A new UCLA Health study in mice has identified a new potential trigger for pulmonary fibrosis: lipid dysregulation (a fat imbalance) within alveolar macrophages. These are the immune cells that serve as the first line of defense against pathogens and tissue damage. Under normal conditions, they are essential for the maintenance and repair of the lung's airspaces. However, when these cells suffer from a lipid imbalance, they lose their protective qualities, malfunction, and begin actively promoting disease.
Lipid-filled macrophages, cells filled with too much fat, have previously been observed in lungs with pulmonary fibrosis, but this has generally been considered a result of the disease rather than a potential cause of it.
BACKGROUND
Pulmonary fibrosis is a debilitating lung disease with limited options for therapy. It is characterized by progressive scarring of lung tissue, ultimately leading to respiratory failure and high mortality rates. Understanding what triggers pulmonary fibrosis has remained largely unsolved.
Previous UCLA studies researching the cholesterol metabolism of macrophages found that lipids detectable in the lungs of patients with other severe pulmonary diseases ( autoimmune pulmonary alveolar proteinosis & idiopathic pulmonary fibrosis ) were directly associated with disease burden and decreased lung function. This led researchers to investigate whether lipid accumulation typically associated with pulmonary fibrosis isn't a merely a consequence, but one of the triggers of the disease.
METHOD
To determine whether lipid dysregulation causes lung fibrosis, researchers examined mice without the specific protein that manages cholesterol balance in macrophages (ABCG1). They found that when mice were deficient in this protein, lipid (particularly cholesterol) accumulation rapidly increased in the alveolar macrophages before other biological changes were observed in the lungs. It was then found that the lipids can then directly signal to neighboring cells, fibroblasts, to activate and produce scar tissue, providing a direct mechanistic link to the development of fibrosis in the lung.
Researchers then transferred macrophages with the ABCG1 protein back into mice through bone marrow transplantation to test whether restoring normal macrophage lipid handling could prevent disease. When scientists restored these cells, they were almost completely protected from fibrosis. Conversely, transferring ABCG1-deficient bone marrow into otherwise normal mice was sufficient to promote fibrosis.
IMPACT
One of the key findings of this study was identifying the sequence of the events that lead to pulmonary fibrosis. Lipids began accumulating in the alveolar macrophages at a time when there was minimal to no fibrosis. This changes how researchers and clinicians think about when and where fibrosis may begin, and thus how to treat it. Current therapies primarily slow disease progression once fibrosis is already established. These findings suggest there may be alternative options. One may be a therapeutic option that would protect or restore normal lipid handling in alveolar macrophages or would prevent the uptake of harmful lipids by fibroblasts in the first place. The other option could be diagnostic: if lipid changes can be detected in people at earlier stages of disease, they might eventually help identify patients at increased risk.
AUTHORS
Elizabeth Tarling , professor of cardiology at the department of medicine at UCLA Health, is the lead author of the study.
In addition to Tarling, other authors include: Elizabeth F. Redente, Isaiah Little, Marissa O'Callaghan, Lucas Dantas, Michelle Steel, Angela Cheng, Elinor Lee, Richard L. Watson, Kevin J. Williams, Michael P. Keane, James P. Bridges, Alexandra L. McCubbrey, Thomas Q. de Aguiar Vallim, and Cormac McCarthy.
JOURNAL
The study was published in the American Journal of Respiratory Cell and Molecular Biology.
