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The potential role of iNOS as a viable therapeutic target for the treatment of asthma was severely hampered by the negative clinical trial results showing that a selective iNOS inhibitor did not affect airway hyperreactivity (AHR) or airway inflammation after allergen challenge in human subjects with asthma. Our laboratory has shown that iNOS inhibition is protective against airway inflammation upon acute, but not chronic, exposures to ovalbumin. More importantly, iNOS inhibition protected against lung fibrosis suggesting that iNOS inhibition may be protective against some aspects of asthma. Here, we show that iNOS inhibition, pharmacologically by L-Nil or by gene knockout, provided an excellent protection against AHR upon an acute, but not chronic, exposure to ovalbumin. Our laboratory also established a reciprocal relationship between iNOS and PARP-1. However, PARP inhibition, protected against inflammation and AHR upon acute and chronic exposure to ovalbumin. It is interesting that PARP-1 inhibition does not completely abrogate expression of iNOS leaving the possibility that the protective effect of PARP inhibition against inflammation and AHR may be associated with reduction but not the complete inhibition of iNOS and associated production of moderate levels of NO. Studies are being conducted to verify this hypothesis and clarify the intricate roles of iNOS in asthma pathogenesis allowing the possibility of being a viable target for the treatment of the disease.

Background: There has been a growing appreciation for the role of energy metabolic pathways in the differentiation and function of immune cells. Unpublished findings from our laboratory suggest that inhibiting fatty acid oxidation (FAO) modulates the activation and function of tumor-infiltrating myeloid cells, indicating a potentially important role for FAO in inflammation and thus inflammatory diseases such as asthma. Objective: We sought to test the hypothesis that FAO plays an important role in asthma manifestation. Methods: Etomoxir, an inhibitor of the FAO rate-limiting enzyme carnithine palmitoyltransferase-1, was used to test our hypothesis in an ovalbumin-based murine model of asthma. Results: Etomoxir treatment thirty minutes after ovalbumin challenge resulted in a significant reduction in the recruitment of eosinophils and macrophages into the lungs without a prominent effect on the total number of lymphocytes. Etomoxir treatment also prevented ovalbumin-induced hyperresponsiveness. The protective effects of etomoxir were associated with a decrease in Th2 cytokines and ovalbumin-specific IgE production. Additionally, the frequency of splenic macrophages was lower in etomoxir-treated mice, compared with control. Conclusions: Our preliminary data suggest the inhibition of FAO as a likely strategy to block asthma traits. As such, we are currently uncovering the mechanisms by which FAO inhibition reduces the pathogenesis of asthma.