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Role of p38 mitogen-activated protein kinase in ozone-induced airway hyperresponsiveness and inflammation.
Eur J Pharmacol 2008; 600(1-3):117-22EJ

Abstract

Ozone is a potent oxidant and causes airway hyperresponsiveness and neutrophilia. To determine the role of p38 mitogen-activated protein kinase (MAPK) activation, we studied the effect of a p38alpha inhibitor SD-282 (Scios Inc, Fremont, CA USA) on ozone-induced airway hyperresponsiveness and neutrophilia. Balb/c mice received SD-282 (30 or 90 mg/kg i.p) or vehicle 1 h before exposure to either ozone (3 ppm, 3 h) or air. Three hours after exposure, lungs were analysed for cytokine levels and bronchoalveolar lavage was performed. Another set of mice were dosed 6 h after exposure and 1 h before assessing airway hyperresponsiveness. SD-282 (90 mg/kg) significantly inhibited ozone-induced airway hyperresponsiveness (-LogPC(150): SD-282: -1.73+/-0.14 vs. vehicle: -0.99+/-0.15, P<0.05). Bronchoalveolar lavage neutrophil numbers were time-dependently increased in vehicle-dosed, ozone-exposed mice, greatest at 20-24 h after exposure. SD-282 (30 and 90 mg/kg) significantly inhibited ozone induced neutrophil numbers at 3 h and 20-24 h after ozone SD-282 significantly inhibited ozone-induced increases in phosphorylated p38 MAPK expression, and in cyclooxygenase-2 (COX-2), interleukin-6 (IL-6) and IL-1beta but not MIP-1alpha gene expression. We conclude that p38 MAPK is involved in ozone-induced airway hyperresponsiveness and lung neutrophilia. Inhibition of p38 MAPK with small molecule kinase inhibitors may be a means of reducing ozone-induced inflammation and airway hyperresponsiveness.

Authors+Show Affiliations

Airway Disease Section, National Heart and Lung Institute, Imperial College London, London, UK.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

18926814

Citation

Williams, Alison S., et al. "Role of P38 Mitogen-activated Protein Kinase in Ozone-induced Airway Hyperresponsiveness and Inflammation." European Journal of Pharmacology, vol. 600, no. 1-3, 2008, pp. 117-22.
Williams AS, Issa R, Durham A, et al. Role of p38 mitogen-activated protein kinase in ozone-induced airway hyperresponsiveness and inflammation. Eur J Pharmacol. 2008;600(1-3):117-22.
Williams, A. S., Issa, R., Durham, A., Leung, S. Y., Kapoun, A., Medicherla, S., ... Chung, K. F. (2008). Role of p38 mitogen-activated protein kinase in ozone-induced airway hyperresponsiveness and inflammation. European Journal of Pharmacology, 600(1-3), pp. 117-22. doi:10.1016/j.ejphar.2008.09.031.
Williams AS, et al. Role of P38 Mitogen-activated Protein Kinase in Ozone-induced Airway Hyperresponsiveness and Inflammation. Eur J Pharmacol. 2008 Dec 14;600(1-3):117-22. PubMed PMID: 18926814.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Role of p38 mitogen-activated protein kinase in ozone-induced airway hyperresponsiveness and inflammation. AU - Williams,Alison S, AU - Issa,Razao, AU - Durham,Andrew, AU - Leung,Sum-Yee, AU - Kapoun,Ann, AU - Medicherla,Satyanarayana, AU - Higgins,Linda S, AU - Adcock,Ian M, AU - Chung,Kian Fan, Y1 - 2008/09/30/ PY - 2008/04/29/received PY - 2008/09/03/revised PY - 2008/09/23/accepted PY - 2008/10/18/pubmed PY - 2009/3/28/medline PY - 2008/10/18/entrez SP - 117 EP - 22 JF - European journal of pharmacology JO - Eur. J. Pharmacol. VL - 600 IS - 1-3 N2 - Ozone is a potent oxidant and causes airway hyperresponsiveness and neutrophilia. To determine the role of p38 mitogen-activated protein kinase (MAPK) activation, we studied the effect of a p38alpha inhibitor SD-282 (Scios Inc, Fremont, CA USA) on ozone-induced airway hyperresponsiveness and neutrophilia. Balb/c mice received SD-282 (30 or 90 mg/kg i.p) or vehicle 1 h before exposure to either ozone (3 ppm, 3 h) or air. Three hours after exposure, lungs were analysed for cytokine levels and bronchoalveolar lavage was performed. Another set of mice were dosed 6 h after exposure and 1 h before assessing airway hyperresponsiveness. SD-282 (90 mg/kg) significantly inhibited ozone-induced airway hyperresponsiveness (-LogPC(150): SD-282: -1.73+/-0.14 vs. vehicle: -0.99+/-0.15, P<0.05). Bronchoalveolar lavage neutrophil numbers were time-dependently increased in vehicle-dosed, ozone-exposed mice, greatest at 20-24 h after exposure. SD-282 (30 and 90 mg/kg) significantly inhibited ozone induced neutrophil numbers at 3 h and 20-24 h after ozone SD-282 significantly inhibited ozone-induced increases in phosphorylated p38 MAPK expression, and in cyclooxygenase-2 (COX-2), interleukin-6 (IL-6) and IL-1beta but not MIP-1alpha gene expression. We conclude that p38 MAPK is involved in ozone-induced airway hyperresponsiveness and lung neutrophilia. Inhibition of p38 MAPK with small molecule kinase inhibitors may be a means of reducing ozone-induced inflammation and airway hyperresponsiveness. SN - 1879-0712 UR - https://www.unboundmedicine.com/medline/citation/18926814/Role_of_p38_mitogen_activated_protein_kinase_in_ozone_induced_airway_hyperresponsiveness_and_inflammation_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0014-2999(08)00971-0 DB - PRIME DP - Unbound Medicine ER -