Researchers discovered that Notch1 signaling contributes to alveolar epithelial cells type II (ACE2) proliferation and dedifferentiation in patients with idiopathic pulmonary fibrosis (IPF). Their study was published in the American Journal of Respiratory and Critical Care Medicine. 

“In the normal human lung, alveolar type II cells (ACE2) mostly exist in a highly differentiated state and play an essential role in producing, processing, and adequately secreting pulmonary surfactant,” the authors of the study wrote. 

Pulmonary surfactant plays an important role in lowering alveolar surface tension; this makes it possible to breathe at normal transpulmonary pressure gradients. In instances of lung injury, ACE2 allows the alveolar epithelium to undergo repair and replacement. 

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The authors of this study hypothesized that Notch signaling continues to regulate the differentiation status of ACE2 in IPF. To investigate their hypothesis, the research team used explanted lungs and human donor lung lobes obtained during lung transplantation (for ex vivo studies), and ACE2 cell lines and primary murine and human ACE2s (for in vitro studies). In vivo studies were conducted via bleomycin- and pepstatin-application and Notch1 intracellular domain overexpression. 

Read more about IPF etiology 

“We applied microarray analysis, kinome profiling, flow cytometry, immunofluorescence analysis, western blotting, [real-time polymerase chain reaction], proliferation- and surface activity analysis to study epithelial differentiation, proliferation and matrix deposition in vitro, ex vivo, and in vivo,” the authors of the study wrote. 

The results of the study demonstrated that significant surfactant alterations occur in IPF, resulting in a sharp rise in alveolar surface tension and alveolar collapse during expiration. The researchers also discovered that Notch signaling was an important pathway differentially regulated in IPF, and that persistent alveolar injury results in the massive proliferation and dedifferentiation of ACE2 via Notch1 activation. 

This study further increases current scientific understanding of the mechanisms underlying alveolar injury in IPF and how it can potentially be reversed.


Wasnick R, Korfei M, Piskulak K, et al. Notch1 induces defective epithelial surfactant processing and pulmonary fibrosisAm J Respir Crit Care Med. 2022;10.1164/rccm.202105-1284OC. doi:10.1164/rccm.202105-1284OC