Mechanisms of vulvodynia involving dysregulation of pro-resolving lipids

焦点：局限性外阴疼痛(LPV)是长期性交困难的最常见原因 (痛苦的性交)在绝经前的妇女。然而，LPV的病因尚不清楚，也没有有效的药物治疗。 治疗是存在的；临床试验报告说，在减轻疼痛方面，治疗并不比安慰剂更好。LPV赠送 疼痛对轻触仅限于女性下生殖道的一个特定区域，称为外阴前庭。 前提：我们的研究小组发现，从外阴疼痛部位分离出的成纤维细胞株 前庭产生高水平的促痛和促炎介质(例如PGE2和IL-6)。什么时候 暴露于外阴阴道环境中的促炎刺激下，前庭成纤维细胞显著地产生 与几毫米外无痛部位的成纤维细胞相比，有更高水平的促疼痛信号。这是独一无二的 内在反应性将外阴先天反应与神经性炎症联系起来，最终导致局部的， 长期的疼痛。因此，LPV很可能是正常的解剖学定义的先天炎症的恶化。 回应。在不损害正常宿主防御的情况下(即， 专门的促分解调节剂；SPM)可能对LPV有效。SPM是omega-3和omega-6 脂肪酸衍生的脂类，由几种类型组成，称为分解脂、脂脂素、保护素和脂氧素。SPM 是由人体自然产生的，几乎没有毒性，有几种正在进行临床试验 炎症性疾病和其他疾病，这可能导致更快的临床翻译。尽管SPM还没有 作为LPV疗法的测试，我们有强有力的证据支持这些脂质将有效地对抗LPV。 组织假说：我们假设SPM将有效地调节LPV的病理反应 反过来，将成功地解决LPV相关的神经炎性疼痛。在这里，我们将标识以下SPM 有效降低与LPV疼痛相关的促炎介质水平，确定其机制 通过SPM发挥作用，它们在LPV疾病中的作用(S)，并在临床前LPV模型中测试候选治疗方法。 具体目标1：研究SPM在钝化外阴促炎/促痛反应中的作用 来自对照和LPV患者的成纤维细胞、组织和液体。 具体目标2：确定支配SPM产生、反应和治疗的机制(S) 外阴成纤维细胞的潜能。 具体目标3：使用一种新的临床前LPV小鼠模型，评估SPM在缓解疼痛方面的效果。 对该领域的影响：我们将在确定潜在的治疗剂方面向前迈出重要的一步 不仅可以减少LPV背景下过度的促炎信号和疼痛，而且在其他 慢性炎症状态。此外，我们将加强临床前研究的方法学基础 在LPV中进行止痛测试，并确定可以轻松转化为临床试验/使用的SPM分子。不是 存在有效的LPV疗法，这使得我们的工作对改善这种严重疾病的治疗至关重要。

The Focus: Localized provoked vulvodynia (LPV) is the most common cause of longstanding dyspareunia (painful sexual intercourse) in premenopausal women. Yet, LPV etiology is unclear, and no effective medical therapy exists; clinical trials report that treatments are no better in alleviating pain than placebo. LPV presents with pain to light touch limited to a defined region of the female lower genital tract termed the vulvar vestibule. The Premise: Our research team has discovered that fibroblast strains isolated from painful sites in the vulvar vestibule produce elevated levels of pro-pain and proinflammatory mediators (e.g. PGE2 and IL-6). When exposed to proinflammatory stimuli found in the vulvovaginal milieu, vestibular fibroblasts produce significantly higher levels of pro-pain signals than fibroblasts from pain-free sites a few millimeters away. This unique and intrinsic responsiveness connects innate vulvar responses to neuro-inflammation and culminates in localized, longstanding pain. Thus, LPV is likely an exacerbation of a normal anatomically-defined innate inflammatory response. Therapeutics that resolve inflammation and pain without impairing normal host defense (i.e. specialized pro-resolving mediators; SPMs) may be effective against LPV. SPMs are omega-3 and omega-6 fatty acid-derived lipids that consist of several types called, resolvins, maresins, protectins, and lipoxins. SPMs are naturally produced by the human body, have virtually no toxicity, and several are in clinical trial for inflammatory and other diseases, which could lead to faster clinical translation. Although SPMs have not been tested as an LPV therapy, we have strong supporting evidence that these lipids will be effective against LPV. Organizing Hypothesis: We hypothesize that SPMs will effectively modulate the LPV pathologic response and in turn, will successfully resolve LPV-associated neuro-inflammatory pain. Here, we will identify SPMs that are effective in reducing levels of proinflammatory mediators associated with LPV pain, define the mechanisms whereby SPMs act, their role(s) in LPV disease, and test therapeutic candidates in a preclinical LPV model. Specific Aim 1: Investigate the role of SPMs in blunting proinflammatory/pro-pain responses in vulvar fibroblasts, tissues, and fluids from controls and patients with LPV. Specific Aim 2: Determine the mechanism(s) that govern SPM production, responsiveness, and therapeutic potential in vulvar fibroblasts. Specific Aim 3: Evaluate the efficacy of SPMs in alleviating pain using a novel preclinical LPV mouse model. Impact on the field: We will make a significant step forward in identifying potential therapeutic agents that could not only reduce excessive proinflammatory signaling and pain in the context of LPV, but also in other chronic inflammatory conditions. Furthermore, we will strengthen the methodological basis for preclinical analgesia testing in LPV and identify SPM molecules that could be readily translated to clinical trials/use. No effective LPV therapies exist, making our work vital to improving treatment of this crippling condition.