TY - JOUR
T1 - PET-based imaging of chemokine receptor 2 in experimental and Disease-related lung inflammation
AU - Liu, Yongjian
AU - Gunsten, Sean P.
AU - Sultan, Deborah H.
AU - Luehmann, Hannah P.
AU - Zhao, Yongfeng
AU - Blackwell, T. Scott
AU - Bollermann-Nowlis, Zachary
AU - Pan, Jie Hong
AU - Byers, Derek E.
AU - Atkinson, Jeffrey J.
AU - Kreisel, Daniel
AU - Holtzman, Michael J.
AU - Gropler, Robert J.
AU - Combadiere, Christophe
AU - Brody, Steven L.
N1 - Funding Information:
Supported by National Heart, Lung, and Blood Institute (HHN268201000046C, NHLBI-HV-10-08, R01 HL131908, U19 AI070489, and R01 HL121791). S.L.B. is the Hubert S. and Dorothy R. Moog Professor of Pulmonary Medicine and is supported by the Foundation for Barnes-Jewish Hospital.
Publisher Copyright:
© RSNA, 2017.
PY - 2017/6
Y1 - 2017/6
N2 - Purpose: To characterize a chemokine receptor type 2 (CCR2)-binding peptide adapted for use as a positron emission tomography (PET) radiotracer for noninvasive detection of lung inflammation in a mouse model of lung injury and in human tissues from subjects with lung disease. Materials and The study was approved by institutional animal and human Methods: studies committees. Informed consent was obtained from patients. A 7-amino acid CCR2 binding peptide (extracellular loop 1 inverso [ECL1i]) was conjugated to tetraazacy-clododecane tetraacetic acid (DOTA) and labeled with copper 64 ( 64 Cu) or fluorescent dye. Lung inflammation was induced with intratracheal administration of lipopolysaccharide (LPS) in wild-type (n = 19) and CCR2-deficient (n = 4) mice, and these mice were compared with wild-type mice given control saline (n = 5) by using PET performed after intravenous injection of 64 Cu-DOTA-ECL1i. Lung immune cells and those binding fluorescently labeled ECL1i in vivo were detected with flow cytometry. Lung inflammation in tissue from subjects with nondiseased lungs donated for lung transplantation (n = 11) and those with chronic obstructive pulmonary disease (COPD) who were undergoing lung transplantation (n = 16) was evaluated for CCR2 with immunostaining and autoradiography (n = 6, COPD) with 64 Cu-DOTA-ECL1i. Groups were compared with analysis of variance, the Mann-Whitney U test, or the t test. Results: Signal on PET images obtained in mouse lungs after injury with LPS was significantly greater than that in the saline control group (mean = 4.43% of injected dose [ID] per gram of tissue vs 0.99% of injected dose per gram of tissue; P < .001). PET signal was significantly diminished with blocking studies using nonradiolabeled ECL1i in excess (mean = 0.63% ID per gram of tissue; P < .001) and in CCR2-deficient mice (mean = 0.39% ID per gram of tissue; P < .001). The ECL1i signal was associated with an elevated level of mouse lung monocytes. COPD lung tissue displayed significantly elevated CCR2 levels compared with nondiseased tissue (median = 12.8% vs 1.2% cells per sample; P = .002), which was detected with 64 Cu-DOTA-ECL1i by using autoradiography. Conclusion: 64 Cu-DOTA-ECL1i is a promising tool for PET-based detection of CCR2-directed inflammation in an animal model and in human tissues as a step toward clinical translation.
AB - Purpose: To characterize a chemokine receptor type 2 (CCR2)-binding peptide adapted for use as a positron emission tomography (PET) radiotracer for noninvasive detection of lung inflammation in a mouse model of lung injury and in human tissues from subjects with lung disease. Materials and The study was approved by institutional animal and human Methods: studies committees. Informed consent was obtained from patients. A 7-amino acid CCR2 binding peptide (extracellular loop 1 inverso [ECL1i]) was conjugated to tetraazacy-clododecane tetraacetic acid (DOTA) and labeled with copper 64 ( 64 Cu) or fluorescent dye. Lung inflammation was induced with intratracheal administration of lipopolysaccharide (LPS) in wild-type (n = 19) and CCR2-deficient (n = 4) mice, and these mice were compared with wild-type mice given control saline (n = 5) by using PET performed after intravenous injection of 64 Cu-DOTA-ECL1i. Lung immune cells and those binding fluorescently labeled ECL1i in vivo were detected with flow cytometry. Lung inflammation in tissue from subjects with nondiseased lungs donated for lung transplantation (n = 11) and those with chronic obstructive pulmonary disease (COPD) who were undergoing lung transplantation (n = 16) was evaluated for CCR2 with immunostaining and autoradiography (n = 6, COPD) with 64 Cu-DOTA-ECL1i. Groups were compared with analysis of variance, the Mann-Whitney U test, or the t test. Results: Signal on PET images obtained in mouse lungs after injury with LPS was significantly greater than that in the saline control group (mean = 4.43% of injected dose [ID] per gram of tissue vs 0.99% of injected dose per gram of tissue; P < .001). PET signal was significantly diminished with blocking studies using nonradiolabeled ECL1i in excess (mean = 0.63% ID per gram of tissue; P < .001) and in CCR2-deficient mice (mean = 0.39% ID per gram of tissue; P < .001). The ECL1i signal was associated with an elevated level of mouse lung monocytes. COPD lung tissue displayed significantly elevated CCR2 levels compared with nondiseased tissue (median = 12.8% vs 1.2% cells per sample; P = .002), which was detected with 64 Cu-DOTA-ECL1i by using autoradiography. Conclusion: 64 Cu-DOTA-ECL1i is a promising tool for PET-based detection of CCR2-directed inflammation in an animal model and in human tissues as a step toward clinical translation.
UR - http://www.scopus.com/inward/record.url?scp=85019933456&partnerID=8YFLogxK
U2 - 10.1148/radiol.2016161409
DO - 10.1148/radiol.2016161409
M3 - Article
C2 - 28045644
AN - SCOPUS:85019933456
SN - 0033-8419
VL - 283
SP - 758
EP - 768
JO - Radiology
JF - Radiology
IS - 3
ER -