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      Bacterial contamination hypothesis: a new concept in endometriosis

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          Abstract

          Background

          Endometriosis is a multifactorial disease that mainly affects women of reproductive age. The exact pathogenesis of this disease is still debatable. The role of bacterial endotoxin (lipopolysaccharide, LPS) and Toll‐like receptor 4 ( TLR4) in endometriosis were investigated and the possible source of endotoxin in the pelvic environment was examined.

          Methods

          The limulus amoebocyte lysate test was used to measure the endotoxin levels in the menstrual fluid and peritoneal fluid and their potential role in the growth of endometriosis was investigated. Menstrual blood and endometrial samples were cultured for the presence of microbes. The effect of gonadotrophin‐releasing hormone agonist (Gn RHa) treatment on intrauterine microbial colonization ( IUMC) and the occurrence of endometritis was investigated.

          Main findings (Results)

          Lipopolysaccharide regulates the pro‐inflammatory response in the pelvis and growth of endometriosis via the LPS/ TLR4 cascade. The menstrual blood was highly contaminated with Escherichea coli and the endometrial samples were colonized with other microbes. A cross‐talk between inflammation and ovarian steroids or the stress reaction also was observed in the pelvis. Treatment with Gn RHa further worsens intrauterine microbial colonization, with the consequent occurrence of endometritis in women with endometriosis.

          Conclusion

          For the first time, a new concept called the “bacterial contamination hypothesis” is proposed in endometriosis. This study's findings of IUMC in women with endometriosis could hold new therapeutic potential in addition to the conventional estrogen‐suppressing agent.

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          Most cited references60

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          Differential Roles of TLR2 and TLR4 in Recognition of Gram-Negative and Gram-Positive Bacterial Cell Wall Components

          Toll-like receptor (TLR) 2 and TLR4 are implicated in the recognition of various bacterial cell wall components, such as lipopolysaccharide (LPS). To investigate in vivo roles of TLR2, we generated TLR2-deficient mice. In contrast to LPS unresponsiveness in TLR4-deficient mice, TLR2-deficient mice responded to LPS to the same extent as wild-type mice. TLR2-deficient macrophages were hyporesponsive to several Gram-positive bacterial cell walls as well as Staphylococcus aureus peptidoglycan. TLR4-deficient macrophages lacked the response to Gram-positive lipoteichoic acids. These results demonstrate that TLR2 and TLR4 recognize different bacterial cell wall components in vivo and TLR2 plays a major role in Gram-positive bacterial recognition.
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            Pathogenesis and pathophysiology of endometriosis.

            Originally described over three hundred years ago, endometriosis is classically defined by the presence of endometrial glands and stroma in extrauterine locations. Endometriosis is an inflammatory, estrogen-dependent condition associated with pelvic pain and infertility. This work reviews the disease process from theories regarding origin to the molecular basis for disease sequelae. A thorough understanding of the histopathogenesis and pathophysiology of endometriosis is essential to the development of novel diagnostic and treatment approaches for this debilitating condition. Copyright © 2012 American Society for Reproductive Medicine. All rights reserved.
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              Novel signal transduction pathway utilized by extracellular HSP70: role of toll-like receptor (TLR) 2 and TLR4.

              Recent studies have initiated a paradigm shift in the understanding of the function of heat shock proteins (HSP). It is now clear that HSP can and do exit mammalian cells, interact with cells of the immune system, and exert immunoregulatory effects. We recently demonstrated that exogenously added HSP70 possesses potent cytokine activity, with the ability to bind with high affinity to the plasma membrane, elicit a rapid intracellular Ca(2+) flux, activate NF-kappaB, and up-regulate the expression of pro-inflammatory cytokines in human monocytes. Here for the first time, we report that HSP70-induced proinflammatory cytokine production is mediated via the MyD88/IRAK/NF-kappaB signal transduction pathway and that HSP70 utilizes both TLR2 (receptor for Gram-positive bacteria) and TLR4 (receptor for Gram-negative bacteria) to transduce its proinflammatory signal in a CD14-dependent fashion. These studies now pave the way for the development of highly effective pharmacological or molecular tools that will either up-regulate or suppress HSP70-induced functions in conditions where HSP70 effects are desirable (cancer) or disorders where HSP70 effects are undesirable (arthritis and arteriosclerosis).
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                Author and article information

                Contributors
                nemokhan@koto.kpu-m.ac.jp
                Journal
                Reprod Med Biol
                Reprod. Med. Biol
                10.1111/(ISSN)1447-0578
                RMB2
                Reproductive Medicine and Biology
                John Wiley and Sons Inc. (Hoboken )
                1445-5781
                1447-0578
                18 January 2018
                April 2018
                : 17
                : 2 ( doiID: 10.1111/rmb2.2018.17.issue-2 )
                : 125-133
                Affiliations
                [ 1 ] Graduate School of Medical Science Department of Obstetrics and Gynecology Kyoto Prefectural University of Medicine Kyoto Japan
                [ 2 ] Department of Gynecology Saiseikai Nagasaki Hospital Nagasaki Japan
                [ 3 ] Department of Obstetrics and Gynecology Nagasaki University Graduate School of Biomedical Sciences Nagasaki Japan
                [ 4 ] Department of Tumor and Diagnostic Pathology Atomic Bomb Disease Institute Nagasaki Japan
                [ 5 ] Center for Quality Assurance in Research and Development Kyoto Prefectural University of Medicine Kyoto Japan
                Author notes
                [*] [* ] Correspondence

                Khaleque N. Khan, Graduate School of Medical Science, Department of Obstetrics and Gynecology, Kyoto Prefectural University of Medicine, Kyoto, Japan.

                Email: nemokhan@ 123456koto.kpu-m.ac.jp

                Author information
                http://orcid.org/0000-0002-9493-3340
                Article
                RMB212083
                10.1002/rmb2.12083
                5902457
                29692669
                ac97af2b-c705-4888-b9e2-2dad008b96f2
                © 2018 The Authors. Reproductive Medicine and Biology published by John Wiley & Sons Australia, Ltd on behalf of Japan Society for Reproductive Medicine.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

                History
                : 29 September 2017
                : 03 December 2017
                Page count
                Figures: 2, Tables: 0, Pages: 9, Words: 7136
                Funding
                Funded by: Japan Society for the Promotion of Science
                Award ID: 24592474
                Award ID: 15K10675
                Categories
                Review Article
                Review Articles
                Custom metadata
                2.0
                rmb212083
                April 2018
                Converter:WILEY_ML3GV2_TO_NLMPMC version:version=5.3.4 mode:remove_FC converted:16.04.2018

                bacterial endotoxin,endometriosis,gonadotrophin‐releasing hormone agonist,menstrual blood,toll‐like receptor

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