Lung models are simplified representations of the human lung, developed to investigate its functions, disease progression, and reactions to various substances. They provide researchers with controlled environments to understand the respiratory system without direct human experimentation. These models are valuable tools for studying lung biology and pathology.
Understanding Different Lung Models
Lung models encompass diverse approaches, each mimicking lung physiology and disease. They vary in complexity and their ability to replicate the human lung’s environment, enabling researchers to study lung tissues and functions in various contexts.
In Vitro Models
In vitro models involve studying cells or tissues outside a living organism in a laboratory setting. Two-dimensional (2D) cell cultures, the simplest form, grow cells in a single layer on a flat surface. These cultures are useful for basic cell and molecular biology research and high-throughput screening, but they do not fully capture the lung’s three-dimensional structure.
Three-dimensional (3D) cell cultures, such as spheroids and organoids, offer a more physiologically relevant representation of lung biology by allowing cells to grow and interact in a 3D matrix. Spheroids are 3D cell aggregates, while organoids are self-assembled 3D structures derived from stem cells that can differentiate into various cell types and mimic tissue organization and function. Precision-cut lung slices (PCLS), thin slices of lung tissue, also provide a valuable ex vivo model retaining the lung’s physiological architecture and multicellularity.
“Organ-on-a-chip” (OOC) technologies, also known as lung microphysiological systems (MPS), are advanced microfluidic devices that recreate organ-level functions by mimicking tissue-tissue interfaces and microenvironmental cues. These chips integrate multiple cell types, such as alveolar epithelial and vascular endothelial cells, on a porous membrane, and can simulate breathing motions through cyclic stretching. The first lung-on-a-chip, developed in 2010, recreated the alveolar-capillary interface, with later versions mimicking small airways.
In Vivo Models
In vivo models use living organisms, primarily animals, to study lung physiology and disease in a whole-organism context. Mice and rats are the most frequently used, though other animals like guinea pigs, rabbits, dogs, and non-human primates are also utilized. These models allow investigation of complex interactions between cell types and systemic factors on disease progression. Animal models are often employed to study lung injury, inflammation, and diseases like pulmonary fibrosis.
Computational Models
Computational models use computer simulations and mathematical algorithms to predict lung behavior and disease progression based on collected data. These models range from simpler compartmental representations establishing mathematical relationships between lung properties to complex anatomically based models using medical imaging data, such as CT scans, to reconstruct detailed 3D lung airway structures. Computational fluid dynamics (CFD) simulations, for instance, can model airflow distribution in normal and obstructed airways, helping to understand conditions like asthma and chronic obstructive pulmonary disease (COPD).
Advanced Human-Derived Models
Recent advancements include sophisticated human-derived models that more closely replicate human lung biology. Human lung organoids, grown from induced pluripotent stem cells (iPSCs) or adult stem cells, can mirror the lung’s cellular composition and functionality, making them suitable for studying developmental processes and personalized medicine. Bioprinted lung tissues, created using 3D bioprinting, combine human cells with biomaterials to produce complex microscale lung tissue, including bronchial and alveolar epithelia with associated mesenchymal and vascular cells. This technology allows for functional lung organoid models that replicate the dynamic human lung environment, potentially bridging the gap between simpler in vitro models and whole animals.
Key Applications of Lung Models
Lung models are applied across various scientific and medical fields, providing insights into respiratory health and disease. These applications span from early-stage drug development to understanding complex disease mechanisms and assessing environmental impacts.
Drug Discovery and Testing
Lung models play a significant role in the discovery and testing of new drugs for respiratory diseases. They enable researchers to screen potential drug candidates for conditions such as asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis, and assess their toxicity before human trials. For instance, 3D bioprinted lung models have studied how drugs like remdesivir and molnupiravir travel across tissue barriers to inhibit viral replication. Lung-on-a-chip systems also evaluate the absorption of aerosolized therapeutics and the safety of new drugs.
Disease Understanding
Lung models are instrumental in unraveling the mechanisms underlying various lung diseases. They help researchers understand the progression of chronic conditions and the body’s response to infections. For example, mouse models have investigated the long-term pulmonary consequences of SARS-CoV-2 infection, revealing insights into chronic active pneumonia and pulmonary fibrosis. Studies using these models show SARS-CoV-2 infection can lead to persistent lung abnormalities and fibrotic changes, unlike influenza, which often results in more complete repair.
Lung-on-a-chip models have also been developed to study how respiratory viruses like COVID-19 affect different lung regions, such as the upper airway and alveoli. These microphysiological systems, often incorporating induced pluripotent stem cells (iPSCs), provide a high-fidelity way to model tissue- and virus-specific disease mechanisms and immune responses. This allows for a deeper understanding of conditions like acute respiratory distress syndrome (ARDS) and dysregulated immune responses seen in severe COVID-19.
Environmental and Toxicology Studies
Lung models test the effects of environmental factors and inhaled substances on lung health, assessing the toxicity of air pollutants, chemicals, and particulate matter. For instance, human pluripotent stem cell (hPSC) derived lung progenitor cells and alveolar type 2 epithelial cells have evaluated the toxicity of common air pollutants like benzo(a)pyrene, nano-carbon black, and nano-SiO2. These studies reveal how nanoparticles are internalized by lung cells and interfere with functions such as surfactant secretion. Exposure to air pollutants like ozone, sulfur dioxide, and particulate matter (PM2.5) has been linked to oxidative stress, inflammatory responses, and changes in lung function, effects investigable using various lung models.
Personalized Medicine
Lung models hold promise for advancing personalized medicine, tailoring treatments to an individual patient’s specific needs. By using patient-specific cells, such as induced pluripotent stem cells (iPSCs), researchers can create models mimicking an individual’s unique lung biology and disease. This allows for patient-specific computational lung models derived from medical imaging and ventilatory information, predicting the local state of affected lung tissue during mechanical ventilation. Lung simulators can also replicate human lung mechanics and be adjusted for various patient conditions, helping optimize treatments like ventilator settings for acute respiratory distress.
Limitations and Ethical Considerations
Despite advancements, lung models have inherent limitations in fully replicating the human lung’s complexity. The intricate structure, diverse cell interactions, and dynamic physiological responses are challenging to mimic perfectly in any single model system. For example, traditional 2D cell cultures lack the complex 3D structure and dynamic forces present in human lungs. Even advanced 3D cultures, while more representative, may not fully capture organ-level characteristics like the complete cell-host immune response or the recruitment of circulating immune cells under active fluid flow.
Animal models, while able to recapitulate complex physiological processes and multi-organ interplay, often differ significantly from human physiology, limiting translational capacity. For instance, only about 3% of pulmonary therapeutics succeeding in preclinical animal trials make it to market, compared to 6-14% for other diseases. These interspecies differences in lung structure, mucociliary clearance, and immune responses can impact the accuracy of drug efficacy and toxicity predictions in humans.
The use of animal models also raises significant ethical considerations. Concerns about animal suffering in research have led to the widespread adoption of the “3 Rs” principles: Replacement, Reduction, and Refinement. Replacement involves developing alternative models to avoid or entirely replace animal use. Reduction focuses on minimizing the number of animals used while still obtaining reliable results, for example, by maximizing data gathered from each animal. Refinement aims to decrease the incidence and severity of inhumane procedures, minimizing pain and distress and enhancing animal welfare.
Ongoing efforts aim to develop more sophisticated and human-relevant lung models to overcome current limitations. The integration of advanced bioprinting and organoid technologies, for instance, is a promising area for creating functional lung organoid models that more closely mimic human lung tissue and its dynamic environment. These advancements seek to improve the accuracy of disease modeling and drug testing, potentially reducing reliance on animal models and accelerating new therapies for respiratory diseases.