Metabolic Processes Key to Lung Repair Revealed

Scientists at the Francis Crick Institute have uncovered how cells lining the lung airways change their metabolism, and how this process is key to helping the lungs heal after infection or damage. 

Cells lining the airways, called epithelial cells, produce mucus or develop cilia whose regular beat moves the mucus towards the throat. The right balance between mucus production and movement is important to clear external pathogens and other harmful particles from the lungs. Differentiation of these specialized cells needs to be tightly regulated to allow the lungs to repair themselves after damage caused by injury or infection. 

In their study, published in Nature Communications, the Crick research team examined the way lung epithelial cells use nutrients to make energy and biomass, and how this changes when they differentiate into specialist cells.

They found that during differentiation, lung epithelial cells switched from metabolizing glucose, to using fats instead. By blocking the process called fatty acid oxidation, they completely blocked the differentiation of specialist cells.

Stefania Crotta, joint first author and co-corresponding author working at the Crick, said: “Until now, little has been understood about the role of metabolism in lung epithelia regeneration. But a switch to fatty acid oxidation makes sense because of the abundance of oxygen and available fats in the lungs. We think that this switch frees up glucose to be used in other important processes such as mucus glycosylation in specialised cells.”

The researchers also examined the action of drugs already used to treat lung damage associated with Acute Respiratory Distress Syndrome and other lung conditions. They found that some of these drugs promote fatty acid oxidation, leading to a larger proportion of differentiated, mucus-producing and ciliated cells.

The team then studied the importance of this metabolic process in mice. Using genome editing tools, they removed a gene key to fatty acid oxidation and observed the ability of the lung epithelia to regenerate after the mice were infected with flu virus. They confirmed that far fewer cells had been able to differentiate and more cells remained in an unspecialized state. 

Andreas Wack, head of the Crick’s Immunoregulation Laboratory, said: “The body can only withstand lack of oxygen for a matter of minutes. Therefore, lung repair is a very tightly controlled process, including the speed and efficiency of epithelial cell differentiation to regenerate the tissue exactly as it was before infection or injury. 

“This insight into the importance of fatty acid oxidation in this process, opens up new opportunities for promoting cell differentiation and healthy lung repair after damage.”

Reference: Crotta S, Villa M, Major J, et al. Repair of airway epithelia requires metabolic rewiring towards fatty acid oxidation. Nat Commun. 2023;14(1):721. doi: 10.1038/s41467-023-36352-z

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