OxInflammatory Responses in the Wound Healing Process: A Systematic Review

Abstract

Significant sums are spent every year to find effective treatments to control inflammation and speed up the repair of damaged skin. This study investigated the main mechanisms involved in the skin wound cure. Consequently, it offered guidance to develop new therapies to control OxInflammation and infection and decrease functional loss and cost issues. This systematic review was conducted using the PRISMA guidelines, with a structured search in the MEDLINE (PubMed), Scopus, and Web of Science databases, analyzing 23 original studies. Bias analysis and study quality were assessed using the SYRCLE tool (Prospero number is CRD262 936). Our results highlight the activation of membrane receptors (IFN-δ, TNF-α, toll-like) in phagocytes, especially macrophages, during early wound healing. The STAT1, IP3, and NF-kβ pathways are positively regulated, while Ca²⁺ mobilization correlates with ROS production and NLRP3 inflammasome activation. This pathway activation leads to the proteolytic cleavage of caspase-1, releasing IL-1β and IL-18, which are responsible for immune modulation and vasodilation. Mediators such as IL-1, iNOS, TNF-α, and TGF-β are released, influencing pro- and anti-inflammatory cascades, increasing ROS levels, and inducing the oxidation of lipids, proteins, and DNA. During healing, the respiratory burst depletes antioxidant defenses (SOD, CAT, GST), creating a pro-oxidative environment. The IFN-δ pathway, ROS production, and inflammatory markers establish a positive feedback loop, recruiting more polymorphonuclear cells and reinforcing the positive interaction between oxidative stress and inflammation. This process is crucial because, in the immune system, the vicious positive cycle between ROS, the oxidative environment, and, above all, the activation of the NLRP3 inflammasome inappropriately triggers hypoxia, increases ROS levels, activates pro-inflammatory cytokines and inhibits the antioxidant action and resolution of anti-inflammatory cytokines, contributing to the evolution of chronic inflammation and tissue damage.

Keywords: inflammasome; inflammation; oxidative stress; wound closure.

Figure 1

PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) flow diagram. The flowchart indicates the research records obtained at all standardized stages of the search process required to develop systematic reviews and meta-analyses. Based on the PRISMA statement (http://www.prisma-statement.org (accessed on 3 May 2024)). * Consider, if feasible to do so, reporting the number of records identified from each database or register searched (rather than the total number across all databases/registers). ** If automation tools were used, indicate how many records were excluded by a human and how many were excluded by automation tools.

Figure 2

Results of the primary and secondary outcomes of the individual studies analyzed. The colour green: increased; red: decreased; yellow: undetermined and white: not analysed, indicate the results measured between the studies. MMP: matrix metalloproteinase; MDA: malondialdehyde; TBARS: Thiobarbituric acid reactive substances; LPO: lipid peroxidation; PCN: carbonylated protein; ON: nitric oxide; 3-NT: 3-nitrotyrosine; H2O2: hydrogen peroxide; 4HNE: 4-hydroxynonenal; MPO: metalloproteinase; SOD: superoxide dismutase; CAT: catalase; GST: glutathione transferase; CuZnSOD: copper–zinc superoxide dismutase; MnSOD: manganese superoxide dismutase; IL-1: interleukin-1; IL-1β: interleukin-1-beta; IL-6: interleukin-6; IL-8: interleukin-8; NRF2: nuclear factor erythroid factor 2; HO-1: the inducible isoform of HO; IKβ: Ikappaβ kinase; NF-kβ: nuclear factor kappa β; TNF-α: Tumor Necrosis Factor receptor alpha; VEGF: vascular endothelial growth factor; ANG1 and 2: angiotensin (1–2), COX-2: cyclooxygenase-2; TGF-β: transforming growth factor beta; IL-10: interleukin-10; CRP: C-reactive protein; FIB: fibrinogen. References of the articles in the figure: Back et al., 2020 [42]; Dhall et al., 2016 [43]; Dwivedi et al., 2017 [44]; Ganeshkumar et al., 2012 [45]; Gangwar et al., 2015 [46]; Gautam et al., 2014 [47]; Jridi et al., 2017 [48]; Kandhare et al., 2015 [49]; Leu et al., 2012 [50]; Lim et al., 2006 [51]; Murthy et al., 2013 [52]; Nafiu &Rahman, 2014 [53]; Park et al., 2010 [54]; Park et al., 2011 [55]; Patel et al., 2019 [56]; Sarandy et al., 2018 [57]; Schanuel et al., 2020 [58]; Singh et al., 2017 [59]; Sungkar et al., 2020 [60]; Yadav et al., 2017 [61]; Yadav et al., 2018a [62]; Yadav et al., 2018b [63]; Zhang & Gould, 2013 [64].

Figure 3

Overview of the interrelationship of major pathways and coexisting inflammatory mediators between oxidative stress and inflammatory process in excisional skin wound healing. *** Phenotypic plasticity of macrophages; presence of M1 (pro-inflammatory phase) and presence of M2 (anti-inflammatory phase). 4HNE: 4-hidroxinonenal; Ca²⁺: ion calcium; CAT: catalase; COX-2: cyclooxygenase-2; Fe⁺: ion iron; GST: glutathione transferase; H₂O₂: hydrogen peroxide; HIF-1: Hypoxia-inducible factor 1; ICAM: intercellular adhesion molecule; IFN-δ: Interferon-gamma receptor; IKK: inhibitor complex nuclear factor-κβ kinase; IKβ: IkappaB kinase; IL-1: interleukin 1; IL-6: interleukin-6; IL-10: interleukin 10; iNOS: Inducible nitric oxide synthase; IP3: IP3 signaling pathway; LPO: lipid peroxidation; MPO: metalloproteinase; NF-kβ: nuclear factor kappa β; NLRP3: inflammasome NLRP3; ON: nitric oxide; PCN: carboniled protein; PCR: C-reactive protein; ROS: reactive oxygen species; SOD: superoxide dismutase; TGF-β: transforming growth factor beta; TLR: toll-like receptor; TNF-α: Tumor Necrosis Factor receptor alpha; VECAM: vascular adhesion molecule; VEGF: vascular endothelial growth factor. Figure created on BioRender.com.

Figure 4

Risk of bias and methodological quality indicators for all studies included in the systematic review that assessed inflammation and oxidative stress during skin wound healing.

Figure 5

Risk of bias summary: review authors’ judgments about the risk of bias items for each included study. Green: low risk of bias; Yellow: unclear risk of bias; and Red: high risk of bias. References of the articles in the figure: References of the articles in the figure: Back et al., 2020 [42]; Dhall et al., 2016 [43]; Dwivedi et al., 2017 [44]; Ganeshkumar et al., 2012 [45]; Gangwar et al., 2015 [46]; Gautam et al., 2014 [47]; Jridi et al., 2017 [48]; Kandhare et al., 2015 [49]; Leu et al., 2012 [50]; Lim et al., 2006 [51]; Murthy et al., 2013 [52]; Nafiu &Rahman, 2014 [53]; Park et al., 2010 [54]; Park et al., 2011 [55]; Patel et al., 2019 [56]; Sarandy et al., 2018 [57]; Schanuel et al., 2020 [58]; Singh et al., 2017 [59]; Sungkar et al., 2020 [60]; Yadav et al., 2017 [61]; Yadav et al., 2018a [62]; Yadav et al., 2018b [63]; Zhang & Gould, 2013 [64].

Figure 6

Continuous cycle and interrelating oxidative stress and inflammation, schematizing the major signaling pathways, synthesis of pro- and anti-inflammatory mediators, and antioxidant enzymes involved in the repair of excisional wounds.

Figure 7

The clinical antioxidant and anti-inflammatory modulation of inflammatory mechanisms and the consequent reduction and control of oxidative inflammation.