2) 妊娠高血圧症候群における炎症とアディポサイトカイン : 着床機構と病態発現への関与(シンポジウム2:周産期「妊娠高血圧症候群の基礎と臨床-予防・治療の新戦略に向けて」,第65回日本産科婦人科学会・学術講演会)

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Recently, the pathophysiological mechanism of pregnancy-induced hypertension (PIH) has been gradually revealed. The latest key thesis being the so-called 2-step theory, which suggests that the cause of PIH may occur in the early stage of pregnancy and that the pathological change is manifested later after the increase in physiological load of pregnancy. This study aimed to investigate the early-stage mechanism of placentation, inflammation, and insulin resistance in the course of pregnancy mainly by adipose tissue metabolism and the so-called danger-signal molecules, which may connect the first and second steps of the theory. The early stage of placentation was experimentally demonstrated as the immunological collaboration of extravillous trophoblast and uterine natural killer cells. After their coculture, cytokine profiles were dramatically changed between earlier than 10 weeks and later than 12 weeks of gestational age, which may be related to spiral artery remodeling, a key feature of the human placentation whose absence may be a major cause of PIH. In addition, activated proteinases were also detected in pregnant decidua. Cytokines derived from adipose tissue (adipocytokines) were peripherally altered in the patients with a normal pregnancy course and in those with PIH. In the normal pregnancy group, the decreased adiponectin levels, increased free fatty acid levels, and increased sTNF-R1/R2 ratio suggest an increase of inflammatory action ("homeostatic inflammation"). However, the chemokine MCP-1 level was decreased in the normal pregnancy group but increased in the PIH group, indicating that it may contribute to the pathological inflammation in PIH. The adiponectin level was increased in lean patients with severe PIH, which was experimentally demonstrated as the result of brain natriuretic peptide stimulation by cell line culture of adipocytes. Inflammatory change was demonstrated to genetically occur in adipose tissues, using our novel culture method with or without serum samples from PIH patients. The level of HMGB1, a receptor for advanced glycation end-product ligand that is regarded as a danger signal and surface marker of trophoblastic microparticles, was increased in patients with early-onset PIH. This increase in HMGB1 level may support the 2-step theory, as it is the first finding that may connect the first and second steps of the underlying mechanism of PIH. Therefore, our established thesis of the pathological mechanism of PIH may explain the cause and onset of the disease in relation to placentation and immune response of adipose tissue, which may be associated not only to PIH but to other fetomaternal complications and later hypertensive disorder or metabolic syndromes that may occur throughout a woman's lifetime.
2013-11-01

著者

成瀬勝彦
奈良県立医大

2) 妊娠高血圧症候群における炎症とアディポサイトカイン : 着床機構と病態発現への関与(シンポジウム2:周産期「妊娠高血圧症候群の基礎と臨床-予防・治療の新戦略に向けて」,第65回日本産科婦人科学会・学術講演会)

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