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Phloretin, an Apple Polyphenol, Reduces Chronic Obstructive Pulmonary Disease (COPD) Pathogen-Induced Injury in Airway Epithelial Cells
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A3854 - Phloretin, an Apple Polyphenol, Reduces Chronic Obstructive Pulmonary Disease (COPD) Pathogen-Induced Injury in Airway Epithelial Cells
Author Block: R. Birru, N. Bondarchuk, Q. Lin, K. Bein, Y. Di, G. D. Leikauf; Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA, United States.
Rationale: Bacterial infections cause up to 50% of acute exacerbations in COPD patients. Airway inflammation and mucus hypersecretion play a role in the pathophysiology. A diet enriched in hard fruits protect against declining lung function in persons with COPD. We examined whether the apple polyphenol phloretin could reduce bacterial infections through direct antibacterial and anti-biofilm activity as well as through reducing bacterial-induced mucus and inflammatory mediator formation.
Methods: We examined phloretin activity against the predominant bacterial species isolated from COPD patients experiencing exacerbations: Nontypeable Haemophilus influenzae (NTHi), Moraxella Catarrhalis (M. Catarrhalis), Streptococcus pneumoniae (S. Pneumoniae), and Pseudomonas Aeruginosa PAO1. In a cell-free system, bacterial growth (optical density) and biofilm formation (crystal violet staining) were assessed without (vehicle control) or with 1-1000 µM phloretin. Human lung mucoepidermoid cell line (NCI-H292) and normal human bronchial epithelial (NHBE) cells were pretreated with 100 µM phloretin and exposed to the COPD pathogens (multiplicity of infection 7.5-20). Cells and supernatant were analyzed for markers of mucus (MUC5AC) and inflammation [interleukin 6 (IL6), IL8, and C-C motif chemokine ligand 2 (CCL20 aka MIP3A)] by qPCR and ELISA. MAP kinase pathway involvement was determined by western blot.
Results: Phloretin (30-1000 µM) delayed or inhibited bacterial growth of the COPD pathogens. Phloretin (100 µM) also inhibited biofilm formation of NTHi and M. Catarrhalis. Antibacterial and anti-biofilm activity was only significant at high concentrations of phloretin (≥100 µM) therefore we examined whether phloretin could induce additional protective mechanisms. Phloretin inhibited pathogen-induced increased MUC5AC transcript and protein by inhibiting EGFR phosphorylation and accompanying MAPK 3/1 (aka ERK 1/2) and MAPK8 (aka JNK) activation. In addition, phloretin inhibited pathogen-induced increased IL6, IL8, and CCL20.
Conclusion: Phloretin inhibits COPD-pathogen injury through direct antibacterial and anti-biofilm activity and by inhibiting mucus and inflammatory mediator production. Phloretin is a promising candidate for relieving and preventing the development of bacterial-induced COPD exacerbations.
Author Block: R. Birru, N. Bondarchuk, Q. Lin, K. Bein, Y. Di, G. D. Leikauf; Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA, United States.
Rationale: Bacterial infections cause up to 50% of acute exacerbations in COPD patients. Airway inflammation and mucus hypersecretion play a role in the pathophysiology. A diet enriched in hard fruits protect against declining lung function in persons with COPD. We examined whether the apple polyphenol phloretin could reduce bacterial infections through direct antibacterial and anti-biofilm activity as well as through reducing bacterial-induced mucus and inflammatory mediator formation.
Methods: We examined phloretin activity against the predominant bacterial species isolated from COPD patients experiencing exacerbations: Nontypeable Haemophilus influenzae (NTHi), Moraxella Catarrhalis (M. Catarrhalis), Streptococcus pneumoniae (S. Pneumoniae), and Pseudomonas Aeruginosa PAO1. In a cell-free system, bacterial growth (optical density) and biofilm formation (crystal violet staining) were assessed without (vehicle control) or with 1-1000 µM phloretin. Human lung mucoepidermoid cell line (NCI-H292) and normal human bronchial epithelial (NHBE) cells were pretreated with 100 µM phloretin and exposed to the COPD pathogens (multiplicity of infection 7.5-20). Cells and supernatant were analyzed for markers of mucus (MUC5AC) and inflammation [interleukin 6 (IL6), IL8, and C-C motif chemokine ligand 2 (CCL20 aka MIP3A)] by qPCR and ELISA. MAP kinase pathway involvement was determined by western blot.
Results: Phloretin (30-1000 µM) delayed or inhibited bacterial growth of the COPD pathogens. Phloretin (100 µM) also inhibited biofilm formation of NTHi and M. Catarrhalis. Antibacterial and anti-biofilm activity was only significant at high concentrations of phloretin (≥100 µM) therefore we examined whether phloretin could induce additional protective mechanisms. Phloretin inhibited pathogen-induced increased MUC5AC transcript and protein by inhibiting EGFR phosphorylation and accompanying MAPK 3/1 (aka ERK 1/2) and MAPK8 (aka JNK) activation. In addition, phloretin inhibited pathogen-induced increased IL6, IL8, and CCL20.
Conclusion: Phloretin inhibits COPD-pathogen injury through direct antibacterial and anti-biofilm activity and by inhibiting mucus and inflammatory mediator production. Phloretin is a promising candidate for relieving and preventing the development of bacterial-induced COPD exacerbations.
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