• Steven L Brody, Sean P Gunsten, Hannah P Luehmann, Debbie H Sultan, Michelle Hoelscher, Gyu Seong Heo, Jiehong Pan, Jeffrey R Koenitzer, Ethan C Lee, Tao Huang, Cedric Mpoy, Shuchi Guo, Richard Laforest, Amber Salter, Tonya D Russell, Adrian Shifren, Christophe Combadiere, Kory J Lavine, Daniel Kreisel, Benjamin D Humphreys, Buck E Rogers, David S Gierada, Derek E Byers, Robert J Gropler, Delphine L Chen, Jeffrey J Atkinson, and Yongjian Liu.
• Department of Medicine.
• Am. J. Respir. Crit. Care Med. 2021 Jan 1; 203 (1): 788978-89.

AbstractRationale: Idiopathic pulmonary fibrosis (IPF) is a progressive inflammatory lung disease without effective molecular markers of disease activity or treatment responses. Monocyte and interstitial macrophages that express the C-C motif CCR2 (chemokine receptor 2) are active in IPF and central to fibrosis.Objectives: To phenotype patients with IPF for potential targeted therapy, we developed 64Cu-DOTA-ECL1i, a radiotracer to noninvasively track CCR2+ monocytes and macrophages using positron emission tomography (PET).Methods: CCR2+ cells were investigated in mice with bleomycin- or radiation-induced fibrosis and in human subjects with IPF. The CCR2+ cell populations were localized relative to fibrotic regions in lung tissue and characterized using immunolocalization, single-cell mass cytometry, and Ccr2 RNA in situ hybridization and then correlated with parallel quantitation of lung uptake by 64Cu-DOTA-ECL1i PET.Measurements and Main Results: Mouse models established that increased 64Cu-DOTA-ECL1i PET uptake in the lung correlates with CCR2+ cell infiltration associated with fibrosis (n = 72). As therapeutic models, the inhibition of fibrosis by IL-1β blockade (n = 19) or antifibrotic pirfenidone (n = 18) reduced CCR2+ macrophage accumulation and uptake of the radiotracer in mouse lungs. In lung tissues from patients with IPF, CCR2+ cells concentrated in perifibrotic regions and correlated with radiotracer localization (n = 21). Human imaging revealed little lung uptake in healthy volunteers (n = 7), whereas subjects with IPF (n = 4) exhibited intensive signals in fibrotic zones.Conclusions: These findings support a role for imaging CCR2+ cells within the fibrogenic niche in IPF to provide a molecular target for personalized therapy and monitoring.Clinical trial registered with www.clinicaltrials.gov (NCT03492762).

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