Blocking Piezo2 protein receptor may slow IPF progression: Study
Findings could lead to new therapies for treating lung scarring in patients
Blocking Piezo2, a protein receptor that senses mechanical forces in tissues — ones such as stress, strain, and stiffness — may be a new way to slow the progression of idiopathic pulmonary fibrosis (IPF), according to a study by U.S. researchers.
The scientists, who noted that this was the first investigation into the role Piezo2 plays in pulmonary fibrosis, say their work identified potential therapeutic targets that may ultimately help improve outcomes for IPF patients.
“We are excited to report that this research that suggests inhibiting expression or function of Piezo2 could be a potential new therapeutic route to treating lung fibrosis [scarring] and other fibrotic diseases,” Patricia J. Sime, MD, the study’s lead investigator and a researcher in the division of pulmonary disease and critical care medicine at Virginia Commonwealth University, said in a press release.
The findings, per Sime, are “especially important as there is an unmet need for additional therapies for fibrotic diseases.”
The study, “Piezo2 Is a Key Mechanoreceptor in Lung Fibrosis that Drives Myofibroblast Differentiation,” was published in The American Journal of Pathology.
Approved IPF medications ‘do not always halt progression’
In IPF, scar tissue buildup in the lungs increases tissue stiffness, making it difficult for the lungs to expand and contract during breathing. This leads to a progressive decline in lung function and symptoms that can include cough and shortness of breath.
Fibroblasts are a type of connective tissue cells that transform into another kind of cells, called myofibroblasts, which normally facilitate wound healing and tissue regeneration. Overactive myofibroblasts, which fail to revert to fibroblasts once wound healing is complete, drive scar tissue deposits in IPF.
Although there is no cure for IPF, two antifibrotic medications have been approved to treat the condition: Esbriet (pirfenidone) and Ofev (nintedanib), both of which can slow lung function decline.
“While there have been advances in therapy, the approved medications for IPF can slow, but do not always halt progression,” said Margaret A.T. Freeberg, PhD, the study’s first author and a researcher at Virginia Commonwealth. “One of the reasons that fibrosis can be difficult to effectively treat may be explained by the multiple profibrotic disease pathways that reinforce each other.”
Fibroblasts can also sense tissue stiffness through mechanoreceptors — protein receptors found on the surface of cells that are activated in response to changes in the forces, including touch, being exerted on cells. Piezo channels, a type of mechanoreceptor, are protein channels that open in response to the stretching of the cell membrane, allowing for the flow of ions into cells.
Little is known, however, about the role of Piezo channels in fibrotic lung diseases like IPF. The dearth of data led the team to investigate the role of Piezo2, one of two Piezo channels, in pulmonary fibrosis.
Piezo2 linked to stiffness in lung tissue in lab studies
The researchers first found that Piezo2 was present at higher levels in lung tissue from IPF patients than in nonfibrotic lung tissue taken from people without pulmonary fibrosis.
To confirm the findings, the team accessed a publicly available gene activity dataset containing information from healthy individuals, people with IPF, and those with chronic obstructive pulmonary disease (COPD), a chronic inflammatory lung disease.
Piezo2 was most prevalent in the myofibroblasts of IPF patients, the data showed. It was found at lower levels in COPD patients and healthy controls, indicating that “Piezo2 is preferentially up-regulated in myofibroblast cells in patients with IPF,” the researchers wrote.
Similarly, in a mouse model of pulmonary fibrosis, the levels of Piezo2 were markedly increased in fibrotic lesions.
We believe this [work] points to Piezo2 as an important new therapeutic target that might (by itself or in combination with other therapies) slow the progression of pulmonary fibrosis in … patients.
To explore the role of Piezo2 in fibroblast regulation, the scientists seeded human lung fibroblasts on substrates that mimicked the stiffness of healthy or fibrotic lung tissue. Stiffer substrates stimulated the lung fibroblasts to transform into myofibroblasts, even without TGF-beta, a profibrotic signaling protein and a well-established driver of fibrosis. The production of collagen-3, a protein component of scar tissue, also increased on stiffer substrates.
To determine whether Piezo2 signaling is required for stiffness-driven myofibroblast differentiation, the team cultured human lung fibroblasts on substrates of increasing stiffness with or without D-GsMTx4, a potent Piezo2 blocker.
Piezo2 inhibition significantly reduced stiffness-driven myofibroblast differentiation. Likewise, reducing Piezo2 production by RNA silencing also significantly lowered myofibroblast differentiation. In other words, blocking Piezo2 prevented cells from sensing and responding to the stiffness of their environment and reduced profibrotic programming.
“Blocking Piezo2 may play a key role in fibrosis and, thus, be a novel therapeutic approach to treat pulmonary fibrosis,” the scientists wrote. “This work lays the foundation for future studies to investigate the overall efficacy of Piezo2 as a therapeutic target for fibrotic pathologies [diseases].”
According to Sime, the findings “[identify] mechanical forces and a new specific target (Piezo2) that we can block to prevent fibrotic reprogramming of some lung cells.”
“We believe this points to Piezo2 as an important new therapeutic target that might (by itself or in combination with other therapies) slow the progression of pulmonary fibrosis in … patients,” Sime said.
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