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bioRxiv · 10.64898/2026.02.04.703850

Notch mediates non-regenerative alveolar repair after staphylococcal lung injury

Moore, S. K. L.·Tang, S.·Chavez, D.·Suthakaran, S.·Sussman, C.·Zhang, J.·Hook, J. L.
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Abstract

Severe lung infection causes dysfunction of the lungs air-blood barrier, leading to respiratory failure. In alveoli of lungs infected with Staphylococcus aureus (SA) - either alone or after respiratory viral infection - the SA toxin, alpha hemolysin (Hla) causes epithelial barrier protein degradation and airspace edema formation. How the barrier repairs is not clear. We used confocal imaging of intact, perfused, SA-infected lungs to define barrier repair mechanisms in live alveoli. Though we expected to find the non-surviving alveolar epithelium was regenerated, we found, instead, the surviving alveolar epithelium spontaneously regained barrier function. Thus, SA stimulated Notch protein cleavage in the alveolar epithelium in an Hla- and ADAM10-dependent manner. Subsequent exposure of the Notch transmembrane domain catalyzed epithelial junctional protein recovery to reseal the barrier and restore barrier integrity. While disrupting Notch cleavage in the alveolar epithelium prolonged SA-induced lung injury, augmenting it accelerated lung repair. We interpret that barrier repair in the surviving alveolar epithelium resulted from Notch-mediated junctional protein reassembly. These findings show, for the first time, that the alveolar epithelium is a resilient tissue that harbors robust endogenous repair mechanisms. We propose strategies that leverage Notchs non-regenerative, barrier-strengthening capability may promote lung repair after staphylococcal lung infection.

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Moore, S. K. L., Tang, S., Chavez, D., Suthakaran, S., Sussman, C., Zhang, J., Hook, J. L.. 2026-02-05. Notch mediates non-regenerative alveolar repair after staphylococcal lung injury. https://doi.org/10.64898/2026.02.04.703850

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