Restoring a DNA repair protein that is missing in pulmonary fibrosis reversed the lung scarring that is the hallmark of the disease, a German study in mice has shown.
The finding raises the possibility that restoring the protein could reverse humans’ lung fibrosis as well.
Lack of the RAGE protein prevented the lungs’ DNA repair mechanism from preventing scarring, according to the researchers at Heidelberg University Hospital and the German Center for Diabetes Research.
Their study, “Homeostatic nuclear RAGE–ATM interaction is essential for efficient DNA repair,” was published in the journal Nucleic Acids Research.
Every cell in the body suffers DNA damage every day. The most severe type of damage is a double-strand break, which means both strands of a DNA molecule are cut. If left unrepaired, the damage can lead to tissue scarring, degeneration, and cancer.
A number of studies have linked the development of idiopathic pulmonary fibrosis, or IPF, to persistent DNA damage stemming from defective repair mechanisms.
Since the RAGE protein regulates lung cells’ responses to inflammation, lack of it leads to scarring. Scientists have linked its accumulation in the nucleus of lung cells not only to IPF but also to other diseases arising from DNA damage. RAGE”s full scientific name is receptor for advanced glycation end-products.
Scientists use mice that lack a RAGE gene as a model for IPF. These animals display both lung tissue scarring and diminished respiratory function.
The German researchers decided to use the mice to study the connection between DNA repair, RAGE levels in lung cells’ nuclei, and fibrosis.
Delivering RAGE to the lungs of the IPF mice not only reduced their DNA damage and fibrosis, but also restored their lung function to almost normal.
Key takeaways from the study were that DNA repair plays a crucial role in preventing fibrosis and that scientists may be able to develop a therapy around RAGE that can reverse DNA damage and lung fibrosis.
“This is astonishing in that fibrosis has so far been considered irreversible,” Dr. Peter Nawroth, the study’s senior author, said in a press release. “With RAGE, we could for the first time have found a possible starting point to cure this frequent tissue damage.” Nawroth is medical director of the Department of Endocrinology, Metabolism and Clinical Chemistry at Heidelberg University Hospital.
“The published study not only provides important insights into the molecular relationship between RAGE-mediated DNA repair, cell aging and fibrosis,” said Varum Kumar, the study’s first author.
For the first time ever, a treatment for the lung damage caused by genes and cells may be within reach, he said. This also means that “the prevention of fibrosis or tumors, which also occur as a result of DNA damage, may be within reach” as well, he added. Kumar is a Heidelburg University medical professor who is also affiliated with the German Center for Diabetes Research.
The team has already obtained a patent for a RAGE-based therapy they plan to develop. Their next step is to see whether RAGE plays the same role in liver and kidney fibrosis as it does in lung scarring — and whether a RAGE-based treatment could reverse fibrosis in those organs.
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