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An antagonist of the platelet-activating factor receptor inhibits adherence of both nontypeable Haemophilus influenzae and Streptococcus pneumoniae to cultured human bronchial epithelial cells exposed to cigarette smoke

Citation

Shukla, SD and Fairbairn, RL and Gell, DA and Latham, RD and Sohal, SS and Walters, EH and O'Toole, RF, An antagonist of the platelet-activating factor receptor inhibits adherence of both nontypeable Haemophilus influenzae and Streptococcus pneumoniae to cultured human bronchial epithelial cells exposed to cigarette smoke, International Journal of Chronic Obstructive Pulmonary Disease, 11, (1) pp. 1647-1655. ISSN 1178-2005 (2016) [Refereed Article]


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2016 Shukla et al. Licensed under Creative Commons Attribution-NonCommercial 3.0 Unported (CC BY-NC 3.0) https://creativecommons.org/licenses/by-nc/3.0/

DOI: doi:10.2147/COPD.S108698

Abstract

Background: COPD is emerging as the third largest cause of human mortality worldwide after heart disease and stroke. Tobacco smoking, the primary risk factor for the development of COPD, induces increased expression of platelet-activating factor receptor (PAFr) in the lung epithelium. Nontypeable Haemophilus influenza (NTHi) and Streptococcus pneumonia adhere to PAFr on the luminal surface of human respiratory tract epithelial cells.

Objective: To investigate PAFr as a potential drug target for the prevention of infections caused by the main bacterial drivers of acute exacerbations in COPD patients, NTHi and S. pneumonia.

Methods: Human bronchial epithelial BEAS-2B cells were exposed to cigarette smoke extract (CSE). PAFr expression levels were determined using immunocytochemistry and quantitative polymerase chain reaction. The epithelial cells were challenged with either NTHi or S. pneumonia labeled with fluorescein isothiocyanate, and bacterial adhesion was measured using immunofluorescence. The effect of a well-evaluated antagonist of PAFr, WEB-2086, on binding of the bacterial pathogens to BEAS-2B cells was then assessed. In silico studies of the tertiary structure of PAFr and the binding pocket for PAF and its antagonist WEB-2086 were undertaken.

Results: PAFr expression by bronchial epithelial cells was upregulated by CSE, and significantly associated with increased bacterial adhesion. WEB-2086 reduced the epithelial adhesion by both NTHi and S. pneumonia to levels observed for non-CSE-exposed cells. Furthermore, it was nontoxic toward the bronchial epithelial cells. In silico analyses identified a binding pocket for PAF/WEB-2086 in the predicted PAFr structure.

Conclusion: WEB-2086 represents an innovative class of candidate drugs for inhibiting PAFr-dependent lung infections caused by the main bacterial drivers of smoking-related COPD.

Item Details

Item Type:Refereed Article
Keywords:chronic obstructive pulmonary disease, PAFr, Streptococcus pneumoniae, Haemophilus influenzae
Research Division:Medical and Health Sciences
Research Group:Medical Microbiology
Research Field:Medical Bacteriology
Objective Division:Manufacturing
Objective Group:Human Pharmaceutical Products
Objective Field:Human Pharmaceutical Treatments (e.g. Antibiotics)
UTAS Author:Shukla, SD (Mr Shakti Shukla)
UTAS Author:Fairbairn, RL (Mr Rory Fairbairn)
UTAS Author:Gell, DA (Dr David Gell)
UTAS Author:Latham, RD (Mr Roger Latham)
UTAS Author:Sohal, SS (Dr Sukhwinder Sohal)
UTAS Author:Walters, EH (Professor Haydn Walters)
UTAS Author:O'Toole, RF (Dr Ronan O'Toole)
ID Code:110329
Year Published:2016
Web of Science® Times Cited:14
Deposited By:Medicine
Deposited On:2016-07-25
Last Modified:2018-03-07
Downloads:90 View Download Statistics

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