Zinc may reverse lung damage and improve survival in patients with idiopathic pulmonary fibrosis

Investigators from the Women’s Guild Lung Institute at Cedars-Sinai have found that common mineral zinc can reverse lung damage and improve survival in patients with a deadly age-related disease known as pulmonary fibrosis. idiopathic (IPF).

Their findings, published in The Journal of Clinical Investigationhave the potential to change the landscape of treatment for patients with this disease, which most often affects people over 50 years of age.

This study has the potential to change that. We have identified a root cause of IPF-related lung damage and a potential therapeutic target that could restore the lungs’ ability to heal itself.”


Paul Noble, MD, chair of the Department of Medicine, director of the Women’s Guild Lung Institute and study co-lead author

Idiopathic pulmonary fibrosis, or IPF, affects 100,000 people in the United States and has no known cause. The disease, which causes scarring of the lungs, called fibrosis, and progressive difficulty breathing, is incurable and most patients die or require a lung transplant within three to five years of diagnosis. The incidence of IPF increases dramatically with age and affects men more often than women.

Through this research, Cedars-Sinai researchers found that stem cells that line the air sacs in the lungs of IPF patients lose their ability to process zinc, which is known to play a role in cell growth. and healing of damaged tissue.

Lack of zinc impairs the ability of cells – called alveolar epithelial cells type 2 (AEC2) – to regenerate. Restoring this ability via the molecular pathway the researchers traced in their experiments could lead to therapies that reverse IPF-related lung damage. The research team also generated a model of IPF in laboratory mice that can be used to develop new therapies.

Investigators first analyzed AEC2 from healthy lungs as well as lungs from patients with IPF. They found that IPF lung cells lack a protein called zinc transporter 8 (ZIP8), which pulls zinc into the cell.

In experiments with organoids; miniaturized and simplified versions of organs grown in a box from patient tissue; they also observed that cells lacking the ZIP8 protein were unable to regenerate and form colonies as healthy cells should.

“Organoids with AEC2 cells that had the ZIP8 transporter were able to attract zinc into the cells and then were able to regenerate and form more colonies,” said Carol Liang, MD, MBA, associate professor of medicine and first author of the study. . “Cells without ZIP8 had no way of attracting zinc, so they formed fewer colonies. This is how we determined that it is ZIP8 that allows cells to use zinc.”

The researchers also used drugs and deletion of the ZIP8 gene in mouse AEC2 to mimic IPF in lab mice. When they fed these mice a diet that included zinc supplements, their fibrosis improved.

“There have been few detailed studies on how zinc works in the lungs,” said Dianhua Jiang, MD, PhD, Cedars-Sinai professor of medicine and co-lead author of the study. “Ours is the first to identify the detailed function of zinc in lung biology, specifically in IPF. It was particularly exciting to discover that zinc regulates the production of two other key molecules that promote tissue regeneration, nicotinamide adenine dinucleotide (NAD+) and sirtuin1. These molecules have been implicated in tissue regeneration and aging.”

Further research is needed to help determine why the loss of ZIP8 occurs in lung cells, and whether zinc supplements, alone or in combination with NAD+ activators and Sirtuin1 to help activate the lung repair response, will reverse the lung damage in human patients with this disease, Liang said, adding that the answers to these questions could help thousands of patients. The goal is to develop a clinical trial to determine if targeting the ZIP8/NAD+/Sirtuin1 pathway can improve lung function in IPF.

“The cause of IPF is unknown, but aging is an important factor,” Liang said. “The general population is aging and the incidence of the disease is increasing. We need to find a cure, because we have more patients every year.”

Source:

Journal reference:

Liang, J. et al. (2022) The ZIP8/SIRT1 axis regulates alveolar progenitor cell turnover in aging and idiopathic pulmonary fibrosis. The Journal of Clinical Investigation. doi.org/10.1172/JCI157338.

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