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炎症、脂质失调和瞬时受体电位阳离子通道亚家族 V 成员 4 信号持续引发慢性外阴疼痛。

Inflammation, lipid dysregulation, and transient receptor potential cation channel subfamily V member 4 signaling perpetuate chronic vulvar pain.

机构信息

OB/GYN Research Division, University of Rochester, Rochester, NY, United States.

Pathology Department, Wayne State University, Detroit, MI, United States.

出版信息

Pain. 2024 Apr 1;165(4):820-837. doi: 10.1097/j.pain.0000000000003088. Epub 2023 Oct 26.

DOI:10.1097/j.pain.0000000000003088
PMID:37889581
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10949218/
Abstract

Localized provoked vulvodynia is characterized by chronic vulvar pain that disrupts every aspect of the patient's life. Pain is localized to the vulvar vestibule, a specialized ring of tissue immediately surrounding the vaginal opening involved in immune defense. In this article, we show inflammation is the critical first step necessary for the generation of pain signals in the vulva. Inflammatory stimuli alone or combined with the transient receptor potential cation channel subfamily V member 4 (TRPV4) agonist 4α-phorbol 12,13-didecanoate stimulate calcium flux into vulvar fibroblast cells. Activity is blocked by the TRPV4 antagonist HC067047, denoting specificity to TRPV4. Using lipidomics, we found pro-resolving lipids in the vulvar vestibule were dysregulated, characterized by a reduction in pro-resolving mediators and heightened production of inflammatory mediators. We demonstrate specialized pro-resolving mediators represent a potential new therapy for vulvar pain, acting on 2 key parts of the disease mechanism by limiting inflammation and acutely inhibiting TRPV4 signaling.

摘要

局限性激惹性外阴痛的特征是慢性外阴疼痛，扰乱患者生活的方方面面。疼痛局限于外阴前庭，这是一个特殊的组织环，位于阴道开口周围，参与免疫防御。在本文中，我们表明炎症是在外阴产生疼痛信号的关键第一步。单独的炎症刺激或与瞬时受体电位阳离子通道亚家族 V 成员 4（TRPV4）激动剂 4α-佛波醇 12,13-二癸酸酯联合刺激钙流入外阴成纤维细胞。活性被 TRPV4 拮抗剂 HC067047 阻断，表明对 TRPV4 的特异性。通过脂质组学，我们发现外阴前庭中的促修复脂质失调，表现为促修复介质减少和炎症介质产生增加。我们证明，专门的促修复介质代表外阴疼痛的一种潜在新疗法，通过限制炎症和急性抑制 TRPV4 信号转导，作用于疾病机制的 2 个关键部分。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aebd/10949218/a24b497085e5/jop-165-820-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aebd/10949218/9688e6643f6c/jop-165-820-g001.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aebd/10949218/c8579e66b5a2/jop-165-820-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aebd/10949218/b38b09582796/jop-165-820-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aebd/10949218/59dc01e9adce/jop-165-820-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aebd/10949218/8cb1af24b1d2/jop-165-820-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aebd/10949218/4c30dd99e757/jop-165-820-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aebd/10949218/a24b497085e5/jop-165-820-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aebd/10949218/9688e6643f6c/jop-165-820-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aebd/10949218/752a2f80ab32/jop-165-820-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aebd/10949218/c8579e66b5a2/jop-165-820-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aebd/10949218/b38b09582796/jop-165-820-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aebd/10949218/59dc01e9adce/jop-165-820-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aebd/10949218/8cb1af24b1d2/jop-165-820-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aebd/10949218/4c30dd99e757/jop-165-820-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aebd/10949218/a24b497085e5/jop-165-820-g008.jpg

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