Compensatory Lung Growth After Resection in a Murine Lobectomy Model

Abstract Background: Compensatory lung growth after resection is observed in clinical practice, yet its underlying mechanisms and pathology remain unclear. To investigate this phenomenon, a left pneumonectomy model is commonly used. However, lobectomy is the predominant surgical method in clinical settings, warranting a more relevant animal model. Objective: This study aimed to establish a murine lobectomy model to investigate the spatiotemporal dynamics of alveolar epithelial type II (ATII) cell proliferation and differentiation in compensatory lung growth following resection. Methods: The proliferation of ATII cells post-right lower lobectomy was assessed over time by Ki-67 immunostaining, with cellular proliferation quantified via flow cytometry. ATII stem cell properties were examined by organoid culture assays, including colony-forming efficiency (CFE) and ATP luminescence assay. To analyze ATII differentiation into alveolar epithelial type I (ATI) cells, we utilized SftpcCreERT2-TdTm mice, permitting lineage tracing. Comparisons with the pneumonectomy model underscored distinctive characteristics of the lobectomy model in terms of compensatory lung growth. Results: The murine lobectomy model demonstrated ATII proliferation and differentiation into ATI in residual lung tissue, with Ki-67 expression peaking at post-operative day 5. Notably, ATII proliferation rates varied across lobes, with the highest proliferation observed in the right upper lobe after right lower lobectomy, indicating an anatomical and functional gradient in the regenerative response. Organoids derived from ATII cells post-lobectomy exhibited significantly enhanced CFE and ATP levels, indicating increased stemness and regenerative potential. Long-term analyses revealed progressive ATII-to-ATI differentiation. Conclusion: We successfully developed a murine lobectomy model that accurately reflects compensatory lung growth, offering a physiologically relevant system to elucidate the cellular and molecular pathways driving lung regeneration. This model holds potential to advance our understanding of lung repair mechanisms, facilitating the development of targeted therapeutic strategies for enhancing lung regeneration post-resection.