2013 Fiscal Year Research-status Report
子宮内膜症の病態における抗菌性ペプチドと細菌性エンドトキシンの役割に関する研究
| Project/Area Number |
24592474
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| Research Institution | Nagasaki University |
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Principal Investigator |
KHAN KHALEQUE 長崎大学, 医歯(薬)学総合研究科, 助教 (60336162)
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| Co-Investigator(Kenkyū-buntansha) |
北島 道夫 長崎大学, 大学病院, 講師 (50380845)
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| Keywords | endometriosis / inflammation / bacterial contamination / TLR4 / Human beta-defensin / SLPI |
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| Research Abstract |
私どもは，これまでおよそ10年間にわたる検討から，子宮内膜症の発生および増殖・進展に関する新たな病態のひとつとして「bacterial contamination hypothesis細菌混入仮説」を提唱し発表した（Fertil Steril; 2010．実際に，子宮内膜症では非内膜症に比較して，月経血中への大腸菌混入が強く，結果として月経血中や腹水中でのLPS 濃度が亢進していることが認められた．これらは，月経血への細菌混入が骨盤内炎症の最初のﾄﾘｶﾞｰとなり，TLR4を介した内膜症組織の増殖に関与することを初めて示したものである．私どもは，子宮腔内への細菌混入について，いくつかの可能性のある機序をin vitroの細菌培養実験で検討してきたが，in vivoでの機序について，子宮腔内局所の抗菌性ﾍﾟﾌﾞﾁﾄﾞの変化が細菌混入に及ぼす作用についてはこれまで検討されておらず，これらの蛋白が子宮腔内での微生物混入を制御している可能性がある．
Defensinﾌｧﾐﾘｰなどの抗菌性ﾍﾟﾌﾟﾁﾄﾞや分泌型白血球ﾌﾟﾛﾃｱｰｾﾞ阻害物質（SLPI）は，動物および植物に種横断的に広く存在する宿主生得免疫のﾒﾃﾞｨｴｰﾀｰである．これらの抗菌性ペプチドは，微生物の混入・感染から宿主を防御している生得的な抗菌物質と捉えられる，子宮内膜局所におけるHBD-1およびSLPI濃度が月経周期により変化し，増殖期で最も高く，月経期で最も低くなるのではないかと推測している．もしこの予想が正しければ，本研究により，内膜症での月経血中への細菌混入のin vivoでの機序の一端が示されると考える．(1) 骨盤子宮内膜症の発生に関する新たな視点, 第35回日本ｴﾝﾄﾞﾒﾄﾘｵｰｼｽ学会教育講演抄録(educational lecture) Jan 24-26, 2014 (Kagoshima); (2) Bacterial contamination hypothesis：細菌性ｴﾝﾄﾞﾄｷｼﾝとTLR4が司る子宮内膜症の増殖・進展に関する新たな病態生理, 第66回日本産科婦人科学会 (symposium), Ap 18-20,2014 (Tokyo)
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| Current Status of Research Progress |
Current Status of Research Progress
1: Research has progressed more than it was originally planned.
Reason
Bacterial contamination hypothesis and sub-clinical uterine infection in women with endometriosis is an innovative research idea in the pathogenesis or pathopaphysiology of endometriosis. Our continuing research for the last 15 years and our new established hypothesis will open a new era in exploring new mechanistic basis in the development of endometriosis. Our new concept in the field of endometriosis will open new idea in the development of new therapeutic strategy for the prevention of endometriosis as well as to effectively manage recurence/occurrence of endometriosis and to effectively alleviate pain symptoms of women suffering from this hazardous disease.
(A) Our new concept on endometriosis is already accepted by different highly peer-reviewed Journals
(1) Khan KN, Fujishita A, Kitajima M, Hiraki K, Nakashima M, Masuzaki H. Occult microscopic endometriosis: undetectable by laparoscopy in normal peritoneum. Hum Reprod 29(3):462-472, 2014
(2) Khan KN. Visible and invisible (occult) endometriosis (book chapter). In: Harada T eds. Endometriosis: Pathogenesis and Treatment. Japan: The Springer publishing Co., 2014 (in press)
(3) Khan KN, Kitajima M, Inoue T, Tateishi S, Fujishita A, Nakashima M, Masuzaki H. Additive effects of inflammation and stress reaction on Toll-like receptor 4-mediated growth of endometriotic stromal cells. Hum Reprod 28:2794-2803,2013
(B) Our new concept on endometriosis has been recognized by different Domestic and International congresses. (mentioned above)
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| Strategy for Future Research Activity |
We are planning the following study design to establish whether a sub-clinical vaginal infection or a sub-clinical uteirne infection could be associated with the occurrence or progression of endometriosis.
Our on going study will open a area of research to better understand the pathogenesis and related disease burden of endometriosis. Our new concept of sub-clinical uterine infection in women with endometriosis will also create some new therapeutic options in the management of endometriosis.
(1) measurement of intra-vaginal pH of control women and women with endomteriosis. (2) Analysis of bacterial vaginosis (BV) scores using vaginal smears based on Nugent criteria. (3) Analysis of a panel of common bacteria in endometrial samples by bacteria culture in GnRHa-treated and GnRHa-non-treated control women and women with endometriosis. (4) Analysis of the occurrence of endometritis by immunohistochemical detection of plasma cells and neutrophils in endometrial biopsy samples derived from women with and without endometriosis. (5) Investigating the effect of a broad-spectrum antibiotic (levofloxacine) on the growth pattern of some particular bacteria using a in vitro bacteria culture sustem. (6) Analysis of bacteria growth pattern in cervial and endometrial samples after intra-vaginal application of levofloxacine either alone or in combination with GnRH agonist therapy. This will be done in both control women and in women with endometriosis.
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| Expenditure Plans for the Next FY Research Funding |
Uso of money to continue research for the year 2014 to March 2015
(1) Buying research materials and reagents
(2) Attending domestic and international meeting
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