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.
Highlights
Over half the United States population lives in counties with unhealthy levels of ozone, a major component of smog [1]
Ozone induced airway hyperreactivity is demonstrated by increased bronchoconstriction to intravenous methacholine, but this effect is mediated largely via increased acetylcholine release from parasympathetic nerves, since it is blocked by vagal section [8,9]
All the dual p38 and Jun NH2 terminal kinase (JNK) inhibitors partially attenuated the ozone induced increase in baseline airway inflation pressure, the attenuation only reached statistical significance in the group treated with V-05-013
Summary
Over half the United States population lives in counties with unhealthy levels of ozone, a major component of smog [1]. Ozone induced hyperreactivity is demonstrated by increased reactivity to inhaled methacholine and other agonists, including those causing reflex bronchoconstriction in man [5,6,7]. Ozone induced airway hyperreactivity is demonstrated by increased bronchoconstriction to intravenous methacholine, but this effect is mediated largely via increased acetylcholine release from parasympathetic nerves, since it is blocked by vagal section [8,9]. Direct stimulation of the vagus nerves results in bronchoconstriction that is potentiated in ozone exposed animals and that is associated with loss of function of neural M2 muscarinic receptors that normally inhibit acetylcholine release [10,11]. Inflammatory cells, especially eosinophils through release of the M2 inhibitor major basic protein, mediate loss of neuronal M2 function and airway hyperreactivity in ozone exposed guinea pigs [11]
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