Molecular magnetic resonance imaging of liver inflammation using an oxidatively activated probe
Background & Aims: Many liver diseases are driven by inflammation, but imaging to non-invasively diagnose and quantify liver inflammation has been underdeveloped. The inflammatory liver microenvironment is aberrantly oxidising owing in part to reactive oxygen species generated by myeloid leu...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2023-10-01
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| Series: | JHEP Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589555923001817 |
| _version_ | 1797671387967520768 |
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| author | Veronica Clavijo Jordan Mozhdeh Sojoodi Stuti Shroff Patricia Gonzalez Pagan Stephen Cole Barrett Jeremy Wellen Kenneth K. Tanabe Raymond T. Chung Peter Caravan Eric M. Gale |
| author_facet | Veronica Clavijo Jordan Mozhdeh Sojoodi Stuti Shroff Patricia Gonzalez Pagan Stephen Cole Barrett Jeremy Wellen Kenneth K. Tanabe Raymond T. Chung Peter Caravan Eric M. Gale |
| author_sort | Veronica Clavijo Jordan |
| collection | DOAJ |
| description | Background & Aims: Many liver diseases are driven by inflammation, but imaging to non-invasively diagnose and quantify liver inflammation has been underdeveloped. The inflammatory liver microenvironment is aberrantly oxidising owing in part to reactive oxygen species generated by myeloid leucocytes. We hypothesised that magnetic resonance imaging using the oxidatively activated probe Fe-PyC3A will provide a non-invasive biomarker of liver inflammation. Methods: A mouse model of drug-induced liver injury was generated through intraperitoneal injection of a hepatoxic dose of acetaminophen. A mouse model of steatohepatitis was generated via a choline-deficient, l-amino acid defined high-fat diet (CDAHFD). Images were acquired dynamically before and after intravenous injection of Fe-PyC3A. The contrast agent gadoterate meglumine was used as a non-oxidatively activated negative control probe in mice fed CDAHFD. The (post-pre) Fe-PyC3A injection change in liver vs. muscle contrast-to-noise ratio (ΔCNR) recorded 2 min post-injection was correlated with liver function test values, histologic scoring assigned using the NASH Clinical Research Network criteria, and intrahepatic myeloid leucocyte composition determined by flow cytometry. Results: For mice receiving i.p. injections of acetaminophen, intrahepatic neutrophil composition correlated poorly with liver test values but positively and significantly with ΔCNR (r = 0.64, p <0.0001). For mice fed CDAHFD, ΔCNR generated by Fe-PyC3A in the left lobe was significantly greater in mice meeting histologic criteria strongly associated with a diagnosis NASH compared to mice where histology was consistent with likely non-NASH (p = 0.0001), whereas no differential effect was observed using gadoterate meglumine. In mice fed CDAHFD, ΔCNR did not correlate strongly with fractional composition of any specific myeloid cell subpopulation as determined by flow cytometry. Conclusions: Magnetic resonance imaging using Fe-PyC3A merits further evaluation as a non-invasive biomarker for liver inflammation. Impact and implications: Non-invasive tests to diagnose and measure liver inflammation are underdeveloped. Inflammatory cells such as neutrophils release reactive oxygen species which creates an inflammatory liver microenvironment that can drive chemical oxidation. We recently invented a new class of magnetic resonance imaging probe that is made visible to the scanner only after chemical oxidation. Here, we demonstrate how this imaging technology could be applied as a non-invasive biomarker for liver inflammation. |
| first_indexed | 2024-03-11T21:14:48Z |
| format | Article |
| id | doaj.art-44357a5814c241f59e134c50450aa874 |
| institution | Directory Open Access Journal |
| issn | 2589-5559 |
| language | English |
| last_indexed | 2024-03-11T21:14:48Z |
| publishDate | 2023-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | JHEP Reports |
| spelling | doaj.art-44357a5814c241f59e134c50450aa8742023-09-29T04:44:57ZengElsevierJHEP Reports2589-55592023-10-01510100850Molecular magnetic resonance imaging of liver inflammation using an oxidatively activated probeVeronica Clavijo Jordan0Mozhdeh Sojoodi1Stuti Shroff2Patricia Gonzalez Pagan3Stephen Cole Barrett4Jeremy Wellen5Kenneth K. Tanabe6Raymond T. Chung7Peter Caravan8Eric M. Gale9Athinoula A. Martinos Center for Biomedical Imaging, The Institute for Innovation in Imaging, Department of Radiology, Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USAHarvard Medical School, Boston, MA, USA; Division of Gastrointestinal and Oncologic Surgery, Massachusetts General Hospital, Boston, MA, USAHarvard Medical School, Boston, MA, USA; Department of Pathology, Massachusetts General Hospital, Boston, MA, USAAthinoula A. Martinos Center for Biomedical Imaging, The Institute for Innovation in Imaging, Department of Radiology, Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USAHarvard Medical School, Boston, MA, USA; Division of Gastrointestinal and Oncologic Surgery, Massachusetts General Hospital, Boston, MA, USABristol Meyers Squibb, Cambridge, MA, USAHarvard Medical School, Boston, MA, USA; Division of Gastrointestinal and Oncologic Surgery, Massachusetts General Hospital, Boston, MA, USAHarvard Medical School, Boston, MA, USA; Gastroenterology Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USAAthinoula A. Martinos Center for Biomedical Imaging, The Institute for Innovation in Imaging, Department of Radiology, Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USAAthinoula A. Martinos Center for Biomedical Imaging, The Institute for Innovation in Imaging, Department of Radiology, Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Corresponding author. Address: 149 Thirteenth Street, Suite 2301, Charlestown, MA, 02129, USA. Tel.: +1-617-726-3197; Fax: +1-617-726-7422.Background & Aims: Many liver diseases are driven by inflammation, but imaging to non-invasively diagnose and quantify liver inflammation has been underdeveloped. The inflammatory liver microenvironment is aberrantly oxidising owing in part to reactive oxygen species generated by myeloid leucocytes. We hypothesised that magnetic resonance imaging using the oxidatively activated probe Fe-PyC3A will provide a non-invasive biomarker of liver inflammation. Methods: A mouse model of drug-induced liver injury was generated through intraperitoneal injection of a hepatoxic dose of acetaminophen. A mouse model of steatohepatitis was generated via a choline-deficient, l-amino acid defined high-fat diet (CDAHFD). Images were acquired dynamically before and after intravenous injection of Fe-PyC3A. The contrast agent gadoterate meglumine was used as a non-oxidatively activated negative control probe in mice fed CDAHFD. The (post-pre) Fe-PyC3A injection change in liver vs. muscle contrast-to-noise ratio (ΔCNR) recorded 2 min post-injection was correlated with liver function test values, histologic scoring assigned using the NASH Clinical Research Network criteria, and intrahepatic myeloid leucocyte composition determined by flow cytometry. Results: For mice receiving i.p. injections of acetaminophen, intrahepatic neutrophil composition correlated poorly with liver test values but positively and significantly with ΔCNR (r = 0.64, p <0.0001). For mice fed CDAHFD, ΔCNR generated by Fe-PyC3A in the left lobe was significantly greater in mice meeting histologic criteria strongly associated with a diagnosis NASH compared to mice where histology was consistent with likely non-NASH (p = 0.0001), whereas no differential effect was observed using gadoterate meglumine. In mice fed CDAHFD, ΔCNR did not correlate strongly with fractional composition of any specific myeloid cell subpopulation as determined by flow cytometry. Conclusions: Magnetic resonance imaging using Fe-PyC3A merits further evaluation as a non-invasive biomarker for liver inflammation. Impact and implications: Non-invasive tests to diagnose and measure liver inflammation are underdeveloped. Inflammatory cells such as neutrophils release reactive oxygen species which creates an inflammatory liver microenvironment that can drive chemical oxidation. We recently invented a new class of magnetic resonance imaging probe that is made visible to the scanner only after chemical oxidation. Here, we demonstrate how this imaging technology could be applied as a non-invasive biomarker for liver inflammation.http://www.sciencedirect.com/science/article/pii/S2589555923001817Drug-induced liver injurySteatohepatitisReactive oxygen species |
| spellingShingle | Veronica Clavijo Jordan Mozhdeh Sojoodi Stuti Shroff Patricia Gonzalez Pagan Stephen Cole Barrett Jeremy Wellen Kenneth K. Tanabe Raymond T. Chung Peter Caravan Eric M. Gale Molecular magnetic resonance imaging of liver inflammation using an oxidatively activated probe JHEP Reports Drug-induced liver injury Steatohepatitis Reactive oxygen species |
| title | Molecular magnetic resonance imaging of liver inflammation using an oxidatively activated probe |
| title_full | Molecular magnetic resonance imaging of liver inflammation using an oxidatively activated probe |
| title_fullStr | Molecular magnetic resonance imaging of liver inflammation using an oxidatively activated probe |
| title_full_unstemmed | Molecular magnetic resonance imaging of liver inflammation using an oxidatively activated probe |
| title_short | Molecular magnetic resonance imaging of liver inflammation using an oxidatively activated probe |
| title_sort | molecular magnetic resonance imaging of liver inflammation using an oxidatively activated probe |
| topic | Drug-induced liver injury Steatohepatitis Reactive oxygen species |
| url | http://www.sciencedirect.com/science/article/pii/S2589555923001817 |
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