Objective Mucus hypersecretion is a prominent feature of chronic obstructive pulmonary disease, asthma, and cystic fibrosis. These diseases may be associated with development of hypercapnia, acutely during exacerbations and/or chronically in their advanced stages. In this study, we tested the hypothesis that hypercapnia might contribute to mucus overproduction by increasing expression of genes for mucins produced by airway epithelial cells.
Methods The human mucoepidermoid carcinoma cell line (NCI-H292) was used in this study. Cells were cultured in the presence of 5% CO2 (control; equivalent to PCO2 < 40 mm Hg) or 20% CO2 (hypercapnia; equivalent to PCO2 < 160 mm Hg), in the absence or presence of phorbol 12-myristate 13-acetate (PMA; 10 nM), an inflammatory agent known to induce mucin gene expression, for 6 to 96 hours. mRNA for the mucin genes MUC2, MUC5AC, MUC5B, and MUC19 were quantitated by real-time PCR and normalized to expression of 18S ribosomal RNA.
Results In the absence of PMA, culture of NCI-H292 cells in 20% CO2, as compared to 5% CO2, increased expression of MUC5AC by < 3-fold. In comparison, PMA (in 5% CO2) increased MUC5AC mRNA expression < 70-fold. Culture of NCI-H292 cells in 20% CO2 augmented the PMA-induced increase in MUC5AC mRNA levels by < 3-fold as compared to stimulation with PMA in 5% CO2. The increases in MUC5AC mRNA in response to 20% CO2 peaked at 24 hours. MUC19 mRNA expression was increased in the presence of 20% CO2 in the absence and presence of PMA to a degree similar to that for MUC5AC. Neither 20% CO2 nor PMA increased expression of mRNA for MUC2 or MUC5B.
Conclusion Hypercapnia stimulates mucin gene expression in vitro and may be important in driving gene expression and synthesis of mucins in vivo. These results reveal a previously unrecognized stimulus of mucin gene expression. Furthermore, they suggest that correcting hypercapnia may be an important strategy for reducing mucus hypersecretion in patients with acute and chronic lung diseases.
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