Avian lung single-cell atlas elucidates evolutionary divergence in endothermic respiration

Abstract The evolution of distinct lung architectures in birds (tubular air capillaries) and mammals (alveoli) represents a classic example of convergent evolution, yet their cellular differences remain poorly characterized. We present the comparative single-cell atlas of avian and mammalian lungs, revealing four key findings. First, we discover a persistent hybrid cell population (AT1/AT2) in neonatal and adult birds that disappears postnatally in mice, uncovering distinct strategies for lung maintenance. Second, cross-species comparisons highlight striking divergence in alveolar cell types, reflecting specialized adaptations to different respiratory demands. Third, avian lungs show unique molecular signatures in proliferation and saccular development pathways, potentially explaining their superior respiratory efficiency. Fourth, our viral receptor analysis uncovered differential ACE2 (SARS-CoV-2 receptor) expression but conserved EGFR (influenza A receptor), suggesting species-specific disease vulnerabilities. This work provides unprecedented insights into the evolutionary and developmental mechanisms shaping lung diversity in endotherms, with implications for respiratory biology, regenerative medicine, and zoonotic disease research.