May 20, 2021

New clue to lung scarring

Vanderbilt neonatology team pinpoints signaling pathways involved in the progressive lung fibrosis that occurs in rare genetic diseases.

Pulmonary surfactant is a mixture of proteins and lipids that reduces the surface tension of alveoli, the tiny air sacs in the lungs, enabling the exchange of gases during breathing. Defective trafficking of surfactant components, which occurs in rare genetic diseases such as Hermansky-Pudlak syndrome type 2, can lead to progressive pulmonary fibrosis, scarring of the lungs. 

Susan Guttentag, MD, and colleagues previously identified Adaptor Protein 3 complex (AP-3) as a critical element in trafficking surfactant constituents to lamellar bodies in alveolar type 2 epithelial cells, from which surfactant is secreted. 

They now report that genetic loss of AP-3 impairs the trafficking of a key transmembrane protein, flippase ATP8A1. That in turn alters signaling through the Yes-activating protein (YAP), which activates genes known to contribute to fibrotic lung repair. 

These findings, published May 18 in the Proceedings of the National Academy of Sciences, suggest that dysregulated YAP signaling caused by AP-3 deficiency may be an important contributor to fibrotic lung disease.

The research was supported in part by National Institutes of Health grants GM108807, EY015625, HL133484 and HL143051.