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1.
J Invest Dermatol ; 139(5): 1161-1170, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30465800

RESUMO

Wound healing is a well-coordinated process that involves inflammatory mediators and cellular responses; however, if any disturbances are present during this process, tissue repair is impaired. Chronic wounds are one of the serious long-term complications associated with diabetes mellitus. The chemokine receptor CCR4 and its respective ligands, CCL17 and CCL22, are involved in regulatory T cell recruitment and activation in inflamed skin; however, the role of regulatory T cells in wounds is still not clear. Our aim was to investigate the role of CCR4 and regulatory T cells in cutaneous wound healing in diabetic mice. Alloxan-induced diabetic wild- type mice (diabetic) developed wounds that were difficult to heal, differently from CCR4-/- diabetic mice (CCR4-/- diabetic), and also from anti-CCL17/22 or anti-CD25-injected diabetic mice that presented with accelerated wound healing and fewer regulatory T cells in the wound bed. Consequently, CCR4-/- diabetic mice also presented with alteration on T cells population in the wound and draining lymph nodes; on day 14, these mice also displayed an increase of collagen fiber deposition. Still, cytokine levels were decreased in the wounds of CCR4-/- diabetic mice on day 2. Our data suggest that the receptor CCR4 and regulatory T cells negatively affect wound healing in diabetic mice.


Assuntos
Quimiocina CCL17/antagonistas & inibidores , Quimiocina CCL22/antagonistas & inibidores , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Receptores CCR4/metabolismo , Cicatrização/efeitos dos fármacos , Aloxano/farmacologia , Análise de Variância , Animais , Biópsia por Agulha , Quimiocina CCL17/farmacologia , Quimiocina CCL22/farmacologia , Quimiocinas/metabolismo , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 1/tratamento farmacológico , Humanos , Imuno-Histoquímica , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Reação em Cadeia da Polimerase em Tempo Real/métodos , Cicatrização/fisiologia
2.
J Invest Dermatol ; 134(5): 1436-1445, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24226420

RESUMO

Lipid mediators derived from 5-lipoxygenase (5-LO) metabolism can activate both pro- and anti-inflammatory pathways, but their role in wound healing remains largely unexplored. In this study we show that 5-LO knockout (5-LO(-/-)) mice exhibited faster wound healing than wild-type (WT) animals, and exhibited upregulation of heme oxygenase-1 (HO-1). Furthermore, HO-1 inhibition in 5-LO(-/-) mice abolished the beneficial effect observed. Despite the fact that 5-LO(-/-) mice exhibited faster healing, in in vitro assays both migration and proliferation of human dermal fibroblasts (HDFs) were inhibited by the 5-LO pharmacologic inhibitor AA861. No changes were observed in the expression of fibronectin, transforming growth factor (I and III), and α-smooth muscle actin (α-SMA). Interestingly, AA861 treatment significantly decreased ROS formation by stimulated fibroblasts. Similar to 5-LO(-/-) mice, induction of HO-1, but not superoxide dismutase-2 (SOD-2), was also observed in response to 5-LO (AA861) or 5-LO activating protein (MK886) inhibitors. HO-1 induction was independent of nuclear factor (erythroid derived-2) like2 (Nrf-2), cyclooxygenase 2 (COX-2) products, or lipoxin action. Taken together, our results show that 5-LO disruption improves wound healing and alters fibroblast function by an antioxidant mechanism based on HO-1 induction. Overexpression of HO-1 in wounds may facilitate early wound resolution.


Assuntos
Araquidonato 5-Lipoxigenase/metabolismo , Dermatite/metabolismo , Heme Oxigenase-1/metabolismo , Proteínas de Membrana/metabolismo , Cicatrização/fisiologia , Adulto , Animais , Araquidonato 5-Lipoxigenase/genética , Araquidonato 5-Lipoxigenase/imunologia , Dermatite/genética , Dermatite/imunologia , Derme/citologia , Derme/imunologia , Derme/metabolismo , Modelos Animais de Doenças , Fibroblastos/imunologia , Fibroblastos/metabolismo , Heme Oxigenase-1/imunologia , Humanos , Masculino , Proteínas de Membrana/imunologia , Camundongos , Camundongos da Linhagem 129 , Camundongos Knockout , Estresse Oxidativo/fisiologia , Cultura Primária de Células , Espécies Reativas de Oxigênio/metabolismo
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