Scientists Discover Mechanism by Which SFTPA1 Mutation Causes IPF

Scientists have found the mechanism by which a new mutation in the surfactant protein A1 (SFTPA1) gene leads to the onset and progression of idiopathic pulmonary fibrosis (IPF) in mice.

Their findings were described in the study, “A homozygous SFTPA1 mutation drives necroptosis of type II alveolar epithelial cells in patients with idiopathic pulmonary fibrosis,” published in the Journal of Experimental Medicine.

IPF is a progressive lung disease of unknown origin characterized by the thickening and stiffening of lung tissue, leading to permanent scarring (fibrosis) that gradually compromises a person’s respiratory function.

“The environmental and genetic factors underlying sporadic IPF are unknown, though cases of familial IPF have been linked to mutations [in certain genes],” the researchers stated.

These genes include SFTPA1 and SFTPA2, which encode proteins released from cells lining the lungs’ alveoli (the small air sacs that are responsible for gas exchanges). These proteins help prevent the alveoli from collapsing, and play an important role in protecting them from harmful microbes.

However, it is still unclear how mutations in these two genes lead to the onset and progression of IPF.

In the study, investigators from Japan’s Tokushima University Graduate School of Medicine and their collaborators found the mechanism by which a new mutation in the SFTPA1 gene led to the onset and progression of IPF in mice.

The missense mutation, known as T622C, was found in both copies of the SFTPA1 gene in two Japanese brothers who died of IPF in their early thirties. A missense mutation is a single nucleotide (the building blocks of DNA) mutation that alters protein composition.

After analyzing T622C in more detail, researchers discovered that the mutation led to the replacement of the amino acid (the building blocks of proteins) tyrosine by histidine at position 208 of the protein sequence.

The team then genetically engineered mice to carry the same genetic defect (the T622C mutation) in the SFTPA1 gene, and found that these animals spontaneously developed IPF. Moreover, researchers saw that the animals’ condition was fatally exacerbated by a viral lung infection, similar to what occurs in IPF patients.

After examining cells lining the alveoli of the lungs of diseased mice, researchers discovered that the T622C mutation prevented the SFTPA1 protein from being released, so it accumulated inside cells. As a result, cells forming the alveoli started to die through necroptosis, a process in which cell death triggers tissue inflammation and leads to the formation of scar tissue.

Necroptosis was found to be triggered by stress signaling cascades, which were activated by the excessive accumulation of the abnormal SFTPA1 protein that remained trapped inside alveolar cells.

However, when researchers blocked these stress signaling cascades, or lowered the levels of necroptosis-promoting proteins, they managed to slow the progression of the disease in the animals. In addition, they also found that by doing so, mice were able to survive viral infections caused by influenza A.

“Our study suggests that necroptosis is one of the crucial initiators of pulmonary fibrosis, and that the necroptosis signaling pathway could be a potential target for its treatment,” Koji Yasutomo, MD, PhD, professor at Tokushima University and corresponding author of the study, said in a news release.

“The current focus for treating IPF is to block the activation of kinase enzymes within the fibrotic regions of the lung. In contrast, inhibiting necroptosis in alveolar cells would suppress earlier events in IPF progression, which would be more beneficial to patients,” Yasutomo said.

According to the team, the data obtained provides “not only a new link between necroptosis and IPF, but also a novel strategy for treating patients with IPF.”