Common and differential roles of inducible NO synthase and poly (ADP-ribose)polymerase in allergen-induced inflammation and airway hyperresponsiveness: a potential connection to NO levels (HYP5P.320)

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.