February 2010

Document Type


Degree Name



Dept. of Physiology and Pharmacology


Oregon Health & Science University


In both humans and animals, ozone induces airway inflammation and airway hyperreactivity: defined as increased airway narrowing in response to irritants or neurotransmitters that would normally have a small or no effect in non-ozone exposed lungs. Ozone-induced airway hyperreactivity is mediated by increased release of neurotransmitters by parasympathetic nerves. In guinea pigs, eosinophils increase acetylcholine neurotransmitter release from parasympathetic nerves one day after ozone exposure via release of major basic protein that blocks neuronal M2 muscarinic receptors that normally inhibit acetylcholine release. However, three days after ozone neuronal M2 muscarinic receptor dysfunction and eosinophils no longer contribute to airway hyperreactivity. The hypothesis tested in this thesis is that ozone causes airway hyperreactivity via multiple mechanisms that change between one and three days after exposure from eosinophil mediated hyperreactivity to inflammatory cytokine and neural plasticity mediated hyperreactivity. Using guinea pigs exposed to ozone and measuring lung inflation pressure, heart rate, mucus production, airway inflammation, and cytokine levels, the involvement of mitogen activated protein kinases, the inflammatory cytokine IL-1, nerve growth factor, and tachykinins were tested in ozone-induced airway hyperreactivity one and three days later. These studies were complimented with ex vivo studies of inflammatory mediators on parasympathetic neural plasticity. Data demonstrate that mitogen activated protein kinase signaling may precede eosinophil activation and release of major basic protein since inhibition of p38 and JNK mitogen activated protein kinase prevents M2 receptor dysfunction one day after ozone (Chapter III). However, IL-1 is not involved in ozone-induced airway hyperreactivity one day after ozone. In contrast, blocking IL-1 with an IL-1 receptor antagonist (Chapter IV) or depleting substance P with an antibody to nerve growth factor (Chapter V) prevents airway hyperreactivity three days after ozone without changing inflammatory cell populations in bronchoalveolar lavage. Thus, mechanisms of ozone-induced airway hyperreactivity change from eosinophils and activity of early kinases, to inflammatory cytokines and neural plasticity. These findings are important for human health since over half the population of the United States lives in areas with unhealthy levels of ozone. Ozone increases asthma exacerbations and increases hospitalizations and mortality not only the same day ozone levels are high, but also two and three days later. Currently there are no specific therapies available to treat ozone-induced lung complications. Instead, standard asthma therapies that directly dilate airway smooth muscle or non-specifically decrease inflammation are used. Findings presented here demonstrate that different treatments targeting specific mediators may be more beneficial since the mechanisms of ozone-induced airway hyperreactivity change over time. In summary, this thesis demonstrates that mitogen activated protein kinases are important one day after ozone and that IL-1, tachykinin receptors, and nerve growth factor all contribute to airway hyperreactivity three days, but not one day, after ozone. These data are the first to suggest that hyperreactivity is not mediated by a single mechanism and that even after a single insult to the lungs, the mechanisms of hyperreactivity and the role of inflammation change with time.




School of Medicine



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