Effects of a mitogen-activated protein kinase inhibitor on allergic airways inflammation in the rat studied by magnetic resonance imaging.
We recently described a new model to study non-invasively with magnetic resonance imaging (MRI) the effects of compounds to prevent and/or resolve airway inflammation induced by ovalbumin in the lungs of actively sensitised rats. We report here the effects of 4-(4-fluorophenyl)-2-(1-methylpiperidin-4-yl)-5-(2-(1-(S)-phenylethyl)amino-4-pyridinyl)thiazole fumarate (Compound 1), which exhibits inhibitory activity against p38alpha and p38beta2 and residual activity on c-Jun amino-terminal kinase (JNK)2 mitogen-activated protein (MAP) kinases, on the oedematous signals detected by MRI and generated by antigen challenge in the lungs of sensitized rats. Compound 1 (10 mg kg(-1)) given orally 1 h prior to allergen challenge significantly reduced the oedematous signal measured at 24 h. Similar effects were seen with a synthetic corticosteroid, mometasone furoate (0.3 mg kg(-1)), given intratracheally 3 h prior to challenge. For both compounds, inhibition of the oedematous signal was accompanied by reductions in the inflammatory parameters in the bronchoalveolar lavage fluid measured 24 h after challenge with ovalbumin. Compound 1 (10 mg kg(-1)) administered 24 h after challenge with ovalbumin did not change the rate of resolution of the signal detected by MRI in the lungs. In contrast, mometasone furoate (0.3 mg kg(-1)) significantly increased resolution of these signals, which was evident 3 h after drug administration and maintained to 48 h post challenge. Collectively, our data suggest that the p38 MAP kinase inhibitor Compound 1 shows a different profile than glucocorticosteroids since its ability to resolve existing inflammation is limited.
Tigani
Bruno
B
Discovery Technologies Center, Novartis Institutes for BioMedical Research, Lichstr. 35, WSJ-386.2.09, CH-4002, Basel, Switzerland.
Di Padova
Franco
F
Zurbrügg
Stefan
S
Schaeublin
Elisabeth
E
Revesz
Laszlo
L
Fozard
John R
JR
Beckmann
Nicolau
N
D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011014:Pneumonia / Q000188:drug therapy* / Q000201:enzymology*; D051381:Rats; D011914:Rats, Inbred BN
D004791:Enzyme Inhibitors; D020928:Mitogen-Activated Protein Kinases