Catherine Cannet

MRI‐based monitoring of inflammation and tissue damage in acute and chronic relapsing EAE

Experimental autoimmune encephalomyelitis (EAE) is a commonly used animal model that in several respects mimics human multiple sclerosis (MS), and can be used to design or validate new strategies for treatment of this disease. In the present study, different MRI techniques (macrophage tracking based on labeling cells in vivo by ultrasmall particles of iron oxide (USPIO), blood–brain barrier (BBB) breakdown, and magnetization transfer imaging (MTI)), as well as immunohistological staining were used to study the burden of disease in Lewis rats immunized by guinea pig myelin. The resulting imaging data was compared with behavioral readouts. Animals were studied during the acute phase and the first relapse. Activated monocytes were detected during both episodes in the brain stem or cortex. These areas coincided in part with areas of BBB breakdown. Significant changes of the magnetization transfer ratios (MTRs) of up to 35% were observed in areas of USPIO accumulation. This suggests that infiltrating monocytes are the major source of demyelination in EAE, but monocyte infiltration and breakdown of the BBB are temporally or spatially independent inflammatory processes. Magn Reson Med 50:309–314, 2003.

Predictability of FTY720 efficacy in experimental autoimmune encephalomyelitis by in vivo macrophage tracking: Clinical implications for ultrasmall superparamagnetic iron oxide-enhanced magnetic resonance imaging

To examine the efficacy of FTY720 as a new agent to reduce inflammatory activity in an animal model of multiple sclerosis (MS) by in vivo macrophage tracking.

Macrophage labeling by SPIO as an early marker of allograft chronic rejection in a rat model of kidney transplantation.

Anatomical and functional information (renography, perfusion) was obtained by MRI in a life‐supporting transplantation model, in which Lewis rats received kidneys from Fisher 344 donors. Renography and perfusion analyses were carried out with Gd‐DOTA and small particles of iron oxide (SPIO), respectively. Starting 12 weeks posttransplantation, images from grafts of untreated recipients exhibited distinctive signal attenuation in the cortex. Animals treated with cyclosporin (Sandimmune Neoral; Novartis Pharma, Basel, Switzerland) to prevent acute rejection showed a signal attenuation in the cortex at 33 weeks posttransplantation, while kidneys from rats treated additionally with everolimus (Certican; Novartis), a rapamycin derivative, had no changes in anatomical appearance. A significant negative correlation was found between the MRI cortical signal intensity and the histologically determined iron content in macrophages located in the cortex. Renography revealed a significantly reduced functionality of the kidneys of untreated controls 33 weeks after transplantation, while no significant changes in perfusion were observed in any group of rats. These results suggest the feasibility, by labeling macrophages with SPIO, of detecting signs of graft rejection significantly earlier than when changes in function occur. Monitoring early changes associated with chronic rejection can have an impact in preclinical studies by shortening the duration of the experimental period and by facilitating the investigation of novel immunomodulatory therapies for transplantation. Magn Reson Med 49:459–467, 2003.

In vivo visualization of macrophage infiltration and activity in inflammation using magnetic resonance imaging.

Because macrophages play a key role on host defense, visualization of the migration of these cells is of high relevance for both diagnostic purposes and the evaluation of therapeutic interventions. The present article addresses the use of iron oxide and gadolinium-based particles for the noninvasive in vivo detection of macrophage infiltration into inflamed areas by magnetic resonance imaging (MRI). A general introduction on the functions and general characteristics of macrophages is followed by a discussion of some of the agents and acquisition schemes currently used to track the cells in vivo. Attention is then devoted to preclinical and clinical applications in the following disease areas: atherosclerosis and myocardial infarction, stroke, multiple sclerosis, rheumatoid arthritis, and kidney transplantation.

Administration of bleomycin via the oropharyngeal aspiration route leads to sustained lung fibrosis in mice and rats as quantified by UTE-MRI and histology.

Pulmonary fibrosis can be experimentally induced in small rodents by bleomycin. The antibiotic is usually administered via the intratracheal or intranasal routes. In the present study, we investigated the oropharyngeal aspiration of bleomycin as an alternative route for the induction of lung fibrosis in rats and mice. The development of lung injury was followed in vivo by ultrashort echo time magnetic resonance imaging (UTE-MRI) and by post-mortem analyses (histology of collagen, hydroxyproline determination, and qRT-PCR). In C57BL/6 mice, oropharyngeal aspiration of bleomycin led to more prominent lung fibrosis as compared to intranasal administration. Consequently, the oropharyngeal aspiration route allowed a dose reduction of bleomycin and, therewith, a model refinement. Moreover, the distribution of collagen after oropharyngeal aspiration of bleomycin was more homogenous than after intranasal administration: for the oropharyngeal aspiration route, fibrotic areas appeared all over the lung lobes, while for the intranasal route fibrotic lesions appeared mainly around the largest superior airways. Thus, oropharyngeal aspiration of bleomycin induced morphological changes that were more comparable to the human disease than the intranasal administration route did. Oropharyngeal aspiration of bleomycin led to a homogeneous fibrotic injury also in rat lungs. The present data suggest oropharyngeal aspiration of bleomycin as a less invasive means to induce homogeneous and sustained fibrosis in the lungs of mice and rats.

Noninvasive Magnetic Resonance Imaging Detection of Cerebral Amyloid Angiopathy-Related Microvascular Alterations Using Superparamagnetic Iron Oxide Particles in APP Transgenic Mouse Models of Alzheimer's Disease: Application to Passive Aβ Immunotherapy

Cerebral amyloid angiopathy (CAA) is a common feature of Alzheimers disease (AD). More advanced stages are accompanied by microhemorrhages and vasculitis. Peripheral blood-borne macrophages are intimately linked to cerebrovascular pathology coincident with AD. Magnetic resonance imaging (MRI) was used to noninvasively study microvascular lesions in amyloid precursor protein transgenic mouse AD models. Foci of signal attenuation were detected in cortical and thalamic brain regions of aged APP23 mice. Their strength and number was considerably enhanced by intravenous administration of iron oxide nanoparticles, which are taken up by macrophages through absorptive endocytosis, 24 h before image acquisition. The number of cortical sites displaying signal attenuation increased with age. Histology at these sites demonstrated the presence of iron-containing macrophages in the vicinity of CAA-affected blood vessels. A fraction of the sites additionally showed thickened vessel walls and vasculitis. Consistent with the visualization of CAA-associated lesions, MRI detected a much smaller number of attenuated signal sites in APP23xPS45 mice, for which a strong presenilin mutation caused a shift toward amyloid β42, thus reducing vascular amyloid. Similar results were obtained with APP24 and APP51 mice, which develop significantly less CAA and microvascular pathology than APP23. In a longitudinal study, we noninvasively demonstrated the reinforced formation of microvascular pathology during passive amyloid β immunotherapy of APP23 mice. Histology confirmed that foci of signal attenuation reflected an increase in CAA-related lesions. Our data demonstrate that MRI has the sensitivity to noninvasively monitor the development of vascular pathology and its possible enhancement by amyloid β immunotherapy in transgenic mice modeling AD.

Resolution of the oedema associated with allergic pulmonary inflammation in rats assessed noninvasively by magnetic resonance imaging.

Magnetic resonance imaging (MRI) was used to study noninvasively the effects of compounds to resolve inflammation induced by ovalbumin (OVA) challenge in the lungs of actively sensitised rats. Marked oedematous signals were detected between 24 and 96 h following OVA in vehicle‐treated animals. When administered 24 h after OVA, budesonide, a glucocorticosteroid, or 4‐(8‐benzo[1,2,5]oxadiazol‐5‐yl‐[1,7]naphthyridin‐6‐yl)‐benzoic acid (NVP‐ABE171), a selective phosphodiesterase 4 inhibitor, increased the rate of resolution of established oedematous signals detected by MRI. The effect was evident 3 h after drug administration and the signals were nearly fully resolved at 96 h postchallenge. The drug‐induced rapid resolution of MRI signals was not accompanied by changes in parameters of inflammation in the bronchoalveolar lavage fluid, but was associated with perivascular oedema detected histologically. In conclusion, the effects of anti‐inflammatory drugs on a component of allergic inflammation can be monitored by following with MRI the rate of resolution of the associated oedematous signals.

Allergen-induced lung inflammation in actively sensitized mice assessed with MR imaging

PURPOSE To demonstrate the feasibility of using proton magnetic resonance (MR) imaging to noninvasively detect extravascular and luminal fluid in a murine model of allergen-induced airway inflammation. MATERIALS AND METHODS The Basel Veterinary Authority approved this experiment. Actively sensitized female Balb/c mice received ovalbumin or saline and underwent MR imaging (a) once 24 hours after the fourth administration of ovalbumin or saline (n = 25) or (b) several times between and after ovalbumin or saline administrations (n = 22) to determine the volume of fluid signal induced by an allergen. Images were acquired in spontaneously breathing animals, without cardiac or respiratory gating. Signal detected with a gradient-echo sequence was compared with bronchoalveolar lavage (BAL) fluid parameters and with perivascular and peribronchial edema and mucus observed at histologic analysis. RESULTS Up to 24 hours after the fourth administration of ovalbumin, intense and continuous fluid signals (volume, 40-50 microL) were detected in proximal lung regions. At 72 hours after the fourth administration of ovalbumin, remaining signals (21.1 microL +/- 3.8) had a discontinuous texture. The number of eosinophils in the BAL fluid at 24 and 72 hours and their activation were higher in mice that received ovalbumin than in those that received saline. Histologic analysis revealed edema and secreted mucus in the early phase, whereas only mucus was encountered in the late phase. CONCLUSION These findings suggest that the main component of the early response was plasma leakage (edema), while the main component of the late response was secreted mucus. With the technique validated, the basis for pharmacologic studies in this murine model of lung inflammation with use of MR imaging as a noninvasive readout was provided.

Capsaicin-induced mucus secretion in rat airways assessed in vivo and non-invasively by magnetic resonance imaging

An up‐regulation of the sensory neural pathways in the lung has been implicated in asthma and chronic obstructive pulmonary disease (COPD) and is thought to contribute to mucus hypersecretion, an essential feature of both diseases. The aim of this study was to assess non‐invasively the acute effects (up to 60 min) of sensory nerve stimulation by capsaicin in the lung, using magnetic resonance imaging (MRI).

Bleomycin‐induced lung injury assessed noninvasively and in spontaneously breathing rats by proton MRI

To apply proton magnetic resonance imaging (MRI) techniques to assess noninvasively and in spontaneously breathing rats, structural changes following a single intratracheal administration of bleomycin (BLM).