The impact of cigarette smoke exposure, and COPD or asthma status on ABC transporter gene expression in human airway epithelial cells

Aguiar, Jennifer A.; Tamminga, Andrea; Lobb, Briallen; Huff, Ryan D.; Nguyen, Julie T.; Kim, Yechan; Dvorkin‐Gheva, Anna; Stämpfli, Martin R.; Doxey, Andrew C.; Hirota, Jeremy A.

doi:10.1101/369355

Cited by 10 publications

(26 citation statements)

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“…Expression and functional studies of ABCF1 have focused on human synoviocytes, mouse embryonic fibroblasts, human embryonic kidney cells, and peripheral blood mononuclear cells (27)(28)(29)(30)32). We have demonstrated gene expression of ABCF1 in human airway epithelial cells (35). To date, no in situ gene and protein expression data has confirmed ABCF1 expression in human lung tissues.…”

Section: Results: Abcf1 Gene and Protein Expression Is Localized To Hmentioning

confidence: 93%

“…ABCF1, a member of the ATP Binding Cassette family expressed in diverse mammals and different tissue types, has been reported to have diverse functions including initiation of mRNA translation, dsDNA viral sensing, and polarization of immune cell phenotype (27)(28)(29)(30)(31)(32). We have recently reported ABCF1 gene expression levels in human airway epithelium (35), but the function of this molecule remained unexplored. Herein we confirm ABCF1 gene and protein expression in situ and in vitro in primary human lung tissue and cell lines and explore its function in airway epithelial cells.…”

Section: Discussionmentioning

confidence: 99%

“…Complementary to dsDNA sensing, immune modulation mediated by ubiquitin-conjugating activities of ABCF1 have been defined in the context of macrophage polarization and immune responses linked to interferon-β production and tolerance important in mouse models of sepsis (32). In the context of studies using human lung samples, ABCF1 gene expression has been identified in the human airway epithelium (35), although confirmation of protein and function remains to be determined. The clear in vivo demonstration of ABCF1 functions in immune responses in mouse models and the presence of detectable ABCF1 gene expression the human airways warrants a deeper interrogation into the expression and function of this molecule in human health and disease.…”

Section: Introductionmentioning

confidence: 99%

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ABCF1 regulates dsDNA-induced immune responses in human airway epithelial cells

Cao

Aguiar

Tremblay

et al. 2020

Preprint

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words)Background: The airway epithelium represents a critical component of the human lung that helps orchestrate defences against respiratory tract viral infections, which are responsible for more than 2.5 million deaths/year globally. Innate immune activities of the airway epithelium rely Toll-like receptors (TLRs), nucleotide binding and leucine-rich-repeat pyrin domain containing (NLRP) receptors, and cytosolic nucleic acid sensors. ATP Binding Cassette (ABC) transporters are ubiquitous across all three domains of life -Archaea, Bacteria, and Eukarya -and expressed in the human airway epithelium. ABCF1, a unique ABC family member that lacks a transmembrane domain, has been defined as a cytosolic nucleic acid sensor that regulates CXCL10, interferon-β expression, and downstream type I interferon responses. We tested the hypothesis that ABCF1 functions as a dsDNA nucleic acid sensor in human airway epithelial cells important in regulating antiviral responses.Methods: Expression and localization experiments were performed using in situ hybridization and immunohistochemistry in human lung tissue from healthy subjects, while confirmatory transcript and protein expression was performed in human airway epithelial cells. Functional experiments were performed with siRNA methods in human airway epithelial cells. Complementary transcriptomic analyses were performed to explore the contributions of ABCF1 to gene expression patterns. Results:Using archived human lung and human airway epithelial cells, we confirm expression of ABCF1 gene and protein expression in these tissue samples, with a role for mediating CXCL10 production in response to dsDNA viral mimic challenge. Although, ABCF1 knockdown was associated with an attenuation of select genes involved in the antiviral responses, Gene Ontology analyses revealed a greater interaction of ABCF1 with TLR signaling suggesting a multifactorial role for ABCF1 in innate immunity in human airway epithelial cells.Conclusion: ABCF1 is a candidate cytosolic nucleic acid sensor and modulator of TLR signaling that is expressed at gene and protein levels in human airway epithelial cells. The precise level where ABCF1 protein functions to modulate immune responses to pathogens remains to be determined but is anticipated to involve IRF-3 and CXCL10 production.

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Section: Results: Abcf1 Gene and Protein Expression Is Localized To Hmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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ABCF1 regulates dsDNA-induced immune responses in human airway epithelial cells

Cao

Aguiar

Tremblay

et al. 2020

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“…Global recreational cannabis use is a potentially important public health issue that would benefit from experimental evidence to inform policy, regulations, and individual user practices. Comparative analyses between cannabis and tobacco smoke (25,26), the latter long reported to have negative impacts on respiratory health (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19), may help provide context and provide clinically relevant evidence. To address this unmet need and leverage an extensive history of in vitro tobacco smoke exposure research, we performed a comparative study between cannabis and tobacco smoke exposure in the Calu-3 human airway epithelial cells using concentration-response and pharmacological intervention study designs.…”

Section: Discussionmentioning

confidence: 99%

“…In Canada, the majority of cannabis is consumed by combustion with 94 and 89% of participants reporting this method of delivery in the 2017 and 2018 Canadian Cannabis Surveys, respectively (2,3). The negative effects of tobacco smoke exposure on the lung and its airway epithelium are universally accepted (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19). In comparison, the consequences of cannabis smoke exposure on lung health are less clear (20)(21)(22)(23)(24)(25)(26)(27)(28)(29) and must receive additional attention to effectively inform public health policy, government regulations, and individual user practices.…”

Section: Introductionmentioning

confidence: 99%

A comparative analysis of cannabis and tobacco smoke exposure on human airway epithelial cell gene expression, immune phenotype, and response to formoterol and budesonide treatment

Aguiar

Huff

Tse

et al. 2019

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Word Count -271Global recreational cannabis use is a potentially important public health issue that would benefit from experimental evidence to inform policy, regulations, and individual user practices. Comparative analyses between cannabis and tobacco smoke, the latter long reported to have negative impacts on respiratory health, may help provide context and provide clinically relevant evidence.To address this unmet need we performed a comparative study between cannabis and tobacco smoke exposure in the Calu-3 human airway epithelial cells using concentration-response and pharmacological intervention study designs with outcome measurements of cell viability, epithelial cell barrier function, cytokine profile, and transcriptomics.Our results demonstrate that cannabis smoke exposure reduces epithelial cell barrier function without impacting cell viability, accompanied by a cytokine profile associated with inflammation (elevated IL-6 and IL-8), barrier repair (elevated TGF-α and PDGF-AA) and suppressed antiviral immunity (decreased IP-10 and RANTES). Transcriptomic analyses revealed a cannabis smoke induced signature associated with suppressed antiviral genes and induction of oncogenic and oxidative stress pathways. Similar trends were observed for tobacco smoke exposure. A formoterol/budesonide intervention was unable to prevent cannabis smoke-induced reductions in antiviral pathways or normalize induction of oncogenic and oxidative stress responses.Our results show striking similarities between cannabis and tobacco smoke exposure on impairing barrier function, suppressing antiviral pathways, potentiating of pro-inflammatory mediators, and inducing oncogenic and oxidative stress gene expression signatures. Furthermore, we demonstrate that an intervention with formoterol and budesonide is unable to completely normalized cannabisinduced responses. Collectively our data suggest that cannabis smoke exposure is not innocuous and may possess many of the deleterious properties of tobacco smoke, warranting additional studies to support public policy, government regulations, and individual user practices.

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Regulation of Drug Transport Proteins—From Mechanisms to Clinical Impact: A White Paper on Behalf of the International Transporter Consortium

Brouwer

Evers

Hayden

et al. 2022

Clin Pharma and Therapeutics

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Membrane transport proteins are involved in the absorption, disposition, efficacy, and/or toxicity of many drugs. Numerous mechanisms (e.g., nuclear receptors, epigenetic gene regulation, microRNAs, alternative splicing, post-translational modifications, and trafficking) regulate transport protein levels, localization, and function. Various factors associated with disease, medications, and dietary constituents, for example, may alter the regulation and activity of transport proteins in the intestine, liver, kidneys, brain, lungs, placenta, and other important sites, such as tumor tissue. This white paper reviews key mechanisms and regulatory factors that alter the function of clinically relevant transport proteins involved in drug disposition. Current considerations with in vitro and in vivo models that are used to investigate transporter regulation are discussed, including strengths, limitations, and the inherent challenges in predicting the impact of changes due to regulation of one transporter on compensatory pathways and overall drug disposition. In addition, translation and scaling of in vitro observations to in vivo outcomes are considered. The importance of incorporating altered transporter regulation in modeling and simulation approaches to predict the clinical impact on drug disposition is also discussed. Regulation of transporters is highly complex and, therefore, identification of knowledge gaps will aid in directing future research to expand our understanding of clinically relevant molecular mechanisms of transporter regulation. This information is critical to the development of tools and approaches to improve therapeutic outcomes by predicting more accurately the impact of regulation-mediated changes in transporter function on drug disposition and response.Transport proteins of the solute carrier (SLC) and ATP-binding cassette (ABC) superfamilies are widely recognized as key determinants of the absorption, distribution, and excretion of many endogenous compounds and xenobiotics, including drugs, bile acids, hormones, and nutrients, which may thereby directly or indirectly impact medication efficacy and/or safety. Not surprisingly, intersubject variability in drug response due to transporters has been attributed to altered transporter function in organs, such as the intestine, liver, and kidneys. 1,2 Mechanisms of alterations in drug transporter activity have focused primarily on (i) differences in gene expression and/ or protein abundance due to genetic polymorphisms; and (ii) drug-drug interactions (DDIs) predominantly involving direct

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The impact of cigarette smoke exposure, and COPD or asthma status on ABC transporter gene expression in human airway epithelial cells

Cited by 10 publications

References 51 publications

ABCF1 regulates dsDNA-induced immune responses in human airway epithelial cells

ABCF1 regulates dsDNA-induced immune responses in human airway epithelial cells

A comparative analysis of cannabis and tobacco smoke exposure on human airway epithelial cell gene expression, immune phenotype, and response to formoterol and budesonide treatment

Regulation of Drug Transport Proteins—From Mechanisms to Clinical Impact: A White Paper on Behalf of the International Transporter Consortium

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