Two molecules secreted by epithelial cells of the lungs — CST3 and GDF15 — “are bona fide regulators” of scarring processes and may point to a new way to treat pulmonary fibrosis, an early study reports.
The study, “Epithelial cell-derived cytokines CST3 and GDF15 as potential therapeutics for pulmonary fibrosis,” was published in the journal Cell Death & Disease.
Pulmonary fibrosis is a progressive lung disease associated with a collapse in lung architecture, attributed at least in part to an increase in the growth of cells known as fibroblasts. For lungs to return to a healthy structure after injury, fibroblasts — cells in collective tissue that produces collagen and other wound-healing fibers — must be present, but not at excessive levels.
Epithelial cells line various organs, including the lungs. They are known to secrete small molecules called cytokines, which have been shown to play various roles in regulating fibrosis. But little is known about how cytokines secreted by epithelial cells affect the fibroblast cell population.
Researchers in Seoul, South Korea, conducted a series of experiments to identify cytokines that control fibroblast production to help determine those cytokines that have healing properties and might be developed into therapies.
They grew lung epithelial cells in the lab using media — a liquid with the necessary components for cell growth. But the media also would come to contain all the cytokines secreted by epithelial cells as they grow. The team then allowing researchers then introduced lung fibroblasts into the cytokine-rich media to determine those that worked significantly block fibroblasts growth.
Two were seen to inhibit cell growth: cystatin C (CST3) and growth differentiation factor 15 (GDF15). CST3 has previously been shown to block fibrosis, and GDF15 is known to induce cell death.
An analysis of how these two cytokines work found that both molecules inhibit fibroblast growth and activation through a cell signaling pathway known as TGF–Smad.
As expected, when analyzing mouse and human lung tissue undergoing fibrosis, researchers found lower-than-usual CST3 and GDF15 levels. This finding prompted them to investigate the effects of restoring expression of these cytokines in fibrotic lungs.
Using a mouse model of lung fibrosis, they demonstrated that administering either CST3 or GDF15 led to reduced fibrosis. The two cytokines, given the mice in combination but at half-doses, also were seen to be more effective in preventing fibroblast formation than a single cytokine given at a full dose.
“These results suggest that CST3 and GDF15 are bona fide regulators to prevent excessive proliferation and activation of fibroblasts in injured lungs. These cytokines could be potential therapeutics for ameliorating interstitial lung fibrosis,” the team concluded.