Role of the p38 mitogen‐activated protein kinase signaling pathway in estrogen‐mediated protection following flap ischemia‐reperfusion injury

Abstract

Ischemia-reperfusion (I/R) injury often occurs during skin flap transplantation and results in tissue damage. Although estrogen treatment significantly alleviates this I/R injury-induced damage, the detailed molecular mechanism is not clear. In this study, a superficial epigastric artery flap I/R injury model was created in adult Wistar rats. Severe necrosis was observed in skin tissue after I/R injury. Histological examination of skin tissue revealed that I/R injury damages skin structure and results in neutrophil infiltration. Inflammation-related parameters, including neutrophil count, tumor necrosis factor-α, and interleukin-10 levels, were increased due to I/R injury. These pathological phenomena were reduced by estradiol treatment. Further investigation found that I/R injury triggers the p38 mitogen-activated protein kinase (p38-MAPK) pathway. The expression levels of p38-MAPK and phosphorylated p38-MAPK were increased after I/R injury. Estradiol increased the expression level of MAPK phosphatase-2, a putative phosphatase of p38, and reduced the levels of p38-MAPK and phosphorylated p38-MAPK. These results suggest that estradiol can improve skin flap survival, possibly by inhibiting neutrophil infiltration and the expression of p38-MAPK. This study provides an explanation for how estrogen alleviates I/R injury-induced damage that occurs during skin flap transplantation. In a rat pathological model, I/R injury leads to skin necrosis, skin structure damage, neutrophil infiltration, and inflammatory cytokine secretion, which are probably downstream effects of activation of the p38-MAPK pathway. On the other hand, estradiol treatment triggers the expression of MAPK phosphatase-2, a putative phosphatase of p38-MAPK, and reduced all examined pathological phenomena. Therefore, estrogen may reduce the deleterious effect of I/R injury on skin flap transplantation through modulating the p38-MAPK pathway.

Effects of SB202190 on expression levels of IL-6 and NF-κB in flap ischemia-reperfusion injury

“…The concentration of IL-6 in serum and the mRNA and protein concentrations of NF-κB and IL-6 in the flap tissues were significantly decreased. This is similar to previous experimental results (6,14). When the p38 MAPK signaling pathway was inhibited, the expression levels of inflammatory factors decreased, alleviating the inflammatory response in the flap.…”

“…Studies have shown that the MAPK pathways that promote occurrence and progression of inflammation were activated in ischemia-reperfusion injuries of a variety of tissues and organs (13). The p38 MAPK pathway, an important member in the MAPK family, played a major role in regulation of intracellular inflammatory response (14,15). In order to understand the role of p38 MAPK signaling pathway in flap ischemia-reperfusion injury and the underlying mechanism, a successfully constructed flap ischemia-reperfusion injury animal model was treated with SB202190, a specific inhibitor of the p38 MAPK pathway.…”

Anti-oxidative effects of 17 β-estradiol and genistein in human skin fibroblasts and keratinocytes

“…It is also notable that ERβ has been found to be more expressed in skin cells [61]. Also, the seven-transmembrane receptor, GPER30, has been reported to be involved in the effects of estrogens in human skin cells [62].…”

Protective effect of polysaccharide peptide on cerebral ischemia‑reperfusion injury in rats

“…However, the exact pathogenesis of cerebral IR injury remains unknown. Cumulative evidence suggests that numerous factors are involved in ischemic brain injury, including apoptosis, acid poisoning, ionic imbalance, excitotoxicity, oxidative stress, peri-infarct depolarization, nutritive stress, inflammation and reactive oxygen species (ROS) ( 5 – 12 ). Furthermore, numerous signaling pathways have been implicated in the pathogenesis of cerebral IR injury, including mitogen-activated protein kinases ( 13 , 14 ).…”