Inflammatory Mediators and Pain in Endometriosis: A Systematic Review.

Nikolaos Machairiotis,Nikolaos Thomakos,Sofia Vasilakaki

doi:10.3390/biomedicines9010054

Abstract

Background: pain is one of the main symptoms of endometriosis and it has a deleterious effect on a patients’ personal and social life. To date, the clinical management of pain includes prolonged medication use and, in some cases, surgery, both of which are disruptive events for patients. Hence, there is an urgency for the development of a sufficient non-invasive medical treatment. Inflammation is one of the causative factors of pain in endometriosis. It is well established that inflammatory mediators promote angiogenesis and interact with the sensory neurons inducing the pain signal; the threshold of pain varies and it depends on the state and location of the disease. The inhibition of inflammatory mediators’ synthesis might offer a novel and effective treatment of the pain that is caused by inflammation in endometriosis. Objectives: patients with endometriosis experience chronic pelvic pain, which is moderate to severe in terms of intensity. The objective of this systematic review is to highlight the inflammatory mediators that contribute to the induction of pain in endometriosis and present their biological mechanism of action. In addition, the authors aim to identify new targets for the development of novel treatments for chronic pelvic pain in patients with endometriosis. Data Sources: three databases (PubMed, Scopus, and Europe PMC) were searched in order to retrieve articles with the keywords ‘inflammation, pain, and endometriosis’ between the review period of 1 January 2016 to 31 December 2020. This review has been registered with PROSPERO (registry number: CRD42020171018). Eligibility Criteria: only original articles that presented the regulation of inflammatory mediators and related biological molecules in endometriosis and their contribution in the stimulation of pain signal were included. Data Extraction: two authors independently extracted data from articles, using predefined criteria. Results: the database search yielded 1871 articles, which were narrowed down to 56 relevant articles of interest according to the eligibility criteria. Conclusions: inflammatory factors that promote angiogenesis and neuroangiogenesis are promising targets for the treatment of inflammatory pain in endometriosis. Specifically, CXC chemokine family, chemokine fractalkine, and PGE2 have an active role in the induction of pain. Additionally, IL-1β appears to be the primary interleukin (IL), which stimulates the majority of the inflammatory factors that contribute to neuroangiogenesis along with IL-6. Finally, the role of Ninj1 and BDNF proteins needs further investigation.

Highlights

During the menstrual cycle, endometrial-like tissue may spread outside its normal location, the uterus, and be implanted on other locations, more often on pelvic structures to form lesions [1,2]
IL-1β cytokine is a biomolecule that contributes to cellular signaling via its receptor (IL-1R1)
IL-1β and TGF-β can both stimulate the expression of sphingosine kinases (SphKs) mRNA, which catalyzes the conversion of sphingosine to the bioactive lipid sphingosine 1-phosphate (S1P). These findings show that the synergistic effect between different IL members and the endometrial mesenchymal stem cells (eMSC) may contribute to the regulation of cytokines in endometriosis

Summary

Introduction

Endometrial-like tissue may spread outside its normal location, the uterus, and be implanted on other locations, more often on pelvic structures to form lesions [1,2]. This event activates an immune response, which, in the case of endometriosis, appears to be insufficient for removing these lesions. The activation of an inflammatory response that follows promotes the secretion of cytokines and chemokines within the peritoneal cavity This forms a microenvironment that contributes to the development of the ectopic endometrial tissue by facilitating localized angiogenesis and disrupting the normal apoptotic processes [5]

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Conclusion