Objective Liver injury includes inflammation and resolution stages with different macrophage populations. Hepatic macrophages can be imaged with ultrasmall paramagnetic iron oxide (USPIO) nanoparticles-enhanced magnetic resonance imaging (MRI). We aimed to assess if inflammation and resolution stages of liver injury could be differentiated with USPIO-enhanced MRI in mice. Materials and methods Three groups of C57BL/6JRj mice (control, inflammation, resolution; n = 10 for each group) were imaged. Liver fibrosis was induced by intraperitoneal carbon tetrachloride injections for 6 weeks. Multigradient-echo MRI was performed before, 24, and 48 h after intravenous injection of fluorescent USPIO. Contrast uptake was quantified with <InlineEquation ID="IEq1"> <EquationSource Format="TEX">$\triangle {R}_{2}^{* }$</EquationSource> <EquationSource Format="MATHML"><math> <mo>△</mo> <msubsup> <mrow> <mi>R</mi> </mrow> <mrow> <mn>2</mn> </mrow> <mrow> <mo></mo> </mrow> </msubsup> </math></EquationSource> </InlineEquation> measurements. Macrophages were immunostained with F4/80, and USPIO fluorescence was localized and quantified with confocal microscopy. Liver iron content was measured with inductively coupled mass spectrometry (ICP-MS). <InlineEquation ID="IEq2"> <EquationSource Format="TEX">$\triangle {R}_{2}^{ }$</EquationSource> <EquationSource Format="MATHML"><math> <mo>△</mo> <msubsup> <mrow> <mi>R</mi> </mrow> <mrow> <mn>2</mn> </mrow> <mrow> <mo></mo> </mrow> </msubsup> </math></EquationSource> </InlineEquation> was assessed with Mann–Whitney tests. Kruskal–Wallis and Dunn tests compared fibrosis, fluorescence, and ICP-MS iron concentration. Spearman tests were used for correlation analysis. Results <InlineEquation ID="IEq3"> <EquationSource Format="TEX">$\triangle {R}_{2}^{ }$</EquationSource> <EquationSource Format="MATHML"><math> <mo>△</mo> <msubsup> <mrow> <mi>R</mi> </mrow> <mrow> <mn>2</mn> </mrow> <mrow> <mo></mo> </mrow> </msubsup> </math></EquationSource> </InlineEquation> was significantly higher in the inflammation group (158 ± 85%) compared to the control (58 ± 36%, p = 0.020) and resolution (71 ± 36%, p = 0.048) groups. Confocal microscopy showed a high macrophage number and USPIO uptake in the inflammation group. <InlineEquation ID="IEq4"> <EquationSource Format="TEX">$\triangle {R}_{2}^{ }$</EquationSource> <EquationSource Format="MATHML"><math> <mo>△</mo> <msubsup> <mrow> <mi>R</mi> </mrow> <mrow> <mn>2</mn> </mrow> <mrow> <mo></mo> </mrow> </msubsup> </math></EquationSource> </InlineEquation> correlated with macrophages number (r = 0.67, p = 0.0001), USPIO fluorescence intensity (r = 0.58, p = 0.0011), and iron concentration at ICP-MS (r = 0.39, p = 0.028). Conclusion Our results suggest that the inflammatory and resolution stages of hepatic injury can be assessed with USPIO-enhanced MRI. Relevance statement Our study demonstrates that USPIO-enhanced MRI can be used to monitor the inflammatory and resolution phases of hepatic injury in mice. If future studies confirm these findings, this imaging method might be valuable for tracking hepatic inflammation dynamics. Key Points <UnorderedList Mark="Bullet"> <ItemContent> Liver <InlineEquation ID="IEq5"> <EquationSource Format="TEX">$\triangle {R}_{2}^{ }$</EquationSource> <EquationSource Format="MATHML"><math> <mo>△</mo> <msubsup> <mrow> <mi>R</mi> </mrow> <mrow> <mn>2</mn> </mrow> <mrow> <mo></mo> </mrow> </msubsup> </math></EquationSource> </InlineEquation> was highest during the inflammatory stage and partially reversed during the resolution stage, reflecting macrophage dynamics. </ItemContent> <ItemContent> Immunofluorescence showed increased macrophage number and uptake during inflammation, decreasing during resolution. </ItemContent> <ItemContent> Iron concentration significantly correlated with <InlineEquation ID="IEq6"> <EquationSource Format="TEX">$\triangle {R}_{2}^{ }$</EquationSource> <EquationSource Format="MATHML"><math> <mo>△</mo> <msubsup> <mrow> <mi>R</mi> </mrow> <mrow> <mn>2</mn> </mrow> <mrow> <mo>*</mo> </mrow> </msubsup> </math></EquationSource> </InlineEquation>, macrophage number, and total fluorescence intensity. </ItemContent> </UnorderedList> Graphical Abstract

Inflammatory and resolution stages of hepatic injury: imaging with USPIO-enhanced MRI in mice

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2026年4月10日

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Joao Piraquive Agudelo,
Sabrina Doblas,
Katell Peoc’h,
Bich-Thuy Doan,
Philippe Garteiser,
Bernard E. Van Beers

摘要

Objective

Liver injury includes inflammation and resolution stages with different macrophage populations. Hepatic macrophages can be imaged with ultrasmall paramagnetic iron oxide (USPIO) nanoparticles-enhanced magnetic resonance imaging (MRI). We aimed to assess if inflammation and resolution stages of liver injury could be differentiated with USPIO-enhanced MRI in mice.

Materials and methods

Three groups of C57BL/6JRj mice (control, inflammation, resolution; n = 10 for each group) were imaged. Liver fibrosis was induced by intraperitoneal carbon tetrachloride injections for 6 weeks. Multigradient-echo MRI was performed before, 24, and 48 h after intravenous injection of fluorescent USPIO. Contrast uptake was quantified with $\triangle {R}_{2}^{* }$ $△ R_{2}^{*}$ measurements. Macrophages were immunostained with F4/80, and USPIO fluorescence was localized and quantified with confocal microscopy. Liver iron content was measured with inductively coupled mass spectrometry (ICP-MS). $\triangle {R}_{2}^{* }$ $△ R_{2}^{*}$ was assessed with Mann–Whitney tests. Kruskal–Wallis and Dunn tests compared fibrosis, fluorescence, and ICP-MS iron concentration. Spearman tests were used for correlation analysis.

Results

$\triangle {R}_{2}^{* }$ $△ R_{2}^{*}$ was significantly higher in the inflammation group (158 ± 85%) compared to the control (58 ± 36%, p = 0.020) and resolution (71 ± 36%, p = 0.048) groups. Confocal microscopy showed a high macrophage number and USPIO uptake in the inflammation group. $\triangle {R}_{2}^{* }$ $△ R_{2}^{*}$ correlated with macrophages number (r = 0.67, p = 0.0001), USPIO fluorescence intensity (r = 0.58, p = 0.0011), and iron concentration at ICP-MS (r = 0.39, p = 0.028).

Conclusion

Our results suggest that the inflammatory and resolution stages of hepatic injury can be assessed with USPIO-enhanced MRI.

Relevance statement

Our study demonstrates that USPIO-enhanced MRI can be used to monitor the inflammatory and resolution phases of hepatic injury in mice. If future studies confirm these findings, this imaging method might be valuable for tracking hepatic inflammation dynamics.

Key Points

Liver $\triangle {R}_{2}^{* }$ $△ R_{2}^{*}$ was highest during the inflammatory stage and partially reversed during the resolution stage, reflecting macrophage dynamics.

Immunofluorescence showed increased macrophage number and uptake during inflammation, decreasing during resolution.

Iron concentration significantly correlated with $\triangle {R}_{2}^{* }$ $△ R_{2}^{*}$ , macrophage number, and total fluorescence intensity.

Graphical Abstract