Dual p38/JNK mitogen activated protein kinase inhibitors prevent ozone-induced airway hyperreactivity in guinea pigs.
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, i.p.) 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.
Department of Physiology and Pharmacology, Oregon Health and Science University, Portland, Oregon, United States of America.
Kirsten C
KC
Verhein
Francesco G
FG
Salituro
Mark W
MW
Ledeboer
Allison D
AD
Fryer
David B
DB
Jacoby
D000818:Animals; D001249:Asthma / Q000139:chemically induced* / Q000201:enzymology* / Q000473:pathology; D005260:Female; D006168:Guinea Pigs; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D020556:Neutrophil Infiltration / Q000187:drug effects; D009504:Neutrophils / Q000378:metabolism / Q000473:pathology; D010083:Oxidants, Photochemical / Q000009:adverse effects* / Q000494:pharmacology; D010126:Ozone / Q000009:adverse effects* / Q000494:pharmacology; D010275:Parasympathetic Nervous System / Q000378:metabolism / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D043585:Receptor, Muscarinic M2 / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
D010083:Oxidants, Photochemical; D047428:Protein Kinase Inhibitors; D017382:Reactive Oxygen Species; D043585:Receptor, Muscarinic M2; D010126:Ozone; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4