New discoveries about the causes of PAP lung disease may also offer solutions for treating obesity and heart disease. The research group of Associate Professor Alexander Mildner from the University of Turku, Finland, identified a genetic defect that causes the accumulation of lipids in the alveoli of the lungs.
Air sacs are tiny sac-like air sacs at the end of the bronchi. They are essential for survival because they exchange oxygen for carbon dioxide.
The alveoli are covered by a thin film of fluid called surfactant, which is mostly made up of lipids. Surfactant not only protects the lungs from airborne pathogens and dust, but also facilitates proper breathing by reducing the surface tension of the alveoli.
Surfactant lipids are constantly being produced and removed from the alveoli. Alveolar macrophages, the lungs’ immune scavenger cells, break down and recycle surfactant lipids. Defects in the development and function of alveolar macrophages result in disturbed surfactant balance and pathological accumulation of surfactant lipids, which ultimately clog the alveolar space. The accumulated lipids make the macrophages bloated and foamy.
“We can observe this phenomenon in patients with pulmonary alveolar proteinosis (PAP). They suffer from shortness of breath, restricted respiratory function and an increased risk of lung infections. It is a relatively rare disease,” says Associate Professor Alexander Mildner from the InFLAMES Flagship Program at the University of Turku, Finland, who led the research in collaboration with the group of Prof. Achim Leutz at the Max Delbrück Center in Berlin, Germany .
Macrophages lack important cellular tools
A disruption in gene regulation causes the defect in the macrophages. One of these disruptions has already been identified, but Mildner and his group discovered that the lack of a second regulator means that the macrophages cannot clear the lipids in the surfactant.
This regulatory gene is the transcription factor C/EBPb. We observed that C/EBPb-deficient macrophages lacked the cellular tools required for lipid clearance.”
Alexander Mildner, Associate Professor, University of Turku, Finland
The importance of the new discovery is not just limited to PAP disease. Bloated, frothy macrophages are also found in people with obesity or atherosclerosis.
“Perhaps we can learn from alveolar macrophages in the lungs and transfer our knowledge to other macrophages and help them to better digest lipids. In the future, it might be possible to pharmacologically activate the macrophage C/EBPb-Pparg2 network in patients with obesity.” , PAP or atherosclerosis and promote lipid digestion in these cells. This could provide new strategies for treating these patients,” says Mildner.
Dorr, D., et al. (2022) C/EBPβ regulates lipid metabolism and Pparg isoform 2 expression in alveolar macrophages. science immunology. doi.org/10.1126/sciimmunol.abj0140.