A new role for bicarbonate secretion in cervico‐uterine mucus release

Abstract

Cervical mucus thinning and release during the female reproductive cycle is thought to rely mainly on fluid secretion. However, we now find that mucus released from the murine reproductive tract critically depends upon concurrent bicarbonate (HCO 3 − ) secretion. Prostaglandin E 2 (PGE 2 )-and carbachol-stimulated mucus release was severely inhibited in the absence of serosal HCO 3 − , HCO 3 − transport, or functional cystic fibrosis transmembrane conductance regulator (CFTR). In contrast to mucus release, PGE 2 -and carbachol-stimulated fluid secretion was not dependent on bicarbonate or on CFTR, but was completely blocked by niflumic acid. We found stimulated mucus release was severely impaired in the cystic fibrosis F508 reproductive tract, even though stimulated fluid secretion was preserved. Thus, CFTR mutations and/or poor bicarbonate secretion may be associated with reduced female fertility associated with abnormal mucus and specifically, may account for the increased viscosity and lack of cyclical changes in cervical mucus long noted in women with cystic fibrosis.

Secretory Phospholipases A 2 Are Secreted From Ciliated Cells and Increase Mucin and Eicosanoid Secretion From Goblet Cells

“…51 We show that indomethacin, a cyclooxygenase inhibitor, decreased sPLA 2 -induced mucus secretion, suggesting that cyclooxygenase pathway products may play a role in sPLA 2 -induced mucus secretion. PGE 2 is an airway smooth muscle relaxant and may have bronchoprotective and antiinfl ammatory properties.…”

A new role for bicarbonate in mucus formation

“…Even though HCO 3 Ϫ secretion is apparently impaired in organs affected in CF, and the severity of the disease seems to correlate with the degree of this impairment (11,(35)(36)(37), the possible involvement of this anion with mucus formation has received little attention (35,37). Evidence that defective HCO 3 Ϫ secretion is associated with abnormal mucus hydration has been recently reported (18,29,35). Furthermore, activating peroxisome proliferator-activated receptor-␥ (PPAR-␥) in CF mice was found to ameliorate the disease by normalizing defects in both HCO 3 Ϫ secretion and mucus retention (19).…”

“…This would almost certainly be the case if fixed mucin anions have a higher affinity for Ca 2ϩ than for Na ϩ . With respect to CF, which instigated this study, previous work recently demonstrated that the amount of mucus discharged from the intestine (17) and the uterine cervix (29) in vitro was significantly reduced when HCO 3 Ϫ secretion was impeded. The present work provides a likely basis for those findings and possibly for the characteristically aggregated and tenacious mucus abnormalities found in CF as well.…”

“…Our studies here strongly indicate that in CF organs, when mucins are released into fluids without adequate HCO 3 Ϫ , their diffusivity would be decreased (viscosity increased); normal expansion of mucins would be retarded and impaired due to retained Ca 2ϩ cross-linking, and the long observed pathogenic aggregation and stagnation of "sticky" mucus would tend to occur. A tentative model of this process was proposed recently (29). It should be noted that organ failure in CF is not immediate and generally occurs over many months or years, so pathogenic mucus aggregation is almost surely a multifactorial process.…”

Cystic Fibrosis: Does CFTR Malfunction Alter pH Regulation?

“…Very recently, in 2010, Paul Quinton reported in the Journal of Physiology [53] that CF epithelial cells in the cervix could secrete fluid normally, but unlike wild type cells, they could not secrete bicarbonate. And furthermore that mucus released in CF epithelial was severely impaired even though stimulated fluid secretion was similar to healthy cells.…”