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]
© 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/
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 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 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)|
|Web of Science® Times Cited:||14|
|Downloads:||90 View Download Statistics|
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