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Resolvins in wound healing

  • 07/02/2018

The wound healing process largely depends on the resolution of inflammation: for the wound to close, inflammation must be resolved. A number high-risk wounds that develop persistent inflammation are due to surgery, burns or pressure ulcers; in subjects with impaired vascular function (e.g. long-term diabetes) these wounds can become chronic.

Resolvins (Rv) are endogenous pro-resolving lipid mediators derived from eicosapentaenoic acid (E series) and docosahexaenoic acid (D series) which inhibit neutrophil migration and favour microbe and dead cell phagocytosis by macrophages; thus they promote the resolution of inflammation and facilitate the onset of the proliferative phase of wound healing. In healthy individuals, Rvs are present at low concentrations in situations of tissue homeostasis, but their presence increases significantly in conditions of inflammation. Given that the resolution of inflammation is essential for the onset of the proliferative phase of wound healing, it is reasonable to hypothesise that exogenous application of Rvs could have a therapeutic effect.

There are a number of studies on the effects of Rvs in the context of inflammation and wounds. Intradermal injections of RvD1 in excisional wounds accelerate wound closure in diabetic mice; furthermore, tissue granulation increases and the number of M1 proinflammatory macrophages drops. Systemic administration of RvD2 with burn wounds reduces tissue necrosis, preserves the microvascular network and reduces levels of inflammatory markers.

Recently, a team of researchers at the Biomechanical Engineering Department of Rutgers University (USA) conducted a study with the aim of comparing the potency of different types of Rv (RvD1, RvD2 and RvE1) in inhibiting neutrophil migration in vitro and determining whether this correlates with the degree to which they stimulate wound healing in vivo.

Data show that the three Rvs had similar effects and are better than placebo (saline vehicle) in both inhibiting neutrophil migration and wound curing, but RvE1 was more effective (to a statistically significant extent) in both assessments. RvE1 was related to quicker wound closure, at approximately 19 days, compared to RvD2 (23 days), RvD1 (24 days) and placebo (28 days). The effect on neutrophil migration in vitro had a linear relation with wound closure time in vivo; for each Rv, the greater the neutrophil migration inhibition, the faster the wound healing. Histological images showed that RvE1 rapidly reduced inflammation and generated more new collagen and epidermal layers sooner than with placebo. On day 30, the wounds treated with RvE1 resembled normal skin, with the epidermis completely intact and the underlying collagen well organised, while those treated with placebo had a scab and the new collagen was disorganised. Notably, RvD2 showed greater potency at lower concentrations, at 500 nM it reduced neutrophil migration (compared to placebo) by approximately 70%, while RvE1 reduced it by 80% but at a concentration of 2,000 nM. With regard to wound healing, RvD2 was the second fastest, after RvE1. RvD1, however, had a lower inhibitory effect on neutrophil migration and its activity on the wound was no better than placebo at any of the assessment points.

Possibly a combination of Rvs (with regard to those studied in this research, RvE1 and RvD2) would improve results, as they showed different patterns in wound closure (this could be partly due to the fact that they act on different receptors): RvD2 with greater activity at onset and RvE1 after that. Furthermore, there is evidence showing that RvD2 protects against sepsis and Rvs also have analgesic effects.

The properties shown by Rvs make them a possible therapy for wound healing, mainly targeting early phases, where they would favour the action of subsequent cellular or protein-based therapies in the later stages.

In the near future, research in this field could offer answers that support the use of different types of Rv not only in acute and chronic wounds, but also in bone generation, asthma and diabetes.

Menon R, Krzyszczyk P, Berthiaume F. Pro-resolution potency of resolvins D1, D2 and E1 on neutrophil migration and in dermal wound healing. Nano Life. 2017 Mar;7(1).

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5851488/

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