Visualizing and Quantifying Acute Inflammation Using ICAM-1 Specific Nanoparticles and MRI Quantitative Susceptibility Mapping
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As intense and prolonged inflammation correlates with the progression of various inflammatory diseases, locating specific regions of the body with dysregulated levels of inflammation could provide crucial information for effective medical diagnosis and treatment. In this study, we demonstrate high resolution spatiotemporal imaging of inflammation in mice treated with systemic injection of lipopolysaccharides (LPS) to mimic systemic inflammatory response or sepsis. Diagnosis of organ-level inflammation was achieved by magnetic resonance imaging (MRI) of inflammation-sensitive superparamagnetic iron oxide (SPIO)-based nanomicelle termed leukocyte-mimetic nanoparticle (LMN), designed to preferentially localize to cells with inflammation-induced overexpression of intercellular adhesion molecule (ICAM)-1. Using a novel MRI quantitative susceptibility mapping (QSM) technique for non-invasive quantification of SPIO nanoparticles, we observed greater accumulation of LMN in the liver, specific to ICAM-1 induction due to LPS-induced inflammation. However, the accumulation of nanoparticles into the spleen appeared to be due to an ICAM-1 independent, phagocytic activity, resulting in higher levels of both LMN and control nanoparticles in the spleen of LPS-treated than untreated mice. Overall, the amounts of nanoparticles in liver and spleen estimated by QSM were in a good agreement with the values directly measured by radioactivity, presenting an idea that spatiotemporal mapping of LMN by MRI QSM may provide a reliable, rapid, non-invasive method for identifying organ-specific inflammation not offered by existing diagnostic techniques.
KeywordsMagnetic resonance imaging QSM Sepsis SPIO Super paramagnetic iron oxide
Support for this work was provided in part by NSF GK-12 Fellowship and American Heart Association Scientist Development Grant (M.M.J.).
Conflict of interest
No benefits in any form have been or will be received from a commercial party related directly or indirectly to the subject of this manuscript.
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- 16.Essani, N. A., M. A. Fisher, A. Farhood, A. M. Manning, C. W. Smith, and H. Jaeschke. Cytokine-induced upregulation of hepatic intercellular adhesion molecule-1 messenger RNA expression and its role in the pathophysiology of murine endotoxin shock and acute liver failure. Hepatology 21(6):1632–1639, 1995.PubMedGoogle Scholar
- 19.Holme, P. A., U. Orvim, M. J. Hamers, N. O. Solum, F. R. Brosstad, R. M. Barstad, and K. S. Sakariassen. Shear-induced platelet activation and platelet microparticle formation at blood flow conditions as in arteries with a severe stenosis. Arterioscler. Thromb. Vasc. Biol. 17(4):646–653, 1997.PubMedCrossRefGoogle Scholar
- 21.Jaffer, F. A., C. H. Tung, J. J. Wykrzykowska, N. H. Ho, A. K. Houng, G. L. Reed, and R. Weissleder. Molecular imaging of factor XIIIa activity in thrombosis using a novel, near-infrared fluorescent contrast agent that covalently links to thrombi. Circulation 110(2):170–176, 2004.PubMedCrossRefGoogle Scholar
- 24.Lanza, G. M., X. Yu, P. M. Winter, D. R. Abendschein, K. K. Karukstis, M. J. Scott, L. K. Chinen, R. W. Fuhrhop, D. E. Scherrer, and S. A. Wickline. Targeted antiproliferative drug delivery to vascular smooth muscle cells with a magnetic resonance imaging nanoparticle contrast agent: implications for rational therapy of restenosis. Circulation 106(22):2842–2847, 2002.PubMedCrossRefGoogle Scholar
- 25.Liu, T., P. Spincemaille, L. de Rochefort, B. Kressler, and Y. Wang. Calculation of susceptibility through multiple orientation sampling (COSMOS): a method for conditioning the inverse problem from measured magnetic field map to susceptibility source image in MRI. Magn. Reson. Med. 61(1):196–204, 2009.PubMedCrossRefGoogle Scholar
- 26.Liu, T., P. Spincemaille, L. de Rochefort, R. Wong, M. Prince, and Y. Wang. Unambiguous identification of superparamagnetic iron oxide particles through quantitative susceptibility mapping of the nonlinear response to magnetic fields. Magn. Reson. Imaging 28(9):1383–1389, 2010.PubMedCrossRefGoogle Scholar
- 28.Massey, J. M., J. Amps, M. S. Viapiano, R. T. Matthews, M. R. Wagoner, C. M. Whitaker, W. Alilain, A. L. Yonkof, A. Khalyfa, N. G. Cooper, J. Silver, and S. M. Onifer. Increased chondroitin sulfate proteoglycan expression in denervated brainstem targets following spinal cord injury creates a barrier to axonal regeneration overcome by chondroitinase ABC and neurotrophin-3. Exp. Neurol. 209(2):426–445, 2008.PubMedCrossRefGoogle Scholar
- 36.Olanders, K., Z. Sun, A. Borjesson, M. Dib, E. Andersson, A. Lasson, T. Ohlsson, and R. Andersson. The effect of intestinal ischemia and reperfusion injury on ICAM-1 expression, endothelial barrier function, neutrophil tissue influx, and protease inhibitor levels in rats. Shock 18(1):86–92, 2002.PubMedCrossRefGoogle Scholar
- 40.Swirski, F. K., M. Nahrendorf, M. Etzrodt, M. Wildgruber, V. Cortez-Retamozo, P. Panizzi, J. L. Figueiredo, R. H. Kohler, A. Chudnovskiy, P. Waterman, E. Aikawa, T. R. Mempel, P. Libby, R. Weissleder, and M. J. Pittet. Identification of splenic reservoir monocytes and their deployment to inflammatory sites. Science 325(5940):612–616, 2009.PubMedCrossRefGoogle Scholar
- 44.Werner, J., K. Z’Graggen, C. Fernandez-del Castillo, K. B. Lewandrowski, C. C. Compton, and A. L. Warshaw. Specific therapy for local and systemic complications of acute pancreatitis with monoclonal antibodies against ICAM-1. Ann. Surg. 229(6):834–840, 1999, discussion 841–832.Google Scholar