Abstract
BackgroundIdiopathic pulmonary fibrosis (IPF) is a treatment resistant disease with poor prognosis. Numerous compounds have been demonstrated to efficiently prevent pulmonary fibrosis (PF) in animal models but only a few were successful when given to animals with established fibrosis. Major concerns of current PF models are spontaneous resolution and high variability of fibrosis, and the lack of assessment methods that can allow to monitor the effect of drugs in individual animals over time. We used a model of experimental PF in rats and compare parameters obtained in living animals with conventional assessment tools that require removal of the lungs.MethodsPF was induced in rats by adenoviral gene transfer of transforming growth factor-beta. Morphological and functional changes were assessed for up to 56 days by micro-CT, lung compliance (measured via a mechanical ventilator) and VO2max and compared to histomorphometry and hydroxyproline content.ResultsStandard histological and collagen assessment confirmed the persistent fibrotic phenotype as described before. The histomorphological scores correlated both to radiological (r2 = 0.29, p < 0.01) and functional changes (r2 = 0.51, p < 0.0001). VO2max did not correlate with fibrosis.ConclusionThe progression of pulmonary fibrosis can be reliably assessed and followed in living animals over time using invasive, non-terminal compliance measurements and micro-CT. This approach directly translates to the management of patients with IPF and allows to monitor therapeutic effects in drug intervention studies.
Highlights
Idiopathic pulmonary fibrosis (IPF) is a treatment resistant disease with poor prognosis
Idiopathic pulmonary fibrosis (IPF) is a progressive disease of unknown origin characterized by increased matrix deposition, resulting in functional impairment and respiratory failure [1]
Several hundreds of compounds were identified in various models of experimental PF and proposed to have therapeutic potential for IPF [5]
Summary
Idiopathic pulmonary fibrosis (IPF) is a treatment resistant disease with poor prognosis. Numerous compounds have been demonstrated to efficiently prevent pulmonary fibrosis (PF) in animal models but only a few were successful when given to animals with established fibrosis. We used a model of experimental PF in rats and compare parameters obtained in living animals with conventional assessment tools that require removal of the lungs. Idiopathic pulmonary fibrosis (IPF) is a progressive disease of unknown origin characterized by increased matrix deposition, resulting in functional impairment and respiratory failure [1]. Assessment tools used in experimental PF are primarily based on histology and quantitative collagen analysis, providing a snapshot of a complex and chronic biological process [8], whereas clinical management of IPF relies on physiologic parameters (lung function, exercise test, echocardiography) and radiology (chest x-ray and high resolution computed tomography). Clinical trials are designed to detect changes in survival and/or lung function parameters [9]
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