Potential of Inducible Nitric Oxide Synthase as a Therapeutic Target for Allergen-Induced Airway Hyperresponsiveness: A Critical Connection to Nitric Oxide Levels and PARP Activity

Abstract

Although expression of inducible NO synthase (iNOS) in the lungs of asthmatics and associated nitrosative damage are established, iNOS failed as a therapeutic target for blocking airway hyperresponsiveness (AHR) and inflammation in asthmatics. This dichotomy calls for better strategies with which the enzyme is adequately targeted. Here, we confirm iNOS expression in the asthmatic lung with concomitant protein nitration and poly(ADP-ribose) polymerase (PARP) activation. We show, for the first time, that iNOS is highly expressed in peripheral blood mononuclear cells (PBMCs) of asthmatics with uncontrolled disease, which did not correspond to protein nitration. Selective iNOS inhibition with L-NIL protected against AHR upon acute, but not chronic, exposure to ovalbumin or house dust mite (HDM) in mice. Supplementation of NO by nitrite administration significantly blocked AHR in chronically HDM-exposed mice that were treated with L-NIL. Protection against chronic HDM exposure-induced AHR by olaparib-mediated PARP inhibition may be associated with the partial but not the complete blockade of iNOS expression. Indeed, L-NIL administration prevented olaparib-mediated protection against AHR in chronically HDM-exposed mice. Our study suggests that the amount of iNOS and NO are critical determinants in the modulation of AHR by selective iNOS inhibitors and renews the potential of iNOS as a therapeutic target for asthma.

Silica nanoparticles trigger the vascular endothelial dysfunction and prethrombotic state via miR-451 directly regulating the IL6R signaling pathway

“…Endothelial damage was also associated with imbalances in nitrite levels. Blood nitrite levels have been shown to inversely correlate with platelet aggregation, and positively correlate with bleeding time [32]. As well as deriving from arginine via eNOS, NO can also be generated by a two-step reduction pathway, in which nitrate is converted first into nitrite and then into NO.…”

Poly(ADP-Ribose) Polymerase Inhibition in Acute Lung Injury. A Reemerging Concept

“…Olaparib (similar to the PARP inhibitors of other classes) improves pulmonary inflammation, counteracts pulmonary extravasation, reduces oxidative stress, and improves antioxidant status in the lung in various experimental models of ALI ( 70 , 72 , 80 , 83 ) and, importantly, also exerts beneficial effects against the ALI-associated central-nervous-system dysfunction (e.g., cognitive defects) ( 83 ). Olaparib also exerts beneficial effects in other animal models that have a significant pulmonary-injury component and/or systemic hyperinflammatory component, including asthma models ( 72 , 74 ), a pulmonary inflammation/emphysema model ( 80 ), and murine models of acute burn injury and pancreatitis ( 84 , 90 ). In a murine model of sepsis (induced by CLP), olaparib improved survival and exerted beneficial effects on inflammatory-mediator production and immune-cell balance, but in this model, no significant pulmonary injury was noted, and olaparib had no effect on the various pulmonary parameters investigated ( 81 ).…”

The reliability of adjusting stepped care based on FeNO monitoring for patients with chronic persistent asthma

“…NOS is widely distributed in various tissues of the respiratory system [10]. There are 3 different isozymes, neurogenic NOS, endothelial NOS and inducible NOS (iNOS), which is mainly located in macrophages and epithelial cells [11]. The first two are structural isozymes, while the third has high iNOS activity and is not affected by the concentration of calcium ions.…”