Abstract Rationale Consistent exposure to respiratory viruses predisposes individuals to a lifelong threat of post-viral sequalae, including lung fibrosis. Current consensus identifies the dysfunctional alveolar type 2 (AT2) cells as the main driver to lung fibrosis. As facultative stem cells, AT2 cells normally repair injury by differentiating into alveolar type 1 (AT1) cells via a KRT8+ transitional state. However, they can also aberrantly differentiate into basaloid KRT17+/PDLIM7+ cells, representing a profibrotic pathway that disrupts epithelial regeneration. This dysregulated differentiation could be orchestrated by immune responses following viral infection, with IFN-γ emerging as a key signaling hub in the formation of dysplastic epithelium after influenza exposure. Although, its precise role in lung fibrosis remains to be fully elucidated. We hypothesize that IFN-γ is a pro-fibrotic factor that prevents alveolar regeneration during post-viral phase. Methods To evaluate the role of viral infections on lung fibrosis, we used a two-hit model whereby mice were infected with PR8 virus followed by bleomycin injury to trigger lung fibrosis, which was quantified by hydroxyproline assay. For in vitro experiments, murine AT2 cells were sorted from Sftpc-CreER x ROSA-tdTomato reporter mice to create alveolosphere organoid culture. These organoids were treated with IFN-γ to assess its effect on alveolar regeneration. Results Hydroxyproline level significantly increased when bleomycin was administered following PR8 infection compared to an age-matched bleomycin-only group. IFN-γ treatment resulted in a significant reduction in the size of alveolospheres after 3 weeks. Conclusion The increased fibrosis from the two-hit model suggests that a viral infection has a long-lasting effect on lung recovery and regeneration. IFN-γ suppression of AT2 cell growth supports our hypothesis that a dysregulated immune-epithelial niche after viral infection makes the lung more susceptible to fibrosis. Altogether, IFN-γ could act as a key mediator promoting post-viral lung fibrosis by suppressing alveolar epithelial regeneration. This abstract is funded by: NIH/NHLBI
Wang et al. (Fri,) studied this question.