Techniques: magnetic resonance imaging of the lung provides potential for non-invasive preclinical evaluation of drugs.
ABSTRACT Over the past several years, magnetic resonance imaging (MRI) has become an established tool in the drug discovery and development process. The main advantages of MRI are its high resolution, non-invasiveness and versatility, which allow comprehensive characterization of a disease state and the effects of drug intervention. Recent advances now allow the application of this technique to the characterization of models of lung inflammation in rats and to the profiling of anti-inflammatory drugs. Repeated measurements can be carried out on the same animal, and time-courses of events can be easily assessed. Furthermore, the prospect of using MRI to detect non-invasively a sustained mucus hypersecretory phenotype induced by endotoxin brings an important new perspective to models of chronic obstructive pulmonary disease in animals. Importantly, it might be possible to extend the use of this technique to the clinical study of inflammation in the lung and the consequences of drug treatment.
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ABSTRACT: To study the in vivo effect of intratracheal administration of lipopolysaccharide (LPS) in mice by magnetic resonance imaging (MRI) and to investigate the correlation with ex vivo histological evaluation of lung inflammation and oedema. LPS (or phosphate buffered saline) was administered intratracheally to thirty male Balb/C mice at a concentration of 0.3 mg/ml in a total volume of 100 microl. Animals were divided into fifteen LPS-treated and fifteen control mice. MR images were acquired 24 h after challenge in freely breathing animals with standard ECG-gated Gradient-Echo (GRE) sequences and, in a limited number of animals, with ECG-gated Ultrashort-echo time (UTE) sequences. After MRI, animals were sacrificed, and lungs were fixed and processed for histological analysis of the total volume of healthy lung tissue. GRE images revealed the presence of high intensity signal in lungs of LPS-treated mice that was attributable to oedema caused by alveolar inflammation. In histological slices, regions of alterations in the normal alveolar microstructure were observed that could account for MRI findings. A good correlation was observed between the volumes of lesioned tissue measured by MRI and by histology. The volume of the lesion detected by GRE sequences was lower than the volume detected by UTE sequences. The effect of intratracheal administration of LPS in mice was investigated by MRI and histology. A good correlation was observed between GRE-MRI and histological findings. MR images obtained with UTE sequences appear to be more sensitive to the presence of lesions than those obtained by standard GRE acquisitions.MAGMA Magnetic Resonance Materials in Physics Biology and Medicine 04/2010; 23(2):93-101. · 1.86 Impact Factor
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ABSTRACT: Late phase airflow obstruction and reduction in forced vital capacity are characteristic features of human asthma. Airway microvascular leakage and lung edema are also present in the inflammatory phase of asthma, but the impact of this vascular response on lung functions has not been precisely defined. This study was designed to evaluate the role of increased lung microvascular leakage and edema on the late phase changes in forced vital capacity (FVC) and peak expiratory flow (PEF) in allergen-challenged Brown Norway rats using pharmacological inhibitors of the allergic inflammatory response. Rats were sensitized and challenged with ovalbumin aerosol and forced expiratory lung functions (FVC, PEF) and wet and dry lung weights were measured 48 h after antigen challenge. Ovalbumin challenge reduced FVC (63% reduction) and PEF (33% reduction) and increased wet (65% increase) and dry (51% increase) lung weights. The antigen-induced reduction in FVC and PEF was completely inhibited by oral treatment with betamethasone and partially attenuated by inhibitors of arachidonic acid metabolism including indomethacin (cyclooxygenase inhibitor), 7-TM and MK-7246 (CRTH2 antagonists) and montelukast (CysLT1 receptor antagonist). Antagonists of histamine H1 receptors (mepyramine) and 5-HT receptors (methysergide) had no significant effects indicating that these pre-formed mast cell mediators were not involved. There was a highly significant (P < 0.005) correlation for the inhibition of FVC reduction and increase in wet and dry lung weights by these pharmacological agents. These results strongly support the hypothesis that lung microvascular leakage and the associated lung edema contribute to the reduction in forced expiratory lung functions in antigen-challenged Brown Norway rats and identify an important role for the cyclooxygenase and lipoxygenase products of arachidonic acid metabolism in these responses.Pulmonary Pharmacology & Therapeutics 03/2013; · 2.54 Impact Factor
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ABSTRACT: Asthma is a chronic disease characterized by bronchial hyperresponsiveness (BHR), bronchial inflammation and remodeling. The great improvements in (1) H MRI ultrashort-TE (UTE) sequences in the last decade have allowed lung images with high-resolution and good signal-to-noise ratio to be obtained in parenchymal tissues. In this article, we present a UTE (1) H MRI high-resolution study of a chronic model of asthma in mice with the aim to longitudinally assess the main features of asthma using a fully noninvasive approach. Balb/c mice (n = 6) were sensitized with ovalbumin over a period of 75 days. The control group (n = 3) received normal saline on the same days. MRI acquisitions were performed on days 0, 38 and 78 to study the inflammatory volumes and bronchial remodeling (peribronchial signal intensity index, PBSI). Plethysmographic studies were performed on days 0, 39 and 79 to assess BHR to methacholine using the enhanced pause (Penh) ratio. The average inflammatory volume measured by MRI in the ovalbumin group (15.6 ± 2.4 μL) was increased significantly relative to control mice (-0.3 ± 0.7 μL) on day 38. The inflammatory volume was larger (34.2 ± 3.1 μL) on day 78 in the ovalbumin group. PBSI was significantly higher in the ovalbumin group on day 78 (1.53 ± 0.08) relative to the control group (1.16 ± 0.10), but not on day 38. After sensitization, asthmatic mice presented BHR to methacholine on days 39 and 79. Penh ratios correlated significantly with the inflammatory volume on day 39 and with the PBSI on day 79. This study shows, for the first time, that high-resolution UTE (1) H MRI of the lungs may allow the noninvasive quantification of peribronchial eosinophilic inflammation with airways occlusion by mucus and of bronchial remodeling in a murine asthma model that correlates with functional parameters. Copyright © 2013 John Wiley & Sons, Ltd.NMR in Biomedicine 06/2013; · 3.45 Impact Factor