Kynurenine Increases Matrix Metalloproteinase-1 and -3 Expression in Cultured Dermal Fibroblasts and Improves Scarring In Vivo

Abstract

We previously demonstrated that the formation of hypertrophic scarring on the wounds of a rabbit ear fibrotic model was significantly reduced by grafting a bilayer skin substitute expressing indoleamine 2,3-dioxygenase (IDO). Here, we hypothesize that the improved healing quality is due to extracellular matrix modulatory effect of IDO-mediated tryptophan metabolites. To test this hypothesis, a series of in vitro and in vivo experiments were conducted and the findings revealed a significant increase in the expression of matrix metalloproteinase 1 (MMP-1) in fibroblasts either transduced with human IDO gene or cultured with conditioned media obtained from IDO-expressing cells. Consistent with this finding, kynurenine (Kyn) treatment markedly increased the levels of MMP-1 and MMP-3 expression through activation of the MEK (mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinase)-ERK1/2 MAPK signaling pathway. On the other hand, Kyn significantly suppressed the expression of type I collagen in fibroblasts as compared with that of control. To test the anti-fibrogenic effect of Kyn in an in vivo model, rabbit ear fibrotic wounds were topically treated with cream containing 50 μg Kyn per l00 μl of cream per wound. The result showed a marked improvement in scar formation relative to the controls. These findings collectively suggest that Kyn can potentially be used as an anti-fibrogenic agent for treating hypertrophic scarring.

Intense pulsed light induces synthesis of dermal extracellular proteins in vitro

“…Our study showed that the expression of MMP-1 is increased 48 h after IPL irradiation [27]. Although it is well established that MMP expression was increased in damaged skin [28], some authors reported that the IPL management had no impact on MMP secretion levels in fibroblasts [29]. Some authors speculate that it could be an overlooked mechanism of skin rejuvenation, in which increased of MMP-1 will be implicated, contributing to the degradation of senescent collagens.…”

MicroRNA-22 may promote apoptosis and inhibit the proliferation of hypertrophic scar fibroblasts by regulating the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase/p21 pathway

“…Chang et al (21) demonstrated that 5-aminolevulinic acid-based anti-HS photodynamic therapy induced increased expression of p53/p21 in HSFBs, which may further active the downstream molecules and promoted cell apoptosis. Furthermore, Li et al (22) observed that kynurenine treatment increased the expression of MEK and the phosphorylation of ERK1/2 in human dermal fibroblasts. He et al (23) also demonstrated the role of ERK signaling in loureirin B-induced inhibition of HS formation.…”

Examination of Kynurenine Toxicity on Corneal and Conjunctival Epithelium: In vitro and in vivo Studies

“…Thus, these results suggest that KYN possesses properties that can be considered beneficial in the healing of the corneal epithelium. Indeed, there are reports showing that KYN can facilitate and modulate healing processes [7, 11, 36]. Interestingly, wounds that received IDO genetically modified dermal fibroblasts healed more quickly than those of the controls [7].…”

“…KYN markedly suppresses the expression of collagen types I and III while increasing the expression of matrix metalloproteinase-1 and matrix metalloproteinase-3 in dermal fibroblasts [7]. Anti-scarring properties of KYN were also demonstrated in a fibrotic rabbit skin ear wound model in vivo [36]. On the other hand, it was suggested that the upregulation of the KYN pathway, independent of glucose metabolism, may play an important role in the progression of diabetes-induced fibrosis in the corneal stroma and may contribute to corneal scarring and delayed wound healing [43].…”