Serial Review: Redox Signaling in Immune Function and Cellular Responses in Lung Injury and DiseasesSerial Review Editors: Victor Darley-Usmar, Lin MantellNitric oxide and reactive nitrogen species in airway epithelial signaling and inflammation☆
Introduction
Nitric oxide (NO) is a ubiquitous reactive signaling molecule, synthesized by oxidative conversion of the amino acid L-arginine by NO synthases (NOSs). The functional NOS protein is a homodimer, with each subunit comprising a reductase domain mediating electron transfer from NADPH to the oxygenase domain, where O2 binding and arginine oxidation occur. Between these domains, a calmodulin-binding region controls NOS activation in response to Ca2+ binding [1]. Three NOS isoforms have been identified, and all three are known to be expressed within the respiratory tract. NOS1 (nNOS) and NOS3 (eNOS) are primarily expressed in neuronal and endothelial cell types, respectively, and are highly dependent on increases in intracellular Ca2+ for enzyme activation [2]. In the airway, nonadrenergic, noncholinergic nerve fibers express NOS1 that generates NO as a major mediator of neural smooth muscle relaxation [3]. Lung NOS3 expression is primarily observed within pulmonary endothelial cells, and also in bronchial [4] and alveolar epithelial cells [5]. In the bronchial epithelium, NOS3 is localized at the basal membrane of ciliary microtubules, and mediates regulation of ciliary beat frequency [6], [7]. The third isoform, NOS2, is primarily present in cells of the inflammatory-immune system, where it is induced during inflammatory conditions [1]. However, NOS2 is continuously expressed in human airway epithelial cells under normal conditions [8], and is the primary source of exhaled NO in healthy subjects [9]. Moreover, the airway epithelium appears to be the primary site of induced NOS2 expression in asthmatic airways [8]. Because of the importance of the airway epithelium as a major regulator of airway inflammation, and epithelial functional defects in chronic inflammatory disorders such as asthma [10], the identification of the airway epithelium as a primary location for NOS and airway NO production urges increased understanding of the involvement of NO in epithelial cell signaling pathways and alterations during airway inflammation. These issues will form the central theme of the present review.
Section snippets
Regulation of NOS expression and activation
While NOS1 and NOS3 are typically considered to be constitutively expressed proteins (although their expression is subject to regulation under certain conditions [11]), expression of NOS2 is primarily controlled by complex transcriptional regulation in response to cells stimulation by proinflammatory cytokines such as tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), and interleukin (IL)-1β [12]. Additionally, NOS2 expression is also regulated by cytosine methylation within the promoter
Signaling mechanisms of nitric oxide
In addition to complex regulation of NOS expression and activation, the biology of NO is further complicated by its interaction in various metabolic pathways due its chemical reactivity [34]. Since NO contains an unpaired electron, it is a free radical that reacts readily with other radical intermediates or paramagnetic species. The biological activities NO can in general be attributed to three separate signaling mechanisms, that are schematically illustrated in Fig. 1 and will be discussed
NO in airway epithelial physiology and pathophysiology
Being situated at the interface between the external environment and the underlying airway structures, the respiratory epithelium is a primary target for inhaled microbes, allergens, and particulates, and is therefore principally involved in airway responses to these environmental factors and the orchestration of inflammatory-immune processes [65], [66]. In addition to its more classically recognized functions as a physical barrier and in mucociliary clearance, the airway epithelium is also
NO signaling in the airway epithelium: Regulation of inflammation
The airway epithelium is critically involved in regulating inflammatory-immune processes in response to environmental stimuli, and appears to be a major site of induced NOS2 expression for chronic lung diseases such as asthma. Moreover, the airway epithelium of asthmatic subjects appears to possess altered intrinsic properties [66], [67], which may be related to altered NO-mediated epithelial signaling pathways. Indeed, it has become widely appreciated that NO is capable of regulating various
Alterations in NO-mediated signaling during airway inflammation
Although much is still to be learned about the mechanisms of NO-mediated signaling under normal physiological conditions, increased epithelial NOS2 expression and NO/RNS production during airway inflammation will undoubtedly result in additional and altered NO-dependent signaling pathways. Recent studies also indicate potential changes in other NOS isoforms during airway inflammation, illustrated by reduced airway epithelial NOS3 expression during endotoxemia, in conjunction with NOS2 induction
Final considerations and future perspectives
Based on the observed deficiency in S-nitrosothiols within airway secretions of patients with severe asthma or cystic fibrosis, and findings that SNOs are potentially useful as donors of NO to promote bronchodilation and airway function, inhalation of SNOs may present a suitable and effective strategy for therapeutic management. However, the diverse roles of NO in regulating important airway functional aspects, ranging from beneficial (attenuating airway hyperresponsiveness, downregulating Th1
Acknowledgments
The authors would like to thank Yvonne Janssen-Heininger and Wolfgang Dostmann for frequent research discussions, and are grateful for research support from NIH (Grants HL068865 and HL074295) and the Department of Pathology at UVM.
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This article is part of a series of reviews on “Redox signaling in immune function and cellular responses in lung injury and diseases.” The full list of papers may be found on the home page of the journal.