Attenuation of UVB-induced sun burn reaction, DNA damage and epidermal cell apoptosis but no alteration in UVB-induced skin carcinogenesis in Nrf2 deficient mice

紫外线辐射是皮肤老化和癌症发病机制中最重要的环境因素之一。紫外线辐射的许多有害影响与活性氧的产生有关，细胞抗氧化剂可以防止紫外线诱导的光老化和皮肤疾病的发生并减轻其严重程度。转录因子Nrf2及其胞质锚定蛋白Keap1是细胞抗氧化反应的中央调节因子。本研究利用Nrf2基因缺陷小鼠，研究了Nrf2-Keap1系统在保护皮肤组织免受UVB辐射损伤中的作用。UVB单次照射可引起Nrf2缺陷小鼠更强、更持久的晒伤反应。UVB照射后，Nrf2基因缺陷小鼠的组织学改变更为明显，包括表皮坏死、真皮水肿和炎细胞浸润、晒伤细胞形成和TUNEL阳性的凋亡细胞形成，以及8-羟基-2‘-脱氧鸟苷等DNA氧化产物的积聚。这些结果表明，NRF2-Keap1通路在保护皮肤免受包括皮肤细胞凋亡和皮肤氧化损伤在内的急性UVB反应中起着重要作用。然而，慢性UVB辐射对NRF2基因缺陷小鼠和野生型小鼠的皮肤癌的致癌作用没有显著差异，提示光癌的促进因素和保护因素之间存在着复杂而微妙的平衡。

Ultraviolet (UV) radiation is one of the most important environmental factors involved in the pathogenesis of skin aging and cancer. Many harmful effects of UV radiation are associated with the generation of reactive oxygen species, and cellular antioxidants act to prevent the occurrence and reduce the severity of UV-induced photoaging and diseases of the skin. Transcription factor Nrf2 and its cytoplasmic anchor protein Keap 1 are central regulators of the cellular antioxidant response. We investigated in this study the roles of Nrf2-Keap 1 system in protection of skin tissue from harmful effects of UVB irradiation using nrf2-deficient mice. A single irradiation with UVB induced stronger and longer-lasting sunburn reaction in nrf2-deficient mice. Histological changes including epidermal necrosis, dermal edema and inflammatory cell infiltration, sunburn cell formation and TUNEL-positive apoptotic cell formation, and accumulation of oxidative DNA products such as 8-hydroxy-2'-deoxyguanosine after UVB radiation were more prominent in nrf2-deficient mice. These findings thus demonstrate that the Nrf2-Keap 1 pathway plays an important role in the protection of the skin against acute UVB reactions including cutaneous cell apoptosis and oxidative damages of skin. However, chronic UVB irradiation resulted in no significant difference in skin carcinogenesis between nrf2-deficient and wild-type mice, suggesting a complicate and subtle balance between promoting and protecting factors of photocarcinogenesis.