A new discovery about the causes of PAP lung disease may also offer solutions to treat obesity and heart disease. The research group of Associate Professor Alexander Mildner from the University of Turku, Finland, has identified a genetic defect that causes the accumulation of lipids in the alveoli of the lungs.
The alveoli are tiny bubble-like air sacs located at the end of the bronchi. They are vital for survival as they exchange oxygen for carbon dioxide.
The alveoli are covered with a thin fluid film called a surfactant which consists mainly of lipids. Surfactant not only protects the lungs against airborne pathogens and dust, but also facilitates breathing by reducing alveolar surface tension.
Surfactant lipids are constantly being produced and eliminated from the alveoli. Alveolar macrophages, the scavenger immune cells of the lungs, degrade and recycle surfactant lipids. Defects in the development and function of alveolar macrophages lead to a disturbed surfactant balance and a pathological accumulation of surfactant lipids which ultimately obstruct the alveolar space. Accumulated lipids make macrophages swollen and frothy.
“We can observe this phenomenon in patients with pulmonary alveolar proteinosis (PAP). They suffer from shortness of breath, impaired respiratory function and an increased risk of lung infections. It is a relatively rare disease”, explains Associate Professor Alexander Mildner of the InFLAMES Flagship Program at the University of Turku, Finland, who led the research in cooperation with Professor Achim Leutz’s group at the Max-Delbrück Center in Berlin, Germany.
Macrophages lack essential cellular tools
A disturbance in gene regulation causes macrophages to fail. One such disruption has already been identified, but Mildner and his group discovered that the absence of a second regulator renders macrophages unable to clear surfactant lipids.
This regulatory gene is the transcription factor C/EBPb. We observed that C/EBPb-deficient macrophages lacked the cellular tools necessary for lipid clearance.”
Alexander Mildner, Associate Professor, University of Turku, Finland
The significance of the new discovery is not limited to PAP disease. Swollen and frothy macrophages are also found in people with obesity or atherosclerosis.
“Perhaps we can learn from alveolar macrophages in the lungs and translate our findings to other macrophages and help them digest lipids more efficiently. In the future, it might be possible to pharmacologically activate the macrophage C/EBPb-Pparg2 network in obese patients. , PAP or atherosclerosis and promote the digestion of lipids 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 2 isoform expression in alveolar macrophages. Sciences Immunology. doi.org/10.1126/sciimmunol.abj0140.