D'Cruz Osmond J, Uckun Fatih M
Drug Discovery Program, Paradigm Pharmaceuticals, St Paul, MN 55113, USA.
Am J Reprod Immunol. 2007 Aug;58(2):75-97. doi: 10.1111/j.1600-0897.2007.00502.x.
Endometriosis (EMS) is a chronic inflammatory disease of multifactorial etiology characterized by implantation and growth of endometrial glands and stroma outside the uterine cavity. EMS is a significant public health issue as it affects 15-20% of women in their reproductive age. Clinical symptoms may include pelvic pain, dysmenorrhea, dyspareunia, pelvic/abdominal masses, and infertility. Symptomatic treatments such as surgical resection and/or hormonal suppression of ovarian function and analgesics are not as effective as desired. Consequently, there is an enormous unmet need to develop effective medical therapy capable of preventing the occurrence and recurrence of EMS without undesirable side-effects. EMS-associated intra-abdominal bleeding episodes, local inflammation, adhesions, and i.p. immunologic dysfunction leads to pelvic nociception and pelvic pain. Increasing evidence supports the involvement of allergic-type inflammation in EMS. Invasion of mast cells, degranulation, and proliferation of interstitial component are observed in endometriotic lesions. Presence of activated and degranulating mast cells within the nerve structures can contribute to the development of pain and hyperalgesia by direct effects on primary nociceptive neurons. Therefore, treatments targeting endometrial mast cells may prove effective in preventing or alleviating EMS-associated symptoms. The Janus kinase 3 (JAK3) is abundantly expressed in mast cells and is required for the full expression of high-affinity IgE receptor-mediated mast cell inflammatory sequelae. JANEX-1/WHI-P131 is a rationally designed novel JAK3 inhibitor with potent anti-inflammatory activity in several cellular and in vivo animal models of inflammation, including mouse models of peritonitis, colitis, cellulitis, sunburn, and airway inflammation with favorable toxicity and pharmacokinetic profile. We hypothesize that JAK3 inhibitors, especially JANEX-1, may prove useful to prevent or alleviate the symptoms of EMS.
子宫内膜异位症（EMS）是一种病因多因素的慢性炎症性疾病，其特征是子宫内膜腺体和间质在子宫腔外植入并生长。EMS是一个重大的公共卫生问题，因为它影响15%至20%的育龄妇女。临床症状可能包括盆腔疼痛、痛经、性交困难、盆腔/腹部肿块和不孕。诸如手术切除和/或抑制卵巢功能的激素疗法以及镇痛药等对症治疗的效果并不理想。因此，迫切需要开发一种有效的药物疗法，能够预防EMS的发生和复发，且无不良副作用。EMS相关的腹腔内出血发作、局部炎症、粘连和腹腔免疫功能障碍会导致盆腔伤害感受和盆腔疼痛。越来越多的证据支持过敏性炎症参与了EMS。在子宫内膜异位症病变中观察到肥大细胞的浸润、脱颗粒和间质成分的增殖。神经结构内活化和脱颗粒的肥大细胞的存在可通过直接作用于初级伤害性神经元而导致疼痛和痛觉过敏的发展。因此，针对子宫内膜肥大细胞的治疗可能在预防或减轻EMS相关症状方面有效。Janus激酶3（JAK3）在肥大细胞中大量表达，是高亲和力IgE受体介导的肥大细胞炎症后遗症充分表达所必需的。JANEX-1/WHI-P131是一种合理设计的新型JAK3抑制剂，在多种细胞和体内炎症动物模型中具有强大的抗炎活性，包括腹膜炎、结肠炎、蜂窝织炎、晒伤和气道炎症的小鼠模型，具有良好的毒性和药代动力学特征。我们假设JAK3抑制剂，尤其是JANEX-1，可能对预防或减轻EMS症状有用。
