title: Targeting apoptosis for optical imaging of infection.
abstract: OBJECTIVE
  Infection is ubiquitous and a major cause of morbidity and mortality. The most reliable method for localizing infection requires radiolabeling autologous white blood cells ex vivo. A compound that can be injected directly into a patient and can selectively image infectious foci will eliminate the drawbacks. The resolution of infection is associated with neutrophil apoptosis and necrosis presenting phosphatidylserine (PS) on the neutrophil outer leaflet. Targeting PS with intravenous administration of a PS-specific, near-infrared (NIR) fluorophore will permit localization of infectious foci by optical imaging.
  
  
  METHODS
  Bacterial infection and sterile inflammation were induced in separate groups (n = 5) of mice. PS was targeted with a NIR fluorophore, PSVue(®)794 (2.7 pmol). Imaging was performed (ex = 730 nm, em = 830 nm) using Kodak Multispectral FX-Pro system. The contralateral normal thigh served as an individualized control. Confocal microscopy of normal and apoptotic neutrophils and bacteria confirmed PS specificity.
  
  
  RESULTS
  Lesions, with a 10-s image acquisition, were unequivocally visible at 5 min post-injection. At 3 h post-injection, the lesion to background intensity ratios in the foci of infection (6.6 ± 0.2) were greater than those in inflammation (3.2 ± 0.5). Image fusions confirmed anatomical locations of the lesions. Confocal microscopy determined the fluorophore specificity for PS.
  
  
  CONCLUSIONS
  Targeting PS presented on the outer leaflet of apoptotic or necrotic neutrophils as well as gram-positive microorganism with PS-specific NIR fluorophore provides a sensitive means of imaging infection. Literature indicates that NIR fluorophores can be detected 7-14 cm deep in tissue. This observation together with the excellent results and the continued development of versatile imaging devices could make optical imaging a simple, specific, and rapid modality for imaging infection.
authors.affiliation: Department of Radiology, Thomas Jefferson University, Philadelphia, PA 19107, USA. mathew.thakur@jefferson.edu
authors.forename: Mathew L
authors.initials: ML
authors.lastname: Thakur
authors.forename: Kaijun
authors.initials: K
authors.lastname: Zhang
authors.forename: Bishnuhari
authors.initials: B
authors.lastname: Paudyal
authors.forename: Devadhas
authors.initials: D
authors.lastname: Devakumar
authors.forename: Maria Y
authors.initials: MY
authors.lastname: Covarrubias
authors.forename: Chang-po
authors.initials: CP
authors.lastname: Chen
authors.forename: Changpo
authors.initials: C
authors.lastname: Cheng
authors.forename: Brian D
authors.initials: BD
authors.lastname: Gray
authors.forename: Eric
authors.initials: E
authors.lastname: Wickstrom
authors.forename: Koon Y
authors.initials: KY
authors.lastname: Pak
mesh_terms: D000818:Animals; D017209:Apoptosis; D001424:Bacterial Infections / Q000175:diagnosis* / Q000473:pathology*; D003952:Diagnostic Imaging / Q000379:methods*; D004926:Escherichia coli / Q000166:cytology; D005456:Fluorescent Dyes / Q000737:chemistry / Q000378:metabolism; D007249:Inflammation / Q000473:pathology; D051379:Mice; D018613:Microscopy, Confocal; D055620:Optical Phenomena; D013210:Staphylococcus / Q000166:cytology; D013848:Thigh / Q000382:microbiology / Q000473:pathology
chemical_list: D005456:Fluorescent Dyes