Stressor: 645

Title

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Cigarette smoke

Stressor Overview

The stressor field is a structured data field that can be used to annotate an AOP with standardised terms identifying stressors known to trigger the MIE/AOP. Most often these are chemical names selected from established chemical ontologies. However, depending on the information available, this could also refer to chemical categories (i.e., groups of chemicals with defined structural features known to trigger the MIE). It can also include non-chemical stressors such as genetic or environmental factors. More help

AOPs Including This Stressor

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Events Including This Stressor

This table is automatically generated and lists the Key Events associated with this Stressor. More help

Chemical Table

The Chemical Table lists chemicals associated with a stressor. This table contains information about the User’s term for a chemical, the DTXID, Preferred name, CAS number, JChem InChIKey, and Indigo InChIKey.To add a chemical associated with a particular stressor, next to the Chemical Table click ‘Add chemical.’ This will redirect you to a page entitled “New Stressor Chemical.’ The dialog box can be used to search for chemical by name, CAS number, JChem InChIKey, and Indigo InChIKey. Searching by these fields will bring forward a drop down list of existing stressor chemicals formatted as  Preferred name, “CAS- preferred name,” “JChem InChIKey – preferred name,” or “Indigo InChIKey- preferred name,” depending on by which field you perform the search. It may take several moments for the drop down list to display. Select an entity from the drop down list and click ‘Add chemical.’ This will return you to the Stressor Page, where the new record should be in the ‘Chemical Table’ on the page.To remove a chemical associated with a particular stressor, in the Chemical Table next to the chemical you wish to delete, click ‘Remove’ and then click 'OK.' The chemical should no longer be visible in the Chemical table. More help
User term DTXID Preferred name Casrn jchem_inchi_key indigo_inchi_key
Cigarette smoke DTXSID5035038 Cigarette smoke NOCAS_35038

AOP Evidence

This table is automatically generated and includes the AOPs with this associated stressor as well as the evidence term and evidence text from this AOP Stressor. More help
combined unhealthy lifestyle factors leading to metabolic syndrome

There is no evidence text for this AOP

Oxidative stress [MIE] Leading to Decreased Lung Function [AO]

CFTR transcript and protein levels were reduced in human Calu-3 lung cancer cells exposed to the gas phase of cigarette smoke (Cantin et al., 2006b), human immortalized bronchial epithelial 16HBE14o- cells treated with 10% cigarette smoke extract (Hassan et al., 2014; Rasmussen et al., 2014; Xu et al., 2015), differentiated primary human bronchial epithelial cells exposed to whole cigarette smoke (Sloane et al., 2012; Hassan et al., 2014), and in airways of smokers compared to non-smokers (Dransfield et al., 2013). Following exposure to cigarette smoke, Cl conductance (i.e., CFTR-mediated Cl transport) decreased in primary human bronchial epithelial cells grown in monolayers (Lambert et al., 2014), differentiated primary human bronchial epithelial cells (Schmid et al., 2015; Chinnapaiyan et al., 2018), and nasal respiratory and intestinal epithelia of A/J mice (Raju et al., 2013; Raju et al., 2017). In the lower airways, healthy smokers and smokers with chronic obstructive pulmonary disease (COPD) showed reduced CFTR-dependent Cl transport, whereas COPD former smokers showed an intermediate response to chloride-free isoproterenol solution compared to non-smokers. Similarly, amiloride-sensitive lower airway potential difference was also lower in healthy smokers and COPD smokers than in healthy non-smokers. This was linked to reduced CFTR protein levels in the airways of smokers compared to non-smokers, although there were no significant differences between healthy and COPD subjects (Dransfield et al., 2013). CFTR-dependent Cl conductance as measured by nasal potential difference was also significantly reduced in healthy and COPD smokers compared to healthy non-smokers or to former smokers with COPD (Sloane et al., 2012). In addition, healthy never-smokers had higher mean sweat chloride concentrations than COPD smokers and COPD former smokers (Raju et al., 2013; Courville et al., 2014).

Multiple studies showed that exposure of primary human bronchial epithelial cells, either undifferentiated or differentiated at the air-liquid interface, to cigarette smoke decreased ASL height (Hassan et al., 2014; Lambert et al., 2014; Raju et al., 2016; Rasmussen et al., 2014; Schmid et al., 2015). Treatment of immortalized bronchial epithelial 16HBE14o- cells with 10% cigarette smoke extract for 48 hours also resulted in a significant reduction in ASL height (Xu et al., 2015).

Treatment of human sinonasal epithelial cells with cigarette smoke condensate significantly reduced forskolin-stimulated CBF (Cohen et al., 2009). CBF was also decreased in differentiated normal human bronchial epithelial cells exposed to whole cigarette smoke (Schmid et al., 2015), in cilia-bearing explant adenoid tissues treated with 5 and 10% cigarette smoke extract (Wang et al., 2012), in hamster oviducts treated with various mainstream cigarette smoke fractions (Knoll et al., 1995), and in nasal epithelial cells fom smokers with moderate and severe chronic obstructive pulmonary disease (COPD) (Yaghi et al., 2012).

Whole cigarette smoke exposure or treatment with cigarette smoke extract of normal human bronchial epithelial cells significantly lowered FoxJ1 mRNA and protein levels (Milara et al., 2012; Brekman et al., 2014; Valencia-Gattas et al., 2016; Ishikawa and Ito, 2017). Cigarette smoke extract treatment of normal human bronchial epithelial cells also reduced the expression of cilia-related transcription factor genes, including FOXJ1, RFX2, and RFX3, as well as that of cilia motility and structural integrity genes regulated by FOXJ1, including DNAI1, DNAH5, DNAH9, DNAH10, DNAH11, and SPAG6 (Brekman et al., 2014).

Exposure of human bronchial epithelial cells cultured at the air-liquid interface to cigarette smoke extract during differentiation significantly shortened the average cilia length compared to untreated cultures, and treatment of differentiated cultures prevented elongation of cilia seen in untreated cultures (Brekman et al., 2014). Whole smoke exposure of mouse tracheal epithelial cells differentiated at the air-liquid interface resulted in cilia shortening and also complete loss of cilia at 24 h post-exposure (Lam et al., 2013). Cilia length was also reduced in mouse nasal septal epithelial cells treated with cigarette smoke condensate (Tamashiro et al., 2009). Cilia length was reduced in endobronchial biopsies and airway brushings of smokers compared to nonsmokers (Leopold et al., 2009) and in COPD smokers compared to healthy smokers and nonsmokers (Hessel et al., 2014). In adults with adults with chronic sputum production, current and former smokers had a higher frequency of axonemal ultrastructural abnormalities than non-smokers and controls (Verra et al., 1994).

Nasomuciliary clearance time (determined by saccharin transit test) was significantly higher in smokers than in non-smokers and correlated positively with cigarettes per day and packs/year index (Proença et al., 2011; Baby et al., 2014; Yadav et al., 2014; Habesoglu et al., 2012; Pagliuca et al., 2015; Xavier et al., 2013; Dülger et al., 2018; Solak et al., 2018; Polosa et al., 2021).

Smoking decreased pulmonary function including forced vital capacity (FVC), forced expiratory volume in one second (FEV1) and FEF25–75 (Kuperman and Riker, 1973;  Ashley et al., 1975, Tantisuwat and Thaveeratitham, 2014, Gold et al., 1996; Broekema et al., 2009).

Oxidative stress [MIE] Leading to Decreased Lung Function [AO] via CFTR dysfunction

CFTR transcript and protein levels were reduced in human Calu-3 lung cancer cells exposed to the gas phase of cigarette smoke (Cantin et al., 2006b), human immortalized bronchial epithelial 16HBE14o- cells treated with 10% cigarette smoke extract (Hassan et al., 2014; Rasmussen et al., 2014; Xu et al., 2015), differentiated primary human bronchial epithelial cells exposed to whole cigarette smoke (Sloane et al., 2012; Hassan et al., 2014), and in airways of smokers compared to non-smokers (Dransfield et al., 2013). Following exposure to cigarette smoke, Cl conductance (i.e., CFTR-mediated Cl transport) decreased in primary human bronchial epithelial cells grown in monolayers (Lambert et al., 2014), differentiated primary human bronchial epithelial cells (Schmid et al., 2015; Chinnapaiyan et al., 2018), and nasal respiratory and intestinal epithelia of A/J mice (Raju et al., 2013; Raju et al., 2017).

In the lower airways, healthy smokers and smokers with chronic obstructive pulmonary disease (COPD) showed reduced CFTR-dependent Cl transport, whereas COPD former smokers showed an intermediate response to chloride-free isoproterenol solution compared to non-smokers. Similarly, amiloride-sensitive lower airway potential difference was also lower in healthy smokers and COPD smokers than in healthy non-smokers. This was linked to reduced CFTR protein levels in the airways of smokers compared to non-smokers, although there were no significant differences between healthy and COPD subjects (Dransfield et al., 2013). CFTR-dependent Cl conductance as measured by nasal potential difference was also significantly reduced in healthy and COPD smokers compared to healthy non-smokers or to former smokers with COPD (Sloane et al., 2012). In addition, healthy never-smokers had higher mean sweat chloride concentrations than COPD smokers and COPD former smokers (Raju et al., 2013; Courville et al., 2014).

Multiple studies showed that exposure of primary human bronchial epithelial cells, either undifferentiated or differentiated at the air-liquid interface, to cigarette smoke decreased ASL height (Hassan et al., 2014; Lambert et al., 2014; Raju et al., 2016; Rasmussen et al., 2014; Schmid et al., 2015). Treatment of immortalized bronchial epithelial 16HBE14o- cells with 10% cigarette smoke extract for 48 hours also resulted in a significant reduction in ASL height (Xu et al., 2015).

Treatment of human sinonasal epithelial cells with cigarette smoke condensate significantly reduced forskolin-stimulated CBF (Cohen et al., 2009). CBF was also decreased in differentiated normal human bronchial epithelial cells exposed to whole cigarette smoke (Schmid et al., 2015), in cilia-bearing explant adenoid tissues treated with 5 and 10% cigarette smoke extract (Wang et al., 2012), in hamster oviducts treated with various mainstream cigarette smoke fractions (Knoll et al., 1995), and in nasal epithelial cells fom smokers with moderate and severe chronic obstructive pulmonary disease (COPD) (Yaghi et al., 2012).

Nasomuciliary clearance time (determined by saccharin transit test) was significantly higher in smokers than in non-smokers and correlated positively with cigarettes per day and packs/year index (Proença et al., 2011; Baby et al., 2014; Yadav et al., 2014; Habesoglu et al., 2012; Pagliuca et al., 2015; Xavier et al., 2013; Dülger et al., 2018; Solak et al., 2018; Polosa et al., 2021). Smoking decreased pulmonary function including forced vital capacity (FVC), forced expiratory volume in one second (FEV1) and FEF25–75 (Kuperman and Riker, 1973; Ashley et al., 1975, Tantisuwat and Thaveeratitham, 2014, Gold et al., 1996; Broekema et al., 2009).

Event Evidence

This table is automatically generated and includes the Events with this associated stressor as well as the evidence text from this Event Stressor. More help
Cilia Beat Frequency, Decreased

Treatment of human sinonasal epithelial cells with cigarette smoke condensate for 3 minutes significantly reduced forskolin-stimulated CBF (Cohen et al., 2009). CBF was also decreased in differentiated normal human bronchial epithelial cells exposed to whole cigarette smoke (Schmid et al., 2015), in cilia-bearing explant adenoid tissues treated with 5 and 10% cigarette smoke extract (Wang et al., 2012), in hamster oviducts treated various mainstream cigarette smoke fractions (Knoll et al., 1995), and in nasal epithelial cells fom smokers with moderate and severe chronic obstructive pulmonary disease (COPD) (Yaghi et al., 2012).

Airway Surface Liquid Height, Decreased

Multiple studies showed that exposure of primary human bronchial epithelial cells, either undifferentiated or differentiated at the air-liquid interface, to cigarette smoke decreased ASL height (Hassan et al., 2014; Lambert et al., 2014; Raju et al., 2016; Rasmussen et al., 2014; Schmid et al., 2015). Treatment of immortalized bronchial epithelial 16HBE14o- cells with 10% cigarette smoke extract for 48 hours also resulted in a significant reduction in ASL height (Xu et al., 2015).

Cystic Fibrosis Transmembrane Regulator Function, Decreased

CFTR transcript and protein levels were reduced in human Calu-3 lung cancer cells exposed to the gas phase of cigarette smoke (Cantin et al., 2006b), human immortalized bronchial epithelial 16HBE14o- cells treated with 10% cigarette smoke extract (Hassan et al., 2014; Rasmussen et al., 2014; Xu et al., 2015), differentiated primary human bronchial epithelial cells exposed to whole cigarette smoke (Sloane et al., 2012; Hassan et al., 2014), and in airways of smokers compared to non-smokers (Dransfield et al., 2013). Following exposure to cigarette smoke, Cl conductance (i.e., CFTR-mediated Cl transport) decreased in primary human bronchial epithelial cells grown in monolayers (Lambert et al., 2014), differentiated primary human bronchial epithelial cells (Schmid et al., 2015; Chinnapaiyan et al., 2018), and nasal respiratory and intestinal epithelia of A/J mice (Raju et al., 2013; Raju et al., 2017). In the lower airways, healthy smokers and smokers with chronic obstructive pulmonary disease (COPD) showed reduced CFTR-dependent Cl transport, whereas COPD former smokers showed an intermediate response to chloride-free isoproterenol solution compared to non-smokers. Similarly, amiloride-sensitive lower airway potential difference was also lower in healthy smokers and COPD smokers than in healthy non-smokers. This was linked to reduced CFTR protein levels in the airways of smokers compared to non-smokers, although there were no significant differences between healthy and COPD subjects (Dransfield et al., 2013). CFTR-dependent Cl conductance as measured by nasal potential difference was also significantly reduced in healthy and COPD smokers compared to healthy non-smokers or to former smokers with COPD (Sloane et al., 2012). In addition, healthy never-smokers had higher mean sweat chloride concentrations than COPD smokers and COPD former smokers (Raju et al., 2013; Courville et al., 2014).

FOXJ1 Protein, Decreased

Whole cigarette smoke exposure or treatment with cigarette smoke extract of normal human bronchial epithelial cells significantly lowered FoxJ1 mRNA and protein levels (Milara et al., 2012; Brekman et al., 2014; Valencia-Gattas et al., 2016; Ishikawa and Ito, 2017). Cigarette smoke extract treatment of normal human bronchial epithelial cells also reduced the expression of cilia-related transcription factor genes, including FOXJ1, RFX2, and RFX3, as well as that of cilia motility and structural integrity genes regulated by FOXJ1, including DNAI1, DNAH5, DNAH9, DNAH10, DNAH11, and SPAG6 (Brekman et al., 2014).

Motile Cilia Number/Length, Decreased

Cilia length was reduced in endobronchial biopsies and airway brushings of smokers (average 30 pack-years) compared to nonsmokers (Leopold et al., 2009).

Exposure of human bronchial epithelial cells cultured at the air-liquid interface to 1, 3, and 6% cigarette smoke extract (from the basolateral side) between days 5 and 28 of differentiation significantly shortened the average cilia length of day 28 ALI cultures to 5.7, 5.5, and 4.9 µm, respectively, compared an average cilia length of 6.7 µm in untreated cultures. Continuous treatment of differentiated cultures with 3 and 6% cigarette smoke extract between days 28 and 42 showed that ciliated cells in the untreated day 42 cultures had longer cilia than day 28 cultures (ca. +1.5 µm), whereas in the presence of 3 and 6% of CSE, this elongation of cilia was suppressed (+0.5 µm and -0.5 µm, respectively) (Brekman et al., 2014).

Apical exposure of mouse tracheal epithelial cells differentiated at the air-liquid interface to cigarette smoke from 3R4F research cigarettes at a total particular matter concentration of 50 and 100 mg/m3 for 10 min resulted in cilia shortening (approx. -20% and -50%, respectively) and complete loss of cilia (approx. -25% and -60% of ciliated cells, respectively) at 24 h post-exposure (Lam et al., 2013).

Mean cilia length in the large airway epithelium was 7% shorter in healthy smokers (32.5+10 pack-years) compared to nonsmokers (7.09 vs 7.63 µm), 12% shorter in COPD smokers (39+21 pack-years) compared to healthy smokers (6.16 vs 7.09 µm), and 19% shorter in COPD smokers as compared to nonsmokers. In the small airway epithelium, mean cilia length was 9% shorter in healthy smokers relative to nonsmokers (6.49 vs 7.15 µm), 6% shorter in COPD smokers relative to healthy smokers (6.05 vs 6.49 µm), and 15% shorter in COPD smokers compared to nonsmokers (Hessel et al., 2014). 

Exposure of mouse nasal septal epithelial cells to cigarette smoke condensate at concentrations >30 µg/mL for the first 15 days growing at the air-liquid interface inhibited ciliogenesis (ciliated area: 89.9+8.0% in untreated vs 48.8+10.0% [30 µg/mL] and 37.5+12.0% [100 µg/mL]) and resulted in cilia shortening (not quantified) (Tamashiro et al., 2009).

Whole-body exposure of female C57BL/6 mice to  mainstream and sidestream cigarette smoke from 1R1 reference cigarettes at 150 mg/m3 total particular matter for 2 h per day, 5 days per week, for up to 1 year resulted in some areas of sparse or detached ciliated cells by month 6 and an almost complete loss of ciliated cells by 12 months (Simet et al., 2010).

In a small cohort study in adults with adults with chronic sputum production, current and former smokers had a higher frequency of axonemal ultrastructural abnormalities (16.53 ± 2.66% and 17.66 ± 6.99%, respectively) than non-smokers and controls (5.18 ± 0.9% and 0.7% ± 0.2%, respectively) (Verra et al., 1994).

Activation, EGFR

EGFR phosphorylation increased in lungs of Sprague-Dawley rats that were whole-body exposed (inExpose smoking system; SCIREQ, Montreal, Canada) at a total particulate matter (TPM) concentration of 2000 mg/m3 for 1 h (20 cigarettes) daily for 56 days (Chen et al., 2020); in lungs of Sprague-Dawley rats exposed to 12 cigarettes daily for 40 days (Nie et al., 2012); inlungs of Sprague-Dawley rats that were whole body-exposed to six nonfiltered cigarettes per day, 5 d/wk, for 2 to 28 days (Hegab et al., 2007); in lungs of Sprague-Dawley rats exposed to 10 cigarettes per h, 6 h per day for 60 days (Wu et al., 2011); in lungs of C57Bl6/J mice exposed to cigarette smoke at a TPM concentration of 100 mg/m(Teague Enterprises, Davis, CA) for 6 h a day, 5 days a week for two weeks (Mishra et al., 2016); in lungs of A/J mice that were exposed to cigarette smoke at a TPM concentration of 80 mg/m3 (Teague Enterprises, Davis, CA) for 4 h a day, 5 days per week for 1 year (Geraghty et al., 2014); in lungs of Balb/c mice exposed to mainstream cigarette smoke for 2 h twice daily, 6 days per week for 4 weeks (Wang et al., 2018); in primary human bronchial epithelial cells and NuLi-1 bronchial epithelial cell monolayers following exposure to cigarette smoke (Mishra et al., 2016); in primary bronchial epithelial cell monolayers following treatment with cigarette smoke extract (Zhang et al., 2012); in primary human airway epithelial cells differentiated at the air-liquid interface following treatment with cigarette smoke extract (Zhang et al., 2013; Hussain et al., 2018; Cortijo et al., 2011; Chen et al., 2010) or exposure to whole mainstream cigarette smoke (Amatngalim et al., 2016); in human small airway epithelial cell monolayers following treatment with cigarette smoke extract (Geraghty et al., 2014; Agraval and Yadav, 2019); in human NCI-H292 lung cancer cells following treatment with cigarette smoke extract (Takeyama et al., 2001; Shao et al., 2004; Lee et al., 2006; Yang et al., 2012; Wang et al., 2018); in human A549 lung cancer cells following treatment with cigarette smoke extract for 15 min (Dey et al., 2011) or 3 h (Agraval and Yadav, 2019); in immortalized human bronchial epithelial 1HAEo cells following exposure to cigarette smoke (Zhang et al., 2005); human immortalized 16HBE bronchial epithelial cells following treatment with 10% cigarette smoke extract for 24 h (Yu et al., 2015) or 5% cigarette smoke extract for up to 6 h (Heihjink et al., 2012); A549 lung adenocarcinoma and HBE1 papilloma virus-immortalized human bronchial epithelial cells following exposure to cigarette smoke (Khan et al., 2008).

EGFR phosphorylation was approx. two-fold higher in lung tissues, alveolar type II and bronchial epithelial cells of healthy smokers compared to non-smokers and was also elevated in the lungs and lung epithelial cells of COPD smokers (Mishra et al., 2016).

Decrease, Lung function

A smoking history of > 20 pack-years decreased pulmonary function including forced vital capacity (FVC), forced expiratory volume in one second (FEV1), FEV1/FVC, and forced expiratory flow at 25–75% (FEF25–75%) (Kuperman and Riker, 1973).

In the Framingham Heart Study, cigarette smoking showed an inverse association with FVC and FEV1% (Ashley et al., 1975).

In the international Seven Countries Study, there was a dose-effect relationship between pack-years and forced expiratory volume in 0.75 s (FEV0.75) in continuous smokers without chronic bronchitis (Pelkonen et al., 2006).

In 34 male subjects aged between 15–18 years who smoked FVC was lower than in an age-matched male group that did not smoke. The most common duration of cigarette smoking was 1–3 years (47%) and the maximal number of cigarettes smoked per day was less than or equal to 10 cigarette(s) per day (88%) (Tantisuwat and Thaveeratitham, 2014). 

A dose–response relation was found between smoking and lower levels of FEV1/FVC and FEF25–75 in children between 10-18 years of age (Gold et al., 1996).

In a study of 147 asthmatics, FEV1%predicted was significantly lower in ex-smokers and current smokers compared with never-smokers (Broekema et al., 2009).

In a 6-year longitudinal study in Japanese-American men, FEV1 was lowest in current smokers (2702 mL) and in former smokers (2817 mL) at baseline. These 2 groups experienced a steeper annual decline in FEV1 (-34.4 and -22.8 mL/year, respectively, adjusted by height and age at baseline) compared with never-smokers (-20.3 mL/year) (Burchfiel et al., 1995).

Occurrence, Hyperplasia of goblet cells

Cigarette smoke exposure causes goblet cell hyperplasia in the trachea, bronchi and bronchioles of mice, rats, dogs and humans (Park et al., 1977; Saetta et al., 2000; Tesfaigzi et al., 2000; Takeyama et al., 2008; Werley et al., 2016). 

Treatment of primary human bronchial epithelial cells differentiated at the air-liquid interface with up to 20 µg/mL cigarette smoke total particulate matter induced a concentration dependent increase in the percentage of MUC5A-positive cells (Haswell et al., 2010). Similarly, repeated exposure of primary human bronchial epithelial cells differentiated at the air-liquid interface to smoke from 1R6F reference cigarettes (University of Kentucky) 3 times per week for up to 6 weeks significantly increased the MUC5AC-positive cell population starting from week 4 (Haswell et al., 2021).

Decrease, Apoptosis of ciliated epithelial cells

Bik mRNA expression was significantly reduced in bronchial brushings and lung tissues of subjects with chronic bronchitis compared with nondiseased control subjects, and in C57BL/6 mice that were exposed to 250 mg/m3 of mainstream cigarette smoke for 6 h a day, 5 days a week, for 10 weeks. In addition, Bik mRNA and protein expression were significantly reduced in human airway epithelial cells differentiated at the air–liquid interface and treated with cigarette smoke extract (1,000 ng/ml total particulate matter) for 24 h at 5 days post-exposure (Mebratu et al., 2011).

Occurrence, Metaplasia of goblet cells

In female Han Wistar rats exposed to the smoke of 24 cigarettes (1R1; University of Kentucky) per day, for four consecutive days and treated with 20 µg LPS 24 h after the first exposure, increased AB/PAS staining in the large and smaller airways indicated goblet cell metaplasia (Baginski et al., 2006).

The number of AB-PAS positive cells in the lungs of male Sprague-Dawley rats exposed to smoke of 20 commercial unfiltered cigarettes for 30 min twice a day, for a total of four weeks was significantly increased (Jun et al., 2011).

Increase, Proliferation of goblet cells

Treatment of primary human bronchial epithelial cells differentiated at the air-liquid interface with up to 20 µg/mL cigarette smoke total particulate matter induced a concentration dependent increase in the percentage of MUC5A-positive cells (Haswell et al., 2010). Similarly, repeated exposure of primary human bronchial epithelial cells differentiated at the air-liquid interface to smoke from 1R6F reference cigarettes (University of Kentucky) 3 times per week for up to 6 weeks significantly increased the MUC5AC-positive cell population starting from week 4 (Haswell et al., 2021).

Increase, Mucin production

Treatment of immortalized human bronchial epithelial 16HBE cells with cigarette smoke extract increased MUC5AC gene and protein expression in a concentration-dependent manner (Yu et al., 2011; Yu et al., 2015). Treatment of NCI-H292 lung cancer cells with cigarette smoke extract increased MUC5AC gene and protein expression in a concentration- and time-dependent manner (Takeyama et al., 2001; Shao et al., 2004; Baginski et al., 2006; Lee et al., 2006; Montalbano et al., 2014). Cigarette smoke extract treatment of A549 lung cancer cells (2 h) and primary human bronchial epithelial cells differentiated at the air-liquid interface (6 h and 16 h) increased MUC5AC gene and protein expression (Di et al., 2012).

Whole-body exposure (TE-10 Teague Enterprises, Davis, CA) of rats to smoke from 1R1 research cigarettes (University of Kentucky; increasing dose between 123 to 323 mg/m3 total smoking particulate matter) for 2 h per day, 5 days per week, for 8 weeks significantly elevated Muc5ac levels in the bronchoalveolar fluid (Kato et al., 2020).

Muc5ac gene expression increased in the lungs of male Sprague-Dawley rats that were whole-body exposed to the smoke of 5 cigarettes a day, for 5 consecutive days (Takeyama et al., 2001).

Chronic, Mucus hypersecretion

Smokers had a higher mucus volume density than non-smokers (27.78 ± 10.24 μL/mm2 vs 3.42 ± 3.07 μL/mm2) (Kim et al., 2015).

A cross-sectional study in twins indicated that smoking was a risk factor for chronic mucus hypersecretion, and there was a dose-response relationship between daily tobacco consumption and prevalence of chronic mucus hypersecretion (Harmsen et al., 2010). A dose-response relationship between chronic mucus hypersecretion and pack-years of smoking was also observed in the Dutch LifeLines cohort study. This study additionally highlighted that exposure to environmental cigarette smoke ("seond-hand smoke") was also associated with the risk of chronic mucus hypersecretion (Dijkstra et al., 2014).

Mucociliary Clearance, Decreased

Nasomuciliary clearance time (determined by saccharin transit test) was significantly higher in smokers than in non-smokers 8 h after smoking (16 ± 6 min vs 10 ± 4 min) and insignicantly higher immediately after smoking (11 ± 6 min vs 10 ± 4 min). Nasomuciliary clearance time correlated positively with cigarettes per day and packs/year index (Proença et al., 2011).

In a small Indian cross-sectional study, the mean nasomuciliary clearance (determined by saccharin transit test) in smokers was significantly higher than that of nonsmokers (481.2 ± 29.83 s vs 300.32 ± 17.4 s). In addition, mean nasomuciliary clearance increased as the duration of smoking increased (NMC in smoking <1 year = 492.25 ± 79.93 s, NMC in smoking for 1-5 years = 516.7 ± 34.01 s, and NMC in smoking >5 years = 637.5 ± 28.49 s) (Baby et al., 2014).

Nasomuciliary clearance (determined by saccharin transit test) in active and passive smokers was significantly higher than in non-smokers (23.08 ± 4.60 min; 20.31 ± 2.51 min vs 8.57 ± 2.12 min) (Yadav et al., 2014).

Nasomuciliary clearance (determined by saccharin transit test) was significantly higher in active smokers than in passive smokers and non-smokers (23.59 ± 12.41 min vs 12.6 ± 4.67 min; 6.4 ± 1.55 min) (Habesoglu et al., 2012).

Nasomuciliary clearance time (determined by saccharin transit test) in smokers was significantly higher than in former smokers and non-smokers (15.6 min vs 11.77 min and 11.71 min, respectively) (Pagliuca et al., 2015).

Moderate and heavy smokers had higher saccharin transit test times than light smokers and non-smokers, and there was a positive correlation between STT and cigarettes/day (Xavier et al., 2013).

The median nasal mucociliary clearance time (determined by saccharin transit test) was significantly higher in smokers (who smoked a mean of 20.6 cigarettes (median: 20) per day) than in  nonsmokers (12 (interquartile range: 5–33) min vs 9 (interquartile range: 4–12) min) (Dülger et al., 2018). 

Nasal mucociliary clearance time (determined by saccharin transit test) in smokers was significantly higher than in non-smokers (536.19 ± 254.81 s vs 320.43 ± 184.98 s) and correlated with the numbers of cigarettes per day, pack-years and smoking duration (Solak et al., 2018).

Current smokers had a median (IQR) mucociliary clearance transit time (determined by saccharin transit test) of 13.15 (9.89–16.08) min, which was significantly longer compared with that of never smokers at 7.24 (5.73–8.73) min, former smokers at 7.26 (6.18–9.17) min, exclusive e-cigarette users at 7.00 (6.38–9.00) min, and exclusive heated tobacco product users at 8.00 (6.00–8.00) min (Polosa et al., 2021).

Stressor Info

Text sections under this subheading include the Chemical/Category Description and Characterization of Exposure. More help
Chemical/Category Description
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Characterization of Exposure
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References

List of the literature that was cited for this Stressor description. Ideally, the list of references, should conform, to the extent possible, with the OECD Style Guide (https://www.oecd.org/about/publishing/OECD-Style-Guide-Third-Edition.pdf) (OECD, 2015).To edit the “References” section, on a Stressor page, in the upper right hand menu, click ‘Edit.’ This brings you to a page entitled, “Editing Stressor.”  Scroll down to the “References” section, where a text entry box allows you to submit text. Click ‘Update’ to save your changes and return to the Stressor page.  The new text should appear under the “References” section on the page. More help