Membrane-repair Protein May Be IPF Treatment Target, Early Study Finds

Increasing the levels of a membrane-repair protein called tripartite motif containing 72 (TRIM72) protected against lung cell injury and lessened lung fibrosis in a mouse model of idiopathic pulmonary fibrosis (IPF).

These data suggest that targeting TRIM72 or other membrane-repair molecules could be a treatment approach for IPF.

The study, “TRIM72 promotes alveolar epithelial cell membrane repair and ameliorates lung fibrosis,” was published in the journal Respiratory Research.

While the exact cause of IPF remains unknown, evidence suggests it is associated with injury to cells lining the alveoli — alveolar epithelial cells— and abnormal wound healing, ultimately leading to scarring (fibrosis).

The alveoli, the small air sacs responsible for gas exchange in the lungs, are lined by two main types of alveolar epithelial cells: type I (ATI) and type II (ATII). ATI cells are involved in gas exchange, and ATII cells are thought to play a role in the regeneration of ATI cells, helping to protect against infection and injury.

Previous studies have shown that problems with ATII cell function — and a potentially impaired ability to repair the alveoli’s lining — are associated with IPF development.

Increasing evidence suggests that TRIM72 is a protein that works not only as a sensor of cell membrane injury, but also as an active player in membrane repair in several types of cells, including ATI cells. TRIM72 is usually found inside small vesicles, which upon injury move to the site of cell membrane injury and form repair patches.

However, the underlying mechanisms and contribution of ATII cells’ repair in the development of IPF remain unexplored.

Researchers in the U.S. investigated TRIM72’s potential role in the repair mechanisms of ATII cells, and in the development of IPF.

They analyzed the levels, localization, and function of TRIM72 in lung and ATII cells from rats, mice, and humans, as well as in a mouse model of IPF. In this model, scarring is induced by the administration of a highly toxic chemotherapy called bleomycin.

Compared with healthy mice and individuals, TRIM72 levels were higher-than-usual in the lungs of mice following several types of injuries and in samples of IPF patients’ lungs, results showed.

This suggested that “injury upregulates TRIM72 expression,” the researchers wrote.

In ATII cells from IPF patients, however, TRIM72 was mainly found inside the cell’s nucleus, and not in the intracellular space between the nucleus and the cell membrane as in normal with human ATII cells.

This abnormal localization raised questions of whether this is a consequence of repeat lung injury in IPF patients, and whether this localization prevents TRIM72 from exerting its protective function.

Forcing the overproduction of TRIM72 in rat ATII cells resulted in a significantly higher repair capacity compared with unchanged cells, the researchers wrote, confirming that TRIM72 belongs to the membrane repair machinery of ATII cells.

Further studies in the IPF-induced mouse model showed that promoting higher-than-normal levels of TRIM72 suppressed stress-induced p53 activation and lowered APII cell death, lung injury, and fibrosis.

p53, a protein that regulates cell division, is known to be involved in fibrosis and to promote cell death in distressed cells if overly activated.

TRIM72’s anti-fibrotic properties were also observed when TRIM72 overproduction was induced after fibrosis was already established in these mice, supporting its potential benefits in IPF.

In general, opposite effects were observed when researchers prevented TRIM72 production in this mouse model.

“Our data revealed an anti-injury and anti-fibrosis role of TRIM72, likely through promoting repair and survival of ATII cells and curtailing the stress-activated p53 pathway,” the researchers wrote.

Raising TRIM72 levels even further after an injury provided additional protection to the lungs, “suggesting that a membrane repair therapy may be beneficial for the progressive tissue destruction in IPF, which is thought to be a result of repeated micro-injuries,” they added.

“Targeting the membrane repair of alveolar epithelial cells and post-injury responses through TRIM72 represents a new direction for the development of IPF therapies,” the researchers concluded.