title: SPECT imaging of inflammatory response in ischemic-reperfused rat hearts using a 99mTc-labeled dual-domain cytokine ligand.
abstract: Soluble tumor necrosis factor (TNF) receptor-2 (TNFR2) and interleukin-1 receptor antagonist (IL-1ra) were fused to the Fc portion of IgG1 using recombinant DNA technology. The resulting dual-domain cytokine ligand, TNFR2-Fc-IL-1ra, specifically binds to TNF and to the type I IL-1 receptor (IL-1RI). This study was designed to characterize the kinetic profile of (99m)Tc-labeled TNFR2-Fc-IL-1ra (TFI) for imaging inflammatory response in an ischemic-reperfused (IR) rat heart model.
  
  
  METHODS
  The IR model was created by ligating the left coronary artery for 45 min, followed by 2-h reperfusion. Cardiac SPECT images of TFI in the IR model (n = 6) were dynamically acquired for 3 h. Correlative data of myocardial TFI distribution versus microsphere-determined tissue blood flow were acquired in 3 extra IR hearts. Inflammation targeting affinity of TFI was compared with 2 individual cytokine radioligands, (99m)Tc-IL-1ra-Fc (IF) and (99m)Tc-TNFR2-Fc (TF) (n = 6 each group). Myocardial cytokine expression was evaluated by immunochemical assay.
  
  
  RESULTS
  Increased TFI uptake was found in the ischemic area and correlated with the severity of ischemia. At 3 h after injection, the ratio of hot-spot accumulation in the ischemic area to a remote viable zone was 5.39 ± 1.11 for TFI, which was greater than that for IF (3.28 ± 0.81) and TF (3.29 ± 0.75) (P < 0.05). The in vivo uptake profiles of TFI, TF, and IF were consistent with ex vivo radioactive measurements and correlated with upregulated IL-1 and TNF expression.
  
  
  CONCLUSIONS
  The dual-domain TFI is promising for noninvasive detection of inflammatory reactions in IR myocardium because of its more potent affinity to the inflammatory sites compared with TF and IF.
authors.affiliation: Department of Medical Imaging, University of Arizona, Tucson, Arizona.
authors.forename: Zhonglin
authors.initials: Z
authors.lastname: Liu
authors.forename: Christy
authors.initials: C
authors.lastname: Barber
authors.forename: Li
authors.initials: L
authors.lastname: Wan
authors.forename: Shan
authors.initials: S
authors.lastname: Liu
authors.forename: Mizhou M
authors.initials: MM
authors.lastname: Hui
authors.forename: Lars R
authors.initials: LR
authors.lastname: Furenlid
authors.forename: Hua
authors.initials: H
authors.lastname: Xu
authors.forename: James M
authors.initials: JM
authors.lastname: Woolfenden
mesh_terms: D000818:Animals; D001692:Biological Transport; D003326:Coronary Circulation; D016207:Cytokines / Q000378:metabolism*; D005786:Gene Expression Regulation; D006321:Heart / Q000000981:diagnostic imaging* / Q000503:physiopathology; D007249:Inflammation / Q000000981:diagnostic imaging; D053590:Interleukin 1 Receptor Antagonist Protein / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D007553:Isotope Labeling; D008024:Ligands; D008297:Male; D015609:Organotechnetium Compounds; D051381:Rats; D017207:Rats, Sprague-Dawley; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015427:Reperfusion Injury / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000503:physiopathology; D015899:Tomography, Emission-Computed, Single-Photon; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D016207:Cytokines; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D008024:Ligands; D015609:Organotechnetium Compounds; D047889:Receptors, Tumor Necrosis Factor, Type II; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha
keywords: 99mTc; inflammation; interleukin-1; myocardial ischemia-reperfusion; tumor necrosis factor