No abstract

No abstract

No abstract

1 We have explored the role of allergen sensitization and challenge in de®ning the response of the airways of the Brown Norway (BN) rat to adenosine. 2 In naõÈ ve animals or in rats sensitized to ovalbumin (OA) adenosine induced only weak bronchoconstrictor responses. Challenge of sensitized animals with OA induced a marked airway hyperresponsiveness to adenosine which was not seen with methacholine or bradykinin. 3 The augmented bronchoconstrictor response to adenosine was not a ected by acute bivagotomy or atropine nor mimicked by an i.v. injection of capsaicin. It was, however, blocked selectively by disodium cromoglycate methysergide or ketanserin and reduced in animals treated sub-chronically with compound 48/80. 4 The augmented response to adenosine was associated with increases in the plasma concentrations of both histamine and 5-hydroxytryptamine (5-HT), which were attenuated by pretreatment with disodium cromoglycate, and degranulation of mast cells in the lung. 5 Parenchymal strips from lungs removed from sensitized rats challenged with OA gave augmented bronchoconstrictor responses to adenosine relative to strips from sensitized animals challenged with saline. Responses were inhibited by methysergide and disodium cromoglycate. 6 These data demonstrate a marked augmentation of the bronchoconstrictor response to adenosine in actively sensitized BN rats challenged with OA. The augmented response is primarily a consequence of mast cell activation, leading to the release of 5-HT, which in turn induces bronchoconstriction. Our data further suggest the involvement of a discrete lung-based population of mast cells containing and releasing mainly 5-HT and brought into play by prior exposure to allergen.

Signal of lung parenchymal tissue from the living rat and mouse lung was detected at 4.7 T with a good signal-to-noise ratio and motion-suppressed artifacts using a short TE gradient-echo sequence. Neither cardiac nor respiratory gating were applied, and animals respired freely during data collection. Mean T(2)* relaxation times of parenchyma in the anterior, middle and posterior regions of both lungs ranged between 403 and 657 micros and 397 and 751 micros, respectively for the rat and mouse. For the rat in the prone position, there was a gradient in T(2)* values, from the posterior to the anterior regions of both lungs. In the supine position, however, T(2)* values were larger in the posterior and in the anterior portions. For the mouse in both prone and supine positions, there was a tendential gradient in T(2)* from the anterior to the posterior portions. The robustness of the approach renders it well suited for routine applications, e.g. in pharmacological studies concerning asthma models in small rodents. The method was applied to lung inflammation models involving challenge with ovalbumin or lipopolysaccharide.

Using magnetic resonance imaging (MRI), we detected a signal in the lungs of Brown Norway rats after intratracheal administration of endotoxin [lipopolysaccharide (LPS)]. The signal had two components: one, of diffuse appearance and higher intensity, was particularly prominent up to 48 h after LPS; the second, showing an irregular appearance and weaker intensity, was predominant later. Bronchoalveolar lavage fluid analysis indicated that generalized granulocytic (especially neutrophilic) inflammation was a major contributor to the signal at the early time points, with mucus being a major factor contributing at the later time points. The facts that animals can breathe freely during data acquisition and that neither respiration nor cardiac triggering is applied render this MRI approach attractive for the routine testing of anti-inflammatory drugs. In particular, the prospect of noninvasively detecting a sustained mucus hypersecretory phenotype in the lung brings an important new perspective to models of chronic obstructive pulmonary diseases in animals.

1 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.

Recently, four subtypes of the human phosphodiesterase type 4 (PDE4A-D) enzyme have been described. So far, only very few PDE4 subtype-selective inhibitors are known. Herein, we describe the synthesis of 6,8-disubstituted 1,7-naphthyridines and their characterization as potent and selective inhibitors of PDE4D which suppress the oxidative burst in human eosinophils with IC(50) values as low as 0.7 nM. SAR development and the extended use of palladium-catalyzed cross-coupling reactions led to compound 11 which inhibited human PDE4D with an IC(50) value of 1 nM. Thus, compound 11 was 55, 175, and 1000 times more potent in inhibiting PDE4D over PDE4B, PDE4A, and PDE4C. In a Brown Norway rat model of allergic asthma, compound 11 when given by the oral route (1 mg/kg) reduced by more than 50% the influx of eosinophils, T-cells, and neutrophils into bronchoalveolar lavage fluid (BALF) samples obtained from antigen-challenged animals. Thus, PDE4D-selective inhibitors of the 1,7-naphthyridine class have the potential as an oral therapy for treating asthma.