Magnetic resonance imaging as a non-invasive tool to investigate pulmonary and renal fibrosis in small rodents : method and readout validation, animal model optimization, and substance testing

Abstract

Pulmonary fibrosis, an end result of various types of lung damage including interstitial pneumonia and respiratory bronchiolitis (Gross and Hunninghake, 2001; Katzenstein and Myers, 1998; Lazenby et al., 1990) is a lethal disease characterized by fibroblast proliferation and extracellular matrix (ECM) remodeling. About 20% of the cases are of unknown cause and are thus termed idiopathic pulmonary fibrosis (IPF). A comparable pathology can be observed in fibrotic kidneys. Chronic kidney diseases, as diabetic nephropathy, hypertensive nephropathy, or chronic glomerulonephritis, lead in most cases to renal fibrosis, a disease characterized by infiltration of inflammatory cells, fibroblast activation, glomerulosclerosis and tubulointerstitial fibrosis (for reviews see Liu, 2006 and Efstratiadis et al., 2009). The work in this thesis concentrates on the validation of magnetic resonance imaging (MRI) as a non-invasive tool to follow longitudinally anatomical and functional changes related to lung and kidney injury induced in the corresponding small rodent models of fibrosis. Bleomycin, instilled into the lungs of mice or rats has been used to induce pulmonary fibrosis. Intra-venous injection of adriamycin induced nephropathy in rats. The bleomycin model was optimized introducing the oropharyngeal aspiration route for the antibiotic. Ultrashort echo time MRI was validated for the detection of lung lesions and tissue deposition in the pulmonary fibrosis model in rats and mice, while contrast enhanced gradient-echo MRI was validated to detect nephropathy and macrophage infiltration in the rat adriamycin model of renal fibrosis. In addition, two reference substances regarding the treatment of pulmonary fibrosis were found. In summary, the studies discussed in this thesis deliver contributions to three pillars of preclinical pharmaceutical research: the availability of appropriate animal models, the availability of readouts or parameters that quantitatively reflect disease evolution in those models, and the availability of reference compounds, known to interfere with the disease development.