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Phloretin, an Apple Polyphenol, Inhibits Pathogen-Induced Mucin Overproduction
Rahel L Birru1, Kiflai Bein1, Heather Wells1
1Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, 15261, USA.
Scope:
Bacterial infection induces mucus overproduction, contributing to acute exacerbations and lung function decline in chronic respiratory diseases. A diet enriched in apples may provide protection from pulmonary disease development and progression. This study examined whether phloretin, an apple polyphenol, inhibits mucus synthesis and secretion induced by the predominant bacteria associated with chronic respiratory diseases.
Methods And Results:
The expression of mucus constituent mucin 5AC (MUC5AC) in FVB/NJ mice and NCI-H292 epithelial cells is analyzed. Nontypeable Haemophilus influenzae (NTHi)-infected mice developed increased MUC5AC mRNA, which a diet containing phloretin inhibited. In NCI-H292 cells, NTHi, Moraxella catarrhalis, Streptococcus pneumoniae, and Pseudomonas aeruginosa increased MUC5AC mRNA, which phloretin inhibited. Phloretin also diminished NTHi-induced MUC5AC protein secretion. NTHi-induced increased MUC5AC required toll-like receptor 4 (TLR4) and NADH oxidase 4 (NOX4) signaling and subsequent activation of the epidermal growth factor receptor (EGFR)/mitogen-activated protein kinase (MAPK) pathway. Phloretin inhibited NTHi-induced TLR4/NOX4 and EGFR/MAPK signaling, thereby preventing increased MUC5AC mRNA. EGFR activation can also result from increased EGFR ligand synthesis and subsequent ligand activation by matrix metalloproteinases (MMPs). In NCI-H292 cells, NTHi increased EGFR ligand and MMP1 and MMP13 mRNA, which phloretin inhibited.
Conclusions:
In summary, phloretin is a promising therapeutic candidate for preventing bacterial-induced mucus overproduction.
Insights
Phloretin, an apple polyphenol, effectively inhibits bacterial-induced mucus overproduction in respiratory cells and mice. This compound shows promise for preventing mucus buildup in chronic respiratory diseases.
Area of Science:
- Pulmonary Medicine
- Molecular Biology
- Pharmacology
Background:
- Bacterial infections cause mucus overproduction, worsening chronic respiratory diseases.
- Dietary factors, like apples, may offer protection against lung disease.
- Phloretin is a key polyphenol found in apples.
Purpose of the Study:
- To investigate if phloretin inhibits mucus synthesis and secretion induced by common respiratory bacteria.
- To explore the molecular mechanisms underlying phloretin's effect on mucus production.
Main Methods:
- Analyzed mucin 5AC (MUC5AC) expression in mice and NCI-H292 epithelial cells.
- Exposed cells to Nontypeable Haemophilus influenzae (NTHi) and other bacteria, with and without phloretin.
- Investigated the roles of toll-like receptor 4 (TLR4), NADH oxidase 4 (NOX4), epidermal growth factor receptor (EGFR)/mitogen-activated protein kinase (MAPK) pathways, and matrix metalloproteinases (MMPs).
Main Results:
- Phloretin inhibited NTHi-induced MUC5AC mRNA in mice and various bacteria-induced MUC5AC mRNA in epithelial cells.
- Phloretin reduced NTHi-induced MUC5AC protein secretion.
- Phloretin blocked NTHi-induced signaling pathways including TLR4/NOX4 and EGFR/MAPK, and reduced EGFR ligand and MMP mRNA levels.
Conclusions:
- Phloretin effectively suppresses bacterial-induced mucus overproduction.
- Phloretin acts by inhibiting key signaling pathways involved in MUC5AC production.
- Phloretin is a potential therapeutic agent for managing mucus hypersecretion in respiratory conditions.
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