The long-acting β2-adrenoceptor agonist, indacaterol, enhances glucocorticoid receptor-mediated transcription in human airway epithelial cells in a gene- and agonist-dependent manner

Various metals produced from human activity are ubiquitously detected in ambient air. The metals may lead to induction and/or exacerbation of respiratory diseases, but the significant metals and factors contributing to such diseases have not been identified. To compare the effects of each metal and different oxidation states of metals on human airway, we examined the viability and production of interleukin (IL)-6 and IL-8 using BEAS-2B cell line, derived from human airway epithelial cells. Airway epithelial cells were exposed to Mn2+, V4+, V5+, Cr3+, Cr6+, Zn2+, Ni2+, and Pb2+ at a concentration of 0.5, 5, 50, or 500 μmol/L for 24 hours. Mn and V decreased the cell viability in a concentration-dependent manner, and V5+ tended to have a greater effect than V4+. The Cr decreased the cell viability, and (Cr+6) at concentrations of 50 and 500 μmol/L was more toxic than (Cr+3). Zn at a concentration of 500 μmol/L greatly decreased the cell viability, whereas Ni at the same concentration increased it. Pb produced fewer changes. Mn and Ni at a concentration of 500 μmol/L induced the significant production of IL-6 and IL-8. However, most of the metals including (V+4, V+5), (Cr+3, Cr+6), Zn, and Pb inhibited the production of both IL-6 and IL-8. The present results indicate that various heavy metals have different effects on toxicity and the proinflammatory responses of airway epithelial cells, and those influences also depend on the oxidation states of the metals.

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Cultured Human Airway Epithelial Cells (Calu-3): A Model of Human Respiratory Function, Structure, and Inflammatory Responses

Critical Care Research and Practice ◽

10.1155/2010/394578 ◽

2010 ◽

Vol 2010 ◽

pp. 1-8 ◽

Cited By ~ 36

Author(s):

Yan Zhu ◽

Aaron Chidekel ◽

Thomas H. Shaffer

Keyword(s):

Epithelial Cells ◽

Cellular Response ◽

Inflammatory Responses ◽

Airway Epithelial Cells ◽

Treatment Modalities ◽

Positive Pressure ◽

Dependent Manner ◽

Airway Epithelial ◽

Human Airway ◽

Human Airway Epithelial Cells

This article reviews the application of the human airway Calu-3 cell line as a respiratory model for studying the effects of gas concentrations, exposure time, biophysical stress, and biological agents on human airway epithelial cells. Calu-3 cells are grown to confluence at an air-liquid interface on permeable supports. To model human respiratory conditions and treatment modalities, monolayers are placed in an environmental chamber, and exposed to specific levels of oxygen or other therapeutic modalities such as positive pressure and medications to assess the effect of interventions on inflammatory mediators, immunologic proteins, and antibacterial outcomes. Monolayer integrity and permeability and cell histology and viability also measure cellular response to therapeutic interventions. Calu-3 cells exposed to graded oxygen concentrations demonstrate cell dysfunction and inflammation in a dose-dependent manner. Modeling positive airway pressure reveals that pressure may exert a greater injurious effect and cytokine response than oxygen. In experiments with pharmacological agents, Lucinactant is protective of Calu-3 cells compared with Beractant and control, and perfluorocarbons also protect against hyperoxia-induced airway epithelial cell injury. The Calu-3 cell preparation is a sensitive and efficient preclinical model to study human respiratory processes and diseases related to oxygen- and ventilator-induced lung injury.

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Aclidinium, a New Long-Acting Antimuscarinic, Inhibits Cholinergic and Cigarette Smoke-Induced Up Regulation of Mucin MUC5AC Expression in Human Airway Epithelial Cells.

10.1164/ajrccm-conference.2009.179.1_meetingabstracts.a6179 ◽

2009 ◽

Author(s):

M Mata ◽

J Milara ◽

B Bedrina ◽

A Gavalda ◽

M Miralpeix ◽

...

Keyword(s):

Epithelial Cells ◽

Cigarette Smoke ◽

Airway Epithelial Cells ◽

Airway Epithelial ◽

Human Airway ◽

Long Acting ◽

Human Airway Epithelial Cells

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Modulation of cAMP Levels for Potentiation of Long-Acting Beta-Agonist and Glucocorticoids in Human Airway Epithelial Cells

10.1164/ajrccm-conference.2019.199.1_meetingabstracts.a2843 ◽

2019 ◽

Author(s):

Y. Kim ◽

V. Hou ◽

J.P. Nguyen ◽

R.D. Huff ◽

M. Bianca ◽

...

Keyword(s):

Epithelial Cells ◽

Airway Epithelial Cells ◽

Beta Agonist ◽

Airway Epithelial ◽

Human Airway ◽

Long Acting ◽

Camp Levels ◽

Human Airway Epithelial Cells

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Potentiation of long-acting β2-agonist and glucocorticoid responses in human airway epithelial cells by modulation of intracellular cAMP

Respiratory Research ◽

10.1186/s12931-021-01862-1 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Yechan Kim ◽

Vincent Hou ◽

Ryan D. Huff ◽

Jennifer A. Aguiar ◽

Spencer Revill ◽

...

Keyword(s):

Epithelial Cells ◽

Airway Epithelial Cells ◽

Poly I:C ◽

Intracellular Camp ◽

Airway Epithelial ◽

Human Airway ◽

Long Acting ◽

Camp Levels ◽

Human Airway Epithelial Cells

Abstract Introduction Over 300 million people in the world live with asthma, resulting in 500,000 annual global deaths with future increases expected. It is estimated that around 50–80% of asthma exacerbations are due to viral infections. Currently, a combination of long-acting beta agonists (LABA) for bronchodilation and glucocorticoids (GCS) to control lung inflammation represent the dominant strategy for the management of asthma, however, it is still sub-optimal in 35–50% of moderate-severe asthmatics resulting in persistent lung inflammation, impairment of lung function, and risk of mortality. Mechanistically, LABA/GCS combination therapy results in synergistic efficacy mediated by intracellular cyclic adenosine monophosphate (cAMP). Hypothesis Increasing intracellular cAMP during LABA/GCS combination therapy via inhibiting phosphodiesterase 4 (PDE4) and/or blocking the export of cAMP by ATP Binding Cassette Transporter C4 (ABCC4), will potentiate anti-inflammatory responses of mainstay LABA/GCS therapy. 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 analyses were performed in primary human airway epithelial cells and cell lines. Intervention experiments were performed on the human airway epithelial cell line, HBEC-6KT, by pre-treatment with combinations of LABA/GCS with PDE4 and/or ABCC4 inhibitors followed by Poly I:C or imiquimod challenge as a model for viral stimuli. Cytokine readouts for IL-6, IL-8, CXCL10/IP-10, and CCL5/RANTES were quantified by ELISA. Results Using archived human lung and human airway epithelial cells, ABCC4 gene and protein expression were confirmed in vitro and in situ. LABA/GCS attenuation of Poly I:C or imiquimod-induced IL-6 and IL-8 were potentiated with ABCC4 and PDE4 inhibition, which was greater when ABCC4 and PDE4 inhibition was combined. Modulation of cAMP levels had no impact on LABA/GCS modulation of Poly I:C-induced CXCL10/IP-10 or CCL5/RANTES. Conclusion Modulation of intracellular cAMP levels by PDE4 or ABCC4 inhibition potentiates LABA/GCS efficacy in human airway epithelial cells challenged with viral stimuli. The data suggest further exploration of the value of adding cAMP modulators to mainstay LABA/GCS therapy in asthma for potentiated anti-inflammatory efficacy.

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