Stefan Zurbruegg

Capillary cerebral amyloid angiopathy is associated with vessel occlusion and cerebral blood flow disturbances

The role of cerebral amyloid angiopathy (CAA) in the pathogenesis of Alzheimers disease (AD) is not fully understood. Here, we studied whether CAA is associated with alterations in microvascularisation in transgenic mouse models and in the human brain. APP23 mice at 25-26 months of age exhibited severe CAA in thalamic vessels whereas APP51/16 mice did not. Wild-type littermates were free of CAA. We found CAA-related capillary occlusion within the thalamus of APP23 mice but not in APP51/16 and wild-type mice. Magnetic resonance angiography (MRA) showed blood flow alterations in the thalamic vessels of APP23 mice. CAA-related capillary occlusion in the branches of the thalamoperforating arteries of APP23 mice, thereby, corresponded to the occurrence of blood flow disturbances. Similarly, CAA-related capillary occlusion was observed in the human occipital cortex of AD cases but less frequently in controls. These results indicate that capillary CAA can result in capillary occlusion and is associated with cerebral blood flow disturbances providing an additional mechanism for toxic effects of the amyloid beta-protein in AD.

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.

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.

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).

Proton MRI as a noninvasive tool to assess elastase-induced lung damage in spontaneously breathing rats

Elastase‐induced changes in lung morphology and function were detected in spontaneously breathing rats using conventional proton MRI at 4.7 T. A single dose of porcine pancreatic elastase (75 U/100 g body weight) or vehicle (saline) was administered intratracheally (i.t.) to male Brown Norway (BN) rats. MRI fluid signals were detected in the lungs 24 hr after administration of elastase and resolved within 2 weeks. These results correlated with perivascular edema and cellular infiltration observed histologically. Reductions in MRI signal intensity of the lung parenchyma, and increases in lung volume were detected as early as 2 weeks following elastase administration and remained uniform throughout the study, which lasted 8 weeks. Observations were consistent with air trapping resulting from emphysema detected histologically. In a separate experiment, animals were treated daily intraperitoneally (i.p.) with all‐trans‐retinoic acid (ATRA; 500 μg/kg body weight) or its vehicle (triglyceride oil) starting on day 21 after elastase administration and continuing for 12 days. Under these conditions, ATRA did not elicit a reversal of elastase‐induced lung damage as measured by MRI and histology. The present approach complements other validated applications of proton MRI in experimental lung research as a method for assessing drugs in rat models of respiratory diseases. Magn Reson Med, 2006.

Proton MRI of lung parenchyma reflects allergen-induced airway remodeling and endotoxin-aroused hyporesponsiveness: A step toward ventilation studies in spontaneously breathing rats

Proton signals from lung parenchyma were detected with the use of a gradient‐echo sequence to noninvasively obtain information on pulmonary function in models of airway diseases in rats. Initial measurements carried out in artificially ventilated control rats revealed a highly significant negative correlation between the parenchymal signal and the partial pressure of oxygen (pO2) in the blood, for different amounts of oxygen administered. The magnitude of the signal intensity variations caused by changes in the oxygen concentration was larger than expected solely from the paramagnetic properties of molecular oxygen. Inhomogeneous line‐broadening induced by lung inflation may explain the observed signal amplification. Experiments carried out in spontaneously breathing animals challenged with allergen or endotoxin revealed parenchymal signal changes that reflected the oxygenation status of the lungs and were consistent with airway remodeling or hyporesponsiveness. The results suggest that proton MRI of parenchymal tissue is a sensitive tool for probing the functional status of the lung in rat models of respiratory diseases. The method is complementary to the recently described noninvasive assessment by MRI of pulmonary inflammation in small rodents. Overall, these techniques provide invaluable information for profiling anti‐inflammatory drugs in models of airway diseases. Magn Reson Med 52:258–268, 2004.

Activation of the lung S1P1 receptor reduces allergen-induced plasma leakage in mice

Background and purpose:  It has been suggested that intratracheal administration of the immunomodulator, FTY720, could have anti‐inflammatory effects without causing a decrease in blood lymphocyte counts. However, the receptor responsible for this effect has not been defined.

In vivo assessments of mucus dynamics in the rat lung using a Gd-Cy5.5-bilabeled contrast agent for magnetic resonance and optical imaging

Dysfunctions in mucociliary clearance are associated with the accelerated loss of lung function in several respiratory diseases. Approaches enabling the in vivo visualization of mucus dynamics in rodents at high resolution and sensitivity would be beneficial for experimental lung research. We describe the synthesis and characterization of two bilabeled amino dextran–based probes binding specifically to mucin. Labeling of secreted mucus and of mucin in goblet cells in the lungs of lipopolysaccharide‐challenged rats has been demonstrated in vivo with near‐infrared fluorescence and MRI and confirmed by histology. The effects of uridine triphosphate were then studied in lipopolysaccharide‐challenged rats by simultaneously administering the imaging probe and the compound. The data suggest that uridine triphosphate increased the mucociliary clearance, but at the same time induced a release of mucin from goblet cells, thus not contributing to the overall reduction of mucus in the lung. The approach outlined here enables one to derive information on mucus clearance, as well as secretion. Such a global view on mucus dynamics may prove invaluable when testing new pharmacological agents aimed at improving mucociliary clearance. Magn Reson Med, 2009.

In vivo pharmacological evaluation of compound 48/80‐induced airways oedema by MRI

Allergen‐induced airways oedema in actively sensitized rats has been studied earlier by magnetic resonance imaging (MRI). We used MRI to follow the consequences of non‐immunological mast cell activation induced by compound 48/80 in the rat lungs in vivo.

Near-infrared fluorescence imaging and histology confirm anomalous edematous signal distribution detected in the rat lung by MRI after allergen challenge

To address the issue concerning the predominant location, on the left anatomic side, of edematous signals detected by magnetic resonance imaging (MRI) in the lungs of actively sensitized rats following intratracheal (IT) allergen challenge.