Lung repair and regeneration: advanced models and insights into human disease The respiratory system serves as both a gas exchange site and a barrier against environmental threats. Recent research highlights the complexity of the mammalian respiratory system, focusing on gas exchange and immune defense. This review discusses models of repair and regeneration to interpret human and animal data and guide future drug development. The respiratory system's multicellular barrier functions as a first line of defense against microbial invasion and pollutants. It has evolved unique tissue systems for gas exchange and immune defense. The respiratory system has developed strategies to repair and regenerate after injury and disease, as seen in the COVID-19 pandemic and chronic obstructive pulmonary disease (COPD). Recent advances in basic and translational research have improved understanding of lung repair and regeneration. The review explores the development of model systems and assays to study human-specific diseases, including how to "humanize" models. It also examines the relationship between acute and chronic lung diseases and the theory of "failed regeneration." Understanding these processes could lead to therapies that restore respiratory function. The respiratory system consists of two main regions: the airways and the alveolar gas-exchanging compartment. The airways include the trachea and bronchi, lined with secretory and ciliated cells. The alveolar compartment is responsible for gas exchange. The airway epithelium contains various cell types, including basal cells, secretory cells, and neuroendocrine cells. The alveolar epithelium includes AT1 and AT2 cells, which play critical roles in lung function. AT2 cells are progenitors that can differentiate into AT1 cells after injury. AT1 cells are structural cells that form an epithelial barrier and support gas exchange. Recent studies show that AT1 cells can reprogram into AT2 cells after injury. The vascular capillary plexus in the alveolus mediates gas exchange with AT1 cells. Capillary endothelial cells in the lung are heterogeneous and play roles in gas exchange. The alveolar mesenchyme contains fibroblasts that secrete signaling factors important for epithelial and endothelial responses. Infectious injury, such as influenza A, targets AT2 cells and epithelial cells, leading to cytotoxic cell death and rapid repair. Non-infectious acute injury, such as bleomycin-induced lung injury, causes alveolar damage and myofibroblast expansion. Hyperoxic injury causes damage to pediatric and adult lungs. Chemical injuries, such as naphthalene, target airway epithelial cells. Allergen exposure leads to airway hyperresponsiveness and disease. Genetic models have been used to study lung injury and repair, including the use of diphtheria toxin to deplete cells. Gene therapy is a promising strategy for monogenic lung diseases. Precision-cut lung slices (PCLS) are emerging as a tool for drug discovery and clinical translation. Blastocyst complementation is a method toLung repair and regeneration: advanced models and insights into human disease The respiratory system serves as both a gas exchange site and a barrier against environmental threats. Recent research highlights the complexity of the mammalian respiratory system, focusing on gas exchange and immune defense. This review discusses models of repair and regeneration to interpret human and animal data and guide future drug development. The respiratory system's multicellular barrier functions as a first line of defense against microbial invasion and pollutants. It has evolved unique tissue systems for gas exchange and immune defense. The respiratory system has developed strategies to repair and regenerate after injury and disease, as seen in the COVID-19 pandemic and chronic obstructive pulmonary disease (COPD). Recent advances in basic and translational research have improved understanding of lung repair and regeneration. The review explores the development of model systems and assays to study human-specific diseases, including how to "humanize" models. It also examines the relationship between acute and chronic lung diseases and the theory of "failed regeneration." Understanding these processes could lead to therapies that restore respiratory function. The respiratory system consists of two main regions: the airways and the alveolar gas-exchanging compartment. The airways include the trachea and bronchi, lined with secretory and ciliated cells. The alveolar compartment is responsible for gas exchange. The airway epithelium contains various cell types, including basal cells, secretory cells, and neuroendocrine cells. The alveolar epithelium includes AT1 and AT2 cells, which play critical roles in lung function. AT2 cells are progenitors that can differentiate into AT1 cells after injury. AT1 cells are structural cells that form an epithelial barrier and support gas exchange. Recent studies show that AT1 cells can reprogram into AT2 cells after injury. The vascular capillary plexus in the alveolus mediates gas exchange with AT1 cells. Capillary endothelial cells in the lung are heterogeneous and play roles in gas exchange. The alveolar mesenchyme contains fibroblasts that secrete signaling factors important for epithelial and endothelial responses. Infectious injury, such as influenza A, targets AT2 cells and epithelial cells, leading to cytotoxic cell death and rapid repair. Non-infectious acute injury, such as bleomycin-induced lung injury, causes alveolar damage and myofibroblast expansion. Hyperoxic injury causes damage to pediatric and adult lungs. Chemical injuries, such as naphthalene, target airway epithelial cells. Allergen exposure leads to airway hyperresponsiveness and disease. Genetic models have been used to study lung injury and repair, including the use of diphtheria toxin to deplete cells. Gene therapy is a promising strategy for monogenic lung diseases. Precision-cut lung slices (PCLS) are emerging as a tool for drug discovery and clinical translation. Blastocyst complementation is a method to