Noninvasive Quantitative Tomography of the Therapeutic Response to Dexamethasone in Ovalbumin-Induced Murine Asthma

Abstract

Animal models of pulmonary inflammation are critical for understanding the pathophysiology of asthma and for developing new therapies. Current conventional assessments in mouse models of asthma and chronic obstructive pulmonary disease rely on invasive measures of pulmonary function and terminal characterization of cells infiltrating into the lung. The ability to noninvasively visualize and quantify the underlying biological processes in mouse pulmonary models in vivo would provide a significant advance in characterizing disease processes and the effects of therapeutics. We report the utility of near-infrared imaging agents, in combination with fluorescence molecular tomography (FMT) imaging, for the noninvasive quantitative imaging of mouse lung inflammation in an ovalbumin (OVA)-induced chronic asthma model. BALB/c mice were intraperitoneally sensitized with OVA-Alum (aluminum hydroxide) at days 0 and 14, followed by daily intranasal challenge with OVA in phosphate-buffered saline from days 21 to 24. Dexamethasone and control therapies were given intraperitoneally 4 h before each intranasal inhalation of OVA from days 21 to 24. Twentyfour hours before imaging, the mice were injected intravenously with 5 nmol of the cathepsin-activatable fluorescent agent, ProSense 680. Quantification by FMT revealed in vivo cysteine protease activity within the lung associated with the inflammatory eosinophilia, which decreased in response to dexamethasone treatment. Results were correlated with in vitro laboratory tests (bronchoalveolar lavage cell analysis and immunohistochemistry) and revealed good correlation between these measures and quantification of ProSense 680 activation. We have demonstrated the ability of FMT to noninvasively visualize and quantify inflammation in the lung and monitor therapeutic efficacy in vivo.

The Novel Role of the Mu Opioid Receptor in Lung Cancer Progression

“…To test this, LLC cells were injected into the hind flank of wildtype and MOR knockout mice and tumor formation was examined in vivo using Visen FMT imaging of tumor volume at 12 days post visible tumor formation after injection of Prosense680 33,34 (activated by cathepsins, known to be up-regulated in cancer 35 ) near infrared probe (Figure 3-A). Quantitation of in vivo fluorescence indicated virtually no tumor formation in the MOR knockout mouse (p < 0.001)(Figure 3-B).…”

Preclinical Evaluation of 68Ga-Labeled 1,4,7-Triazacyclononane-1,4,7-Triacetic Acid-Ubiquicidin as a Radioligand for PET Infection Imaging

“…Rabbits sensitized with ovalbumin (NZR-3) will develop an early onset airway response that resembles human asthma with histopathologic changes, thus they can serve as a noninfectious model of inflammation (32). Airway and lung inflammations have been studied noninvasively, using mainly 18 F-FDG in both animals and humans (33) and other imaging techniques such as functional MRI (fMRI) (34) and fluorescencemediated tomography (FMT) (35). We found no significant increases in the L/M ratios in asthmatic inflamed lungs (P 5 0.662) and rabbit lungs of animals with an extrapulmonary infection and inflammation (P 5 0.820), compared with rabbit lungs in healthy condition.…”

Optical tomographic imaging of near infrared imaging agents quantifies disease severity and immunomodulation of experimental autoimmune encephalomyelitis in vivo

“…In addition, as proteases play a central role in cancer and inflammatory disease processes, we anticipated that protease-activatable NIR imaging agents [32,33] could serve as a sensitive means for detecting neuroinflammation in EAE and changes with therapeutic intervention. Protease-activatable agents have been used to image protease increases in a number of disease states, including cancer [34,35], asthma [36,37], atherosclerosis [38,39] and arthritis [40,41]. However, it remained to be determined whether this collection of NIR imaging agents can pass the BBB and effectively detect disease within the CNS.…”