Cigarette smoke condensate inhibits transepithelial chloride transport and ciliary beat frequency

Cohen, Noam A.; Zhang, Shaoyan; Sharp, Dawn B.; Tamashiro, Edwin; Chen, Bei; Sorscher, Eric J.; Woodworth, Bradford A.

doi:10.1002/lary.20223

Cited by 135 publications

(144 citation statements)

References 29 publications

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“…The effects of 320 µg/mL CSC, a concentration close to those previously retained in in vitro studies (Allam et al 2013;Cohen et al 2009), on SLC transporter activities was first analyzed in various HEK 293 clones overexpressing hepatic SLC transporters. As shown in Fig.…”

Section: Effects Of Csc On Slc Transporters Activitiesmentioning

confidence: 99%

Alteration of human hepatic drug transporter activity and expression by cigarette smoke condensate

et al. 2016

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Smoking is well-known to impair pharmacokinetics, through inducing expression of drug metabolizing enzymes. In the present study, we demonstrated that cigarette smoke condensate (CSC) also alters activity and expression of hepatic drug transporters, which are now recognized as major actors of hepatobiliary elimination of drugs. CSC thus directly inhibited activities of sinusoidal transporters such as OATP1B1, OATP1B3, OCT1 and NTCP as well as those of canalicular transporters like P-glycoprotein, MRP2, BCRP and MATE1, in hepatic transporters-overexpressing cells. CSC similarly counteracted constitutive OATP, NTCP and OCT1 activities in human highly-differentiated hepatic HepaRG cells. In parallel, CSC induced expression of BCRP at both mRNA and protein level in HepaRG cells, whereas it concomitantly repressed mRNA expression of various transporters, including OATP1B1, OATP2B1, OAT2, NTCP, OCT1 and BSEP, and enhanced that of MRP4. Such changes in transporter gene expression were found to be highly correlated to those caused by 2,3,7,8-tetrachlorodibenzo-p-dioxin, a reference activator of the aryl hydrocarbon receptor (AhR) pathway, and were counteracted, for some of them, by siRNA-mediated AhR silencing. This suggests that CSC alters hepatic drug transporter levels via activation of the AhR cascade. Importantly, drug transporter expression regulations as well as some transporter activity inhibitions occurred for a range of CSC concentrations similar to those required for inducing drug metabolizing enzymes and may therefore be hypothesized to be relevant for smokers. Taken together, these data established human hepatic transporters as targets of cigarette smoke, which could contribute to known alteration of pharmacokinetics and some liver adverse effects caused by smoking. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. SummarySmoking is well-known to impair pharmacokinetics, through inducing expression of drug metabolizing enzymes. In the present study, we demonstrated that cigarette smoke condensate (CSC) also alters activity and expression of hepatic drug transporters, which are now recognized as major actors of hepatobiliary elimination of drugs. CSC thus directly inhibited activities of sinusoidal transporters such as OATP1B1, OATP1B3, OCT1 and NTCP as well as those of canalicular transporters like P-glycoprotein, MRP2, BCRP and MATE1, in hepatic transporters-overexpressing cells. CSC similarly counteracted constitutive OATP, NTCP and OCT1 activities in human highly-differentiated hepatic HepaRG cells. In parallel, CSC induced expression of BCRP at both mRNA and protein level in HepaRG ce...

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Section: Effects Of Csc On Slc Transporters Activitiesmentioning

confidence: 99%

Alteration of human hepatic drug transporter activity and expression by cigarette smoke condensate

et al. 2016

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“…[43][44][45] In addition, chronic exposure to cigarette smoke also leads to chronic inflammation and progressive emphysema, which contributes to the impaired lung and immune system homeostasis that plays a role in COPD exacerbations. [6][7][8] It is known that exacerbations still occur in patients with COPD even after smoking cessation. 46,47 In the present study, no correlations were found between STT and frequency of exacerbations in COPD groups; however, ex-smokers with COPD showed a low frequency of exacerbations compared with smokers with COPD, which supports the hypothesis that frequency of exacerbations may be influenced by the maintenance of smoking.…”

Section: Discussionmentioning

confidence: 99%

“…4,5 The impairment of MCC leads to retention of secretions and recurrent airway infections that play a role in exacerbations of COPD. [6][7][8][9] Exacerbations of COPD have a negative impact on mortality rates, 10,11 on health-related quality of life, and on FEV 1 , in addition to representing a hugely expensive burden on healthcare resources. 12 Studies have shown that the impairment of MCC in smokers was related to the intensity of the smoking habit 13 and that smoking cessation improved nasal MCC by 15 d after quitting smoking and that the improvement persisted over 6 months.…”

Section: Introductionmentioning

confidence: 99%

Nasal Mucociliary Clearance in Subjects With COPD After Smoking Cessation

et al. 2014

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“…In vitro models of ciliated cells suggest that CSE slows ciliary beating, (10) thus predisposing the airways to infection and compromising lung sterility. Cohen et al (11) found reductions in CBF and transepithelial chloride secretions with CS exposure. In addition to modifying CBF, CSE also disrupts ciliogenesis, leading to stunted cilia and a lower overall number of ciliated cells.…”

Section: Introductionmentioning

confidence: 98%

“…Because in vitro studies have been inconclusive on whether CSE exposure results in CBF stimulation or inhibition (7)(8)(9)11,21) we assayed CBF in a cell-free preparation of ciliary axonemes exposed to CSE. Given the high incidence of pulmonary disease in tobacco users, we hypothesized that CSE would alter CBF in a cell-free axoneme model.…”

Section: Introductionmentioning

confidence: 99%

Particulate Matter in Cigarette Smoke Increases Ciliary Axoneme Beating Through Mechanical Stimulation

Navarrette¹,

Sisson²,

Nance

et al. 2012

Journal of Aerosol Medicine and Pulmonary Drug Delivery

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Background: The lung's ability to trap and clear foreign particles via the mucociliary elevator is an important mechanism for protecting the lung against respirable irritants and microorganisms. Although cigarette smoke (CS) exposure and particulate inhalation are known to alter mucociliary clearance, little is known about how CS and nanoparticles (NPs) modify cilia beating at the cytoskeletal infrastructure, or axonemal, level. Methods: We used a cell-free model to introduce cigarette smoke extract (CSE) and NPs with variant size and surface chemistry to isolated axonemes and measured changes in ciliary motility. We hypothesized that CSE would alter cilia beating and that alterations in ciliary beat frequency (CBF) due to particulate matter would be size-and surface chemistry-dependent. Demembranated axonemes were isolated from ciliated bovine tracheas and exposed to adenosine triphosphate (ATP) to initiate motility. CBF was measured in response to 5% CSE, CSE filtrate, and carboxyl-modified (COOH), sulphate (SO 4 )-modified (sulfonated), or PEG-coated polystyrene (PS) latex NPs ranging in size from 40 nm to 500 nm. Results: CSE concentrations as low as 5% resulted in rapid, significant stimulation of CBF ( p < 0.05 vs. baseline control). Filtering CSE through a 0.2-lm filter attenuated this effect. Introduction of sulphate-modified PS beads *300 nm in diameter resulted in a similar increase in CBF above baseline ATP levels. Uncharged, PEG-coated beads had no effect on CBF regardless of size. Similarly, COOH-coated particles less than 200 nm in diameter did not alter ciliary motility. However, COOH-coated PS particles larger than 300 nm increased CBF significantly and increased the number of motile points. Conclusions: These data show that NPs, including those found in CSE, mechanically stimulate axonemes in a size-and surface chemistry-dependent manner. Alterations in ciliary motility due to physicochemical properties of NPs may be important for inhalational lung injury and efficient drug delivery of respirable particles.

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Cigarette smoke condensate inhibits transepithelial chloride transport and ciliary beat frequency

Abstract: The present study provides direct evidence that tobacco smoke diminishes two major components of MCC. This links tobacco smoke as a potential contributing and/or exacerbating factor in exposed individuals with chronic rhinosinusitis.

Cited by 135 publications

References 29 publications

Alteration of human hepatic drug transporter activity and expression by cigarette smoke condensate

Alteration of human hepatic drug transporter activity and expression by cigarette smoke condensate

Nasal Mucociliary Clearance in Subjects With COPD After Smoking Cessation

Particulate Matter in Cigarette Smoke Increases Ciliary Axoneme Beating Through Mechanical Stimulation

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