Assessment of macrophage infiltration in a murine model of abdominal aortic aneurysm.
OBJECTIVE
To evaluate the use of an ultrasmall superparamagnetic iron oxide (USPIO) contrast agent as a marker for the detection of macrophage in a preclinical abdominal aortic aneurysm animal (AAA) model.


METHODS
Osmotic pumps were implanted subcutaneously in apoE(-/-) mice for continuous infusion of Angiotensin II (Ang-II). Weekly bright-blood gradient echo scans were performed on the suprarenal abdominal aorta to evaluate aneurysm development. Once an AAA was detected, animals were administered 1000 mumol/kg of the USPIO contrast agent ferumoxtran-10 (Combidex) followed by in vivo scanning 24 h post-USPIO administration. After in vivo imaging, aortas were harvested for ex vivo imaging, histology, iron quantification, and gene expression analysis.


RESULTS
Reduced signal intensity was evident in the post-USPIO transverse images of the abdominal aorta. The areas of reduced signal were primarily along the aneurysm shoulder and outer perianeurysm areas and corresponded to regions of macrophage infiltration and colocalized USPIO determination by means of histological staining. The absolute iron content measured significantly correlated to the area of signal reduction in the ex vivo images (r = 0.9; P < 0.01). In the AAA tissue, the macrophage-driven cytokine gene expression was up-regulated along with a matrix metalloproteinase known to mediate extracellular matrix breakdown in this disease model.


CONCLUSIONS
These results demonstrate the feasibility of using an USPIO contrast agent as a surrogate for detecting the acute inflammatory process involved in the development of abdominal aneurysms.
Turner
Gregory H
GH
Cardiovascular and Urogenital Center of Excellence for Drug Discovery, GlaxoSmithKline, King of Prussia, Pennsylvania, USA.
Olzinski
Alan R
AR
Bernard
Roberta E
RE
Aravindhan
Karpagam
K
Boyle
Ryan J
RJ
Newman
Matt J
MJ
Gardner
Scott D
SD
Willette
Robert N
RN
Gough
Peter J
PJ
Jucker
Beat M
BM
D000704:Analysis of Variance; D000804:Angiotensin II / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D017544:Aortic Aneurysm, Abdominal / Q000175:diagnosis* / Q000378:metabolism*; D001057:Apolipoproteins E / Q000172:deficiency; D003287:Contrast Media / Q000493:pharmacokinetics; D003911:Dextrans / Q000493:pharmacokinetics; D004195:Disease Models, Animal; D052203:Ferrosoferric Oxide / Q000493:pharmacokinetics; D007091:Image Processing, Computer-Assisted; D007249:Inflammation / Q000175:diagnosis / Q000378:metabolism; D015918:Infusion Pumps, Implantable; D008264:Macrophages / Q000378:metabolism*; D008279:Magnetic Resonance Imaging / Q000379:methods*; D058185:Magnetite Nanoparticles; D008297:Male; D051379:Mice
D001057:Apolipoproteins E; D003287:Contrast Media; D003911:Dextrans; D058185:Magnetite Nanoparticles; C097921:ferumoxtran-10; D000804:Angiotensin II; D052203:Ferrosoferric Oxide