NOX enzymes: potential target for the treatment of acute lung injury

Abstract

Acute lung injury (ALI) and its more severe form, acute respiratory distress syndrome (ARDS), is characterized by acute inflammation, disruption of the alveolarcapillary barrier, and in the organizing stage by alveolar pneumocytes hyperplasia and extensive lung fibrosis. The cellular and molecular mechanisms leading to the development of ALI/ARDS are not completely understood, but there is evidence that reactive oxygen species (ROS) generated by inflammatory cells as well as epithelial and endothelial cells are responsible for inflammatory response, lung damage, and abnormal repair. Among all ROS-producing enzymes, the members of NADPH oxidases (NOXs), which are widely expressed in different lung cell types, have been shown to participate in cellular processes involved in the maintenance of lung integrity. It is not surprising that change in NOXs' expression and function is involved in the development of ALI/ARDS. In this context, the use of NOX inhibitors could be a possible therapeutic perspective in the management of this syndrome. In this article, we summarize the current knowledge concerning some cellular aspects of NOXs localization and function in the lungs, consider their contribution in the development of ALI/ARDS and discuss the place of NOX inhibitors as potential therapeutical target.

LPS-mediated endothelial activation in pulmonary endothelial cells: role of Nox2-dependent IKK-β phosphorylation

“…Pulmonary endothelial activation has been shown to be a critical event in the pathogenesis of sepsis-induced lung injury in animal models and can contribute to the vascular injury and remodeling seen in BPD (23,35). Pharmacological modulation of Nox activity may find use as adjunct therapy to limit lung injury and vascular remodeling in BPD (9).…”

NOX2 As a Target for Drug Development: Indications, Possible Complications, and Progress

“…The NOX2 system and other NOX enzymes have been implicated in ALI/ARDS in several studies. NOX2 and other NOX isoforms are expressed in endothelial and epithelial cells of the lung, where they may participate in early signaling events preceding ALI/ARDS (39,298). Neutrophil infiltration into the alveolar spaces of the lung during the acute phase of ALI/ARDs is clearly visible in postmortem lung sections from ARDS patients as well as in bronchoalveolar lavage fluid (181).…”

Lipopolysaccharide (LPS)-mediated Angiopoietin-2-dependent Autocrine Angiogenesis Is Regulated by NADPH Oxidase 2 (Nox2) in Human Pulmonary Microvascular Endothelial Cells

“…Although we showed that mouse lung endothelial cells express increased Ang2 and Tie2 after systemic LPS, the rest of our data were obtained in primary cells in vitro, and, therefore, verification of the results of this study in animal models expressing angiogenic factors in a tissue-restricted manner will enable us to better understand the significance of these findings. This assumes translational significance because inhibiting Ang2 using antibodies or modulating Nox2 activity are emerging as promising strategies to decrease lung injury in bacterial sepsis (51,52).…”