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Comparative Study
. 2008 Jul;154(5):1063-72.
doi: 10.1038/bjp.2008.174. Epub 2008 May 12.

In Vivo Pharmacological Evaluation of Compound 48/80-induced Airways Oedema by MRI

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Free PMC article
Comparative Study

In Vivo Pharmacological Evaluation of Compound 48/80-induced Airways Oedema by MRI

H Karmouty-Quintana et al. Br J Pharmacol. .
Free PMC article

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.

Figures

Figure 1
Figure 1
Time course following compound 48/80 (1 mg kg−1 i.t.) or saline (0.2 mL i.t.) administration. The number of animals used is shown in parenthesis. The significance levels *P<0.05, **0.001<P<0.01 and ***P<0.001 refer to statistical comparisons between compound 48/80 and vehicle-treated animals for each time point (two-way ANOVA).Transversal sections through the thorax of rats treated with compound 48/80 (1 mg kg−1 i.t.) are shown at baseline and 3, 24, 48 and 96 h after treatment are shown. The black arrows denote fluid signals related to compound 48/80 induced airways oedema as evidenced by post-mortem bronchoalveolar lavage (BAL) fluid and histological analyses.
Figure 2
Figure 2
(Top)—Verhoeff-stained slices of rat lungs previously treated with saline (0.2 mL i.t.; left) or compound 48/80 (1 mg kg−1 i.t.; right) and killed 24 h after either challenge. The black arrows denote the presence of oedema around the vessel (V) and the bronchi (B) following compound 48/80 treatment. (Bottom)—Perivascular oedema assessed from the left and right caudal lobes. Values (means±s.e.mean for four rats in each group) represent oedema percent. The oedema value 24 h after compound 48/80 (1 mg kg−1 i.t.) treated rats was significantly greater than saline-treated animals (0.2 mL i.t.; ***P<0.001; Student's t-test (two tailed)).
Figure 3
Figure 3
Magnetic resonance imaging lung fluid signal volumes (means±s.e.mean) determined from MR images at 24 h after compound 48/80 (1 mg kg−1 i.t.) and after treatment with (a) indomethacin (10 mg kg−1 p.o.; n=5) or its vehicle (10% TRIS buffer 2 mL kg−1 p.o.; n=5) 1 h prior to compound 48/80; CGS8515 (25 mg kg−1 p.o., n=5) or its vehicle (2% MP in Neoral placebo p.o.; n=5) 2 h prior compound 48/80. (b) Disodium cromoglycate (DSCG; 10 mg kg−1 i.t.) administered immediately prior to (n=12) or 3 h (n=8) after compound 48/80. The vehicle for DSCG was saline i.t. (n=8); wortmannin (100 μg kg−1 i.t; n=8) or its vehicle (4% dimethyl sulphoxide (DMSO) i.t.; n=6) was applied 1 h prior to compound 48/80. (c) Capsazepine (3.5 mg kg−1 i.t.; n=5) or its vehicle (0.5% ethanol i.t.; n=5); DNK333 (10 mg kg−1 i.p., n=5) or its vehicle (2% DMSO in Neoral placebo 2 mL kg−1 i.p; n=5); a dual therapy with wortmannin (100 μg kg−1 i.t.) and DNK333 (10 mg kg−1 i.p; n=5) or both vehicle groups (4% DMSO i.t. and 2% DMSO i.p; n=5). Compound 48/80 was administered 30 min after treatment with capsazepine, DNK333 or their corresponding vehicles and 1 h after wortmannin or its vehicle. (d) budesonide (3 mg kg−1 i.t.) administered immediately prior to (n=10) or 3 h (n=8) after compound 48/80. The vehicle for budesonide was 4% DMSO in saline i.t. (n=6). The significance levels *P<0.05; **0.001<P<0.01 and ***P<0.001 refer to differences between the drug substance and their corresponding vehicle groups derived from the Student's t-test (two tailed). The significance levels ###P<0.05 refer to one-way ANOVA analysis of variance with a Bonferroni correction.
Figure 4
Figure 4
Protein concentration in bronchoalveolar lavage (BAL) fluid (means±s.e.mean) determined at 24 h after compound 48/80 (1 mg kg−1 i.t.) and after treatment with (a) indomethacin (10 mg kg−1 p.o.; n=5) or its vehicle (10% TRIS buffer 2 mL kg−1 p.o.; n=5) 1 h prior to compound 48/80; CGS8515 (25 mg kg−1 p.o., n=5) or its vehicle (2% MP in Neoral placebo p.o.; n=5) 2 h prior compound 48/80. (b) Disodium cromoglycate (DSCG; 10 mg kg−1 i.t.) administered immediately prior to (n=12) or 3 h (n=8) after compound 48/80. The vehicle for DSCG was saline i.t. (n=8). Wortmannin (100 μg kg−1 i.t; n=8) or its vehicle (4% dimethyl sulphoxide (DMSO) i.t.; n=6) was applied 1 h prior to compound 48/80. (c) Capsazepine (3.5 mg kg−1 i.t.; n=5) or its vehicle (0.5% ethanol i.t.; n=5); DNK333 (10 mg kg−1 i.p., n=5) or its vehicle (2% DMSO in Neoral placebo 2 mL kg−1 i.p; n=5); a dual therapy with wortmannin (100 μg kg−1 i.t.) and DNK333 (10 mg kg−1 i.p; n=5) or both vehicle groups (4% DMSO i.t. and 2% DMSO i.p; n=5). Compound 48/80 was administered 30 min after treatment with capsazepine, DNK333 or their corresponding vehicles and 1 h after wortmannin or its vehicle. (d) Budesonide (3 mg kg−1 i.t.) administered immediately prior to (n=10) or 3 h (n=8) after compound 48/80. The vehicle for budesonide was 4% DMSO in saline i.t. (n=6). The significance levels *P<0.05 and **0.001<P<0.01 refer to differences between the drug substance and their corresponding vehicle groups derived from the Student's t-test (two tailed). The significance levels #P<0.05 and ##0.001 <P<0.01 refer to one-way ANOVA analysis of variance with a Bonferroni correction.

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