The inhibition of the exacerbated

The inhibition of the exacerbated inflammatory response that follows injury may be an alternative approach to induce a more efficient repair [17,83]. In line with that, 5-LO is one of the most consolidated targets for dampening inflammation, mainly through the therapeutic effects of 5-LO inhibitors that may regulate leukotriene synthesis [36,84]. In our study, the antagonism of both LTB4 or cysLTs receptors resulted in faster wound closure coupled to a reduction in TNF-α levels. Likewise, but using a different antagonist of LTB4 receptor, named BIIL284, a reduction in several inflammatory markers, including TNF-α, was observed in an experimental model of atherosclerosis [85]. The reduction in VE-822 following the inhibition of LTB4 production was also observed in a murine model of intestinal polyposis [86]. For this purpose, mice were treated with Zileuton, a pharmacological inhibitor of 5-LO, thus reducing the levels of LTB4, which was followed by a diminishment in sera pro-inflammatory cytokines IL-1β, IL-17 and TNF-α [86]. The beneficial effects of antagonizing cysLTs besides of reducing TNF-α to constrain inflammation were also observed in an experimental model of focal cerebral ischemia in rats, which used the cysLT2R antagonist HAMI 3379 [87]. Though in our study a cysLT1R antagonist (montelukast) was used, a reduction in TNF-α was also observed. In fact, accelerated wound healing is observed in the absence of TNF signaling [88]. Furthermore, different studies have showed that montelukast exerts its anti-inflammatory effects also through cysLT1R-independent mechanisms including the inhibitions of 5-LO [89] and eosinophil adhesion to vascular endothelium and migration [31], which reinforces its potential as anti-inflammatory therapeutic option. As previously described, LTB4 is a well-known proinflammatory lipid mediator involved in leukocyte chemotaxis and in the regulation of proinflammatory cytokines by binding to its receptor BLT1. Chronic activation of the LTB4/BLT1 pathway contributes to the persistent inflammation in diseases like atherosclerosis and arthritis. Similarly, our hypothesis of improved wound healing due to inflammation control was confirmed after using CP105 (BLT1-antagonist). On the other hand, neutrophils do not produce LTC4, but like other leukocytes, express cysLTR1 [90]. Then, exposure of human neutrophils to LTC4 may lead to cell activation [91,92] and, most importantly, the “priming” of neutrophils with cysLTs sensitizes these cells for augmented production of inflammatory mediators, after exposure to other chemoattractants such as fMLP [93]. In line with that, the drug montelukast, that inhibits cysLTR1, attenuates the sensitizing interactions of cysLTs with neutrophils [93]. Therefore, although we did not directly investigate this phenomena, we believe that the same event could occur in our model and inhibition of both LTB4 or LTC4 could by direct or indirect mechanisms decrease the tissue inflammation and promote a better wound healing response. Otherwise, considering the hypothesis of increase compensatory production of another arachidonic acid derived mediator, a biological compensatory pathway may indeed occur in case of accumulated metabolic substrate, just like that observed in some models of blocked AA-derived catabolism. Here, when we showed data from 5-LO−/− mice, we excluded the actions of all derived-metabolites, such as LTs, lipoxins and resolvins. On these specific protocols, we also cannot discard the contribution of 12- and 15-LO metabolites. However, in our study we blocked only the LTs- receptors pathway, but not the production of LT. Then, we believe that our findings could represent the direct role of LTs on wound healing instead of an AA-metabolic deviation. Finally, we suggested a positive relationship between the reduction of leukotrienes, the expression of the inflammatory cytokine TNF-α and faster wound closure. Furthermore, 5-LO and in special LTB4 or cysLTs may also be important targets for the treatment of cutaneous healing in cases of deficient or unresolved repair, such as in large and threatening lesions, burnt patients, decubitus or diabetic ulcers.