AgingCell：延緩皮膚衰老的新策略

　　最近，加拿大英屬哥倫比亞大學（UBC）的一個研究小組，制備了一種轉基因小鼠，雖然這些小鼠反復暴露于可產生皺紋的紫外（UV）光，但它們的皮膚較少起皺紋。

　　這些有著年輕相貌的小鼠，缺乏產生顆粒酶B（Granzyme B）的基因，免疫細胞用這種酶來消滅有害的病原體。由David Granville教授和博士后研究人員Leigh Parkinson帶領的UBC CProvidence研究小組發現，顆粒酶B也有害處：當皮膚細胞產生和釋放顆粒酶B以響應紫外線時，它會觸發膠原蛋白的分解，而膠原蛋白是一種可使皮膚緊致的結構蛋白。

　　相關研究結果發表在最近的《Aging Cell》，將來有希望開發出一種藥物，阻斷某些部位的顆粒酶B活性，從而阻止衰老以及依賴于膠原蛋白的組織退化――不僅僅是皮膚，還有血管和肺通道。

　　UBC病理系和醫學實驗室教授、UBC和St. Paul醫院心肺創新中心首席研究員Granville，專注于研究顆粒酶B在動脈粥狀硬化和心臟病中的作用。他和他的研究團隊想知道，是否缺乏顆粒酶B的小鼠血管更耐硬化和狹窄――這是人類心臟病發作的主要原因。在此過程中，他們發現這些小鼠保持著年輕的皮膚，而正常小鼠的皮膚卻發生了老化。

　　Granville的研究小組構建了一個實驗性的“陽光日曬床”，來刺激小鼠的日光照射。每只小鼠被放置于一個旋轉木馬中――在UV燈下緩慢轉動，使它們每周三次、每次暴露三到四分鐘，這足以引起發紅，但不發燒。經過20周的反復暴露，很明顯，與對照組小鼠相比，缺乏顆粒酶B的小鼠――它們的膠原蛋白更完整，皮膚老化得較慢。

　　viDA Therapeutics――Granville共同創辦的一個公司，目前正在開發一種基于UBC技術許可的顆粒酶B抑制劑。該公司計劃兩年內在盤狀紅斑狼瘡（一種自身免疫性疾病，日光可加重該病，可導致面部疤痕惡化，音樂家Seal患有這種疾病）患者身上測試一種局部用藥。

　　如果該藥物被證明可有效地預防狼瘡相關的皮膚病變，就有可能開發一種化妝品，阻止皮膚的正常逐步老化，而皮膚老化主要是由于太陽暴曬引起。此外，該藥物也可能用于危及生命的疾病，例如動脈瘤和慢性阻塞性肺病，它們都是由膠原蛋白及其他為血管和肺通道提供結構的蛋白分解而引起。

　　原文摘要：

　　Granzyme B mediates both direct and indirect cleavage of extracellular matrix in skin after chronic low-dose ultraviolet light irradiation

　　Summary: Extracellular matrix (ECM) degradation is a hallmark of many chronic inflammatory diseases that can lead to a loss of function, aging, and disease progression. Ultraviolet light (UV) irradiation from the sun is widely considered as the major cause of visible human skin aging, causing increased inflammation and enhanced ECM degradation. Granzyme B (GzmB), a serine protease that is expressed by a variety of cells, accumulates in the extracellular milieu during chronic inflammation and cleaves a number of ECM proteins. We hypothesized that GzmB contributes to ECM degradation in the skin after UV irradiation through both direct cleavage of ECM proteins and indirectly through the induction of other proteinases. Wild-type and GzmB-knockout mice were repeatedly exposed to minimal erythemal doses of solar-simulated UV irradiation for 20 weeks. GzmB expression was significantly increased in wild-type treated skin compared to nonirradiated controls, colocalizing to keratinocytes and to an increased mast cell population. GzmB deficiency significantly protected against the formation of wrinkles and the loss of dermal collagen density, which was related to the cleavage of decorin, an abundant proteoglycan involved in collagen fibrillogenesis and integrity. GzmB also cleaved fibronectin, and GzmB-mediated fibronectin fragments increased the expression of collagen-degrading matrix metalloproteinase-1 (MMP-1) in fibroblasts. Collectively, these findings indicate a significant role for GzmB in ECM degradation that may have implications in many age-related chronic inflammatory diseases.