Researchers at the Spanish National Cancer Centre (CNIO) and the Complutense University of Madrid in Spain discovered that telomere damage is a cause of idiopathic pulmonary fibrosis (IPF) development. The study was recently published in the journal Cell Reports and is entitled “Mice with Pulmonary Fibrosis Driven by Telomere Dysfunction.”
IPF is a progressive fatal lung disease in which the alveoli and the lung tissue are damaged, becoming thick and scarred (fibrosis), leading to severe breathing difficulties and compromising oxygen transfer between the lungs and the bloodstream. IPF is characterized by a shortness of breath that gradually worsens, with respiratory failure being the main cause of death. There is no cure for the disease and it is estimated that 128,000 individuals in the United States suffer from IPF. The disease has a poor prognosis and around two-thirds of the patients die within five years after being diagnosed. New therapeutic targets and treatments are therefore urgently needed.
Telomeres are the caps at the end of the DNA strand that protect the edge of the chromosomes from degradation and from fusion with other chromosomes. As the individual ages, the telomeres experience a progressive shortening in length. Telomerase is an enzyme that adds nucleotides to the end of telomeres, compensating their gradual shortening. Mutations on the telomerase and on key proteins in telomere protection and maintenance have been reported in IPF patients.
Researchers have investigated the possible association between IPF and telomere defects. The lack of proper animal models that mimic human IPF has hampered new advances. In the study, the team developed a mouse model that lacks a protein called TRF1, which is required to build telomeres in a specific cell population — type II alveolar cells. These particular cells are crucial for lung tissue regeneration.
Researchers found that these mice developed progressive pulmonary fibrosis, indicating that the lack of telomeres is lethal for type II alveolar cells. The findings led the team to suggest that the lung epithelium cannot regenerate without these particular cells and showed, for the first time, that telomere damage may contribute to the development of IPF. “We have seen that acute telomere damage is sufficient to trigger pulmonary fibrosis, even in the absence of environmental damage,” noted the study’s co-author Dr. Paula Martínez in a news release.
However, the mouse model developed by the team did not reproduce the IPF disease in humans. Researchers have therefore developed a new model where they combined premature shortening of the telomeres by telomerase deficiency and low doses of environmental damage, which is known to play a key role in disease development. To induce environmental damage the team used bleomycin, a drug that affects the DNA. Researchers found that although both factors are independently unable to induce fibrosis, the shortening of telomeres together with bleomycin at low doses can trigger pulmonary fibrosis in mice.
“These findings support a model in which persistent damage derived from short or dysfunctional telomeres is added to other cellular damage and this triggers pulmonary fibrosis,” said the study’s lead author Juan M. Povedano.
The research team concluded that telomere defects contribute to the development of IPF, and suggest that the new animal models created in the study can be instrumental in the development of new therapeutic strategies against the disease. Furthermore, the team also suggests a link between IPF and the aging process supported by the fact that IPF usually only occurs in individuals over 50 years and knowing that the older the individual, the shorter the telomeres.
“Understanding the molecular mechanisms that lead to the aging process, such as the shortening of telomeres, has enabled us to generate animal models that faithfully reproduce diseases such as idiopathic pulmonary fibrosis, and this is already helping us to test novel therapies that we hope will prove effective and that are based on the activation of the enzyme telomerase,” concluded the study’s senior author, Dr. Maria A. Blasco.