Tissue-wide Responses to Airway Injury

Abstract

The lungs contain numerous types of epithelial cells lining the trachea, bronchi (large airways), and bronchioles (small airways), which work in succession to transport air to alveoli, the sites of gas exchange. Acute injury in the airways or the lung activates local progenitors and stimulates changes in cell-cell interactions to restore homeostasis, but it is not appreciated how more distant niches are impacted by injury restricted to one region. We utilized mouse models of airway-specific epithelial injury to examine secondary tissue-wide alveolar, immune, and mesenchymal responses. Single-cell transcriptomics and in vivo validation revealed transient, tissue-wide proliferation of alveolar type 2 (AT2) progenitor cells after club cell-specific ablation in the airways. The AT2 cell proliferative response was reliant on alveolar macrophages (AMs) via upregulation of Spp1, which encodes the secreted factor Osteopontin. A previously uncharacterized mesenchymal population we termed Mesenchymal Airway/Adventitial Niche Cell 2 (MANC2) also exhibited dynamic changes in abundance and a pro-fibrotic transcriptional signature after club cell ablation in an AM-dependent manner. Although aberrant responses in the lung were observed to resolve after a single acute injury, future studies could elucidate how these responses intersect or become exacerbated with more severe, durable, or complex lung injuries and disease states. Overall, these results demonstrate that acute airway damage can trigger distal lung responses including altered cell-cell interactions that may contribute to potential vulnerabilities for further dysregulation and disease.