The respiratory barrier, a thin epithelial layer separating the human body from the environment, is vulnerable to toxicants and chronic respiratory diseases. Animal experimentation is crucial for training medical technicians, evaluating toxicants, and developing inhaled treatments. Species differences in the respiratory tract explain why some species are better at predicting human toxicity. This review describes anatomical differences between the human and mammalian lungs and lists characteristics of mammalian models for chronic respiratory diseases such as asthma, COPD, cystic fibrosis, pulmonary hypertension, pulmonary fibrosis, and tuberculosis. The generation of animal models is challenging due to the lack of spontaneous disease development in these species. Mouse models are common, but other species like zebrafish and fruit flies are useful for studying immunological aspects. The future of drug development may involve combinations of in silico, in vitro, and in vivo (mammalian and invertebrate) models. - **Respiratory Barrier**: A thin epithelial layer that separates the human body from the environment, vulnerable to toxicants. - **Chronic Respiratory Diseases**: Common conditions like asthma, COPD, cystic fibrosis, pulmonary hypertension, pulmonary fibrosis, and tuberculosis. - **Animal Experimentation**: Used for training, toxicity testing, and drug development. - **Species Differences**: Some species are better at predicting human toxicity due to differences in respiratory tract architecture. - **Mammalian Models**: Commonly used for chronic respiratory diseases, with specific models for asthma, COPD, cystic fibrosis, pulmonary hypertension, pulmonary fibrosis, and tuberculosis. - **Non-Mammalian Models**: Zebrafish and fruit flies are useful for studying immunological aspects. - **Regulatory Environment**: Varies across countries, with some requiring ethical reviews and others mandating detailed documentation. - **Historical Context**: Animal experimentation has evolved over time, from early uses in surgery to modern physiological studies. - **Anatomical Differences**: Species differences in the respiratory tract, including lung volume, surface area, and barrier thickness. - **Physiological Parameters**: Differences in breathing patterns, cough reflex, and mucus transport rates. - **Histological Differences**: Variations in the cellular composition of the airway mucosa. - **Disease Models**: Induced and genetically modified models for asthma, COPD, cystic fibrosis, pulmonary hypertension, pulmonary fibrosis, and tuberculosis. - **Challenges**: Limitations in translational relevance, such as differences in cytokine release, cellular composition, and experimental settings. - **Future Directions**: Combining in silico, in vitro, and in vivo models for more effective drug development.The respiratory barrier, a thin epithelial layer separating the human body from the environment, is vulnerable to toxicants and chronic respiratory diseases. Animal experimentation is crucial for training medical technicians, evaluating toxicants, and developing inhaled treatments. Species differences in the respiratory tract explain why some species are better at predicting human toxicity. This review describes anatomical differences between the human and mammalian lungs and lists characteristics of mammalian models for chronic respiratory diseases such as asthma, COPD, cystic fibrosis, pulmonary hypertension, pulmonary fibrosis, and tuberculosis. The generation of animal models is challenging due to the lack of spontaneous disease development in these species. Mouse models are common, but other species like zebrafish and fruit flies are useful for studying immunological aspects. The future of drug development may involve combinations of in silico, in vitro, and in vivo (mammalian and invertebrate) models. - **Respiratory Barrier**: A thin epithelial layer that separates the human body from the environment, vulnerable to toxicants. - **Chronic Respiratory Diseases**: Common conditions like asthma, COPD, cystic fibrosis, pulmonary hypertension, pulmonary fibrosis, and tuberculosis. - **Animal Experimentation**: Used for training, toxicity testing, and drug development. - **Species Differences**: Some species are better at predicting human toxicity due to differences in respiratory tract architecture. - **Mammalian Models**: Commonly used for chronic respiratory diseases, with specific models for asthma, COPD, cystic fibrosis, pulmonary hypertension, pulmonary fibrosis, and tuberculosis. - **Non-Mammalian Models**: Zebrafish and fruit flies are useful for studying immunological aspects. - **Regulatory Environment**: Varies across countries, with some requiring ethical reviews and others mandating detailed documentation. - **Historical Context**: Animal experimentation has evolved over time, from early uses in surgery to modern physiological studies. - **Anatomical Differences**: Species differences in the respiratory tract, including lung volume, surface area, and barrier thickness. - **Physiological Parameters**: Differences in breathing patterns, cough reflex, and mucus transport rates. - **Histological Differences**: Variations in the cellular composition of the airway mucosa. - **Disease Models**: Induced and genetically modified models for asthma, COPD, cystic fibrosis, pulmonary hypertension, pulmonary fibrosis, and tuberculosis. - **Challenges**: Limitations in translational relevance, such as differences in cytokine release, cellular composition, and experimental settings. - **Future Directions**: Combining in silico, in vitro, and in vivo models for more effective drug development.