Targeting the Redox Balance in Inflammatory Skin Conditions

Abstract

Reactive oxygen species (ROS) can be both beneficial and deleterious. Under normal physiological conditions, ROS production is tightly regulated, and ROS participate in both pathogen defense and cellular signaling. However, insufficient ROS detoxification or ROS overproduction generates oxidative stress, resulting in cellular damage. Oxidative stress has been linked to various inflammatory diseases. Inflammation is an essential response in the protection against injurious insults and thus important at the onset of wound healing. However, hampered resolution of inflammation can result in a chronic, exaggerated response with additional tissue damage. In the pathogenesis of several inflammatory skin conditions, e.g., sunburn and psoriasis, inflammatory-mediated tissue damage is central. The prolonged release of excess ROS in the skin can aggravate inflammatory injury and promote chronic inflammation. The cellular redox balance is therefore tightly regulated by several (enzymatic) antioxidants and pro-oxidants; however, in case of chronic inflammation, the antioxidant system may be depleted, and prolonged oxidative stress occurs. Due to the central role of ROS in inflammatory pathologies, restoring the redox balance forms an innovative therapeutic target in the development of new strategies for treating inflammatory skin conditions. Nevertheless, the clinical use of antioxidant-related therapies is still in its infancy.

Skin Redox Balance Maintenance: The Need for an Nrf2-Activator Delivery System

“…Redox active transition metals are involved in ROS generation in skin. For example, an excess of free iron can catalyze ROS formation via Haber-Weiss reaction [8,11]. Chelation of redox active metals maintains metals' redox state and prevents them from generating ROS [8,11].…”

“…For example, an excess of free iron can catalyze ROS formation via Haber-Weiss reaction [8,11]. Chelation of redox active metals maintains metals' redox state and prevents them from generating ROS [8,11]. Physical defense is an additional mechanism by which skin protects itself from ROS; α-tocopherol present in skin layers can stabilize cell membranes by interacting with the fatty acid chain leading to enhanced protection of skin from ROS damage [8,43].…”

“…and, in contrast to LMWA, they are not consumed offering an efficient protection against oxidative damage [14]. This group of enzymes operate in a few dimensions; catalysis of ROS-scavenging reaction which is characterized by high affinity and reaction rates that depend on the pH of the specific activity site [11,14,59], recycling and regeneration of several LMWA such as vitamins A, C and E, and supporting and producing a suitable cellular environment for antioxidant enzymes [14,61]. ROS-scavenging reactions are mediated by specific enzymes, for example, superoxide anions dismutate to molecular oxygen, and hydrogen peroxide is catalyzed by superoxide dismutase [62].…”

“…Skin ROS are involved in redox homeostatic maintenance and thus may be involved in the development of various skin diseases including inflammatory processes and cancer [8,9]. Therefore, under homeostatic conditions, their production and detoxification processes are tightly regulated by an arsenal of skin defense mechanisms [10,11]. However, these highly efficient skin defense mechanisms have a limited capacity, and can be stunned by a continuous The occurrence of lipid peroxidation process via ROS is of high significance.…”

“…One of the major endogenous ROS signaling molecules is hydrogen peroxide (H 2 O 2 ) which is capable of regulating several transcription factors involved in cell replication, metabolism, apoptosis, and necrosis through oxidation of redox-sensitive cysteine residues [38]. The effects of ROS in biological systems, and in particular on skin, are diverse and offer a feedback control; for example, ROS can affect protein functionality either indirectly at the level of protein expression or stability, or directly at the level of posttranslational modifications [11]. Moreover, paradoxically, ROS-signaling results in enzymatic cellular antioxidant activity, as will be discussed in Section 5.…”