Tiny particles, or nanoparticles, coated with a peptide called GSE4 prevented some features of idiopathic pulmonary fibrosis (IPF) and eased others in a rat model of this disease, scientists report.
No harmful effects were associated with the use of these GSE4-loaded nanoparticles in the animals, the team added, suggesting they should be further explored as a potential IPF therapy.
Their findings were in the study “GSE4‐loaded nanoparticles a potential therapy for lung fibrosis that enhances pneumocyte growth, reduces apoptosis and DNA damage,” published in The FASEB Journal.
IPF generally occurs in older adults — although a familial form can cause it to arise at much younger ages — and is associated with defects in tissue repair and regeneration. These defects lead to the buildup of scar tissue, or fibrosis, in the lungs, gradually making it harder for patients to breathe.
Exactly why these tissue repair and regeneration processes go haywire remains poorly understood.
One hypothesis states that cells start aging at a faster rate, entering a state called senescence that doesn’t allow them to replicate and give rise to new cells. In accordance with this hypothesis, roughly 25% of IPF patients and 50% of those with familial forms of the disease have been found to show signs of a phenomenon known as telomere shortening.
Telomeres are DNA sequences that cap the ends of chromosomes, which harbor several genes. Because chromosomes shorten each time a cell divides, there is always a risk that some genetic information needed for a cell to work properly will be lost. Telomeres, as DNA sequences that do not code any proteins, serve as buffers against this loss.
But when telomeres become too short, cells stop dividing and enter a senescent state, where they are less able to promote tissue repair.
In past studies, researchers found that a short peptide (a protein fragment) called GSE4 reduced telomere shortening by increasing the activity of telomerase, an enzyme that adds DNA pieces to the ends of telomeres. GSE4 also lessened DNA damage, oxidative stress, and senescence, and increased DNA production. (Oxidative stress is a form of cellular damage brought on by the buildup of oxidant molecules inside cells.)
Given the role that DNA damage and oxidative stress play in lung fibrosis, a team of scientists in Spain explored the therapeutic potential of GSE4 for IPF.
They first caused fibrosis in rat lung cells by exposing them to bleomycin, a profibrotic agent commonly used in preclinical lab studies. At the same time, they forced some of these cells to produce GSE4 to assess whether the peptide could counteract the harm done by bleomycin.
They found that GSE4 was able to increase telomerase activity, reduce DNA damage and cell death, and lower inflammation and fibrosis in bleomycin-treated cells.
The researchers then moved to a rat model of IPF, where the disease was also triggered by bleomycin, to see if nanoparticles coated with GSE4 could reach the animals’ lungs and lessen fibrosis there.
Nanoparticles carrying GSE4 were not only able to reach rats’ lungs, but also increased telomerase activity by approximately 20%, the researchers found.
DNA damage in lung cells of treated animals was seen to occur at levels similar to those of healthy rats serving as a control group. Markers of fibrosis also decreased in the GSE4-treated rats, although to a lesser extent.
In another experiment, investigators explored whether GSE4 might serve both as a preventive and therapeutic treatment for IPF.
To test its ability in preventing this disease, investigators treated rats with GSE4-nanoparticles one day before exposing them to bleomycin. When tested as a therapeutic treatment, GSE4-nanoparticles were given to animals five days after bleomycin was induced and lung fibrosis evident.
In both cases, they continued to inject the rats with the nanoparticle treatment every four days, through to the experiment’s end 14 days later.
GSE4 treatment limited lung damage and fibrosis in both sets of rats. Post-mortem lung examinations also showed lesser fibrosis and inflammation, and better tissue regeneration in the GSE4-treated group of animals.
“Preventive and therapeutic protocols with GSE4‐nanoparticles in rats treated with bleomycin showed promising results,” the researchers wrote. “In both situations, treatment with GSE4‐nanoparticles was able to prevent and interfere with the lung damage induced by bleomycin as shown by the analyses of CT images obtained in the treated rats.”
To date, danazol, a synthetic steroid, is the only tested treatment for disorders involving telomeres. Although promising, its long-term use carries potentially harmful side effects that include liver toxicity and muscle problems, while no harmful effects with GSE4 were observed in the present study.
“It would be interesting to investigate the use of GSE4 in lung fibrosis patients with short telomeres,” the researchers wrote, “since besides helping to recover lung damage [it] would also contribute to overcom[ing] the blood abnormalities found in these patients without the side effects of the anti‐fibrotic therapies.”
Although bleomycin does not fully mimic all features of IPF, bleomycin mouse models have contributed to the development of other approved IPF therapies, such as Esbriet (pirfenidone) and Ofev (nintedanib), the researchers wrote. Still, they suggested that the development of “a short telomere mice model” would be helpful in testing potential treatments like GSE4 nanoparticles.
Altogether, this study provided evidence that GSE4 might prevent, and possibly reverse, a number of disease features associated with IPF.
“Therefore, the use of GSE4‐nanoparticles should be considered and more deeply explored as an alternative treatment for lung fibrotic patients,” the researchers concluded.
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