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Open Access 01-12-2016 | Research

Soluble adenylyl cyclase mediates hydrogen peroxide-induced changes in epithelial barrier function

Authors: Pedro Ivonnet, Hoshang Unwalla, Matthias Salathe, Gregory E. Conner

Published in: Respiratory Research | Issue 1/2016

Abstract

Background

Elevated H₂O₂ levels are associated with inflammatory diseases and H₂O₂ exposure is known to disrupt epithelial barrier function, leading to increased permeability and decreased electrical resistance. In normal human bronchial epithelial (NHBE) cells, fully differentiated at the air liquid interface (ALI), H₂O₂ activates an autocrine prostaglandin pathway that stimulates transmembrane adenylyl cyclase (tmAC) as well as soluble adenylyl cyclase (sAC), but the role of this autocrine pathway in H₂O₂-mediated barrier disruption is not entirely clear.

Methods

To further characterize the mechanism of H₂O₂-induced barrier disruption, NHBE cultures were treated with H₂O₂ and evaluated for changes in transepithelial resistance and mannitol permeability using agonist and inhibitors to dissect the pathway.

Results

A short (<10 min) H₂O₂ treatment was sufficient to induce resistance and permeability changes that occurred 40 min to 1 h later and the changes were partially sensitive to EP1 but not EP4 receptor antagonists. EP1 receptors were localized to the apical compartment of NHBE. Resistance and permeability changes were sensitive to inhibition of sAC but not tmAC and were partially blocked by PKA inhibition. Pretreatment with a PLC inhibitor or an IP3 receptor antagonist reduced changes in resistance and permeability suggesting activation of sAC occurred through increased intracellular calcium.

Conclusion

The data support an important role for prostaglandin activation of sAC and PKA in H₂O₂-induced barrier disruption.

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Title: Soluble adenylyl cyclase mediates hydrogen peroxide-induced changes in epithelial barrier function
Authors: Pedro Ivonnet
Hoshang Unwalla
Matthias Salathe
Gregory E. Conner
Publication date: 01-12-2016
Publisher: BioMed Central
Published in: Respiratory Research / Issue 1/2016
Electronic ISSN: 1465-993X
DOI: https://doi.org/10.1186/s12931-016-0329-4

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