Mechanisms of vulvodynia involving dysregulation of pro-resolving lipids

外阴痛的机制涉及促溶解脂质的失调

• 批准号: 10414893
• 负责人: Constantine G HAIDARIS
• 金额: $ 47.39万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-13 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10414893
• 关键词: Anatomy; Anti-Inflammatory Agents; Biological Assay; Bradykinin; CD59 Antigen; Cell Wall; Cells; Chronic; Clinical Trials; Coitus; Data; Defect; Dinoprostone; Disease; Dyspareunia; Enzymes; Etiology; Exposure to; Female; Fibroblasts; Fibromyalgia; Fire - disasters; Flow Cytometry; Goals; Host Defense; Human; Human body; Impairment; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Response; Injections; Injury; Interleukin-6; Irrigation; Lead; Light; Lipids; Lipoxins; Liquid substance; Mass Spectrum Analysis; Measures; Mechanics; Mediator of activation protein; Medical; Methodology; Methods; Migraine; Modeling; Omega-3 Fatty Acids; Omega-6 Fatty Acids; Outcome Measure; Pain; Pain Measurement; Pain Threshold; Pain-Free; Pathologic; Pathway interactions; Patients; Physiological; Placebos; Plant Roots; Premenopause; Production; Psychophysics; Randomized Clinical Trials; Regimen; Reporting; Research; Research Project Grants; Resolution; Role; Sampling; Sensory; Serum; Signal Transduction; Site; Small Interfering RNA; Stimulant; Stimulus; Technology; Testing; Therapeutic; Therapeutic Agents; Tissues; Topical application; Touch sensation; Toxic effect; Translating; Vestibule; Vulva; Vulvodynia; Western Blotting; Woman; Work; Yeasts; Zymosan; allodynia; chronic painful condition; clinical translation; diagnostic criteria; dietary; dosage; efficacy evaluation; improved; in vitro Model; millimeter; mouse model; neuroinflammation; novel; novel diagnostics; pain reduction; pain signal; particle; pre-clinical; receptor; recruit; relating to nervous system; reproductive tract; response; therapeutic candidate; therapeutic evaluation; virtual; wound healing

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.

焦点：局部激发性外阴痛（LPV）是长期性交困难的最常见原因 （痛苦的性交）在绝经前妇女。然而，LPV的病因尚不清楚，并且没有有效的药物治疗。 治疗是存在的;临床试验报告说，治疗在缓解疼痛方面并不比安慰剂更好。LPV介绍 轻微触摸的疼痛限于女性下生殖道的限定区域，称为外阴前庭。 假设：我们的研究小组发现，从外阴疼痛部位分离的成纤维细胞株 前庭产生升高水平的促痛和促炎介质（例如PGE 2和IL-6）。当 暴露于外阴阴道环境中发现的促炎刺激物，前庭成纤维细胞产生显著的 比几毫米以外的无痛部位的成纤维细胞更高水平的促痛信号。这一独特和 内在反应性将先天性外阴反应与神经炎症联系起来， 长期的疼痛。因此，LPV很可能是正常解剖学定义的先天性炎性疾病的恶化。 反应在不损害正常宿主防御的情况下解决炎症和疼痛的治疗剂（即， 专门的促消退介质（SPMs）可能对LPV有效。SPM是omega-3和omega-6 脂肪酸衍生的脂质，由几种类型组成，称为resolvins、maresins、protectins和lipoxins。SPMS 是人体自然产生的，几乎没有毒性，有几种正在进行临床试验， 炎症和其他疾病，这可能导致更快的临床转化。虽然SPM还没有 作为LPV治疗的测试，我们有强有力的支持证据表明这些脂质对LPV有效。 组织假说：我们假设SPM将有效地调节LPV的病理反应 并且反过来，将成功地解决LPV相关的神经炎性疼痛。在这里，我们将识别 有效降低与LPV疼痛相关的促炎介质水平， 其中SPM起作用，它们在LPV疾病中的作用，并在临床前LPV模型中测试治疗候选物。 具体目标1：研究SPM在抑制外阴炎性/疼痛反应中的作用 来自对照组和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 在外阴成纤维细胞中的潜力。 具体目标3：使用新型临床前LPV小鼠模型评价SPM缓解疼痛的疗效。 对该领域的影响：我们将在确定潜在治疗药物方面迈出重要一步， 不仅可以减少LPV背景下过度的促炎信号和疼痛，而且可以减少其他 慢性炎症此外，我们将加强临床前研究的方法学基础。 在LPV中进行镇痛测试，并鉴定可容易地转化为临床试验/使用的SPM分子。没有 有效的LPV疗法存在，使我们的工作至关重要，以改善治疗这种严重的条件。

项目成果

Specialized Pro-resolving Mediators Reduce Pro-nociceptive Inflammatory Mediator Production in Models of Localized Provoked Vulvodynia.

• DOI: 10.1016/j.jpain.2021.03.144
• 发表时间: 2021-10
• 期刊: The journal of pain
• 作者: Falsetta ML;Wood RW;Linder MA;Bonham AD;Honn KV;Maddipati KR;Phipps RP;Haidaris CG;Foster DC
• 通讯作者: Foster DC