Docosahexaenoic acid slows inflammation resolution and impairs the quality of healed skin tissue

Abstract

There is no consensus on the effects of omega-3 (ω-3) fatty acids (FA) on cutaneous repair. To solve this problem, we used 2 different approaches: (1) FAT-1 transgenic mice, capable of producing endogenous ω-3 FA; (2) wild-type (WT) mice orally supplemented with DHA-enriched fish oil. FAT-1 mice had higher systemic (serum) and local (skin tissue) ω-3 FA levels, mainly docosahexaenoic acid (DHA), in comparison with WT mice. FAT-1 mice had increased myeloperoxidase (MPO) activity and content of CXCL-1 and CXCL-2, and reduced IL-10 in the skin wound tissue three days after the wound induction. Inflammation was maintained by an elevated TNF-α concentration and presence of inflammatory cells and edema. Neutrophils and macrophages, isolated from FAT-1 mice, also produced increased TNF-α and reduced IL-10 levels. In these mice, the wound closure was delayed, with a wound area 6-fold bigger in relation with WT group, on the last day of analysis (14 days post-wounding). This was associated with poor orientation of collagen fibers and structural aspects in repaired tissue. Similarly, DHA group had a delay during late inflammatory phase. This group had increased TNF-α content and CD45+F4/80+ cells at the third day after skin wounding and increased concentrations of important metabolites derived from ω-3, like 18-HEPE, and reduced concentrations of those from ω-6 FA. In conclusion, elevated DHA content, achieved in both FAT-1 and DHA groups, slowed inflammation resolution and impaired the quality of healed skin tissue.

Effect of Polymeric Nanoparticles with Entrapped Fish Oil or Mupirocin on Skin Wound Healing Using a Porcine Model

“…In the present study, the relative lack of significant differences among the tested treatments or among the treatments and the control can be considered from at least three viewpoints: animal model, control empty collagen scaffolds and amounts of the active substances applied. Most experiments testing the effects of different active substances on excisional wound healing are performed on rodents [ 13 , 24 , 25 , 26 , 27 ], using a very homogeneous set of inbred animals. Because the wound-healing process in humans and pigs is similar (and different from the healing process in rodents), we used a porcine model to evaluate the potential efficacy of the tested treatments in humans [ 12 ].…”

“…LC-PUFA n-3 was found to inhibit skin wound healing in one study [ 29 ] but was found to have no effect in another [ 30 ]. Elevated levels of DHA slowed inflammation resolution and impaired the quality of healed skin tissue in a mouse model [ 26 ]. Using a similar (mouse) model, skin lesions topically treated with alpha-linolenic acid (n-3) were significantly larger at 120 h after injury in comparison with those treated with oleic acid (n-9).…”

“…COX2 is a critical enzyme involved in the inflammatory response to wound injury [ 51 ]. Elevated DHA content either in transgenic mice capable of producing endogenous PUFA n-3 or in wild-type mice orally supplemented with DHA-enriched fish oil slowed inflammation resolution [ 26 ]. However, neither FO alone nor NP/FO showed any significant effect on the expression of the COX2 gene in the present study.…”

Influência da resposta inflamatória sobre a composição da matriz extracelular durante a cicatrização de feridas em camundongos FAT-1

“…Em recente estudo publicado pelo nosso grupo, demonstramos que os camundongos FAT-1 apresentaram aumento na incorporação de ácidos graxos ω-3 na pele, principalmente de ácido docosapentaenoico (DPA) e DHA, o que resultou em redução de 50% da razão ω-6/ω-3 (Figura 6A) [56]. A nível sistêmico, foi também observado no soro dos animais transgênicos redução de AA (40%) e elevada concentração de DHA, ALA e EPA, resultando em uma razão ω-6/ω-3 inferior em comparação com o grupo WT (cerca de 33% menor) (Figura 6B) [56]. células endoteliais e fibroblastos, por meio de integrinas, para mediar a sobrevivência, adesão e migração celular [62].…”

“…Embasados por resultados prévios de que os camundongos FAT-1 aumentaram a produção de mediadores pró-inflamatórios durante a fase inflamatória tardia [56] (Figura 8B-E), avaliamos se este perfil inflamatório também se estendeu sobre a fase intermediária do processo de cicatrização, quando a MEC começa a ser depositada.…”