1990 年度実績報告書

劇症肝炎における肝再生不全成立機序の解明

研究課題

研究課題/領域番号	01480223
研究機関	東京大学
研究代表者	藤原研司東京大学, 医学部・附属病院, 講師 (80101088)
研究分担者	持田智東京大学, 医学部・附属病院, 医員 (20219968) 富谷智明東京大学, 医学部・附属病院, 医員 (90227637) 名越澄子東京大学, 医学部・附属病院, 医員平田啓一東京大学, 医学部・附属病院, 医員 (50199064)
キーワード	劇症肝炎 / 肝再生 / 血管内凝固 / マクロファ-ジ / オルニシン脱炭酸酵素 / 肝細胞膜 / 内皮細胞 / 培養肝細胞
研究概要	劇症肝炎の死亡率が高い理由の一つとして重症障害肝での肝再生不全状態を想定し、動物モデルで肝炎劇症化の機序を明らかにすると共に肝再生調節因子の検出系を確立する事によってこの肝再生不全因子を追求した。研究成果は以下のとうりである。 1.動物モデルにおける肝炎劇症化の機序肝類洞内フィブリン沈着が循環障害から広汎肝壊死を惹起する事、この肝血管内凝固は肝類洞壁内皮細胞の障害を伴う場合にのみ起こり、さらに、肝類洞壁内皮細胞障害は伊東細胞の障害や活性化された肝マクロファ-ジから放出される活性酸素やサイトカインによりもたらされることを複数のモデルで証明した。肝炎劇症化に関与しうると推定された。 2.肝再生調節因子検出系の確立ラットの部分切除肝を用いて肝再生調節因子の作用点をも含めて評価できる肝再生指標をpolyamine代謝に注目し検討したところ、肝再生に必須なputrescineの律速酵素であるornithine decarboxylaseの分子生物学的レベルでの解析とputrescine動態が有用である事が判明した。これを用いて幾つかの因子の作用点を知る事ができた。また、因子のスクリ-ニングや精製のための簡便法を確立することを試みたが、初代培養肝細胞に肝細胞膜添加を組合せることによりin vivoに類似した系が得られた。この際、肝細胞膜には肝細胞増殖抑制因子に加え増殖因子増強作用を有する因子が存在する事を見出した。膜蛋白と推定された。 3.劇症肝炎における肝再生不全因子の検討劇症肝炎モデルで肝障害の程度とDNA合成の関係から肝障害が重症な程肝再生が起こりにくいことが判明した。肝再生不全因子としては肝障害進展因子となる肝循環障害と肝細胞膜に存在する肝細胞増殖因子増強作用の低下が注目された。

研究成果

(21件)

すべてその他

すべて文献書誌 (21件)

[文献書誌] Fujiwara K.: "Reciprocal changes in serum albumin and alphaーfetoprotein levels in the recovery course of acute viral hepatitisーstimulated by glucagon and insulin therapy:Analysis of a double blidd controlled trial." Gastroenterol.Jpn.24. 143-148 (1989)
[文献書誌] Tomiya T.: "Plasma alpha2ーplasmin inhibitorーplasmin complex and FDPーDーDimer in fulminant hepatic failure." Thrombosis Res.53. 253-260 (1989)
[文献書誌] Tomiya T.: "Increased thrombin generation in fulminant hepatic failure evaluated by plasma thrombinーantithrombin III complex levels after treatment with antithrombin III." Biomed.Progr.3. 39-40 (1989)
[文献書誌] Hirata K.: "Hepatic sinusoidal cell destruction in the development of intravascular coagulation in acute liver failure of rats." J.Pathol.158. 157-165 (1989)
[文献書誌] Yamada S.: "Intravascular coagulation in the development of massive hepatic necrosis induced by Corynebacterium parvum and endotoxin in rats." Scand.J.Gastroenterol.24. 293-298 (1989)
[文献書誌] Mochida S.: "In situ evaluation of stimulatory state of hepatic macrophage based on ability to produce superoxide anions in rats." J.Pathol.158. 67-71 (1989)
[文献書誌] Sato Y.: "Additive stimulation of hepatic putrescine production by glucagon and insulin after partial hepatectomy in rats." Life Sci.41. 77-83 (1989)
[文献書誌] Fujiwara K.: "Activated Kupffer cells as a factor of massive hepatic necrosis after liver resection." HepatoーGastroenterology. 37. 194-197 (1990)
[文献書誌] Mochida S.: "Provocation of massive hepatic necrosis by endotoxin after partial hepatectomy in rats." Gastroenterology. 99. 771-777 (1990)
[文献書誌] Hirata K.: "Contribution of protein kinase C activation to priming for DNA synthesis induced by epidermal growth factor with insulin and its inhibition by plasma membrane in primary cultured rat hepatocytes." Biochem.Biophys.Res.Commun.171. 1093-1098 (1990)
[文献書誌] Fujiwara K.: "Insulin and glucagon therapy of acute hepatic failure." Dig.Dis.Sci.
[文献書誌] Ohno A.: "Ruffle formation in the evaluation of stimulatory state of hepatic macrophages in rats." Liver.
[文献書誌] Yamada S.: "Evidence for enhanced function of hepatic macrophages after longーterm ethanol feeding in rats." Liver.
[文献書誌] Mochida S.: "Method for in situ evaluation of pulmonary macrophages' ability to produce superoxide in the rat." Acta Pathol.Jpn.
[文献書誌] Mochida S.: "In situ detection of lipid peroxidation in hepatocytes." Gastroenterology.
[文献書誌] Mochida S.: "Gutーderived substances in activation of hepatic macrophages after partial hepatectomy in rats." J.Hepatol.
[文献書誌] Tomiya T.: "Ornithine decarboxvlase induction in partially hepatectomized rat liver and modes of its stimulation by glucagon and insulin." J.Biochem.
[文献書誌] Nagoshi S.: "Simulation of putrescine production by epidermal growth factor in rat liver after partial hepatectomy." Hepatology.
[文献書誌] Tomiya T.: "Significance of serum human hepatocyte growth factor levels in patients with hepatic failure." Hepatology.
[文献書誌] Hirata K.: "Rat liver plasma membrane has both stimulatory and inhibitory factors for DNA synthesis by primary cultured rat hepatocytes in the presence of epidermal growth factor and insulin" Biochem.Biophys.Res.Commun.
[文献書誌] Hirata K.: "Rat liver plasma membrane has both stimulatory and inhibitory factors for DNA synthesis by primary cultured rat hepatocytes in the presence of epidermal growth factor and insulin" Biochem.Biophys.Res.Commun.Fujiwara K.:

1990 年度 実績報告書

劇症肝炎における肝再生不全成立機序の解明

研究代表者

藤原 研司 東京大学, 医学部・附属病院, 講師 (80101088)

研究成果

[文献書誌] Fujiwara K.: "Reciprocal changes in serum albumin and alphaーfetoprotein levels in the recovery course of acute viral hepatitisーstimulated by glucagon and insulin therapy:Analysis of a double blidd controlled trial." Gastroenterol.Jpn.24. 143-148 (1989)

[文献書誌] Tomiya T.: "Plasma alpha2ーplasmin inhibitorーplasmin complex and FDPーDーDimer in fulminant hepatic failure." Thrombosis Res.53. 253-260 (1989)

[文献書誌] Tomiya T.: "Increased thrombin generation in fulminant hepatic failure evaluated by plasma thrombinーantithrombin III complex levels after treatment with antithrombin III." Biomed.Progr.3. 39-40 (1989)

[文献書誌] Hirata K.: "Hepatic sinusoidal cell destruction in the development of intravascular coagulation in acute liver failure of rats." J.Pathol.158. 157-165 (1989)

[文献書誌] Yamada S.: "Intravascular coagulation in the development of massive hepatic necrosis induced by Corynebacterium parvum and endotoxin in rats." Scand.J.Gastroenterol.24. 293-298 (1989)

[文献書誌] Mochida S.: "In situ evaluation of stimulatory state of hepatic macrophage based on ability to produce superoxide anions in rats." J.Pathol.158. 67-71 (1989)

[文献書誌] Sato Y.: "Additive stimulation of hepatic putrescine production by glucagon and insulin after partial hepatectomy in rats." Life Sci.41. 77-83 (1989)

[文献書誌] Fujiwara K.: "Activated Kupffer cells as a factor of massive hepatic necrosis after liver resection." HepatoーGastroenterology. 37. 194-197 (1990)

[文献書誌] Mochida S.: "Provocation of massive hepatic necrosis by endotoxin after partial hepatectomy in rats." Gastroenterology. 99. 771-777 (1990)

[文献書誌] Hirata K.: "Contribution of protein kinase C activation to priming for DNA synthesis induced by epidermal growth factor with insulin and its inhibition by plasma membrane in primary cultured rat hepatocytes." Biochem.Biophys.Res.Commun.171. 1093-1098 (1990)

[文献書誌] Fujiwara K.: "Insulin and glucagon therapy of acute hepatic failure." Dig.Dis.Sci.

[文献書誌] Ohno A.: "Ruffle formation in the evaluation of stimulatory state of hepatic macrophages in rats." Liver.

[文献書誌] Yamada S.: "Evidence for enhanced function of hepatic macrophages after longーterm ethanol feeding in rats." Liver.

[文献書誌] Mochida S.: "Method for in situ evaluation of pulmonary macrophages' ability to produce superoxide in the rat." Acta Pathol.Jpn.

[文献書誌] Mochida S.: "In situ detection of lipid peroxidation in hepatocytes." Gastroenterology.

[文献書誌] Mochida S.: "Gutーderived substances in activation of hepatic macrophages after partial hepatectomy in rats." J.Hepatol.

[文献書誌] Tomiya T.: "Ornithine decarboxvlase induction in partially hepatectomized rat liver and modes of its stimulation by glucagon and insulin." J.Biochem.

[文献書誌] Nagoshi S.: "Simulation of putrescine production by epidermal growth factor in rat liver after partial hepatectomy." Hepatology.

[文献書誌] Tomiya T.: "Significance of serum human hepatocyte growth factor levels in patients with hepatic failure." Hepatology.

[文献書誌] Hirata K.: "Rat liver plasma membrane has both stimulatory and inhibitory factors for DNA synthesis by primary cultured rat hepatocytes in the presence of epidermal growth factor and insulin" Biochem.Biophys.Res.Commun.

[文献書誌] Hirata K.: "Rat liver plasma membrane has both stimulatory and inhibitory factors for DNA synthesis by primary cultured rat hepatocytes in the presence of epidermal growth factor and insulin" Biochem.Biophys.Res.Commun.Fujiwara K.:

1990 年度実績報告書

藤原研司東京大学, 医学部・附属病院, 講師 (80101088)