Effect of the p38 kinase inhibitor, SB 203580, on allergic airway inflammation in the rat

Escott, Katherine J.; Belvisi, M. G.; Birrell, Mark A.; Webber, S. E.; Foster, Martyn; Sargent, Carol A.

doi:10.1038/sj.bjp.0703605

Cited by 58 publications

(38 citation statements)

References 14 publications

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“…Consistent with this hypothesis, administration of this inhibitor had no direct effect on allergic inflammation in our study because it was administered 48 h before RW challenge. These findings extend our knowledge from prior reports that administration of p38 MAP kinase inhibitors just before allergen challenge blocked allergen-induced eosinophilic inflammation (31).…”

Section: Discussionsupporting

confidence: 80%

“…We show that administration of p38 MAP kinase inhibitor just before CpG ODN administration in the present study blocked the anti-inflammatory effects of CpG ODN in murine asthma. These observations are somewhat surprising because p38 MAP kinase inhibitors can block allergic lung inflammation when they are administered at the time of allergen challenge in animal models of asthma (31,32). Furthermore, p38 MAP kinase inhibitors can inhibit other inflammatory diseases such as LPS-induced neutrophilic inflammation and LPS-induced IL-6 and MMP-9 production (33-35).…”

Section: Discussionmentioning

confidence: 99%

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In Vivo Role of p38 Mitogen-Activated Protein Kinase in Mediating the Anti-inflammatory Effects of CpG Oligodeoxynucleotide in Murine Asthma

Choudhury

Wild

Alam

et al. 2002

The Journal of Immunology

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DNA containing unmethylated CpG motifs is intrinsically immunostimulatory, inducing the production of a variety of cytokines and chemokines by immune cells. The strong Th1 response triggered by CpG oligodeoxynucleotide (ODN) inhibits the development of Th2-mediated allergic asthma in mice. This work documents that CpG ODN-induced IL-12 production plays a critical role in this process, because intrapulmonary CpG ODN inhibits allergic inflammation in wild-type but not IL-12−/− mice. CpG ODN rapidly localized to alveolar macrophages (AM), thereby triggering the phosphorylation of p38 mitogen-activated protein kinase (MAP kinase). AM cultured with CpG but not control ODN up-regulated IL-12 p40 expression and release, and these effects were blocked by the highly specific p38 MAP kinase inhibitor SB202190. Intrapulmonary administration of this inhibitor blocked the ability of CpG ODN to produce IL-12 in the lungs and reversed the anti-inflammatory effects of CpG ODN on allergic lung inflammation. These findings indicate that IL-12 production by AM is stimulated by intrapulmonary CpG ODN administration through a p38 MAP kinase-dependent process, and IL-12 is a key cytokine that mediates CpG ODN-induced protection against allergic lung inflammation.

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Section: Discussionsupporting

confidence: 80%

Section: Discussionmentioning

confidence: 99%

In Vivo Role of p38 Mitogen-Activated Protein Kinase in Mediating the Anti-inflammatory Effects of CpG Oligodeoxynucleotide in Murine Asthma

Choudhury

Wild

Alam

et al. 2002

The Journal of Immunology

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“…The eect of the p38 inhibitor SB 203580 was recently tested in the same animal model. No in¯uence on antigen-induced airway eosinophilia could be observed (Escott et al, 2000). In another study, a second generation p38 inhibitor was found to be eective (Underwood et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

Regulation of IL‐13 synthesis in human lymphocytes: implications for asthma therapy

Pahl

Zhang

Kuss³

et al. 2002

British J Pharmacology

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1 IL-13 is an important mediator in in¯ammatory diseases such as asthma. IL-13 is mainly produced by T cells. However, signalling pathways leading to induction of this cytokine are not wellcharacterized. We analysed the regulation of IL-13 in human peripheral blood mononuclear cells and CD4 + T cells. 2 Cyclosporine (CsA) and FK-506 inhibited IL-13 synthesis, when cells were stimulated by TPA/ ionomycin. However, stimulation by a-CD3/a-CD28 led to an enhanced IL-13 synthesis. 3 NF-kB inhibitor N-tosyl-L-lysine chloromethylketone (TLCK) inhibited IL-13 synthesis more eectively after TPA/ionomycin stimulation. After a-CD3/a-CD28 stimulation, only 300 mM TLCK inhibited IL-13 synthesis. Dexamethasone inhibited IL-13 equally eective after a-CD3/a-CD28 and TPA/ionomycin stimulation. 4 p38 MAPK inhibitor SB203580 inhibited IL-13 synthesis only partially. MEK inhibitor U0126 inhibited TPA/ionomycin induced IL-13 synthesis very eectively, whereas a-CD3/a-CD28 stimulated IL-13 induction was resistant to this drug. 5 These results were con®rmed in puri®ed CD4 + T cells. In dierence to PBMCs a-CD3/a-CD28 stimulated IL-13 synthesis was eectively inhibited by CsA, FK-506 and U0126. 6 Therefore U0126 was tested in an animal model of allergic asthma. We could demonstrate for the ®rst time that inhibition of the MEK ± ERK cascade is a therapeutic option for asthma. Intraperitoneal administration of 10 mg kg 71 U0126 reduced lung eosinophilia in ovalbuminchallenged Brown Norway rats by 44%. 7 These results demonstrate that dierent signalling pathways are involved in regulating IL-13 synthesis in primary human T cells. Characterizing highly potent inhibitors of IL-13 synthesis can be exploited to identify new drugs to treat immunological diseases such as asthma.

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“…The level of TNF-α is elevated in the sputa and bronchoalveolar lavage fluid (BALF) of patients with bronchial asthma (Taki et al, 1991;Broide et al, 1992). In mouse (Lucacs et al, 1995), guinea pig (Watson et al, 1993) and rat (Escott et al, 2000) models of lung inflammation, increased levels of TNF-α have been detected in the BALF of sensitized animals following challenge with an antigen. In addition, in vivo pretreatment of rat and human airways with aerosolized TNF-α produced an enhanced increase in airway resistance, similar to that observed in asthma, when challenged with endogenous agonists (Kips et al, 1992;Thomas et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

TNF-.ALPHA. augments the expression of RhoA in the rat bronchus

Sakai

Otogoto

Chiba

et al. 2004

J. Smooth Muscle Res.

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While nonspecific airway hyperresponsiveness (AHR) is a central feature of allergic bronchial asthma, the mechanism underlying the developmont of AHR is not clearly understood. We have previously demonstrated in vitro hyperresponsiveness of bronchial smooth muscle to acetylcholine (ACh) in rats that were actively sensitized and repeatedly challenged with aerosolized antigen. It has also been demonstrated that the AChinduced, RhoA-mediated Ca 2+ sensitization is markedly augmented concomitantly with an increased expression and activation of RhoA protein in the bronchial smooth muscle of the antigen-treated rats. In the present study, we have investigated whether TNF-α, a proinflammatory cytokine which is involved in bronchial asthma, causes upregulation of RhoA mRNA and protein in the rat bronchus. Treatment of rat bronchial smooth muscle preparations with TNF-α (300 ng/ml for 24 hr) significantly shifted the concentrationresponse curve to ACh upwards, but did not alter the response to high K + , when compared to that of control tissues. Levels of RhoA mRNA and protein in the TNF-α-treated bronchus were significantly greater than those in the control group. In conclusion, it is suggested that the augmentation of the ACh-induced contractile response evoked by TNF-α might be mediated by an upregulation of RhoA in rat bronchial smooth muscle.

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Effect of the p38 kinase inhibitor, SB 203580, on allergic airway inflammation in the rat

Cited by 58 publications

References 14 publications

In Vivo Role of p38 Mitogen-Activated Protein Kinase in Mediating the Anti-inflammatory Effects of CpG Oligodeoxynucleotide in Murine Asthma

In Vivo Role of p38 Mitogen-Activated Protein Kinase in Mediating the Anti-inflammatory Effects of CpG Oligodeoxynucleotide in Murine Asthma

Regulation of IL‐13 synthesis in human lymphocytes: implications for asthma therapy

TNF-.ALPHA. augments the expression of RhoA in the rat bronchus

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