How Far Are We from Research That Is Independent of the Use of Animal Models? A Comparative Analysis between Animal and 3D/On-a-Chip Models for the Study of Respiratory Diseases
Abstract
:1. Macroscopical and Microscopical Structure of the Bronchial Tree and Airway Epithelium
- Columnar cells with vibrating cilia;
- Goblet cells, intercalated in the epithelium and responsible for the production of mucus;
- Basal cells.
- (1)
- In the bronchi, the mucosa consists of a pseudostratified ciliated epithelium with intercalated goblet, brush, neuroendocrine (Kultchitsky’s), and basal cells. Brush cells are characterized by the presence of microvilli on the cell surface, and their function is still unclear. One of the current hypotheses is that they could be intermediate elements that then differentiate into ciliated cells or cells able to regulate mucus clearance. Kulchitsky’s cells participate in the local control of mucus production and cell differentiation (they drive basal cells to differentiate into goblet or columnar cells as needed). In the lamina propria, there are bronchial glands.
- (2)
- In the bronchioles, the epithelium becomes a simple ciliated cuboidal epithelium with intercalated club cells (formerly known as Clara cells) that are more prevalent in the terminal bronchioles. In physiological conditions, club cells are believed to secrete the primary components of the extracellular substance lining the respiratory bronchioles, as well as to regulate the rheological properties of the mucus by rendering it richer in serum and, therefore, more fluid in the distal segments of the respiratory tract. The submucosa is absent in the bronchioles. Smooth muscle fiber cells (also present at the bronchial level) are prevalent at the bronchiolar level, where they regulate the flow of air entering and leaving the alveoli, thus determining the mechanisms of bronchodilation and bronchoconstriction controlled by the autonomic nervous system.
- (3)
- Two types of epithelial cells compose the alveolar epithelium: type I and type II alveolar cells. Type I are large flat cells that comprise about 95% of the alveolar surface. Type II are small cuboidal cells with distinctive lamellar inclusions and apical microvilli which cover around 5% of the alveolar surface. Type II cells produce and secrete pulmonary surfactant. Besides these two structural elements, also located on the luminal surface of the alveolar space are alveolar macrophages, the most abundant innate immune cells in the distal lung parenchyma (Figure 1). They are the first to encounter incoming pathogens and pollutants, and help orchestrate the initiation and resolution of the immune response in the lung [1].
2. The Complexity of Methodological Approaches to Multifactorial Pathologies Such as COPD—The Reasons That Led Laboratory Animals to Be Considered the “Gold Standard”
The Complexity of Methodological Approaches to Multifactorial Pathologies Such as COPD—Alternative 3D Culture Methods
3. Asthma and Animal Models—The (im) Perfect Standard
The Building of Robust 2D/3D Cultural Models for the Investigation of Asthma
4. The Impact of Animal Models on the Study of Lung Carcinoma
Is There an Alternative to Animal Models for the Study of Lung Carcinoma?
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
3D | Three-dimensional |
AHR | Airway Hyperresponsiveness |
ALI | Air–Liquid Interface |
Aos | Airway Organoids |
BHR | Bronchial Hyperresponsiveness |
BME | Basement Membrane Extract |
BMnCs | Bone marrow Mononuclear Cells |
BOC | Body-On-a-Chip |
COPD | Chronic Obstructive Pulmonary Disease |
CS | Cigarette Smoke |
EMTU | Epithelial–Mesenchymal Trophic Unit |
HDM | House Dust Mite |
IP-10 | IFN-inducible protein 10 |
IPSCs | Induced Pluripotent Stem Cells |
LOC | Lung-On-a-Chip |
MCS | Multicellular Spheroids |
MITO | Microimpedance Tomography |
NSCLC | Non-Small Cell Lung Cancer |
OOC | Organ-On-a-Chip |
OVA | Ovalbumin |
P-V | Pressure–Volume |
PAECs | Primary Airway Epithelial Cells |
PDMS | Polydimethylsiloxane |
ROCK | Rho-associated protein kinase |
TEER | Trans-Epithelial Electrical Resistance |
TME | Tumor microenvironment |
TSLP | Thymic stromal lymphopoietin |
WE | Working Electrodes |
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Models | Advantages | Disadvantages | References |
---|---|---|---|
Animal models | • Genetic variability and diversified stress response • Possibility of highlighting the onset of fibrotic processes following inhalation of cigarette smoke (rats, guinea pigs) • Possibility to study the response to allergens and the inflammatory response in a responsive model (rabbit and guinea pigs) • Ability to study the processes leading to tumor metastasis in dynamic in vivo models | • Poor genetic similarity with humans • High operator-dependent variability • High anatomical and histological differences of the individual models compared to humans • Relatively high maintenance costs • Ethical issues • Different composition of mucus | [8,9,11,12,13,14,15] |
2D cultures models | • Easy development, maintenance and monitoring procedures • Relatively lower maintenance costs | • Inability to recreate the complexity of structures and mimic the functions of the organ-specific human environment in vivo | [16,17] |
In vivo/ex vivo 3D culture models | • Preserved cytoarchitecture • Relatively lower costs • High scalability (possibility of integrating fluidics and sensors to the system capable of implementing its reliability and data output) • In co-colture models, it is possible to investigate the role of immune system on respiratory diseases | • Absence of a standard reference • Difficult to find human samples for the creation of 3D models • Ethical limitations | [18,19,20] |
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Burgio, S.; Manna, O.M.; Intili, G.; Cappello, F.; Bucchieri, F. How Far Are We from Research That Is Independent of the Use of Animal Models? A Comparative Analysis between Animal and 3D/On-a-Chip Models for the Study of Respiratory Diseases. Appl. Biosci. 2023, 2, 157-172. https://doi.org/10.3390/applbiosci2020012
Burgio S, Manna OM, Intili G, Cappello F, Bucchieri F. How Far Are We from Research That Is Independent of the Use of Animal Models? A Comparative Analysis between Animal and 3D/On-a-Chip Models for the Study of Respiratory Diseases. Applied Biosciences. 2023; 2(2):157-172. https://doi.org/10.3390/applbiosci2020012
Chicago/Turabian StyleBurgio, Stefano, Olga Maria Manna, Giorgia Intili, Francesco Cappello, and Fabio Bucchieri. 2023. "How Far Are We from Research That Is Independent of the Use of Animal Models? A Comparative Analysis between Animal and 3D/On-a-Chip Models for the Study of Respiratory Diseases" Applied Biosciences 2, no. 2: 157-172. https://doi.org/10.3390/applbiosci2020012