CFTR found to help remove water from airways in specific cell type

Ionocytes don't occur as often in the lung as secretory cells

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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CFTR — the protein whose defect or absence causes cystic fibrosis (CF) — helps cells called ionocytes remove liquid from the airways, a study shows.

The finding sheds new light on the biological processes that are disrupted in CF and may have important implications for treating the disease.

The study, “CFTR-rich ionocytes mediate chloride absorption across airway epithelia,” was published in The Journal of Clinical Investigation.

The CFTR protein sits on the surface of cells where it acts like a gated channel, helping to regulate the flow of water and chloride (a type of salt molecule; half of “sodium chloride,” or table salt).

Secretory cells, a type of lung cell, use CFTR to secrete water into the lining of the lungs, which helps to make wet, slippery mucus. In CF, the protein’s dysfunction causes unusually sticky and thick mucus to be produced, driving most of the disease’s symptoms.

CFTR is also expressed by ionocytes, another type of lung cell. These cells are much less common in the lung than secretory cells, but are packed with CFTR protein. In fact, despite making up only about 1% of cells in the airway lining, ionocytes contain about half of the lungs’ messenger RNA molecules that hold information from the CFTR gene to produce the protein.

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Rare CFTR-active airway cell grown from CF patients

A different role for ionocytes

Since ionocytes contain CFTR, it’s long been assumed that, like secretory cells, they work to put water and chloride out onto the lung’s lining, helping make mucus wet and moist. Scientists at the University of Iowa found that they actually do the opposite; they help move chloride and water out of the lung surface to dry it out.

In experiments using a cellular model of the airway lining, the researchers found that increasing the number of ionocytes led the airway surface to be less moist. Conversely, fewer ionocytes led to more airway surface liquid.

When the ionocytes were engineered to lack CFTR protein, these effects went away, demonstrating the protein plays a key role in this effect.

CFTR’s effects on ionocytes, secretory cells

In subsequent experiments, the researchers showed how CFTR could play opposite roles in different cell types.

They found that, while both ionocytes and secretory cells express CFTR on the side of the cell located by the airway surface, ionocytes also have a second type of chloride channel on the opposite site of the cell, which isn’t present in secretory cells. This leads to differences in the osmotic forces that regulate the flow of chloride and water through the protein channels.

Ultimately, this means CFTR plays different functions in the two cell types. When CFTR is open, water flows out of the airway surface and into ionocytes. In secretory cells, opening CFTR prompts water to flow out of the cell to hydrate the airway surface.

“These findings indicate that ionocytes mediate liquid absorption and secretory cells mediate liquid secretion,” the scientists wrote. “The observation that CFTR is critical for Cl– [chloride] absorption, in addition to Cl– secretion, indicates that both processes are disrupted in CF.”

The proportion of ionocytes relative to that of secretory cells in the lungs may be key in the impact of CFTR deficiency on airway surface liquid, they said.

“Divergent role of CFTR in ionocytes and secretory cells suggests that cystic fibrosis disrupts both liquid secretion and absorption,” the scientists said, adding genetic therapies for CF may be most effective if they can correct CFTR activity in both secretory cells and ionocytes, which may be an important consideration as therapies are developed.