NOX Modifiers—Just a Step Away from Application in the Therapy of Airway Inflammation?

Abstract

Significance: NADPH oxidase (NOX) enzymes, which are widely expressed in different airway cell types, not only contribute to the maintenance of physiological processes in the airways but also participate in the pathogenesis of many acute and chronic diseases. Therefore, the understanding of NOX isoform regulation, expression, and the manner of their potent inhibition might lead to effective therapeutic approaches. Recent Advances: The study of the role of NADPH oxidases family in airway physiology and pathophysiology should be considered as a work in progress. While key questions still remain unresolved, there is significant progress in terms of our understanding of NOX importance in airway diseases as well as a more efficient way of using NOX modifiers in human settings. Critical Issues: Agents that modify the activity of NADPH enzyme components would be considered useful tools in the treatment of various airway diseases. Nevertheless, profound knowledge of airway pathology, as well as the mechanisms of NOX regulation is needed to develop potent but safe NOX modifiers. Future Directions: Many compounds seem to be promising candidates for development into useful therapeutic agents, but their clinical potential is yet to be demonstrated. Further analysis of basic mechanisms in human settings, high-throughput compound scanning, clinical trials with new and existing molecules, and the development of new drug delivery approaches are the main directions of future studies on NOX modifiers. In this article, we discuss the current knowledge with regard to NOX isoform expression and regulation in airway inflammatory diseases as well as the aptitudes and therapeutic potential of NOX modifiers. Antioxid. Redox Signal. 23,[428][429][430][431][432][433][434][435][436][437][438][439][440][441][442][443][444][445]

Acute Respiratory Barrier Disruption by Ozone Exposure in Mice

“…Indeed, neutrophil depletion by antibody against granulocytes attenuates the second phase. Similar disruptions of the respiratory barrier as shown for ozone has been described before by other air pollutants such nitrogen dioxide, disulfide, particle, chemicals, and cigarette smoke- all of which can cause chronic pulmonary diseases, but usually require longer exposure time and at higher concentrations than ozone (38, 44). A schematic view of the initial events at the respiratory barrier and early repair process is given in Figure 1.…”

“…E-cadherin, as well as TJs were reduced in patients with asthma (30–32). Common respiratory viruses, such as human rhinovirus (HRV) (33, 34) or respiratory syncytial virus (RSV) (35) disrupt and impair airway epithelial barrier and delay healing of infected epithelium (36), through NADPH oxidase-1 and ROS-dependent mechanisms (33, 37, 38). Disruption of tight junctions with leak of the epithelium allows systemic access of irritants, pathogen, and allergens (15, 39), as well as the drainage of host proteins, lipid mediators, or cells into the airway lumen, where they may perpetuate inflammatory response, acting back on epithelium.…”

“…The protective role of antioxidants against ROS/RNS induced injury and inflammation environmental pollutants has been reviewed (38, 95). A comprehensive analysis of oxidative stress in ozone induced lung injury and mitochondrial dysfunction allowed to identify potential druggable pathways (2, 38, 95, 96).…”

Ozone exposure induces respiratory barrier biphasic injury and inflammation controlled by IL-33

“…16 Ozone exposure impairs the function of crucial molecules that make up the epithelial barrier. 17 Ozoneinduced lung inflammation in mice, rats, and human subjects relies on production of reactive oxygen species (ROS), [18][19][20] which is characterized by epithelial injury, 21 with disruption of the epithelial barrier; increased levels of inflammatory cytokines, such as IL-17A 22,23 or TNF-a 24 ; and neutrophil recruitment associated with AHR 23 through activation of Toll-like receptors 2 and 4 and the adaptor protein myeloid differentiation primary response gene-88. 25 Furthermore, IL-1 family members are induced and contribute to lung inflammation.…”

Thymidine catabolism promotes NADPH oxidase-derived reactive oxygen species (ROS) signalling in KB and yumoto cells

“…Alternatively, some papers reported the pro-oxidative effect of NADPH oxidase, which is induced by NFκB transcriptional activation 29 – 31 . Expression of NADPH oxidase subunit p22phox was increased by NFκB in aortic smooth muscle and pancreatic cancer cells 32 , 33 .…”