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.
- Publisher:
- DOVE MEDICAL PRESS LTD
- Publication Type:
- Journal Article
- Citation:
- Int J Chron Obstruct Pulmon Dis, 2016, 11, (1), pp. 1647-1655
- Issue Date:
- 2016
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Field | Value | Language |
---|---|---|
dc.contributor.author | Shukla, SD | |
dc.contributor.author | Fairbairn, RL | |
dc.contributor.author | Gell, DA | |
dc.contributor.author | Latham, RD | |
dc.contributor.author | Sohal, SS | |
dc.contributor.author | Walters, EH | |
dc.contributor.author | O'Toole, RF | |
dc.date.accessioned | 2022-08-16T22:26:29Z | |
dc.date.available | 2022-08-16T22:26:29Z | |
dc.date.issued | 2016 | |
dc.identifier.citation | Int J Chron Obstruct Pulmon Dis, 2016, 11, (1), pp. 1647-1655 | |
dc.identifier.issn | 1176-9106 | |
dc.identifier.issn | 1178-2005 | |
dc.identifier.uri | http://hdl.handle.net/10453/160393 | |
dc.description.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 influenzae (NTHi) and Streptococcus pneumoniae 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. pneumoniae. 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. pneumoniae 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. pneumoniae 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. | |
dc.format | Electronic-eCollection | |
dc.language | eng | |
dc.publisher | DOVE MEDICAL PRESS LTD | |
dc.relation.ispartof | Int J Chron Obstruct Pulmon Dis | |
dc.relation.isbasedon | 10.2147/COPD.S108698 | |
dc.rights | info:eu-repo/semantics/openAccess | |
dc.subject | 1102 Cardiorespiratory Medicine and Haematology | |
dc.subject.classification | Respiratory System | |
dc.subject.mesh | Anti-Bacterial Agents | |
dc.subject.mesh | Azepines | |
dc.subject.mesh | Bacterial Adhesion | |
dc.subject.mesh | Binding Sites | |
dc.subject.mesh | Bronchi | |
dc.subject.mesh | Cell Line | |
dc.subject.mesh | Epithelial Cells | |
dc.subject.mesh | Haemophilus Infections | |
dc.subject.mesh | Haemophilus influenzae | |
dc.subject.mesh | Host-Pathogen Interactions | |
dc.subject.mesh | Humans | |
dc.subject.mesh | Molecular Docking Simulation | |
dc.subject.mesh | Platelet Membrane Glycoproteins | |
dc.subject.mesh | Pneumococcal Infections | |
dc.subject.mesh | Protein Binding | |
dc.subject.mesh | Protein Conformation | |
dc.subject.mesh | Receptors, G-Protein-Coupled | |
dc.subject.mesh | Smoke | |
dc.subject.mesh | Smoking | |
dc.subject.mesh | Streptococcus pneumoniae | |
dc.subject.mesh | Triazoles | |
dc.subject.mesh | Bronchi | |
dc.subject.mesh | Cell Line | |
dc.subject.mesh | Epithelial Cells | |
dc.subject.mesh | Humans | |
dc.subject.mesh | Haemophilus influenzae | |
dc.subject.mesh | Streptococcus pneumoniae | |
dc.subject.mesh | Haemophilus Infections | |
dc.subject.mesh | Pneumococcal Infections | |
dc.subject.mesh | Azepines | |
dc.subject.mesh | Triazoles | |
dc.subject.mesh | Platelet Membrane Glycoproteins | |
dc.subject.mesh | Receptors, G-Protein-Coupled | |
dc.subject.mesh | Anti-Bacterial Agents | |
dc.subject.mesh | Smoking | |
dc.subject.mesh | Smoke | |
dc.subject.mesh | Bacterial Adhesion | |
dc.subject.mesh | Binding Sites | |
dc.subject.mesh | Protein Conformation | |
dc.subject.mesh | Protein Binding | |
dc.subject.mesh | Host-Pathogen Interactions | |
dc.subject.mesh | Molecular Docking Simulation | |
dc.title | 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. | |
dc.type | Journal Article | |
utslib.citation.volume | 11 | |
utslib.location.activity | New Zealand | |
utslib.for | 1102 Cardiorespiratory Medicine and Haematology | |
pubs.organisational-group | /University of Technology Sydney | |
pubs.organisational-group | /University of Technology Sydney/Faculty of Health | |
utslib.copyright.status | open_access | * |
dc.date.updated | 2022-08-16T22:26:27Z | |
pubs.issue | 1 | |
pubs.publication-status | Published online | |
pubs.volume | 11 | |
utslib.citation.issue | 1 |
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 influenzae (NTHi) and Streptococcus pneumoniae 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. pneumoniae. 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. pneumoniae 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. pneumoniae 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.
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