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.
In the June 2012 issue of HEPATOLOGY, Pellicoro et al. 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. 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 burden 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. 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, 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, 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.