Severe Hypoxia Reduces Adenylyl Cyclase 6 Expression and Function in Bronchial Epithelial Cells

Area of Science:

• Respiratory Medicine
• Cellular Physiology
• Immunology

Background:

• Hypoxia exacerbates airway diseases like cystic fibrosis (CF) by impairing immune function and epithelial barrier integrity.
• Cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction in people with CF (pwCF) leads to mucus buildup and chronic infections.
• Adenylyl cyclase 6 (AC6) and bitter taste receptors (T2Rs) regulate CFTR and innate immunity, but their response to hypoxia in airways is unknown.

Purpose of the Study:

• To investigate the impact of varying oxygen levels on AC6, G proteins, T2R14 expression, and function in human bronchial epithelial cells.
• To characterize hypoxia-induced alterations in airway epithelial responses, particularly in the context of CFTR dysfunction.
• To establish potential links between AC6, CFTR, and airway epithelial responses to hypoxia.

Main Methods:

• Human bronchial epithelial cells were exposed to normal (21%), mild (10%), and severe (1%) oxygen levels.
• Protein expression of AC6, Gαi/Gαs, and T2R14 was analyzed.
• Functional assays assessed T2R14 responses to fungal quorum sensing molecules (QSMs) and forskolin-induced CFTR currents.

Main Results:

• Severe hypoxia (1% O2) significantly decreased AC6 expression but did not alter Gαi/Gαs/T2R14 levels.
• Hypoxia modulated T2R14 responses to fungal QSMs (farnesol, tyrosol) in an oxygen and ligand-dependent manner.
• Severe hypoxia inhibited forskolin-stimulated CFTR currents and reduced cAMP levels, with increased IL-5 release in QSM-treated CF cells at 1% O2.

Conclusions:

• Severe hypoxia alters AC6 expression and function in airway epithelia.
• Reduced AC6 expression and function under severe hypoxia correlate with CFTR dysfunction.
• These findings suggest a link between AC6, CFTR, and airway epithelial responses to hypoxic conditions, relevant to CF pathogenesis.