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

Abstract

Background and purpose: 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. Experimental approach: Male naïve rats were scanned by MRI prior to and at several time points following intratracheal administration of the mast cell secretagogue, compound 48/80. The effects of a range of drugs on the response induced by compound 48/80 were studied. Key results: Strong fluid signals were detected by MRI in the lungs at 24 h after compound 48/80, correlating with increased protein concentration and inflammatory cell infiltration in bronchoalveolar lavage, and with perivascular oedema observed histologically. Pharmacological intervention demonstrated that the increase in MRI signal volume induced by compound 48/80 24 h after challenge was blocked by disodium cromoglycate and the glucocorticoid, budesonide. Pretreatment with wortmannin, capsazepine, DNK333 (a dual neurokinin (NK) 1 and NK2 antagonist) or the anti-allergy drug CGS8515, but not indomethacin, resulted in partial inhibition. Conclusions and implications:Compound 48/80 induced a complex inflammatory reaction which did not solely involve mast cell degranulation but also activation of sensory nerves and was qualitatively similar to allergen challenge. Changes observed by MRI correlated with decreases in protein concentration in BAL fluid. However, the magnitude of the changes detected was greater using MRI. Our results demonstrate that MRI is a sensitive and efficient tool to assess the effects of drugs on lung inflammation.

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Sustained steroid release in pulmonary inflammation model

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“…It is a basic secretagogue that causes mast cell degranulation [15] via direct activation of the Gi protein [16]. Compound 48/80 has been used extensively in vivo to induce inflammation in the lungs [17], rat paw edema [18], and inflammation of the skin [19]. We chose to use this stimulus and the subsequent inflammatory response as the model system to test the efficacy of newly developed porous nanofibrous microspheres composed of calcium pyrophosphate in the size range from 5 to 15 mm to act as sustained release depots to deliver dexamethasone phosphate.…”