Shenoy Chandra C, Khan Zaraq, Zheng Ye, Jones Tiffanny L, Khazaie Khashayarsha, Daftary Gaurang S
Department of Obstetrics and Gynecology, Mayo Clinic, Rochester, Minnesota 55905.
Department of Immunology, Mayo Clinic, Rochester, Minnesota 55905.
Endocrinology. 2017 Oct 1;158(10):3605-3619. doi: 10.1210/en.2017-00171.
Progressive scarring is ubiquitous postoperatively and in an array of chronic systemic diseases. Recent studies indicate that such scarring has a high female propensity; females are also almost exclusively affected by endometriosis, a common sex steroid-dependent fibrotic disease. Endometriosis-related fibrosis is regulated epigenetically through transcription factor Krüppel-like factor 11 (KLF11). In response to surgical induction of endometriosis, Klf11-/- female mice develop significant fibrosis in contrast to wild-type mice. We therefore hypothesized that female fibrotic predilection was mediated by differential sex steroid regulation of KLF11/collagen 1a1 signaling and investigated the fibrotic response in wild-type and Klf11-/- male and female animals using a sterile peritonitis model. Fibrosis selectively developed in Klf11-/- females. Fibrosis in these animals was almost completely abrogated by ovariectomy. Ovariectomized animals were selectively supplemented with estradiol, medroxyprogesterone acetate (MPA), or dihydrotestosterone; fibrosis was only observed in mice exposed to MPA. Fibrosis therefore selectively developed in Klf11-/- female mice in response to physiological or pharmacological progesterone. The fibrotic response in these animals was also mitigated in response to antiprogestin therapy. Profibrotic gene expression was activated in a primary human peritoneal cell line in response to KLF11 short hairpin RNA and MPA but not estradiol. KLF11/collagen 1a1 signaling previously shown to be linked to fibrosis was thus selectively dysregulated in MPA-treated cells. Our in vivo and in vitro findings in an animal model and human cells, respectively, suggest that progressive fibrotic scarring is a sexually dimorphic response irrespective of etiology; moreover, it is responsive to novel, individualized therapeutic intervention.
术后以及在一系列慢性全身性疾病中，进行性瘢痕形成普遍存在。最近的研究表明，这种瘢痕形成在女性中更为常见；女性也是几乎唯一受子宫内膜异位症影响的群体，子宫内膜异位症是一种常见的性激素依赖性纤维化疾病。子宫内膜异位症相关的纤维化通过转录因子Krüppel样因子11（KLF11）进行表观遗传调控。与野生型小鼠相比，在子宫内膜异位症手术诱导后，Klf11基因敲除的雌性小鼠会出现明显的纤维化。因此，我们推测女性对纤维化的易感性是由KLF11/胶原蛋白1a1信号通路的性激素差异调节介导的，并使用无菌性腹膜炎模型研究了野生型和Klf11基因敲除的雄性和雌性动物的纤维化反应。纤维化在Klf11基因敲除的雌性小鼠中选择性地发展。这些动物的纤维化几乎完全被卵巢切除所消除。对卵巢切除的动物选择性地补充雌二醇、醋酸甲羟孕酮（MPA）或二氢睾酮；仅在接触MPA的小鼠中观察到纤维化。因此，Klf11基因敲除的雌性小鼠在生理或药理孕酮作用下选择性地出现纤维化。这些动物的纤维化反应在抗孕激素治疗后也有所减轻。在原代人腹膜细胞系中，KLF11短发夹RNA和MPA可激活促纤维化基因表达，但雌二醇则不能。因此，先前显示与纤维化相关的KLF11/胶原蛋白1a1信号通路在MPA处理的细胞中选择性失调。我们分别在动物模型和人类细胞中的体内和体外研究结果表明，无论病因如何，进行性纤维化瘢痕形成是一种性别差异反应；此外，它对新型个体化治疗干预有反应。
