Iliyana Atanasova1, Mozhdeh Sojoodi2, Helena S Leitão3, Sergei Shuvaev1, Carlos F G C Geraldes4, Ricard Masia5, Alexander S Guimaraes1, Kenneth K Tanabe2, Bryan C Fuchs2, Peter Caravan. 1. From the Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital. 2. Division of Surgical Oncology, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA. 3. Department of Biomedical Sciences and Medicine and University Hospital Center, University of Algarve, Faro. 4. Department of Life Sciences and Coimbra Chemistry Center, Faculty of Science and Technology, University of Coimbra, Coimbra, Portugal. 5. Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA.
Abstract
RATIONALE AND OBJECTIVES: Liver inflammation is associated with nonalcoholic steatohepatitis and other pathologies, but noninvasive methods to assess liver inflammation are limited. Inflammation causes endothelial disruption and leakage of plasma proteins into the interstitial space and can result in extravascular coagulation with fibrin deposition. Here we assess the feasibility of using the established fibrin-specific magnetic resonance probe EP-2104R for the noninvasive imaging of fibrin as a marker of liver inflammation. METHODS: Weekly 100 mg/kg diethylnitrosamine (DEN) dosing was used to generate liver fibrosis in male rats; control animals received vehicle. Magnetic resonance imaging at 1.5 T with EP-2104R, a matched non-fibrin-binding control linear peptide, or the collagen-specific probe EP-3533 was performed at 1 day or 7 days after the last DEN administration. Imaging data were compared with quantitative histological measures of fibrosis and inflammation. RESULTS: After 4 or 5 DEN administrations, the liver becomes moderately fibrotic, and fibrosis is the same if the animal is killed 1 day (Ishak score, 3.62 ± 0.31) or 7 days (Ishak score, 3.82 ± 0.25) after the last DEN dose, but inflammation is significantly higher at 1 day compared with 7 days after the last DEN dose (histological activity index from 0-4, 3.54 ± 0.14 vs 1.61 ± 0.16, respectively; P < 0.0001). Peak EP-2104R signal enhancement was significantly higher in animals imaged at 1 day post-DEN compared with 7 days post-DEN or control rats (29.0% ± 3.2% vs 22.4% ± 2.0% vs 17.0% ± 0.2%, respectively; P = 0.017). Signal enhancement with EP-2104R was significantly higher than control linear peptide at 1 day post-DEN but not at 7 days post-DEN indicating specific fibrin binding during the inflammatory phase. Collagen molecular magnetic resonance with EP-3533 showed equivalent T1 change when imaging rats 1 day or 7 days post-DEN, consistent with equivalent fibrosis. CONCLUSIONS: EP-2104R can specifically detect fibrin associated with inflammation in a rat model of liver inflammation and fibrosis.
RATIONALE AND OBJECTIVES:Liver inflammation is associated with nonalcoholic steatohepatitis and other pathologies, but noninvasive methods to assess liver inflammation are limited. Inflammation causes endothelial disruption and leakage of plasma proteins into the interstitial space and can result in extravascular coagulation with fibrin deposition. Here we assess the feasibility of using the established fibrin-specific magnetic resonance probe EP-2104R for the noninvasive imaging of fibrin as a marker of liver inflammation. METHODS: Weekly 100 mg/kg diethylnitrosamine (DEN) dosing was used to generate liver fibrosis in male rats; control animals received vehicle. Magnetic resonance imaging at 1.5 T with EP-2104R, a matched non-fibrin-binding control linear peptide, or the collagen-specific probe EP-3533 was performed at 1 day or 7 days after the last DEN administration. Imaging data were compared with quantitative histological measures of fibrosis and inflammation. RESULTS: After 4 or 5 DEN administrations, the liver becomes moderately fibrotic, and fibrosis is the same if the animal is killed 1 day (Ishak score, 3.62 ± 0.31) or 7 days (Ishak score, 3.82 ± 0.25) after the last DEN dose, but inflammation is significantly higher at 1 day compared with 7 days after the last DEN dose (histological activity index from 0-4, 3.54 ± 0.14 vs 1.61 ± 0.16, respectively; P < 0.0001). Peak EP-2104R signal enhancement was significantly higher in animals imaged at 1 day post-DEN compared with 7 days post-DEN or control rats (29.0% ± 3.2% vs 22.4% ± 2.0% vs 17.0% ± 0.2%, respectively; P = 0.017). Signal enhancement with EP-2104R was significantly higher than control linear peptide at 1 day post-DEN but not at 7 days post-DEN indicating specific fibrin binding during the inflammatory phase. Collagen molecular magnetic resonance with EP-3533 showed equivalent T1 change when imaging rats 1 day or 7 days post-DEN, consistent with equivalent fibrosis. CONCLUSIONS:EP-2104R can specifically detect fibrin associated with inflammation in a rat model of liver inflammation and fibrosis.
Authors: Takeshi Yokoo; Suraj D Serai; Ali Pirasteh; Mustafa R Bashir; Gavin Hamilton; Diego Hernando; Houchun H Hu; Holger Hetterich; Jens-Peter Kühn; Guido M Kukuk; Rohit Loomba; Michael S Middleton; Nancy A Obuchowski; Ji Soo Song; An Tang; Xinhuai Wu; Scott B Reeder; Claude B Sirlin Journal: Radiology Date: 2017-09-11 Impact factor: 11.105
Authors: Christian T Farrar; Danielle K DePeralta; Helen Day; Tyson A Rietz; Lan Wei; Gregory Y Lauwers; Boris Keil; Arun Subramaniam; Anthony J Sinskey; Kenneth K Tanabe; Bryan C Fuchs; Peter Caravan Journal: J Hepatol Date: 2015-05-25 Impact factor: 25.083
Authors: Christian T Farrar; Eric M Gale; Richard Kennan; Ian Ramsay; Ricard Masia; Gunisha Arora; Kailyn Looby; Lan Wei; Jayashree Kalpathy-Cramer; Michelle M Bunzel; Chunlian Zhang; Yonghua Zhu; Taro E Akiyama; Michael Klimas; Shirly Pinto; Himashinie Diyabalanage; Kenneth K Tanabe; Valerie Humblet; Bryan C Fuchs; Peter Caravan Journal: Radiology Date: 2017-11-20 Impact factor: 11.105
Authors: Kirsten Overoye-Chan; Steffi Koerner; Richard J Looby; Andrew F Kolodziej; Stephan G Zech; Qing Deng; Jaclyn M Chasse; Thomas J McMurry; Peter Caravan Journal: J Am Chem Soc Date: 2008-04-08 Impact factor: 15.419
Authors: Josef Vymazal; Elmar Spuentrup; Gerardo Cardenas-Molina; Andrea J Wiethoff; Michael G Hartmann; Peter Caravan; Edward C Parsons Journal: Invest Radiol Date: 2009-11 Impact factor: 6.016
Authors: Derek J Erstad; Christian T Farrar; Sarani Ghoshal; Ricard Masia; Diego S Ferreira; Yin-Ching Iris Chen; Ji-Kyung Choi; Lan Wei; Phillip A Waghorn; Nicholas J Rotile; Chuantao Tu; Katherine A Graham-O'Regan; Mozhdeh Sojoodi; Shen Li; Yang Li; Guogiang Wang; Kathleen E Corey; Yat Sun Or; Lijuan Jiang; Kenneth K Tanabe; Peter Caravan; Bryan C Fuchs Journal: Hepatol Commun Date: 2018-05-21
Authors: Johannes Lohmeier; Rafaela V Silva; Anna Tietze; Matthias Taupitz; Takaaki Kaneko; Harald Prüss; Friedemann Paul; Carmen Infante-Duarte; Bernd Hamm; Peter Caravan; Marcus R Makowski Journal: Eur J Nucl Med Mol Imaging Date: 2022-05-04 Impact factor: 10.057