doi:10.1016/j.ejphar.2004.11.040 
Copyright © 2004 Elsevier B.V. All rights reserved.
Potential role of c-Jun NH2-terminal kinase in allergic airway inflammation and remodelling: effects of SP600125
Puneeta Natha, Paul Eynotta, Sum-Yee Leunga, Ian M. Adcocka, Brydon L. Bennettb and Kian Fan Chunga, 
, 
aNational Heart and Lung Institute, Imperial College, Dovehouse St, London SW3 6LY, UK
bSignal Research Division, Celgene Inc, San Diego, CA, USA
Received 16 July 2004;
revised 28 October 2004;
accepted 2 November 2004.
Available online 15 December 2004.
References and further reading may be available for this article. To view references and further reading you must
purchase this article.
Abstract
Asthma is a chronic inflammatory disease of the airways associated with structural changes such as increased airway smooth muscle mass, which may contribute to impairment of lung function. To determine whether c-Jun NH2-terminal kinase (JNK) of the mitogen-activated protein kinase signalling pathway participated in these changes, the effects of an inhibitor, SP600125 (anthra [1, 9-cd] pyrazole-6 (2H)-one), were examined in a murine model of chronic airway inflammation and remodelling. Mice sensitised to ovalbumin were exposed to ovalbumin aerosol and were treated with SP600125 [30 mg kg−1 intraperitoneal (i.p.)] on days of exposure. SP600125 significantly reduced eosinophil and lymphocyte numbers in bronchoalveolar lavage fluid, suppressed eosinophilic inflammation within the bronchial submucosa, inhibited goblet cell hyperplasia, and increased airway smooth muscle cell number in allergen-exposed mice. SP600125 also inhibited allergen-induced increase in bronchial responsiveness. SP600125 inhibited JNK activity in the challenged lungs. Although SP 600125 may also have other effects, we conclude that c-Jun NH2-terminal kinase may play a role in allergen-induced inflammation and remodelling associated with bronchial hyperresponsiveness.
Keywords: Asthma; c-Jun NH2-terminal kinase; Airway inflammation; Airway smooth muscle; Bronchial responsiveness
Fig. 1. (A) Mean percentage increase in lung resistance to increasing concentrations of acetylcholine. Four groups of sensitised mice were assessed: vehicle-treated and PBS exposed (○; n=8), SP600125-treated and PBS-exposed (□; n=8), vehicle-treated and ovalbumin-exposed (●; n=8), and SP600125-treated and ovalbumin-exposed (■; n=9). Data is expressed as means±S.E.M. *P<0.05, ***P<0.001 compared to SP600125-treated and ovalbumin-exposed animals. (B) Individual and mean −logPC200 measured 72 h following allergen exposure. Following allergen exposure, vehicle-treated ovalbumin-exposed animals exhibited a significantly lower −logPC200 compared to vehicle-treated PBS-exposed group. **P<0.01. SP600125 inhibited the decrease in the −logPC200 after allergen challenge. (##P<0.01). Data expressed as means±S.E.M.
Fig. 2. Mean numbers of total cells (Total), macrophages (Mac), eosinophils (Eos), lymphocytes (Lym), and neutrophils (Neu) in bronchoalveolar lavage fluid. In sensitised vehicle-treated ovalbumin-exposed animals (n=8), there was a significant increase in the total cell count (***P<0.001), eosinophils (***P<0.001), and lymphocytes (***P<0.001) as compared to vehicle-treated ovalbumin-exposed and PBS-exposed group (n=8). SP600125 significantly reduced the allergen-induced increase in total cells (n=9; #P<0.05), eosinophils (###P<0.001), and lymphocytes (##P<0.01). Data shown as means±S.E.M.
Fig. 3. Mean eosinophils counts in the airway submucosa. Vehicle-treated allergen-exposed mice (n=6) demonstrate increased infiltration of eosinophils (**P<0.001) compared to vehicle-treated PBS-exposed mice (n=5). SP600125 (n=8) caused a decrease in the number of eosinophils compared to the vehicle-treated and allergen-exposed group (##P<0.01). Data shown as means±S.E.M.
Fig. 4. Mean number of airway smooth muscle cells. An increase in the number of airway smooth muscle cells (*P<0.05) was observed in vehicle-treated allergen-exposed mice (n=6) compared to vehicle-treated PBS-exposed mice (n=8). SP600125 caused a decrease in the number of airway smooth muscle cells in mice challenged with allergen (n=7) compared to the vehicle-treated allergen-exposed group (##P<0.01). Data shown as means±S.E.M.
Fig. 5. Mean number of goblet cells. Vehicle-treated allergen-exposed mice (n=6) demonstrated an increase in the number of goblet cells (*P<0.05) compared to vehicle-treated PBS-exposed mice (n=4). SP600125-treated mice exposed to allergen (n=4) demonstrated a significant decrease in the number of smooth muscle cells compared to the vehicle-treated allergen-exposed group (**P<0.01). Data shown as means±S.E.M.
Fig. 6. Interleukin-13 (A), interleukin-4 (B), RANTES (C), tumor necrosis factor-α (D), and interleukin-1β (E) levels in lung homogenates. No significant difference in the above cytokines was observed in vehicle-treated animals exposed to ovalbumin compared to vehicle-treated and PBS-exposed mice. SP600125 significantly inhibited the levels of interleukin-13 (n=5), interleukin-4 (n=5), RANTES (n=5), and tumor necrosis factor-α (n=6; #P<0.05, ##P<0.01) following ovalbumin-exposure. A significant decrease in baseline tumor necrosis factor-α was observed following treatment with SP600125 in animals exposed to PBS (n=6), compared to vehicle-treated PBS-exposed mice (n=6; *P<0.05). No change in interleukin-1β was observed in animals treated with SP600125 and exposed to ovalbumin. Data shown as means±S.E.M.
Fig. 7. Western blot analysis of P-c-Jun. P-c-Jun expression was nonsignificantly elevated in vehicle-treated ovalbumin-exposed mice (●; n=4) compared to vehicle-treated PBS-exposed animals (○; n=4). SP600125-treated mice exposed to allergen (■; n=4) demonstrated a significant decrease in P-c-Jun compared to vehicle-treated allergen-exposed animals (#P<0.05). Data shown as means±S.E.M.
Abstract
Purchase PDF (605 K)
E-mail Article
Add to my Quick Links
Cited By in Scopus (20)
Purchase PDF (143 K)
