PT  - JOURNAL ARTICLE
AU  - Steven L. Brody
AU  - Sean P. Gunsten
AU  - Hannah P. Luehmann
AU  - Debbie H. Sultan
AU  - Michelle Hoelscher
AU  - Gyu Seong Heo
AU  - Jiehong Pan
AU  - Jeffrey R. Koenitzer
AU  - Ethan C. Lee
AU  - Tao Huang
AU  - Cedric Mpoy
AU  - Shuchi Guo
AU  - Richard Laforest
AU  - Amber Salter
AU  - Tonya D. Russell
AU  - Adrian Shifren
AU  - Christophe Combadiere
AU  - Kory J. Lavine
AU  - Daniel Kreisel
AU  - Benjamin D. Humphreys
AU  - Buck E. Rogers
AU  - David S. Gierada
AU  - Derek E. Byers
AU  - Robert J. Gropler
AU  - Delphine L. Chen
AU  - Jeffrey J. Atkinson
AU  - Yongjian Liu
TI  - Chemokine receptor 2-targeted molecular imaging in pulmonary fibrosis
AID  - 10.1101/2020.03.04.960179
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.03.04.960179
4099  - http://biorxiv.org/content/early/2020/03/05/2020.03.04.960179.short
4100  - http://biorxiv.org/content/early/2020/03/05/2020.03.04.960179.full
AB  - Idiopathic pulmonary fibrosis (IPF) is a progressive, inflammatory lung disease that is monitored clinically by measures of lung function, without effective molecular markers of disease activity or therapeutic efficacy. Lung immune cells active in the pro-fibrotic process include inflammatory monocyte and interstitial macrophages that express the C-C motif chemokine receptor 2 (CCR2). CCR2+ monocyte lung influx is essential for disease phenotypes in models of fibrosis and identified in lungs from subjects with IPF. Here, we show that our peptide-based radiotracer 64Cu-DOTA-ECL1i identifies CCR2+ inflammatory monocytes and interstitial macrophages in multiple preclinical mouse models of lung fibrosis, using positron emission tomography (PET) imaging. Mice with bleomycin-induced fibrosis treated with blocking antibodies to interleukin-1β, a mediator of fibrosis associated with CCR2+ cell inflammation, or with pirfenidone, an approved anti-fibrotic agent, demonstrated decreased CCR2-dependent interstitial macrophage accumulation and reduced 64Cu-DOTA-ECL1i PET uptake, compared to controls. Lung tissues from patients with fibrotic lung disease demonstrated abundant CCR2+ cells surrounding regions of fibrosis, and an ex vivo tissue-binding assay showed correlation between radiotracer localization and CCR2+ cells. In a phase 0/1 clinical study of 64Cu-DOTA-ECL1i PET, healthy volunteers showed little lung uptake, while subjects with pulmonary fibrosis exhibited increased uptake, notably in zones of subpleural fibrosis, reflecting the distribution of CCR2+ cells in the profibrotic niche. These findings support a pathologic role of inflammatory lung monocytes/macrophages in fibrotic lung disease and the translational use of 64Cu-DOTA-ECL1i PET to track CCR2-specific inflammation for image-guided therapy.One Sentence Summary PET imaging of CCR2+ cells in lung fibrosis identifies a therapeutic response in mouse models and displays a perifibrotic signal in subjects with IPF.