In Vivo Hypoxia PET Imaging Quantifies the Severity of Arthritic Joint Inflammation in Line with Overexpression of Hypoxia-Inducible Factor and Enhanced Reactive Oxygen Species Generation.
Hypoxia is essential for the development of autoimmune diseases such as rheumatoid arthritis (RA) and is associated with the expression of reactive oxygen species (ROS), because of the enhanced infiltration of immune cells. The aim of this study was to demonstrate the feasibility of measuring hypoxia noninvasively in vivo in arthritic ankles with PET/MRI using the hypoxia tracers18F-fluoromisonidazole (18F-FMISO) and18F-fluoroazomycinarabinoside (18F-FAZA). Additionally, we quantified the temporal dynamics of hypoxia and ROS stress using L-012, an ROS-sensitive chemiluminescence optical imaging probe, and analyzed the expression of hypoxia-inducible factors (HIFs).Methods:Mice underwent noninvasive in vivo PET/MRI to measure hypoxia or optical imaging to analyze ROS expression. Additionally, we performed ex vivo pimonidazole-/HIF-1α immunohistochemistry and HIF-1α/2α Western blot/messenger RNA analysis of inflamed and healthy ankles to confirm our in vivo results.Results:Mice diseased from experimental RA exhibited a 3-fold enhancement in hypoxia tracer uptake, even in the early disease stages, and a 45-fold elevation in ROS expression in inflamed ankles compared with the ankles of healthy controls. We further found strong correlations of our noninvasive in vivo hypoxia PET data with pimonidazole and expression of HIF-1α in arthritic ankles. The strongest hypoxia tracer uptake was observed as soon as day 3, whereas the most pronounced ROS stress was evident on day 6 after the onset of experimental RA, indicating that tissue hypoxia can precede ROS stress in RA.Conclusion:Collectively, for the first time to our knowledge, we have demonstrated that the noninvasive measurement of hypoxia in inflammation using18F-FAZA and18F-FMISO PET imaging represents a promising new tool for uncovering and monitoring rheumatic inflammation in vivo. Further, because hypoxic inflamed tissues are associated with the overexpression of HIFs, specific inhibition of HIFs might represent a new powerful treatment strategy.
Department of Preclinical Imaging and Radiopharmacy, Werner Siemens Imaging Center, Eberhard Karls University Tuebingen, Tuebingen, Germany.
Kerstin
K
Fuchs
Department of Preclinical Imaging and Radiopharmacy, Werner Siemens Imaging Center, Eberhard Karls University Tuebingen, Tuebingen, Germany.
Anna
A
Kuehn
Department of Preclinical Imaging and Radiopharmacy, Werner Siemens Imaging Center, Eberhard Karls University Tuebingen, Tuebingen, Germany.
Moritz
M
Mahling
Department of Preclinical Imaging and Radiopharmacy, Werner Siemens Imaging Center, Eberhard Karls University Tuebingen, Tuebingen, Germany.
Philipp
P
Guenthoer
Children's Hospital of the Eberhard Karls University Tuebingen, Tuebingen, Germany.
Andreas
A
Hector
Department of Preclinical Imaging and Radiopharmacy, Werner Siemens Imaging Center, Eberhard Karls University Tuebingen, Tuebingen, Germany.|Department of Nuclear Medicine and Clinical Molecular Imaging, Eberhard Karls University, Tuebingen, Tuebingen, Germany.
Johannes
J
Schwenck
Children's Hospital of the Eberhard Karls University Tuebingen, Tuebingen, Germany.|Immunology, Inflammation and Infectious Diseases Discovery and Translational Area, Roche Pharma Research & Early Development (pRED), Roche Innovation Center Basel, Basel, Switzerland.
Dominik
D
Hartl
Department of Pharmacy & Biochemistry, Eberhard Karls University Tuebingen, Tuebingen, Germany.
Stefan
S
Laufer
Institute of Pathology and Neuropathology, Eberhard Karls University Tuebingen and Comprehensive Cancer Center, University Hospital Tuebingen, Tuebingen, Germany; and.
Ursula
U
Kohlhofer
Institute of Pathology and Neuropathology, Eberhard Karls University Tuebingen and Comprehensive Cancer Center, University Hospital Tuebingen, Tuebingen, Germany; and.
Leticia
L
Quintanilla-Martinez
Department of Preclinical Imaging and Radiopharmacy, Werner Siemens Imaging Center, Eberhard Karls University Tuebingen, Tuebingen, Germany.
Gerald
G
Reischl
Department of Dermatology, Eberhard Karls University Tuebingen, Tuebingen, Germany.
Martin
M
Röcken
Department of Preclinical Imaging and Radiopharmacy, Werner Siemens Imaging Center, Eberhard Karls University Tuebingen, Tuebingen, Germany.
Bernd J
BJ
Pichler
Department of Preclinical Imaging and Radiopharmacy, Werner Siemens Imaging Center, Eberhard Karls University Tuebingen, Tuebingen, Germany manfred.kneilling@med.uni-tuebingen.de.|Department of Dermatology, Eberhard Karls University Tuebingen, Tuebingen, Germany.
Manfred
M
Kneilling
D000818:Animals; D001172:Arthritis, Rheumatoid / Q000000981:diagnostic imaging* / Q000276:immunology*; D015687:Cell Hypoxia / Q000276:immunology; D051793:Hypoxia-Inducible Factor 1 / Q000276:immunology*; D051379:Mice; D008920:Misonidazole / Q000031:analogs & derivatives* / Q000276:immunology; D057054:Molecular Imaging / Q000379:methods; D009593:Nitroimidazoles / Q000276:immunology*; D049268:Positron-Emission Tomography / Q000379:methods*; D019275:Radiopharmaceuticals / Q000276:immunology; D017382:Reactive Oxygen Species / Q000276:immunology*; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D012720:Severity of Illness Index; D015854:Up-Regulation / Q000276:immunology
D051793:Hypoxia-Inducible Factor 1; D009593:Nitroimidazoles; D019275:Radiopharmaceuticals; D017382:Reactive Oxygen Species; C031843:fluoromisonidazole; C498052:fluoroazomycin arabinoside; D008920:Misonidazole
HIF; PET; ROS; in vivo hypoxia imaging; rheumatoid arthritis