Animal Models of Emphysema
Chronic obstructive pulmonary disease (COPD) is a prevalent chronic respiratory condition characterized by irreversible airflow limitation. Emphysema, a primary pathological feature of COPD, contributes significantly to global mortality and imposes a substantial economic burden on healthcare systems. This article provides a comprehensive review of the establishment and evaluation methods of animal models of emphysema and COPD, focusing on animal selection, modeling methods, and model evaluation.
Significance of Establishing Animal Models of Emphysema COPD is induced by various factors, and its mechanisms are complex, involving oxidative stress, inflammation, protease-antiprotease imbalance, apoptosis, and immunosenescence. Given the ethical issues surrounding research on COPD patients, animal models are essential for investigating the disease’s mechanisms. Emphysema, as a key feature of COPD, has been a focal point of research. Animal models of emphysema enhance our understanding of COPD’s physiology, pathophysiology, and treatment. These models, though not replicating all aspects of human COPD, are valuable for studying the disease’s mechanisms.
Animal Selection for Modeling Various animal models of emphysema have been developed, including sheep, dogs, pigs, rabbits, monkeys, guinea pigs, mice, rats, and squirrels. These models reflect the pathology and physiology of human diseases to some extent. Features of COPD, such as inflammatory cell aggregation, oxidative stress, cytokine and protease production, small airway and vascular remodeling, emphysema, pulmonary hypertension, and decreased lung function, can be induced in different models. However, differences in anatomy, physiology, reactivity to damage, and sensibility to cigarette smoke (CS) among species must be considered.
Anatomy and Physiology Rats are commonly used due to their small size, low cost, and short reproduction cycle, but they have limitations, such as reliance on nasal breathing and differences in bronchial structure compared to humans. Pigs have more mature lung tissue and a structure similar to humans, making them suitable for COPD studies, though their large size and high cost are disadvantages. Mice are considered the best choice for emphysema studies due to their genetic similarity to humans, low cost, and availability of various strains.
Reactivity to Damage Animal models of emphysema induced by passive smoking exhibit enlarged alveolar spaces, but the degree of enlargement varies by species. Unlike humans, some animals do not develop severe illness, limiting the window for therapeutic intervention studies. Goblet cell metaplasia, a characteristic of COPD, is weaker in mice and rats compared to guinea pigs, dogs, and non-human primates.
Sensibility to Tobacco Different strains within a species may respond differently to the same stimulus. For example, NZWLac/J mice are not sensitive to CS, while AKR/J mice are more sensitive and exhibit CS-induced COPD. DBA/2 mice develop emphysema faster during CS exposure but show decreased airway goblet cell metaplasia compared to C57BL/6J mice.
Cytokines Common animal models, except monkeys, do not fully replicate human cytokines. Rodents, for instance, have chemokines KC (CKC) and cytokine-induced neutrophil chemotactic factors (CINCs) that are closest to human interleukin (IL)-8. Different strains within the same species may have different inflammatory cell and cytokine responses to the same stimulus.
Proteases Matrix metalloproteinases (MMP)-12 is a major component of mice macrophage metalloproteinases, while MMP-7 is more important in humans for destroying elastic tissues. Despite differences, mice are considered more suitable for experimental studies on emphysema due to their genetic similarity to humans and the availability of various strains.
Mechanisms of Emphysema Elastase-Antielastase Imbalance The imbalance between elastases (MMP family) and anti-elastases is a key mechanism in COPD. Excessive elastases released by inflammatory cells damage lung parenchyma, leading to emphysema. Genetic alpha 1-antitrypsin (AT) deficiency causes elastase-antielastase imbalance, resulting in emphysema-like changes.
Oxidation-Antioxidant Imbalance Oxidative stress is a significant mechanism in COPD. Cigarette smoke and other harmful particles produce excessive oxides that damage lung tissue. Antioxidants like endostatin, carboxymethyl steam, n-acetylcysteine, and ambroxol can alleviate COPD exacerbations and slow pulmonary function decline.
Inflammatory Mechanism Inflammation is central to the onset and progression of COPD. Foreign particles entering the lower respiratory tract activate macrophages, neutrophils, and lymphocytes, releasing mediators like leukotriene B4 (LTB4), IL-8, tumor necrosis factor (TNF)-α, intercellular adhesion molecule (ICAM) 1, and transforming growth factor (TGF)-β, which damage lung tissue and promote inflammation.
Hormone-Related Mechanism Corticosteroid therapy is often ineffective in COPD patients, a phenomenon known as “hormone resistance.” This resistance may be related to the inactivation of the kB pathway and decreased activity of histone deacetylase in the lungs of COPD patients.
Immunologic Mechanism Macrophages and lymphocytes, particularly CD8+ lymphocytes, play a crucial role in COPD pathogenesis. Even after smoking cessation, the inflammatory response in the lungs continues to progress.
Vagus Nerve Stimulation Increased vagus nerve tension in COPD patients leads to bronchial smooth muscle contraction and hypersecretion of glands under the airway mucosa. Acetylcholine, released from parasympathetic nervous system, bronchial epithelial cells, and inflammatory cells, contributes to airway remodeling.
Modeling Methods of Animal Models of Emphysema Elastase-Induced Animal Model of Emphysema Emphysema can be induced by instilling elastase into the trachea, disrupting the protease-antiprotease balance in lung tissue. Commonly used elastases include papain, pig pancreatic elastinase (PPE), and human neutrophil elastase (HNE). Papain, the earliest elastase used, induces stable emphysema in rats at a dose of 2 mg/kg. PPE, derived from swine pancreas, induces emphysema-like changes in 4 to 6 weeks. HNE, though less commonly used, can also induce emphysema in hamsters.
Passive Smoking-Induced Animal Model of Emphysema Cigarette smoke exposure is a traditional method for inducing emphysema in animals. Long-term CS exposure leads to inflammatory responses in the lungs, similar to human COPD. Guinea pigs are the most sensitive to smoke, while rats show varying susceptibility. Exposure methods include part exposure (nose or head only) and whole-body exposure. Passive smoking models are popular due to their low cost and simplicity.
Chemicals-Induced Animal Model of Emphysema Chemicals like NO2, lipopolysaccharides (LPS), O3, and cadmium chloride (CdCl2) can induce emphysema. NO2 exposure induces oxidative stress and emphysema in mice, while LPS triggers inflammation and protease-antiprotease imbalance. CdCl2 induces emphysema in golden ground squirrels.
Cigarette Smoke Extract-Induced Animal Model of Emphysema Intraperitoneal injection of cigarette smoke extract (CSE) induces emphysema in mice within 6 weeks. CSE acts as an antigen, triggering an immune response that leads to emphysema. This method is effective but may have underestimated extrapulmonary effects.
Other Exogenous Factors-Induced Animal Model of Emphysema Severe hunger can induce emphysema-like changes by accelerating the metabolism of elastic and collagen fibers in lung tissues. However, this method is rarely used as it does not reflect the exact mechanisms of human emphysema.
Genetic Manipulation in Animal Model of Emphysema Gene knockout and overexpression techniques are used to study emphysema. For example, Abhd2 knockout mice exhibit emphysema-like changes due to excessive inflammatory cytokines and protease gene expression. Overexpression of PDGF-b, TNF-α, IL-6, and IL-11 can disrupt alveolar development, leading to emphysema.
Evaluation on Animal Model of Emphysema Evaluation methods include pulmonary function indicators, airway inflammation indicators, oxidative stress indicators, and pathomorphological indicators. Pathomorphological indicators, such as mean linear intercept (MLI), destructive index (DI), and apoptotic index (AI), are considered the most important for evaluating emphysema models.
Summary and Prospect Various animal models of emphysema have been developed, but none fully replicate all aspects of human COPD. Cigarette smoke exposure is the most reasonable method for inducing emphysema in animals, though it has limitations. Future research should focus on developing more standardized and representative animal models to better understand COPD’s mechanisms and improve treatment strategies.
doi.org/10.1097/CM9.0000000000000469
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