No abstract

These results suggest that vasculopathy-induced dysfunction of pericytes and endothelial cells, the main secretory cells of MFG-E8, may be associated with the decreased expression of MFG-E8 in SSc and that the deficient inhibitory regulation of latent-TGF-β-induced skin fibrosis by MFG-E8 may be involved in the pathogenesis of SSc and may be a therapeutic target for fibrosis in SSc patients. This article is protected by copyright. All rights reserved.

Several studies have demonstrated potential roles for apelin/ApJ signaling in the regulation of oxidative stress associated with ischemia-reperfusion (i/R) injury in several organs. objective was to assess the role of apelin/ApJ signaling in the development of pressure ulcers (pUs) formation after cutaneous i/R injury in mice. We identified that cutaneous I/R injury increased the expression of apelin in the skin at I/R site. Administration of apelin significantly inhibited the formation of PUs. The reductions of blood vessels, hypoxic area and apoptosis in i/R site were inhibited by apelin injection. oxidative stress signals in OKD48 mice and the expressions of oxidative stress related genes in the skin were suppressed by apelin injection. H 2 o 2 -induced intracellular ROS and apoptosis in endothelial cells and fibroblasts were suppressed by apelin in vitro. Furthermore, MM07, biased agonist of APJ, also significantly suppressed the development of PUs after cutaneous I/R, and the inhibitory effect of MM07 on PUs formation was higher than that in apelin. We conclude that apelin/ApJ signaling may inhibit cutaneous i/R injuryinduced pUs formation by protecting the reduction of vascularity and tissue damage via suppression of oxidative stress. Exogenous application of apelin or MM07 might have therapeutic potentials against the development of pUs.Pressure ulcers (PUs) are one of the common skin diseases which usually occur elder people and patients with perceptual or movement disorder. In addition, the patients with PUs sometimes cause fatal outcome by local and systemic infections. There has long been considered that the pathogenesis of PUs was associated with tissue damage caused by external force and ischemia. However, there has been increasing evidence that cutaneous ischemia-reperfusion (I/R) is important in the pathogenesis of PUs 1-3 . I/R injury is defined as cellular injury caused by the reperfusion of blood to previously ischemic tissue 4,5 . It is described that reperfusion of blood into the hypoxic tissue triggers off adverse events, including thrombosis and capillary narrowing which lead to vasculopathy, infiltration of inflammatory cells, production of proinflammatory cytokines and the apoptosis of resident cells and necrosis of tissues 6 . I/R injury causes multiple diseases, such as vascular infarction or spasm of brain, heart, kidney and skin. Reactive oxygen species (ROS), such as H 2 O 2 and NO, are also known as a key player that exacerbate the tissues damage caused by I/R injury 7 .Apelin, an endogenous ligand of G protein-coulpled receptor APJ (putative receptor protein related to the angiotensin receptor AT1) 8,9 has multiple functions in the regulation of cardiovascular hemostasis, angiogenesis and adipose tissue function via apelin/APJ signaling 10-13 . APJ is expressed ubiquitously, especially in endothelial cells and vascular smooth muscle cells 8,9,11,12 . Furthermore, recent studies demonstrated that apelin/APJ signaling prevented oxidative stress, resulting in the inhibition of diabetic...

Ischemia‐reperfusion (I/R) is associated with various pathogenic conditions, and there has been increasing evidence that cutaneous I/R injury is associated with the pathogenesis of pressure ulcers (PUs), especially at the early stage presenting as non‐blanchable erythema. Several studies demonstrated that oxidative stress is a key player in I/R injury, and the inhibition of oxidative stress may be capable of protecting tissue damage after I/R injury in various organs including skin. Dimethyl fumarate (DMF) approved by the Food and Drug Administration is Nrf2 activator, and recent studies revealed the antioxidative and anti‐inflammatory effects of DMF on I/R injury in animal models. Our objective was to assess the effects of oral administration of DMF on the development of PUs after cutaneous I/R injury in mice. We found that DMF administration significantly decreased the size of PUs after cutaneous I/R. Cutaneous I/R‐induced oxidative stress was also significantly inhibited by DMF in OKD48 mice, in which oxidative stress can be visually assessed. In addition, DMF treatment decreased hypoxic area, the numbers of apoptotic cells, and vascular loss in I/R area. DMF treatment suppressed the infiltration of MPO+ neutrophils and the production of proinflammatory cytokines in I/R site after cutaneous I/R injury. in vitro experiments, DMF treatment suppressed the production of reactive oxygen species in pericyte‐like cells. These results suggest that DMF treatment might prevent the formation of PUs induced by cutaneous I/R injury via suppressing oxidative stress and subsequent inflammation. DMF treatment during the early phase of decubitus ulcers might protect against further progression.

Tissue injury/hypoxia and oxidative stress induced-extracellular adenosine triphosphate (ATP) can act as damage-associated molecular pattern molecules, which initiate inflammatory response. Our objective was to elucidate the role of extracellular ATP in skin fibrosis in systemic sclerosis (SSc). We identified that hypoxia enhanced ATP release and that extracellular ATP enhanced IL-6 production more significantly in SSc fibroblasts than in normal fibroblasts. There were no significant differences of P2X and P2Y receptor expression levels between normal and SSc fibroblasts. Nonselective P2 receptor antagonist and selective P2Y 2 receptor antagonists, kaempferol and AR-C118925XX, significantly inhibited ATP-induced IL-6 production and phosphorylation of p38 in SSc fibroblasts. ATP-induced IL-6 production was significantly inhibited by p38 inhibitors, SB203580, and doramapimod. Collagen type I production in SSc fibroblasts by ATP-induced IL-6/IL-6 receptor trans-signaling was inhibited by kaempferol and SB203580. The amount of ATP in bleomycin-treated skin was increased, and administration of AR-C118925XX significantly inhibited bleomycin-induced dermal fibrosis in mice. These results suggest that vasculopathy-induced hypoxia and oxidative stress might enhance ATP release in the dermis in SSc and that extracellular ATP-induced phosphorylation of p38 via P2Y 2 receptor might enhance IL-6 and collagen type I production in SSc fibroblasts. P2Y 2 receptor antagonist therapy could be a treatment for skin sclerosis in patients with SSc.