Inflammation, lipids, and pain in vulvar disease

Abstract

Localized provoked vulvodynia (LPV) affects ∼14 million people in the US (9% of women), destroying lives and relationships. LPV is characterized by chronic pain (>3 months) upon touch to the vulvar vestibule, which surrounds the vaginal opening. Many patients go months or years without a diagnosis. Once diagnosed, the treatments available only manage the symptoms of disease and do not correct the underlying problem. We have focused on elucidating the underlying mechanisms of chronic vulvar pain to speed diagnosis and improve intervention and management. We determined the inflammatory response to microorganisms, even members of the resident microflora, sets off a chain of events that culminates in chronic pain. This agrees with findings from several other groups, which show inflammation is altered in the painful vestibule. The vestibule of patients is acutely sensitive to inflammatory stimuli to the point of being deleterious. Rather than protect against vaginal infection, it causes heightened inflammation that does not resolve, which coincides with alterations in lipid metabolism that favor production of proinflammatory lipids and not pro-resolving lipids. Lipid dysbiosis in turn triggers pain signaling through the transient receptor potential vanilloid subtype 4 receptor (TRPV4). Treatment with specialized pro-resolving mediators (SPMs) that foster resolution reduces inflammation in fibroblasts and mice and vulvar sensitivity in mice. SPMs, specifically maresin 1, act on more than one part of the vulvodynia mechanism by limiting inflammation and acutely inhibiting TRPV4 signaling. Therefore, SPMs or other agents that target inflammation and/or TRPV4 signaling could prove effective as new vulvodynia therapies.

Keywords: Fibroblasts; Inflammation; Lipids; Pain; SPMs; TRPV4; Vulvodynia.

Figure 1.. Anatomy of Localized Provoked Vulvodynia.

Pain is usually located at the posterior part of the vulvar vestibule between 5 and 7-o’clock (red shading). The red numbers orient the clock with the 12-o’clock position near the clitoris.

Figure 2.. LPV Model.

6 mm punch biopsies are collected during surgery from both LPV cases and from healthy controls (no vulvar disease). These are then sectioned into 3 pieces, each for a specific type of analysis, namely fibroblast isolation and culture, analysis of gene expression, and quantification of lipid profiles. An n of 1 represents 4 tissue samples, with only one painful sample from the vestibule of a case, while the remaining 3 samples, whether from case or control, are from non-painful areas of the vestibule and external vulva.

Figure 3.. Inflammatory Mechanisms of Vulvodynia.

In patients with localized provoked vulvodynia, an abberation of a normally protective response against infection is exeracerbated by the elevated expression and function of nearly a dozen different receptors involved in innate immune responses (dectin-1, TLRs) and pain signaling (bradykinin receptors). This significantly increases levels of IL-6 and PGE₂, which has been associated with pain in vulvodynia. On the left side, healthy controls are depicted, which express normal levels of receptors, responding only to infectious threats, which subsequently triggers immune clearance, after which inflammation resolves. On the right, LPV cases express abnormally high levels of receptors and respond to low numbers of organisms, even the resident flora. This triggers an abnormally strong response that does not resolve and leads to elevated inflammatory mediators associated with pain.

Figure 4.. Neuro-inflammatory Mechanism of Vulvodynia and Proposed Action of Maresin 1.

Abberant responses to inflammatory stimuli, as a result of heightened expression of receptors involved in innate immune recognition and a subsequent failure to resolve these responses due to reduced pro-resolving mediator levels, leads to chronic inflammation and changes in lipid profiles that favor the activation of the TRPV4 pain signaling pathway. When TRPV4 is activated, inflammatory mediators are further elevated, and TRPV4 expression is up-regulated, creating a feed-forward loop that amplifies inflammatory and pain signals. Much like a snowball rolling down a hill (depicted by the blue circle with snowflake symbol), this feed-forward loop gains momentum leading to a failure to resolve inflammation and thus sustained pain signaling. Application of SPMs, specifically maresin 1, inhibits several aspects of this mechanism, which is denoted by the red arrows. Maresin 1 application would thus significantly attenuate the feed-forward loop and reduce the size of or eliminate the “snowball.” We do not have any conflicts of interest to disclose.