Respiratory diseasesModels of pulmonary fibrosis
Section editor:
Nelly Frossard – Université Louis Pasteur, Strasbourg, France
Introduction
Idiopathic pulmonary fibrosis (IPF) is a chronic progressive disease with unknown etiology and the worst prognosis among all interstitial lung diseases, with a median survival of 2–4 years after diagnosis. The prevalence is estimated at 20/100,000 for males and 13/100,000 for females [1] and age at onset is usually greater than 50. There is no effective drug treatment available to treat fibrosis, and lung transplantation is the only measure to achieve cure. Multiple factors contribute to the pathogenesis of IPF, among them cytokines and growth factors, particularly transforming growth factor β (TGF-β).
A variety of animal models of pulmonary fibrosis have been developed, using profibrotic chemical agents such as bleomycin, gene overexpression (TGF-β, Interleukin 1β (IL-1β) etc.), irradiation or instillation of inorganic particles (asbestos, silica). This review will focus on an overview and comparison of the main existing animal models in pulmonary fibrosis and an evaluation of their clinical usefulness to study fibrogenesis and IPF.
Section snippets
Pathogenesis of pulmonary fibrosis
The underlying mechanisms for the onset and progression of fibrosis or even the natural history of IPF are poorly understood. Epithelial damage, tissue injury and inflammation are clearly involved in the initiation of repair, but how much these initiating events contribute to the chronicity and progression of disease is unknown. One hypothesis suggests a role for resident intrapulmonary fibroblasts, responding to a variety of stimuli such as TGFβ and differentiating into myofibroblasts, with
Animal models in pulmonary fibrosis
There are numerous pathologic similarities between fibrotic reactions in human and rodent lungs, and as such, animal models present an excellent tool to investigate pathologic changes in vivo. The assumption that lung injury is a necessary precursor of fibrosis requires the induction of lung damage in animal models to get a realistic picture of human disease. There are several methods to induce lung tissue damage in animal models, among them chemicals (bleomycin etc.), growth factor gene
Bleomycin model
Bleomycin is a glycosylated linear nonribosomal peptide antibiotic produced by the bacterium, Streptomyces verticillus. It was first discovered in 1962 and is used as anticancer agent in the treatment of lymphomas (especially Hodgkin's disease), squamous cell carcinomas and testicular cancer as well as pleurodesis. The most serious complication of bleomycin use in humans is pulmonary fibrosis and impaired lung function. Early experiments used bleomycin as a fibrogenic agent in animal models [21
Gene overexpression models
A second approach to models of fibrosis involves transgenic modulation to produce animals with genetic defects, such as tissue specific overexpression of cytokines and growth factors or other extracellular matrix components, leading to downstream activation of specific cytokine pathways. Conventional constitutive transgenic models do not fit well with the adult nature of the human disease, so most useful data makes use of tissue specific inducible transgenic systems to provide temporal and
Irradiation model
In humans, irradiation-induced lung fibrosis occurs as complication of treating thoracic malignancies such as esophageal and bronchial carcinomas, lymphomas or total body irradiation for bone marrow transplantation [37]. Tissue damage manifests itself in the form of acute pneumonitis (∼2–16week postradiation exposure) and eventually evolves to pulmonary fibrosis [38]. TGF-β has been shown to be involved in acute and chronic radiation-induced fibrosis [24]. Associated symptoms range from subtle
Bleomycin model
Bleomycin administration has been widely used in the assessment of therapeutic potential of several antifibrotic compounds. Hundreds of drugs have been tested and a great number have been shown to successfully stop the progression of fibrosis in this model. A brief summary of tested drugs is shown in Table 1. However, no clinical trial has demonstrated comparable success in treating human disease so far. Many compounds showing activity in this model appear to have anti-inflammatory activity and
Model comparison
Bleomycin is the most widely used of all existing animal models of pulmonary fibrosis, as it induces fibrotic changes in a very consistent manner, produces different patterns of fibrotic lesions depending on dose and route of application, and is easily accessible. However, instillation of bleomycin causes inflammation and reversible pulmonary fibrosis, and therefore correlates poorly with chronic progressive human disease. Drug activity correlates poorly to activity in human disease, as it is
Model translation to humans
To extrapolate findings from animal models to the clinical setting, certain requirements must be fulfilled. One is the capacity to produce fibrotic changes, including matrix deposition and the induction of fibroblastic foci, that last over a longer period of time to imitate the progressive character of human disease [20]. This can be achieved best by gene transfer models overexpressing TGF-β1. Others, including bleomycin, IL-1β and irradiation, cause extensive inflammation and therefore do not
Conclusion
Animal models of human pulmonary fibrosis ideally should reflect detailed characteristics of human disease including inflammation, aberrant epithelial repair, and progressive tissue scarring with the induction of fibroblastic foci. Also, they should be highly reproducible and consistent, inexpensive to maintain, easy to perform and accessible. Until now, the optimal animal model of IPF has not been established, and findings in animal models can only partly be transferred to the clinical
Outstanding issues
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What is the role of inflammation in the progression of fibrosis?
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Do circulating cells of bone marrow origin contribute to pulmonary fibrosis?
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Do epithelial cells participate in repair mechanisms by undergoing epithelial-mesenchymal transition?
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Is fibrotic tissue damage reversible?
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Which step/pathway in fibrosis progression is best to target by drugs?
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