Abstract. Tissue repair improvement is crucial for several pathologies characterized by chronic delayed wound closure, such as diabetes. The present study compares the effect of different ozonated oils (olive [OO], sesame [SO] and linseed [LO]) with the same level of ozonation, on wound healing rate in SKH1 mice.

Only treatment with ozonated sesame oil shows a faster wound closure in the first 7 days. This effect paralleled with the increased VEGF and PCNA levels, NFκB nuclear translocation and 4-HNE formation. The present study shows that not only the ozonation grade is of importance for the improvement of wound healing process, but also the typical composition of the oil.

Introduction. Endogenous factors are able to modulate and coordinate the healing process, such as vascular endothelial growth factor (VEGF), transforming growth factor 𝛽 (TGF 𝛽), platelet-derived growth factor (PDGF), cellular cycle proteins and even reactive oxygen species (ROS). The ability to modulate the levels and the release of the mentioned growth factors can influence the WH process. In an experimental, well-characterized skin lesion in mice, it has been demonstrated that the repeated application of ozonated sesame oil (ozSO) was able to significantly accelerate the first phase of the wound closure, which is more susceptible to infections

Results. OzSO showed an increase in closure rate of about 18% at d3, 42% at d4 and d5, 65% at d6 and 57% at d7 compared to SO. There was a similar trend in ozOO, but was not statistically significant with respect to both air and OO controls. OzLO did not show any effect on wound closure rate.

OzSO was able to clearly increase skin PCNA levels; ozOO and ozLO did not show any significant effect on PCNA levels, although ozLO seems to induce PCNA levels in the last part of wound healing process.

OzSO and ozOO increased VEGF production in the first 7 days of the wound closure process; ozLO significantly induced VEGF levels at d3.

Wound healing is a redox controlled process, therefore we evaluated the levels of 4-HNE as a marker of lipid peroxidation and an index of oxidative stress; ozSO showed the highest level of 4-HNE; this was much evident than in the samples treated with ozOO and ozLO. Untreated OO, SO and LO did not shown any difference from the controls.

NFκB is a redox transcription factor, modulated by oxidative stress and peroxidation products, and the role of 4-HNE in the activation of NFκB has been studied. Since the levels of 4-HNE were increased only with the ozSO treatment, the activation of NFκB has been performed only in the samples treated with ozSO.

Wounds treated with ozSO showed a less extension of the injury at d3 and d7 compared to the control, with a most amount of type I collagen fibres. In the wounds treated with SO it is observed a persistence of type III collagen fibres characterizing the granulation tissue.

Discussion. Our data shows the beneficial effect of ozSO on the first phase of the wound healing process, but this effect was not appreciable in the other oils used in the present study.

There is almost 3 times more n-6 fatty acids in the SO compared to the OO and LO; different rheological behaviours due to inherent differences in the molecular configuration of unsaturated acyl chains after ozonation could provide an explanation for the differences observed on the wound parameters. Besides 4-HNE, derived mainly from the oxidation of n-6 PUFA, is an efficient cell signalling molecule, able to modulate the expression of several genes and, therefore, important cellular functions, such as cell growth, differentiation and angiogenesis, all involved in wound healing.

The dose-dependent effect relationship between level of oxidative stress (4-HNE) and NFκB exhibits a biphasic profile, consistent with the hormesis dose–response model: while a moderate levels of α, 𝛽-unsaturated aldehydes can activate NFκB through an IκB kinase independent mechanism, extremely high levels of α, 𝛽-unsaturated aldehydes have been shown to inhibit NFκB activation by blocking IκBα phosphorylation.

In conclusion, application of ozonated oils, especially the ozonated sesame oil with a peroxidation value around 1500, can improve acute cutaneous wound repair in the SKH1 murine model, by affecting the early phases of the process. Topical application of specific vegetable matrices in the form of ozone derivatives may be considered as an alternative therapeutic modality to enhance cutaneous wound healing.

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