Airway injury induces alveolar epithelial responses mediated by macrophages

Airway injury activates local progenitors and stimulates cell-cell interactions to restore homeostasis, but it is unknown how distal niches are impacted. We utilized mouse models of airway-specific epithelial injury to examine secondary tissue-wide alveolar and immune responses. Single-cell transcriptomics and in vivo validation of mouse models of airway-specific epithelial injury revealed transient, tissue-wide proliferation of alveolar type 2 (AT2) progenitor cells after club cell-specific injury or ablation. Myeloid cells exhibited altered gene expression after club cell loss and were detectable in the bronchoalveolar lavage fluid. The AT2 cell proliferative response was reliant on alveolar macrophages (AMs) exhibiting an injury-induced gene expression program. Overall, these results demonstrate that acute airway damage can trigger myeloid-mediated lung alveolar responses that may contribute to disease susceptibility or dysfunction.