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Molecular imaging of oxidized collagen quantifies pulmonary and hepatic fibrogenesis
Howard H. Chen, … , Bryan C. Fuchs, Peter Caravan
Howard H. Chen, … , Bryan C. Fuchs, Peter Caravan
Published June 2, 2017
Citation Information: JCI Insight. 2017;2(11):e91506. https://doi.org/10.1172/jci.insight.91506.
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Research Article Hepatology Pulmonology

Molecular imaging of oxidized collagen quantifies pulmonary and hepatic fibrogenesis

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Abstract

Fibrosis results from the dysregulation of tissue repair mechanisms affecting major organ systems, leading to chronic extracellular matrix buildup, and progressive, often fatal, organ failure. Current diagnosis relies on invasive biopsies. Noninvasive methods today cannot distinguish actively progressive fibrogenesis from stable scar, and thus are insensitive for monitoring disease activity or therapeutic responses. Collagen oxidation is a universal signature of active fibrogenesis that precedes collagen crosslinking. Biochemically targeting oxidized lysine residues formed by the action of lysyl oxidase on collagen with a small-molecule gadolinium chelate enables targeted molecular magnetic resonance imaging. This noninvasive direct biochemical elucidation of the fibrotic microenvironment specifically and robustly detected and staged pulmonary and hepatic fibrosis progression, and monitored therapeutic response in animal models. Furthermore, this paradigm is translatable and generally applicable to diverse fibroproliferative disorders.

Authors

Howard H. Chen, Philip A. Waghorn, Lan Wei, Luis F. Tapias, Daniel T. Schühle, Nicholas J. Rotile, Chloe M. Jones, Richard J. Looby, Gaofeng Zhao, Justin M. Elliott, Clemens K. Probst, Mari Mino-Kenudson, Gregory Y. Lauwers, Andrew M. Tager, Kenneth K. Tanabe, Michael Lanuti, Bryan C. Fuchs, Peter Caravan

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Figure 1

Gd-Hyd specifically detects peptidyl aldehydes, in oxidized albumin and porcine tissue in vitro, and in bleomycin-injured mouse lungs in vivo.

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Gd-Hyd specifically detects peptidyl aldehydes, in oxidized albumin and ...
(A) Structures of Gd-Hyd (active probe) and Gd-DiMe (inactive control). Gd-Hyd bound to allysine in oxidized bovine serum albumin (Ald-BSA) but not to unmodified BSA, as assessed by direct protein binding (B, n = 3) and by relaxivity increase (C, n = 3). Gd-DiMe showed no binding to either construct. (D) Gd-Hyd, but not Gd-DiMe, bound to allysine-rich porcine aorta. (E) Consecutive coronal MR images, taken 24 hours apart, show strong lung enhancement (false colored) by Gd-Hyd but not Gd-DiMe in the same mouse 2 weeks after bleomycin lung injury. (F) Sequential MRI of bleomycin-injured mice quantified by lung/muscle change in contrast-to-noise ratio (ΔCNR) (n = 8). (G) Gd-Hyd and Gd-DiMe ΔCNR in bleomycin-injured mice (n = 8) and sham controls (n = 10). *P < 0.05, ***P < 0.001, ****P < 0.0001, ns, not significant; ANOVA.

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