What causes pulmonary fibrosis on a cellular level?

A new UCLA Health study on mice has uncovered a potential trigger for pulmonary fibrosis: an imbalance of fats within immune cells called alveolar macrophages. Typically, these cells defend against pathogens and aid lung tissue repair. However, when a lipid imbalance occurs, these macrophages malfunction and actively contribute to disease progression.

Though lipid-filled macrophages have been observed in lungs affected by pulmonary fibrosis, this imbalance was previously deemed a consequence rather than a cause of the disease. Pulmonary fibrosis, a debilitating lung condition, causes progressive scarring of lung tissue, leading to respiratory failure and high mortality rates.

The cause of pulmonary fibrosis has remained largely unknown. Previous UCLA research found that cholesterol metabolism in macrophages of patients with severe pulmonary diseases was associated with disease severity and reduced lung function. This prompted researchers to investigate whether lipid accumulation in the lungs was a cause, rather than a consequence, of the disease.

To test this hypothesis, researchers studied mice lacking a protein called ABCG1, which regulates cholesterol balance in macrophages. Mice deficient in this protein experienced rapid lipid accumulation in alveolar macrophages before other lung changes occurred. Additionally, these lipids directly signaled to neighboring fibroblasts, activating them to produce scar tissue, establishing a direct link between lipid dysregulation and lung fibrosis development.

By retransferring macrophages with functional ABCG1, mice were almost completely protected from fibrosis. Conversely, transferring ABCG1-deficient bone marrow into healthy mice promoted fibrosis. Researchers identified the sequence of events leading to pulmonary fibrosis, noting that lipid accumulation in macrophages precedes the onset of fibrosis.

This finding alters the understanding of when and where fibrosis begins, potentially guiding treatment strategies. Current therapies focus on slowing disease progression after fibrosis has already developed, but these new findings suggest alternative treatment options. Therapies could be developed to protect or restore normal lipid handling in alveolar macrophages or prevent harmful lipid uptake by fibroblasts.

Diagnostically, detecting lipid changes at earlier stages of the disease could help identify patients at higher risk. Lead author Elizabeth Tarling, a professor of cardiology at UCLA Health, noted that these findings provide new avenues for both treatment and early detection of pulmonary fibrosis.