Dysplastic alveolar remodeling is characterized by the ectopic expansion of KRT5+ cells in the lung alveoli, forming a scar-like structure that persists in the injured alveoli and impedes normal alveolar epithelium regeneration. This remodeling response has been observed in patients following severe influenza or COVID-19 infection, as well as in experimental mouse models of respiratory viral infection. Interestingly, in other non-viral infection-induced lung injury settings, this dysplastic remodeling response is either weakly induced or not induced at all. The molecular mechanisms by which viral infection activates the formation of these cells, and how dysplastic cells maintain their cell fate in the lung alveoli, remain unclear.
In a study published in J Clin Invest, teams led by Prof. SUI Pengfei from the Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology of the Chinese Academy of Sciences, in collaboration with Prof. LIU Bo from Key Laboratory of Immune Response and Immunotherapy, Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences, found that virus infection-induced immune factor IFN-γ regulates the expansion of dysplastic KRT5+ cells through the YAP axis.
The researchers found that virus infection-induced IFN-γ plays a role in regulating dysplastic alveolar remodeling by comparing the immune response between IAV- and bleomycin-injured lung tissue. They confirmed that IFN-γ-Yap signaling is required for the expansion of dysplastic KRT5+ cells using Ifngr1 conditional Knockout and Yap conditional knockout mice. Disrupting IFN-γ-Yap signaling ameliorated lung fibrosis, reduced aberrant tuft cell and goblet cell formation, and improved lung recovery.
The long persistence of dysplastic cells in the alveoli hinders lung recovery and lays the groundwork for chronic disease. In this study, researchers successfully converted dysplastic KRT5+ cells into distal club cells, which can function as distal airway progenitor cells to repair injured lung alveoli by generating new AT2 cells through inhibition of YAP in persistent dysplastic cells.
By analyzing single-cell RNA-seq data, human 3D organoid cultures, and immunofluorescence staining of lung tissue from COVID-19 patients, researchers found that dysplastic alveolar remodeling might also be regulated through IFN-γ-YAP signaling following SARS-CoV-2 infection.
Overall, the study reveals the role of immune-epithelial interactions in regulating dysplastic alveolar remodeling and the underlying mechanism of “long COVID-19”, suggesting a potential therapeutic target for controlling viral pneumonia-induced dysplastic alveolar remodeling in human lungs.
Reference: https://www.jci.org/articles/view/176828
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