NADPH oxidase enzymes in skin fibrosis: molecular targets and therapeutic agents

Abstract

Fibrosis is characterized by the excessive deposition of extracellular matrix components eventually resulting in organ dysfunction and failure. In dermatology, fibrosis is the hallmark component of many skin diseases, including systemic sclerosis, graft versus host disease, hypertrophic scars, keloids, nephrogenic systemic fibrosis, porphyria cutanea tarda, restrictive dermopathy and other conditions. Fibrotic skin disorders may be debilitating and impair quality of life. There are few FDA-approved anti-fibrotic drugs; thus, research in this area is crucial in addressing this deficiency. Recent investigations elucidating the pathogenesis of skin fibrosis have implicated endogenous reactive oxygen species produced by the multicomponent nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox) enzyme complex. In this review we discuss Nox enzymes and their role in skin fibrosis. An overview of the Nox enzyme family is presented and their role in the pathogenesis of skin fibrosis is discussed. The mechanisms that Nox enzymes influence specific skin fibrotic disorders are also reviewed. Finally, we describe the therapeutic approaches to ameliorate skin fibrosis by directly targeting Nox enzymes with the use of statins, p47phox subunit modulators, or GKT137831, a competitive inhibitor of Nox enzymes. Nox enzymes can also be targeted indirectly via scavenging ROS with antioxidants. We believe that Nox modulators are worthy of further investigation and have the potential to transform the management of skin fibrosis by dermatologists.

Therapeutic potential of NADPH oxidase 1/4 inhibitors

“…Oxidative stress and NOX have been implicated in several skin diseases, especially fibrotic diseases (Wan and Evans, ; De Felice et al , ; Wagner et al , ; Babalola et al , ; Grygiel‐Gorniak and Puszczewicz, ). NOX4 has been proposed as a potential target for systemic sclerosis (scleroderma) (Dooley et al , ; Bohm et al , ; Spadoni et al , ).…”

Oxidative stress in cancer and fibrosis: Opportunity for therapeutic intervention with antioxidant compounds, enzymes, and nanoparticles

“…NOX-derived ROS have been identified as the main source of oxidative stress, which promotes key events in the development of fibrotic diseases (such as skin fibrosis [9], idiopathic pulmonary fibrosis [10], liver fibrosis [11], and kidney fibrosis [12]) as well as the initiation and progression of cancer [13]. To date, there is no cure for most of these diseases.…”

A bioinformatic and mechanistic study elicits the antifibrotic effect of ursolic acid through the attenuation of oxidative stress with the involvement of ERK, PI3K/Akt, and p38 MAPK signaling pathways in human hepatic stellate cells and rat liver

“…Notably, recent studies have indicated that the NOX1/4 dual inhibitor GKT137831 can significantly inhibit the activation of HSCs and the development of liver fibrosis. 12 , 66 – 68 This inhibitor is currently being investigated in Phase II clinical trials. Therefore, NOX-targeting drugs with low toxicity that are effective against fibrosis are expected to lead to a breakthrough in the treatment of liver fibrosis.…”