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Real-time assessment of inflammation and treatment response in a mouse model of allergic airway inflammation
Virna Cortez-Retamozo, … , Ralph Weissleder, Mikael J. Pittet
Virna Cortez-Retamozo, … , Ralph Weissleder, Mikael J. Pittet
Published November 6, 2008
Citation Information: J Clin Invest. 2008;118(12):4058-4066. https://doi.org/10.1172/JCI36335.
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Technical Advance Immunology

Real-time assessment of inflammation and treatment response in a mouse model of allergic airway inflammation

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Abstract

Eosinophils are multifunctional leukocytes that degrade and remodel tissue extracellular matrix through production of proteolytic enzymes, release of proinflammatory factors to initiate and propagate inflammatory responses, and direct activation of mucus secretion and smooth muscle cell constriction. Thus, eosinophils are central effector cells during allergic airway inflammation and an important clinical therapeutic target. Here we describe the use of an injectable MMP-targeted optical sensor that specifically and quantitatively resolves eosinophil activity in the lungs of mice with experimental allergic airway inflammation. Through the use of real-time molecular imaging methods, we report the visualization of eosinophil responses in vivo and at different scales. Eosinophil responses were seen at single-cell resolution in conducting airways using near-infrared fluorescence fiberoptic bronchoscopy, in lung parenchyma using intravital microscopy, and in the whole body using fluorescence-mediated molecular tomography. Using these real-time imaging methods, we confirmed the immunosuppressive effects of the glucocorticoid drug dexamethasone in the mouse model of allergic airway inflammation and identified a viridin-derived prodrug that potently inhibited the accumulation and enzyme activity of eosinophils in the lungs. The combination of sensitive enzyme-targeted sensors with noninvasive molecular imaging approaches permitted evaluation of airway inflammation severity and was used as a model to rapidly screen for new drug effects. Both fluorescence-mediated tomography and fiberoptic bronchoscopy techniques have the potential to be translated into the clinic.

Authors

Virna Cortez-Retamozo, Filip K. Swirski, Peter Waterman, Hushan Yuan, Jose Luiz Figueiredo, Andita P. Newton, Rabi Upadhyay, Claudio Vinegoni, Rainer Kohler, Joseph Blois, Adam Smith, Matthias Nahrendorf, Lee Josephson, Ralph Weissleder, Mikael J. Pittet

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Figure 1

Eosinophils in inflamed lungs display potent MMP activity.

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Eosinophils in inflamed lungs display potent MMP activity.
E, eosinophil...
E, eosinophils; Mf, monocytes/macrophages; N, neutrophils, O, other cells. (A) Identification of cell populations in single-cell suspensions of digested lungs from OVA-treated and control PBS-treated mice. FSC, forward scatter; SSC, side scatter. (B) H&E staining of flow-sorted cells obtained from digested lung tissue and identified based on expression of specific cell surface markers. Scale bar: 25 μm. (C) Flow cytometric analysis revealed increased MMP activity in eosinophils in inflamed lungs. Numbers denote percent MMP-positive cells in inflamed versus control lung. (D) Total cell counts in lungs. (E) MMP mean fluorescence intensity (MFI) in each cell type in lung, as identified by flow cytometry. (F) Contribution of cell types to MMP activity in inflamed lungs based on results in D and E. Data are representative of at least 3 independent experiments, with n = 3–5 per experiment and per group. Data are mean ± SEM.
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