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Review
. 2024 Nov 19;7(1):1534.
doi: 10.1038/s42003-024-07219-w.

Cellular and molecular roles of reactive oxygen species in wound healing

Matthew Hunt  1 , Monica Torres  1   2 , Etty Bachar-Wikstrom  1 , Jakob D Wikstrom  3   4
Affiliations
Review

Cellular and molecular roles of reactive oxygen species in wound healing

Matthew Hunt et al. Commun Biol. .

Abstract

Wound healing is a highly coordinated spatiotemporal sequence of events involving several cell types and tissues. The process of wound healing requires strict regulation, and its disruption can lead to the formation of chronic wounds, which can have a significant impact on an individual's health as well as on worldwide healthcare expenditure. One essential aspect within the cellular and molecular regulation of wound healing pathogenesis is that of reactive oxygen species (ROS) and oxidative stress. Wounding significantly elevates levels of ROS, and an array of various reactive species are involved in modulating the wound healing process, such as through antimicrobial activities and signal transduction. However, as in many pathologies, ROS play an antagonistic pleiotropic role in wound healing, and can be a pathogenic factor in the formation of chronic wounds. Whilst advances in targeting ROS and oxidative stress have led to the development of novel pre-clinical therapeutic methods, due to the complex nature of ROS in wound healing, gaps in knowledge remain concerning the specific cellular and molecular functions of ROS in wound healing. In this review, we highlight current knowledge of these functions, and discuss the potential future direction of new studies, and how these pathways may be targeted in future pre-clinical studies.

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Conflict of interest statement

Competing interests The authors declare no competing interests.

Figures

Fig. 1
Fig. 1. Summary of ROS activities during the wound healing process.
Stages of wound healing with illustrations of the various beneficial roles that physiological levels ROS play in the respective stages, in addition to the roles excessive ROS and oxidative stress play in chronic wound pathogenesis. During the haemostasis stage, NO prevents platelet adhesion to vessel walls, whilst ROS such as O2.− increases fibrin deposition, and H2O2 induces the recruitment of monocytes and neutrophils. During inflammation, ROS play important roles in activating immune cells, as well as eliminating pathogens and preventing infection. During the proliferation stage, ROS play vital roles in modulating numerous cellular signalling pathways to promote the proliferation, migration, and differentiation of fibroblasts and keratinocytes, as well as angiogenesis, ultimately promoting collagen remodelling and extracellular matrix formation. Oxidative stress caused by excessive levels of ROS contribute to the pathogenesis of chronic wounds in various ways, including by increasing apoptosis, promoting pathogen expansion and thus infection, as well as impairing the correct modulation of cell signalling pathways involved in cell dynamics.
Fig. 2
Fig. 2. Cellular ROS homeostasis.
Schematic diagram depicting the various ROS-generating pathways occurring within cells. At the cell membrane, O2.− is converted from O2 in an NADPH-mediated reaction by NOXs, which is then converted to H2O2 by SOD1. H2O2 can also be produced from O2 in a Ca2+-mediated reaction by DUOXs or by UV radiation or other environmental stressors. Extracellular H2O2 can also be imported into cells through AQPs 3, 8, or 9. Within cells, O2.− leaks from the ETC during oxidative phosphorylation (OXPHOS) and is converted into H2O2 by SOD2/MnSOD2 and effluxed out of mitochondria into the cell cytosol. Additionally, H2O2 can be produced in the ER by either ERO1 or NOXs and effluxed into the cytosol, as can H2O2 produced by NOXs within peroxisomes. XO, DAO, DDO, and HAO are also produced in peroxisomes. Within the cell cytoplasm, H2O2 can be detoxified into H2O and O2 as well as .OH by CAT. ER endoplasmic reticulum, SOD superoxide dismutase, AQP aquaporin, CAT catalase, XO xanthine oxidase, DAO D-amino acid oxidase, HAO 2-hydroxy acid oxidase, ERO ER oxidoreductin.
Fig. 3
Fig. 3. Roles of ROS utilisation in immune cells during wound healing.
Schematic diagram depicting the roles of ROS in neutrophil and macrophage recruitment, as well as in antimicrobial activities during the inflammatory stage of wound healing. Here, wounding-induced Ca2+ flashes lead to the upregulation of DUOX-mediated H2O2 production, stimulating the recruitment of leukocytes to the wound site. Additionally, OH prevents the ubiquitination and subsequent degradation of HIF-1α, leading to increased HIF-1α signalling and macrophage activation, primarily mediated through H2O2 signalling. Finally, immune cells utilise various reactive oxygen species, including O2−, to destroy pathogens through respiratory bursts.
Fig. 4
Fig. 4. ROS and endothelial cell function.
Schematic depicting how H2O2 produced by NOX4 increases Ca2+ uptake into endothelial cells through elevated SERCA2 and TRPM2 channel activity, subsequently leading to increased endothelial cell division and migration – thereby promoting angiogenesis.
Fig. 5
Fig. 5. ROS and re-epithelialisation.
Schematic showing the various signalling molecules and pathways which are modulated by ROS to regulate re-epithelialisation during wound healing. H2O2 produced by either NOXs or DUOXs, or derived from mitochondria, stimulate numerous cell signalling pathways which ultimately lead to the upregulation of processes to accelerate wound healing – such as cell migration, proliferation, differentiation, angiogenesis, or stem cell propagation.
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