title: 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.
authors.affiliation: Department of Hand Surgery, Ruihua Affiliated Hospital of Soochow University, Suzhou, China.
authors.forename: JiHui
authors.initials: J
authors.lastname: Ju
authors.affiliation: Department of Hand Surgery, Ruihua Affiliated Hospital of Soochow University, Suzhou, China.
authors.forename: JianLong
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Hand Surgery, Ruihua Affiliated Hospital of Soochow University, Suzhou, China. gkswk2013@163.com.
authors.forename: RuiXing
authors.initials: R
authors.lastname: Hou
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002452:Cell Count; D004487:Edema / Q000150:complications / Q000188:drug therapy / Q000473:pathology; D004967:Estrogens / Q000494:pharmacology / Q000627:therapeutic use*; D016753:Interleukin-10 / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D020556:Neutrophil Infiltration / Q000187:drug effects; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D020011:Protective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000150:complications / Q000188:drug therapy* / Q000601:surgery; D012867:Skin / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D013524:Surgical Flaps / Q000637:transplantation; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D004967:Estrogens; D020011:Protective Agents; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D048051:p38 Mitogen-Activated Protein Kinases
keywords: estradiol; flaps; ischemia-reperfusion injury; p38-MAPK