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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.
Int J Chron Obstruct Pulmon Dis. 2016; 11:1647-55.IJ

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.

Links

Authors+Show Affiliations

Breathe Well Centre, School of Medicine, Faculty of Health, University of Tasmania, Hobart, TAS, Australia.

Breathe Well Centre, School of Medicine, Faculty of Health, University of Tasmania, Hobart, TAS, Australia.

Breathe Well Centre, School of Medicine, Faculty of Health, University of Tasmania, Hobart, TAS, Australia.

Breathe Well Centre, School of Medicine, Faculty of Health, University of Tasmania, Hobart, TAS, Australia.

Breathe Well Centre, School of Medicine, Faculty of Health, University of Tasmania, Hobart, TAS, Australia; School of Health Sciences, Faculty of Health, University of Tasmania, Launceston, TAS, Australia.

Breathe Well Centre, School of Medicine, Faculty of Health, University of Tasmania, Hobart, TAS, Australia.

Breathe Well Centre, School of Medicine, Faculty of Health, University of Tasmania, Hobart, TAS, Australia.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

27524890

Citation

Shukla, Shakti D., et al. "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, vol. 11, 2016, pp. 1647-55.

Shukla SD, Fairbairn RL, Gell DA, et al. 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. Int J Chron Obstruct Pulmon Dis. 2016;11:1647-55.

Shukla, S. D., Fairbairn, R. L., Gell, D. A., Latham, R. D., Sohal, S. S., Walters, E. H., & O'Toole, R. F. (2016). 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, 1647-55. https://doi.org/10.2147/COPD.S108698

Shukla SD, et al. 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. Int J Chron Obstruct Pulmon Dis. 2016;11:1647-55. PubMed PMID: 27524890.

* Article titles in AMA citation format should be in sentence-case

TY - JOUR T1 - 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. AU - Shukla,Shakti D, AU - Fairbairn,Rory L, AU - Gell,David A, AU - Latham,Roger D, AU - Sohal,Sukhwinder S, AU - Walters,Eugene H, AU - O'Toole,Ronan F, Y1 - 2016/07/25/ PY - 2016/8/16/entrez PY - 2016/8/16/pubmed PY - 2017/8/9/medline KW - NTHi KW - PAFr antagonist KW - WEB-2086 KW - airway epithelium KW - platelet-activating factor receptor KW - pneumococci SP - 1647 EP - 55 JF - International journal of chronic obstructive pulmonary disease JO - Int J Chron Obstruct Pulmon Dis VL - 11 N2 - 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. SN - 1178-2005 UR - https://www.unboundmedicine.com/medline/citation/27524890/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_ DB - PRIME DP - Unbound Medicine ER -