Role of nitric oxide in regulating epidermal permeability barrier function

Abstract

Nitric oxide (NO), a free radical molecule synthesized by nitric oxide synthases (NOS), regulates multiple cellular functions in a variety of cell types. These NOS, including endothelial NOS (eNOS), inducible NOS (iNOS) and neural NOS (nNOS), are expressed in keratinocytes. Expression levels of both iNOS and nNOS decrease with ageing, and insufficient NO has been linked to the development of a number of disorders such as diabetes and hypertension, and to the severity of atherosclerosis. Conversely, excessive NO levels can induce cellular oxidative stress, but physiological levels of NO are required to maintain the normal functioning of cells, including keratinocytes. NO also regulates cutaneous functions, including epidermal permeability barrier homeostasis and wound healing, through its stimulation of keratinocyte proliferation, differentiation and lipid metabolism. Topical applications of a diverse group of agents which generate nitric oxide (called NO donors) such as S-nitroso-N-acetyl-D,L-penicillamine (SNAP) can delay permeability barrier recovery in barrier-disrupted skin, but iNOS is still required for epidermal permeability barrier homeostasis. This review summarizes the regulatory role that NO plays in epidermal permeability barrier functions and the underlying mechanisms involved.

Paclitaxel-Induced Epidermal Alterations: An In Vitro Preclinical Assessment in Primary Keratinocytes and in a 3D Epidermis Model

“…From these results, we speculated that reduced levels of eNOS imply low levels of physiological NO. This could affect the proper epidermis permeability and wound healing, and induce an imbalance of pro-inflammatory cytokines [61], as we have seen in our results. As some authors propose that paclitaxel anti-angiogenic properties may be regulated by ROS production in endothelial cells [38], we can infer that elevated levels of oxidative stress in skin keratinocytes might also drive the anti-angiogenic properties in HDMEC.…”

“…Physiological levels of nitric oxide (NO) are required to maintain the normal functioning of cells, including keratinocytes. NO is vital as a signaling molecule regulating multiple epidermal functions, including keratinocyte proliferation and differentiation, apoptosis, migration, and oxidative stress, as well as cytokine production [61]. NO is produced by eNOS, that is expressed in human keratinocytes in a similar way that VEGF [61,62].…”

“…NO is vital as a signaling molecule regulating multiple epidermal functions, including keratinocyte proliferation and differentiation, apoptosis, migration, and oxidative stress, as well as cytokine production [61]. NO is produced by eNOS, that is expressed in human keratinocytes in a similar way that VEGF [61,62]. In this work, we examined if the anti-angiogenic activity of paclitaxel could happen as well in the skin, by analyzing endothelial tube formation in primary human dermal microvascular endothelial cells (HDMEC).…”

Dracorhodin Perchlorate Regulates the Expression of Inflammatory Cytokines through the TLR4 Pathway and Improves Skin Wound Healing in Diabetic Rats

“…Among the three NOS, endothelial NOS (eNOS) mainly regulates vascular tension [ 20 ]; neuronal NOS (nNOS) mainly transmits biological signals through synaptic structures [ 21 ]; inducible NOS (iNOS) is mainly involved in inflammatory responses and immune cell defense responses against pathogens [ 22 ]. All three NOS are expressed in skin tissue [ 23 ]. eNOS and iNOS are expressed in response to induction of cytokines, growth factors, and inflammation and are non-calcium-dependent [ 24 – 26 ].…”

“…eNOS and iNOS are expressed in response to induction of cytokines, growth factors, and inflammation and are non-calcium-dependent [ 24 – 26 ]. iNOS can be continuously expressed in keratinocytes, Langerhans cells, fibroblasts, and endothelial cells through induction, especially after stimulation by cytokines or inflammatory factors, and induce a large amount of NO production to participate in the regulation of skin internal environment function, inflammatory response, and tissue damage repair [ 23 , 27 ]. eNOS plays an important role in vascular regeneration after traumatic ischemia, mainly by promoting vascular smooth muscle proliferation and migration [ 28 ].…”