Review Article
NADPH oxidases in lung biology and pathology: Host defense enzymes, and more

https://doi.org/10.1016/j.freeradbiomed.2007.11.016Get rights and content

Abstract

The deliberate production of reactive oxygen species (ROS) by phagocyte NADPH oxidase is widely appreciated as a critical component of antimicrobial host defense. Recently, additional homologs of NADPH oxidase (NOX) have been discovered throughout the animal and plant kingdoms, which appear to possess diverse functions in addition to host defense, in cell proliferation, differentiation, and in regulation of gene expression. Several of these NOX homologs are also expressed within the respiratory tract, where they participate in innate host defense as well as in epithelial and inflammatory cell signaling and gene expression, and fibroblast and smooth muscle cell proliferation, in response to bacterial or viral infection and environmental stress. Inappropriate expression or activation of NOX/DUOX during various lung pathologies suggests their specific involvement in respiratory disease. This review summarizes the current state of knowledge regarding the general functional properties of mammalian NOX enzymes, and their specific importance in respiratory tract physiology and pathology.

Introduction

The regulated production of reactive oxygen species (ROS) by NADPH oxidase has long been considered a unique property of phagocytic cells, which use this enzyme system to assist in their killing of invading microorganisms. This critical property of NADPH oxidase was supported by discovery of genetic defects in this enzyme system, which are responsible for the development of chronic granulomatous disease (CGD), a condition characterized by a failure to mount effective defense against bacteria and fungi, and resulting in severe and recurrent infections. Conversely, excessive production of reactive oxygen species (ROS) by NADPH oxidase is commonly thought to be responsible for tissue injury associated with a range of chronic inflammatory diseases, as supported by detection of characteristic stable oxidation products within inflamed tissues, indicative of collateral oxidative cell or tissue injury due to exaggerated or dysregulated activation of this host defense system. This relatively simplistic view of ROS biology has been substantially challenged and refined with the recent discovery of several homologs of the phagocyte NADPH oxidase. We now know that a number of NADPH homologs are present in many diverse aerobic organisms, with appear to have evolved by using these enzyme systems for regulated ROS production in various aspects of cell biology. Indeed, recent studies over the past several years have linked NADPH oxidases (NOX’s) to cellular processes as diverse as cell proliferation, migration, differentiation, immunomodulation, and oxygen sensing [1], [2], [3], [4].

The respiratory tract is a unique organ system that has evolved to provide an optimal area of contact with the external environment to allow for efficient O2 delivery for appropriate tissue oxygenation and function. As a result, the respiratory tract is highly exposed and vulnerable to environmental challenges, including airborne microbes, viruses, and other irritants and allergens, and therefore relies on a potent innate defense system that enables it to succesfully combat these environmental dangers without compromising lung function. It is therefore not surprising that several NOX isozymes are present within the airway, within a number of different cell types, as a critical component of local host defense, analogous to the phagocyte NADPH oxidase system. NOX-dependent host defense mechanisms are not simply restricted to oxidative killing mechanisms, but also entail their contribution to cell signaling mechanisms that regulate innate host defenses or airway responses to injury. Furthermore, several NOX enzymes that are present within structural lung cell types are known regulate cell proliferation, migration, and/or differentiation, suggesting that altered expression or activation of these NOX isoforms may also contribute to several lung pathologies by participating in tissue repair and/or remodeling. This review will discuss some general aspects of NOX regulation and biology, and summarizes current knowledge regarding the presence and functional roles of various NOX isoforms within the respiratory tract, and their proposed involvement in airway biology and disease.

Section snippets

The NOX family

The first described involvement of a mammalian NADPH oxidase in biological ROS formation stems from studies in phagocytic cells, and extensive research over the past several decades have revealed many details about molecular and biochemical aspects of this enzyme system [5], [6]. The phagocyte NADPH oxidase centers around a membrane-associated flavocytochrome b558 (gp91phox), which contains binding sites for NADPH and FAD as well as two haems that are critical for transmembrane electron

Production of cellular and extracellular mediators

The principal enzymatic function of NOX/DUOX is to catalyze transmembrane transfer of electrons from the cytosolic electron donor NADPH to the principal electron acceptor, O2, within the extracellular space or within specialized cell compartments (e.g. phagosomes) (Fig. 2). This action initially generates superoxide anion (O2•−), and subsequently hydrogen peroxide (H2O2), though spontaneous or superoxide dismutase (SOD)-catalyzed reactions. DUOX1/2 and NOX4 appear to directly generate H2O2 as

NOX isozymes within the respiratory tract

Analysis of total lung or airway mRNA revealed the presence of substantial amounts of NOX2 as well as DUOX1 and DUOX2, and low amounts of NOX1 and NOX4 [35], [79], [80], [81]. Although expression of NOX originates primarily from alveolar macrophages and other inflammatory cell types, the other NOX/DUOX enzymes are largely expressed in non-phagocytic cells within the lung, including airway and alveolar epithelial cells, pulmonary endothelial cells, fibroblasts, and smooth muscle cells. The

NOX enzymes in lung disease

The previous sections indicate that various NOX isoforms are expressed within several structural cell types in the respiratory tract, and appear to serve various salutary functions, e.g. in lung development, in cell responses to changes in oxygen tension, or in airway defenses against environmental stress. However, changes in NOX expression or activation during conditions of acute or chronic lung disease are also suggestive of a potential contributing role for NOX in disease pathology. Indeed,

Concluding remarks

As can be judged from this review, much has been learned over the past few years regarding the biological properties of NADPH oxidases (NOX) and their postulated functions, which extend significantly from their classically viewed roles as innate host defense enzymes. Moreover, the mechanisms by which NOX enzymes contribute to host defense are not restricted to oxidant-mediated bacterial killing, but clearly involve a number of additional signaling mechanisms that control inflammatory signaling

Acknowledgments

The author wishes to thank Yvonne Janssen-Heininger, Nick Heintz, Gregory Conner, Richart Harper and Horst Fischer for frequent and stimulating discussions regarding lung NOX/DUOX biology and redox signaling, and the NIH (grants HL068865 and HL074295) for research support.

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      Citation Excerpt :

      NOX2 was first described for its key role in killing invading organisms by phagocytic cells. Notably, genetic defects in NOX2 cause chronic granulomatous disease (CGD); a condition predisposing to recurrent severe fungal and bacterial infections due to defective phagocyte function [49]. NOX2 also has electrogenic features [50,51] that can regulate phagosome/lysosome pH, which is required for antigen processing [52].

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