Protein linked to mechanical stress drives pulmonary fibrosis: Study
Researchers identify PIEZO1 as potential treatment target
Written by |
A protein called PIEZO1, which helps cells in blood vessels detect mechanical forces, plays a key role in driving pulmonary fibrosis (PF), a new study indicates.
Findings suggest that blocking the activity of PIEZO1 and the signaling pathway it controls may be a useful strategy for developing new PF treatments.
The study, “Single-cell multiomics uncovers an endothelial mechanosensitive PIEZO1-IL-33 axis driving pulmonary fibrosis,” was published in Nature Communications.
 Increased PIEZO1 activity in endothelial cells a consistent feature of PF
PF is characterized by scarring (fibrosis) in lung tissue, which disrupts the lungs’ ability to transfer oxygen from the air into the bloodstream. While therapies for PF have been approved, they do not reverse fibrosis, which makes a better understanding of disease-driving processes toward more effective treatments a necessity, the scientists said.
With that in mind, a team led by scientists in China conducted detailed analyses of lung tissue from four people with idiopathic pulmonary fibrosis (IPF), which means there’s no known cause. All of them had undergone a lung transplant. Lung tissue from five people without IPF was also analyzed for comparison. The researchers’ analyses examined each individual cell in the sample to evaluate genetic activity.
Results showed that endothelial cells — the cells lining blood vessels — showed elevated activity in genes related to mechanical stress (physical forces acting on cells). In particular, these cells showed high activity of the gene that encodes PIEZO1, a protein that helps cells detect mechanical forces.
Building off these findings from human samples, the researchers then analyzed lung tissue in two mouse models of chemical-induced PF. Consistent with their human data, results indicated that PIEZO1 activity was increased in endothelial cells in both models. These data suggest that increased PIEZO1 activity in endothelial cells is a consistent feature of PF.
Although more research is needed, our work elucidates the molecular and cellular nodes of abnormal mechanical stress in [endothelial cells], potentially aiding in the discovery of new candidate therapies for treating fibrotic disease.
In subsequent tests, the researchers showed that mice engineered to lack PIEZO1 in their endothelial cells developed significantly less severe PF in a chemical-induced model. Treatment with a molecule that blocks PIEZO1 produced similar results in mice that expressed this protein in their endothelial cells. Finally, a molecule that activates PIEZO1 led to worse fibrosis in mice that expressed this protein, while it had no effect in mice lacking it.
These data “demonstrate that targeting PIEZO1 in [endothelial cells] inhibits the development of pulmonary fibrosis, highlighting PIEZO1 as a promising target for the development of therapeutic interventions for PF,” the researchers concluded.
The scientists also conducted additional tests to determine exactly how PIEZO1 regulates fibrosis. The PIEZO1 protein sits at the cell’s membrane, and when mechanical force is applied to the cell, the protein channel opens. This allows calcium to flow into the cell, and the researchers found that this triggers a molecular signaling cascade that ultimately results in the release of interleukin-33 (IL-33), a signaling molecule that is a potent driver of fibrosis.
The researchers cautioned that their work did not measure mechanical stress in endothelial cells and that their findings on IL33 regulation are still preliminary, among other limitations.
“Although more research is needed, our work elucidates the molecular and cellular nodes of abnormal mechanical stress in [endothelial cells], potentially aiding in the discovery of new candidate therapies for treating fibrotic diseases,” the researchers wrote.
