New discovery on the causes of PAP lung disease can also offer solutions for treating obesity and heart disease. The research group of Associate Professor Alexander Mildner at the University of Turku, Finland, identified a genetic defect that causes the accumulation of lipids in the pulmonary alveoli.
Pulmonary alveoli are tiny bubble-like air sacs at the end of bronchial tubes. They are vital for survival as they exchange oxygen for carbon dioxide.
The alveoli are covered by a thin fluid film called surfactant which consists mainly of lipids. Surfactant does not only protect the lungs against airborne pathogens and dust, but also facilitates proper respiration by reducing the alveolar surface tension.
Surfactant lipids are constantly produced and cleared from the alveoli. Alveolar macrophages, the immune scavenger 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 clogs 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, an impaired respiratory function and an increased risk of lung infections. It is a relatively rare disease," says Associate Professor Alexander Mildner from the InFLAMES Flagship Programme at the University of Turku, Finland, who was leading the research in cooperation with Prof. Achim Leutz group at the Max-Delbrück Center in Berlin, Germany.
Macrophages lack essential cellular tools
A disturbance in gene regulation causes the defect in the macrophages. One of these disturbances has already been identified, but Mildner and his group discovered that the lack of a second regulator makes the macrophages unable to 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 the clearance of lipids."
Alexander Mildner, Associate Professor, University of Turku, Finland
The significance of the new discovery is not just limited to the PAP disease. Bloated, foamy macrophages are also found in people with obesity or atherosclerosis.
"Maybe we can learn from alveolar macrophages in the lungs and translate our findings to other macrophages and help them to digest lipids more effectively. In the future, it could 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 to treat these patients," says Mildner.
Dörr, 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.