Peroxiredoxin 6 is required for blood vessel integrity in wounded skin

Peroxiredoxin 6 (Prdx6) is a cytoprotective enzyme with largely unknown in vivo functions. Here, we use Prdx6 knockout mice to determine its role in UV protection and wound healing. UV-mediated keratinocyte apoptosis is enhanced in Prdx6-deficient mice. Upon skin injury, we observe a severe hemorrhage in the granulation tissue of knockout animals, which correlates with the extent of oxidative stress. At the ultrastructural level endothelial cells appear highly damaged, and their rate of apoptosis is enhanced. Knock-down of Prdx6 in cultured endothelial cells also increases their susceptibility to oxidative stress, thus confirming the sensitivity of this cell type to loss of Prdx6. Wound healing studies in bone marrow chimeric mice demonstrate that Prdx6-deficient inflammatory and endothelial cells contribute to the hemorrhage phenotype. These results provide insight into the cross-talk between hematopoietic and resident cells at the wound site and the role of reactive oxygen species in this interplay

Keratinocyte growth factor protects epedermis and hair follicles from cell death induced by UV irradiation, chemotherapeutic or cytotoxic agents

Owing to its potent cytoprotective properties for epithelial cells, keratinocyte growth factor (KGF) is successfully used for the treatment of chemotherapy- and radiotherapy-induced oral mucositis in cancer patients. It is therefore of major interest to determine possible clinical applications of KGF in other organs and in different stress situations and to unravel common and organ-specific mechanisms of KGF action. Here we show that KGF protects human keratinocytes from the toxicity of xenobiotics with electrophilic and oxidative properties and reduces the cell death induced by UV irradiation. In contrast to other cell types, cytoprotection of keratinocytes by KGF is not a direct anti-apoptotic effect but requires de novo protein synthesis. The in vitro findings are clinically relevant because KGF protected keratinocytes in organ-cultured human scalp hair follicles from the toxicity of the xenobiotic menadione. Moreover, injection of KGF into murine back skin markedly reduced cell death in the epidermis after UVB irradiation. This activity is dependent on FGF receptor signaling because it was abrogated in transgenic mice expressing a dominant-negative FGF receptor mutant in keratinocytes. Taken together, our results encourage the use of KGF for skin protection from chemical and physical insults

Nrf2 Transcription Factor, a Novel Target of Keratinocyte Growth Factor Action Which Regulates Gene Expression and Inflammation in the Healing Skin Wound

Keratinocyte growth factor (KGF) is a potent mitogen for epithelial cells, and it promotes survival of these cells under stress conditions. In a search for KGF-regulated genes in keratinocytes, we identified the gene encoding the transcription factor NF-E2-related factor 2 (Nrf2). Nrf2 is a key player in the cellular stress response. This might be of particular importance during wound healing, where large amounts of reactive oxygen species are produced as a defense against invading bacteria. Therefore, we studied the wound repair process in Nrf2 knockout mice. Interestingly, the expression of various key players involved in wound healing was significantly reduced in early wounds of the Nrf2 knockout animals, and the late phase of repair was characterized by prolonged inflammation. However, these differences in gene expression were not reflected by obvious histological abnormalities. The normal healing rate appears to be at least partially due to an up-regulation of the related transcription factor Nrf3, which was also identified as a target of KGF and which was coexpressed with Nrf2 in the healing skin wound. Taken together, our results reveal novel roles of the KGF-regulated transcription factors Nrf2 and possibly Nrf3 in the control of gene expression and inflammation during cutaneous wound repair