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Bradykinin (<jats:styled-content style=\"fixed-case\">BK<\/jats:styled-content>) is known as an inflammatory mediator, and shows elevated levels in inflammatory diseases such as rheumatoid arthritis. In the present study, we evaluated whether<jats:styled-content style=\"fixed-case\">BK<\/jats:styled-content>is involved in endometriosis\u2010related pain.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Endometriotic lesions were used for immunohistochemistry. Primary cultures of endometriotic stromal cells (<jats:styled-content style=\"fixed-case\">ESC<\/jats:styled-content>) were stimulated with<jats:styled-content style=\"fixed-case\">IL<\/jats:styled-content>\u20101\u03b2 and\/or<jats:styled-content style=\"fixed-case\">BK<\/jats:styled-content>. Quantitative<jats:styled-content style=\"fixed-case\">RT<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">PCR<\/jats:styled-content>was used to evaluate the<jats:styled-content style=\"fixed-case\">mRNA<\/jats:styled-content>expressions of<jats:styled-content style=\"fixed-case\">BK<\/jats:styled-content>receptors (<jats:styled-content style=\"fixed-case\">BKR<\/jats:styled-content>) and endothelin\u20101 in<jats:styled-content style=\"fixed-case\">ESC<\/jats:styled-content>. The concentration of endothelin\u20101 in cystic fluid of endometrioma or non\u2010endometrioma was measured with<jats:styled-content style=\"fixed-case\">ELISA<\/jats:styled-content>. The conditioned medium of<jats:styled-content style=\"fixed-case\">ESC<\/jats:styled-content>stimulated with<jats:styled-content style=\"fixed-case\">IL<\/jats:styled-content>\u20101\u03b2 and\/or<jats:styled-content style=\"fixed-case\">BK<\/jats:styled-content>was injected intraplantarly in mice, and evaluated whether pain\u2010related licking behaviour was elicited.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The expressions of<jats:styled-content style=\"fixed-case\">BK<\/jats:styled-content>and<jats:styled-content style=\"fixed-case\">BKR<\/jats:styled-content>in endometriotic lesions were observed by immunohistochemistry.<jats:italic>In vitro<\/jats:italic>experiments showed that<jats:styled-content style=\"fixed-case\">IL<\/jats:styled-content>\u20101\u03b2 induced<jats:styled-content style=\"fixed-case\">BKR<\/jats:styled-content>\u2010B1 and B2 on<jats:styled-content style=\"fixed-case\">ESC<\/jats:styled-content>. Activation of these receptors by<jats:styled-content style=\"fixed-case\">BK<\/jats:styled-content>significantly induced endothelin\u20101 expression in<jats:styled-content style=\"fixed-case\">ESC<\/jats:styled-content>, which was negated completely by<jats:styled-content style=\"fixed-case\">HOE<\/jats:styled-content>\u2010140, a<jats:styled-content style=\"fixed-case\">BKR<\/jats:styled-content>\u2010B2 antagonist. The cystic fluid of endometrioma contained higher amount of endothelin\u20101 compared to non\u2010endometrioma. Intraplantar injection of the conditioned medium of<jats:styled-content style=\"fixed-case\">ESC<\/jats:styled-content>treated with<jats:styled-content style=\"fixed-case\">IL<\/jats:styled-content>\u20101\u03b2 and<jats:styled-content style=\"fixed-case\">BK<\/jats:styled-content>significantly induced licking behaviour, which was suppressed with<jats:styled-content style=\"fixed-case\">BQ<\/jats:styled-content>\u2010123, an endothelin type\u2010A receptor antagonist.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>The present study demonstrated the presence and the function of the<jats:styled-content style=\"fixed-case\">BK<\/jats:styled-content>axis in endometriosis, and established a potential new therapy target for endometriosis\u2010related pain.<\/jats:p><\/jats:sec><jats:sec><jats:title>Significance<\/jats:title><jats:p>The present study demonstrated (1) the presence and the function of the<jats:styled-content style=\"fixed-case\">BK<\/jats:styled-content>system in endometriosis, (2) activation of<jats:styled-content style=\"fixed-case\">BKR<\/jats:styled-content>induced endothelin\u20101 in endometriotic lesion and (3) blocking endothelin\u20101 was effective to decrease pain.<\/jats:p><\/jats:sec>","DOI":"10.1002\/ejp.1133","type":"journal-article","created":{"date-parts":[[2017,10,16]],"date-time":"2017-10-16T06:54:37Z","timestamp":1508136877000},"page":"501-510","source":"Crossref","is-referenced-by-count":28,"title":["Bradykinin system is involved in endometriosis\u2010related pain through endothelin\u20101 production"],"prefix":"10.1002","volume":"22","author":[{"given":"O.","family":"Yoshino","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology University of Toyama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K.","family":"Yamada\u2010Nomoto","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology University of Toyama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M.","family":"Kobayashi","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology University of Toyama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T.","family":"Andoh","sequence":"additional","affiliation":[{"name":"Department of Applied Pharmacology Graduate School of Medicine and Pharmaceutical Sciences University of Toyama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M.","family":"Hongo","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology University of Toyama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Y.","family":"Ono","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology University of Toyama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A.","family":"Hasegawa\u2010Idemitsu","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology University of Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A.","family":"Sakai","sequence":"additional","affiliation":[{"name":"Department of Applied Pharmacology Graduate School of Medicine and Pharmaceutical Sciences University of Toyama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Y.","family":"Osuga","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology University of Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S.","family":"Saito","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology University of Toyama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2017,10,16]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1093\/humrep\/17.7.1895"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjp.0703012"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1517\/14656566.2012.723692"},{"key":"e_1_2_7_5_1","first-page":"422","article-title":"Expression and significance of ET\u20101 and its receptors in endometriosis","volume":"40","author":"Chen Z.G.","year":"2009","journal-title":"Sichuan Da Xue Xue Bao Yi Xue Ban"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0906393"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/0028-2243(93)90052-E"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0304-3959(98)00098-0"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.pa.32.040192.002455"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1254\/jphs.FP0072051"},{"key":"e_1_2_7_11_1","doi-asserted-by":"crossref","unstructured":"Giudice L.C. 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