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

紫外线辐射是参与皮肤老化和癌症发病的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，细胞抗氧化剂的作用是防止紫外线引起的皮肤光老化和疾病的发生并降低其严重程度。转录因子Nrf2及其细胞质锚定蛋白Keap 1是细胞抗氧化反应的中心调节因子。在这项研究中，我们研究了Nrf2-Keap 1系统在保护皮肤组织免受UVB辐射有害影响中的作用。UVB单次照射可诱导nrf2缺陷小鼠产生更强、更持久的晒伤反应。UVB照射后，nrf2缺失小鼠的表皮坏死、真皮水肿和炎症细胞浸润、晒伤细胞形成和tunel阳性凋亡细胞形成以及8-羟基-2′-脱氧鸟苷等氧化DNA产物的积累等组织学变化更为突出。这些发现表明Nrf2-Keap 1通路在保护皮肤免受急性UVB反应（包括皮肤细胞凋亡和皮肤氧化损伤）中起重要作用。然而，慢性UVB照射导致nrf2缺失小鼠与野生型小鼠的皮肤癌变无显著差异，提示光致癌的促进因子与保护因子之间存在复杂而微妙的平衡。

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.