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Zinc deficiency as a codeterminant for airway epithelial barrier dysfunction in an ex vivo model of COPD

Authors Roscioli E, Jersmann HPA, Lester S, Badiei A, Fon A, Zalewski P, Hodge S

Received 20 August 2017

Accepted for publication 16 October 2017

Published 5 December 2017 Volume 2017:12 Pages 3503—3510

DOI https://doi.org/10.2147/COPD.S149589

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Charles Downs

Peer reviewer comments 4

Editor who approved publication: Dr Richard Russell


Eugene Roscioli,1,2 Hubertus PA Jersmann,1,2 Susan Lester,2,3 Arash Badiei,1,2 Andrew Fon,1,2 Peter Zalewski,2,4 Sandra Hodge1,2

1Department of Thoracic Medicine, Royal Adelaide Hospital, 2Department of Medicine, The University of Adelaide, Adelaide, 3Department of Rheumatology, 4Cardiology Unit, The Queen Elizabeth Hospital, Woodville, SA, Australia

Abstract: There is now convincing evidence that the airway epithelium drives the pathogenesis of COPD. A major aspect of this is the disease-related reduction in barrier function that is potentiated by dysregulation of tight junction (TJ) protein complexes. However, a significant number of studies using in vitro smoke exposure models have not observed alterations in barrier permeability. We have previously shown that zinc (Zn) is an influential cytoprotective factor for the airway epithelium, and its depletion by cigarette smoke produces disease-related modifications consistent with inflammatory changes in COPD. We hypothesized that Zn deficiency is a significant co-stimulus with cigarette smoke extract (CSE) for potentiating the leaky barrier phenotype exhibited in COPD. We employed an ex vivo model of differentiated human airway epithelium exposed to Zn depletion and CSE to determine the contribution of Zn in maintaining normal epithelial permeability. Western blot analysis demonstrated a significant downregulation of the TJ proteins such as ZO-1 (–1.93-fold, P<0.05) and Claudin-1 (–3.37-fold, P<0.01) with the combination exposure. Assessment of barrier function via paracellular ionic conductance and tracer permeability also showed that Zn depletion was an important factor, which potentiated an increase in epithelial permeability (P<0.001 for both) compared to Zn depletion or CSE exposures in isolation. Visual inspection of the epithelium using transmission electron microscopy revealed a marked reduction in junction complexes between the adjacent airway epithelial cells treated with a combination of Zn depletion and CSE. These observations identify Zn deficiency as a significant codeterminant with CSE as a factor leading to an increase in airway epithelial permeability. Hence, as Zn dyshomeostasis has been reported in the airway epithelium exposed to chronic cigarette smoke and inflammation, targeting these phenomena may represent a promising strategy to ameliorate the leaky barrier phenotype that is synonymous with COPD.

Keywords:
COPD, airway epithelium, barrier function, cigarette smoke, zinc

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