Deletion of LCMR1 in alveolar type II cells induces lethal impairment of lung structure and function in adult mice

[摘要] Background: Previous studies of lung cancer metastasis-related protein 1 (LCMR1) mainly focused on its relationship with cancer. However, the function of LCMR1 in normal tissues or cells is poorly understood. We aimed to investigate the effects of alveolar type II cell (AT2 cell)-specific LCMR1 deletion on lung structure and function in adult mice. Methods: Mice carrying the floxed LCMR1 allele with exons 2–4 flanked by loxP sites were constructed and then crossed with Sftpc-CreERT2 mice to obtain Sftpc-CreERT2; LCMR1flox/flox for AT2 cell-specific LCMR1 deletion and LCMR1flox/flox mice as littermate control. We observed the body weight change, histopathology, lung wet/dry weight ratio, pulmonary function, and survival of the mice, together with the protein concentration, inflammatory cells, and cytokine levels in bronchoalveolar lavage fluid. We also detected AT2 cell numbers and expression of pulmonary surfactant protein in the lung tissues. The apoptosis of AT2 cells was also assessed. Results: We found that AT2 cell-specific LCMR1 deletion caused rapid weight loss and increased mortality in mice. Histopathological analysis revealed damaged lung structure, including inflammatory cell infiltration, alveolar hemorrhage, and edema. The lung wet/dry weight ratio was higher and bronchoalveolar lavage fluid (BALF) analysis revealed elevated protein concentration, inflammatory cell counts, and cytokine levels. Pulmonary function measurement showed increased airway resistance, decreased lung compacity, and compliance. We also found massive AT2 cell loss and altered expression of pulmonary surfactant protein. Deletion of LCMR1 promoted apoptosis in AT2 cells. Conclusions: We successfully generated an AT2 cell-specific LCMR1 conditional knockout mouse model and further revealed the crucial role of LCMR1 in maintaining AT2 cell homeostasis.

[学科分类] 呼吸医学

[关键词] Lung cancer metastasis-related protein 1 (LCMR1);alveolar type II cell;CRISPR/Cas9;conditional gene knockout