UCLA Health: lipid buildup in lung macrophages triggers pulmonary fibrosis in mice

A mouse study from UCLA Health points to lipid dysregulation in alveolar macrophages as a possible trigger of pulmonary fibrosis, according to newswise.com. The work was published in the American Journal of Respiratory Cell and Molecular Biology newswise.comnewswise.comnewswise.comOpen source ↗. Alveolar macrophages are immune cells that act as the first line of defense against pathogens and tissue damage and normally help maintain and repair the lung's airspaces. The authors report that when these cells develop a lipid imbalance, they lose their protective qualities and begin promoting disease.

Pulmonary fibrosis is characterized by progressive scarring of lung tissue that ultimately leads to respiratory failure and high mortality, and therapy options are limited. Macrophages overloaded with fat had been seen before in fibrotic lungs, but this was generally treated as a result of the disease rather than a cause. Earlier UCLA studies found that lipids detectable in the lungs of patients with autoimmune pulmonary alveolar proteinosis and idiopathic pulmonary fibrosis were associated with disease burden and decreased lung function.

Experiment with ABCG1-deficient mice

The researchers examined mice lacking ABCG1, a protein that manages cholesterol balance in macrophages. In these mice, lipid, particularly cholesterol, accumulation in alveolar macrophages increased rapidly, before other biological changes appeared in the lungs. The lipids could then signal to neighboring fibroblasts, activating them to produce scar tissue, which gives a direct mechanistic link to fibrosis.

In a bone marrow transplantation test, mice that received macrophages with ABCG1 were almost completely protected from fibrosis. Conversely, transferring ABCG1-deficient bone marrow into otherwise normal mice was sufficient to promote fibrosis newswise.comnewswise.comnewswise.comOpen source ↗.

Order of events and possible directions

Lipids began accumulating in alveolar macrophages when fibrosis was minimal or absent. According to the authors, this changes how researchers and clinicians think about when and where fibrosis may begin. Current therapies mainly slow progression once fibrosis has already developed.

The authors name two possible directions. One is a therapy that would protect or restore normal lipid handling in alveolar macrophages, or prevent fibroblasts from taking up harmful lipids. The other is diagnostic: if lipid changes can be detected in people at earlier stages, they might eventually help identify patients at increased risk. Both remain proposals, and the data come from mice. The lead author is Elizabeth Tarling, professor of cardiology at the department of medicine at UCLA Health.