Department of Surgery, University of California San Francisco, San Francisco, California 94143, USA.
Mol Med. 2013 Jul 24;19(1):212-22. doi: 10.2119/molmed.2013.00036.
Although females suffer twice as much as males from stress-related disorders, sex-specific participating and pathogenic cellular stress mechanisms remain uncharacterized. Using corticotropin-releasing factor receptor 2-deficient (Crhr2-/-) and wild-type (WT) mice, we show that CRF receptor type 2 (CRF2) and its high-affinity ligand, urocortin 1 (Ucn1), are key mediators of the endoplasmic reticulum (ER) stress response in a murine model of acute pancreatic inflammation. Ucn1 was expressed de novo in acinar cells of male, but not female WT mice during acute inflammation. Upon insult, acinar Ucn1 induction was markedly attenuated in male but not female Crhr2-/- mice. Crhr2-/- mice of both sexes show exacerbated acinar cell inflammation and necrosis. Electron microscopy showed mild ER damage in WT male mice and markedly distorted ER structure in Crhr2-/- male mice during pancreatitis. WT and Crhr2-/- female mice showed similarly distorted ER ultrastructure that was less severe than distortion seen in Crhr2-/- male mice. Damage in ER structure was accompanied by increased ubiquitination, peIF2, and mistargeted localization of vimentin in WT mice that was further exacerbated in Crhr2-/- mice of both sexes during pancreatitis. Exogenous Ucn1 rescued many aspects of histological damage and cellular stress response, including restoration of ER structure in male WT and Crhr2-/- mice, but not in females. Instead, females often showed increased damage. Thus, specific cellular pathways involved in coping and resolution seem to be distinct to each sex. Our results demonstrate the importance of identifying sex-specific pathogenic mechanisms and their value in designing effective therapeutics.
尽管女性受到与压力相关的疾病困扰的程度是男性的两倍，但特定于性别的参与和致病细胞应激机制仍未被描述。使用促肾上腺皮质释放激素受体 2 缺陷型（Crhr2-/-）和野生型（WT）小鼠，我们表明，CRF 受体 2（CRF2）及其高亲和力配体，孤啡肽 1（Ucn1），是急性胰腺炎症小鼠模型中内质网（ER）应激反应的关键介质。在急性炎症期间，雄性 WT 小鼠的腺泡细胞中会新表达 Ucn1，但雌性 WT 小鼠则不会。在受到损伤时，雄性 WT 小鼠的腺泡 Ucn1 诱导明显减弱，但雄性 Crhr2-/-小鼠则不然。两性 Crhr2-/-小鼠的腺泡细胞炎症和坏死都明显加重。电子显微镜显示，WT 雄性小鼠的 ER 损伤轻微，而 Crhr2-/-雄性小鼠的 ER 结构则明显扭曲。WT 和 Crhr2-/-雌性小鼠的 ER 超微结构也发生了类似的扭曲，但比 Crhr2-/-雄性小鼠的扭曲程度要轻。ER 结构的损伤伴随着泛素化、peIF2 的增加和波形蛋白的错误定位，在 WT 小鼠中更为明显，而在两性 Crhr2-/-小鼠中更为严重。在胰腺炎期间，外源 Ucn1 挽救了许多组织学损伤和细胞应激反应方面，包括恢复雄性 WT 和 Crhr2-/-小鼠的 ER 结构，但对雌性则没有作用。相反，雌性往往会出现更多的损伤。因此，应对和解决特定细胞途径的能力似乎在两性之间存在明显差异。我们的研究结果表明，确定特定于性别的致病机制及其在设计有效治疗方法中的价值非常重要。
