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

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, including cell proliferation, differentiation, and 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.

Protective effect of 4,4'-diaminodiphenylsulfone against paraquat-induced mouse lung injury

“…Paraquat induces superoxide anion production via NADPH-dependent metabolic pathways. NOX2 and NOX4 are the predominant NOX isoforms in the mouse lung (van der Vliet, 2008;Hecker et al, 2009), and NOX4 expression in pulmonary fibroblasts is selectively upregulated in response to inflammatory mediators such as TNF-α and TGF-β, subsequently increasing ROS production (Thabut et al, 2002;Sturrock et al, 2006;van der Vliet, 2008). In the present study, we found that DDS effectively inhibits the PQ-stimulated induction of NOX4 expression, but not of NOX2 expression, in mouse lung tissues (Figure 4).…”

“…Superoxide anions are generated by PQ via NADPH-dependent metabolic pathways (Bonneh-Barkay et al, 2005) and via mitochondria (Castello et al, 2007). Notably, NADPH oxidases, NOX2 and NOX4, are predominantly expressed in lung tissues (van der Vliet, 2008;Hecker et al, 2009). Moreover, protein kinase C (PKC) participates in the ligand-initiated assembly of NOX, which proceeds the generation of superoxide anions (Miller et al, 2007).…”

DUOX1 mediates persistent epithelial EGFR activation, mucous cell metaplasia, and airway remodeling during allergic asthma

“…To our knowledge, our findings are the first to establish the causal participation of DUOX1 in any disease pathology. Related findings were recently observed in mice deficient in Duoxa genes, resulting in overall functional DUOX1/2 deficiency, which similarly showed lack of neutrophilia, type 2 cytokine responses, and mucous cell metaplasia in an alternative model of allergic asthma (40); however, these studies did not address the specific roles of either DUOX1 or DUOX2, which have distinct and nonredundant functions in various organ systems (38,39). Our present findings therefore provide a strong incentive for the development of DUOX1-targeted pharmacological approaches for clinical use, as DUOX1 has so far been relatively ignored in screening efforts for NOX-selective inhibitors (36).…”

“…Our studies are primarily based on the premise that DUOX1 activation generates H 2 O 2 as its primary product and that H 2 O 2 affects protein function by cysteine oxidation to sulfenic acids and related oxidative modifications such as S-glutathionylation (38,39). Although the present studies focused primarily on sulfenylation as a mechanism of oxidative EGFR activation, based on recent findings (25, 56), we cannot rule out the potential contribution of protein glutathionylation within EGFR or in other bystander proteins in mediating DUOX1-related allergic inflammation (e.g., ref.…”

Pulmonary Transplantation and Ischemia-Reperfusion Injury

“…Recent studies have demonstrated a key role of the NADPH-oxidase enzyme complex in ROS generation after IR (Goyal, et al, 2004;Jackson, et al, 2004;van der Vliet, 2008;Yao, et al, 2007). NADPH oxidase, which is present in epithelial cells, endothelial cells, macrophages, T cells and neutrophils, among others, utilizes NADPH as a substrate to generate superoxide from molecular oxygen.…”