Dual p38/JNK Mitogen Activated Protein Kinase Inhibitors Prevent Ozone-Induced Airway Hyperreactivity in Guinea Pigs

Kirsten C. Verhein, Francesco G. Salituro, Mark W. Ledeboer, Allison Fryer, David Jacoby

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Ozone exposure causes airway hyperreactivity and increases hospitalizations resulting from pulmonary complications. Ozone reacts with the epithelial lining fluid and airway epithelium to produce reactive oxygen species and lipid peroxidation products, which then activate cell signaling pathways, including the mitogen activated protein kinase (MAPK) pathway. Both p38 and c-Jun NH2 terminal kinase (JNK) are MAPK family members that are activated by cellular stress and inflammation. To test the contribution of both p38 and JNK MAPK to ozone-induced airway hyperreactivity, guinea pigs were pretreated with dual p38 and JNK MAPK inhibitors (30 mg/kg, ip) 60 minutes before exposure to 2 ppm ozone or filtered air for 4 hours. One day later airway reactivity was measured in anesthetized animals. Ozone caused airway hyperreactivity one day post-exposure, and blocking p38 and JNK MAPK completely prevented ozone-induced airway hyperreactivity. Blocking p38 and JNK MAPK also suppressed parasympathetic nerve activity in air exposed animals, suggesting p38 and JNK MAPK contribute to acetylcholine release by airway parasympathetic nerves. Ozone inhibited neuronal M2 muscarinic receptors and blocking both p38 and JNK prevented M2 receptor dysfunction. Neutrophil influx into bronchoalveolar lavage was not affected by MAPK inhibitors. Thus p38 and JNK MAPK mediate ozone-induced airway hyperreactivity through multiple mechanisms including prevention of neuronal M2 receptor dysfunction.

Original languageEnglish (US)
Article numbere75351
JournalPLoS One
Volume8
Issue number9
DOIs
StatePublished - Sep 18 2013

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mitogen-activated protein kinase kinase
JNK Mitogen-Activated Protein Kinases
Ozone
Protein Kinase Inhibitors
Mitogen-Activated Protein Kinases
mitogen-activated protein kinase
ozone
guinea pigs
Guinea Pigs
Animals
receptors
Air
Muscarinic M2 Receptors
Cell signaling
nerve tissue
Bronchoalveolar Lavage
air
Linings
Lipid Peroxidation
Acetylcholine

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Dual p38/JNK Mitogen Activated Protein Kinase Inhibitors Prevent Ozone-Induced Airway Hyperreactivity in Guinea Pigs. / Verhein, Kirsten C.; Salituro, Francesco G.; Ledeboer, Mark W.; Fryer, Allison; Jacoby, David.

In: PLoS One, Vol. 8, No. 9, e75351, 18.09.2013.

Research output: Contribution to journalArticle

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