Elastin-based molecular MRI of liver fibrosis
Authors: Josef Ehling, Matthias Bartneck, Viktor Fech, Britta Butzbach, Richard Cesati, Rene Botnar, Twan Lammers, Frank Tacke
Journal: Hepatology (2013)

The deposition of extracellular matrix (ECM) proteins, such as collagen and elastin, is one of the hallmarks of liver fibrosis. In recent years it has become increasingly clear that tissue repair and remodeling are highly dynamic processes, resulting in continuous synthesis and turnover of ECM components during hepatofibrogenesis, and in disease state-specific changes in both the quantitative amount and qualitative composition of the ECM.1 In the June 2012 issue of HEPATOLOGY, Pellicoro et al.2 elegantly demonstrate that elastin accumulation represents a distinct feature of advanced-stage liver fibrosis, because of both increased synthesis and decreased macrophage metalloelastase (MMP12)-mediated degradation. Taking these findings, and the results recently reported by Polasek et al.3 on a collagen-specific magnetic resonance (MR) contrast agent into account, we reasoned that elastin might be a promising novel target for molecular MR monitoring of ECM-remodeling during hepatic fibrosis. We therefore evaluated the accumulation of the gadolinium-containing elastin-specific MR contrast agent ESMA, which has been shown to facilitate noninvasive assessment of atherosclerotic plaque burden4 in experimental murine liver fibrosis using a clinical 3.0T Philips Achieva MRI scanner. Two hours after intravenous administration of 0.2 mmol/kg ESMA into healthy and carbon tetrachloride (CCl4)-treated c57bl/6 mice (0.6 mL CCl4/kg body weight; thrice weekly for 4 weeks; n = 3 mice per group), a three-dimensional high-resolution inversion recovery gradient echo delayed-enhancement MRI (DE-MRI; see Makowski et al.4 for details on MR parameters and methodology) of liver tissue indicated clear differences between normal and diseased animals (Fig. 1): while healthy livers displayed no focal contrast enhancement upon ESMA administration (Fig. 1D,E), very distinct perivascular signals were observed in large and medium-sized vessels in fibrotic livers (Fig. 1A,B). This observation was in line with periportal ECM deposition visualized using Elastica-Van-Gieson staining (Fig. 1C,F). Although these findings require further investigation (with regard to fibrosis stage, ESMA dose, timing, specificity, and quantification), they demonstrate that elastin-based molecular MRI, like collagen-based molecular MRI,3 may be suitable for noninvasive monitoring of ECM remodeling during liver fibrosis. As the collagen-to-elastin-ratio changes during the progression and regression of liver fibrosis,2 the selective or combined use of different molecular MR probes might be a promising strategy for translating the differential regulation of ECM proteins during fibrosis pro- and regression into novel noninvasive imaging techniques for the clinic. Elastin-based molecular MRI of liver fibrosis. C57bl/6 mice were treated with CCl4 thrice weekly (0.6 mL/kg, intraperitoneally) for 4 weeks to induce liver fibrosis (A-C) or treated with the vehicle (corn oil) as controls (D-F) and subjected to MRI using a clinical 3 T MR scanner (Achieva 3.0T, Philips Healthcare, Best, Netherlands). Two hours after the intravenous injection of an elastin-specific gadolinium-containing MR contrast agent (ESMA, BMS753951), significant perivascular T1 contrast enhancement (see arrows) was observed in fibrotic (A,B), but not in healthy control livers (D,E). Periportal elastin accumulation in fibrotic (C) versus healthy livers (F) was confirmed by way of Elastica-Van-Gieson staining, clearly demarcating the presence of collagen and elastin fibers in light red and dark purple, respectively. Results are representative of n = 3 animals per group. For details on MR scanning methodology and ESMA specificity, see Makowski et al.4 Supported by the German Research Foundation (DFG SFB/TRR57; TA434/2-1; EH412/1-1; LA2937/1-1) and British Heart Foundation (RG/12/1/29262). ESMA was kindly provided by David Onthank (Lantheus Medical Imaging, North Billerica, MA). JOSEF EHLING, M.D.1 MATTHIAS BARTNECK, PH.D.2 VIKTOR FECH2 BRITTA BUTZBACH, M.D.3 RICHARD CESATI, PH.D.4 RENE BOTNAR, PH.D.3 TWAN LAMMERS, PH.D., D.SC.1 FRANK TACKE, M.D., PH.D.2 1Department of Experimental Molecular Imaging University Hospital RWTH Aachen Aachen, Germany 2Department of Medicine III University Hospital RWTH Aachen Aachen, Germany 3Division of Imaging Sciences and Biomedical Engineering King's College London London, UK 4Lantheus Medical Imaging North Billerica, MA, USA