcysteine. TLR9 mediates cigarette smoke-induced release of CXCL8 and this may contribute to the accumulation of neutrophils and inflammation within the airways of smokers.

Chronic obstructive pulmonary disease is a major health problem and will become the third largest cause of death in the world by 2020. It is currently believed that an exaggerated inflammatory response to inhaled irritants, in particular, cigarette smoke (CS), causes the progressive airflow limitation, in which macrophages and neutrophils are attracted by chemokines, leading to oxidative stress, emphysema, small airways fibrosis, and mucus hypersecretion. Smoking is also associated with an increase in mast cell numbers in bronchial mucosa. This study was conducted to determine the direct effects of CS on mast cell function, using murine bone marrow-derived mast cells (BMMC) as an in vitro model. BMMC were cultured from BALB/cBy mice for 3 weeks. Cells were treated with CS medium (CSM) for 30 min or 16 h. The effects of CSM on mast cell degranulation and chemokine production were measured. Moreover, we investigated the effect of CSM on IkappaB-alpha degradation and p38, Erk1/2, p65, and CREB expression by Western blotting. We found that CSM stimulated the release of chemokines in a noncytotoxic manner but did not induce mast cell degranulation. CSM induced phosphorylation of Erk1/2, p38, and CREB and increased translocation of p65 without degradation of IkappaB-alpha NF-kappaB in mast cells. The induction of chemokine production by CSM in mast cells could promote and prolong the inflammatory process. Our observations suggest that mast cells may contribute to the pathogenesis of emphysema through a direct effect of CS on the production of proinflammatory chemokines.

Background Mast cells are important effector cells in innate or acquired immunity that contribute to host defence. Excessive activation of mast cells can result in the development of allergic diseases, including atopic asthma. Mast cell activation by IgE and specific antigen induces the cells to release spasmogenic, vasoactive and pro-inflammatory mediators, which enhance airway smooth muscle contraction, vascular permeability and inflammatory cell recruitment. Recently, we have demonstrated that exposure of mast cells to cigarette smoke medium (CSM) triggered mast cells to produce chemokines. On the other hand, smoking may decrease the risk of allergic sensitization, which could be explained by a reduced IgE production or a diminished response of mast cells to activation of the IgE receptor. Objective In this study, we investigated the effect of CSM on the allergic activation of mast cells through IgE and antigen. Methods Primary cultured murine mast cells were exposed to CSM and activated with IgE and antigen or lipopolysaccharide (LPS). The release of granules, production of leukotrienes, chemokines and cytokines was determined in the supernatants by ELISA. The effect of CSM exposure on intracellular signalling, especially the nuclear factor (NF)-κB and extracellular signal-regulated kinase (Erk)1/2 pathways, was analysed by Western blotting. Results CSM suppressed IgE-mediated degranulation and cytokine release, but no effect was observed on leukotriene release. CSM induced phosphorylation of Erk1/2 in mast cells. In CSM-exposed mast cells, activating transcription factor (ATF)-1 was phosphorylated after stimulation with IgE/Ag. LPS-activated mast cells were not influenced by CSM. Conclusion Our study suggests that exposure to cigarette smoke may lead to a reduced allergic activation of mast cells without affecting their response to activation via e.g. bacterial-derived LPS. [ABSTRACT FROM AUTHOR]