cNOS-iNOS paradigm and arginase in asthma

摘要

During the past decade in vitro and in vivo experimental studies have largely unravelled the multifaceted functional roles of nitric oxide (NO) in the airways and, in particular, the dichotomy demonstrated by the two functional isoforms of NO synthase: constitutive NOS (cNOS) and inducible NOS (iNOS). cNOS- and iNOS-derived NO produce varying and, at least in part, opposing effects in asthma, including bronchodilation, bronchopro-tection, anti-inflammatory mechanisms, host defence, inflammatory cell infiltration, vascular permeability and T helper 2 (Th2) cell-driven inflammation.The chemical features of NO, such as its rapid diffusion from the point of synthesis, its ability to permeate cell membranes and its interactions with intracellular molecules within both generating and target cells, eliminate the need for extracellular NO receptors. NO is also characterized by its intrinsic instability, thus ruling out targeted NO degradation. The short half-life of NO is due to its reactivity with a broad spectrum of molecules such as oxygen, superoxide (O_2~-) radicals and transition metals, which can lead to nitration (addition of -NO_2), nitrosation (addition of-NO~+) and nitrosylation (-NO) of most classes of biomolecules. The best known interaction of NO that leads to cell signaling is its binding (nitrosylation) to the ferrous heme within soluble guanylyl cyclase. Furthermore, cNOS-derived NO can react (S-nitrosylation) with thiols in a physiological milieu to form nitrosothiols (SNOs) [1]. These NO-adduct molecules provide a significant route through which NO-derived bioactivity is conveyed in the lung. Thus, SNOs, stored in specific cellular compartments and present in airway lining fluid, not only function as NO carriers (storage and transport) but also deliver NO bioactivities within airway tissues via trans-nitrosation reactions of specific protein thiols and the release of free NO, thus prolonging the physiological effects of NO.