Patho-pharmacological Study of the Femoral Head Avascular Necrosis of Spontaneously Hypertensive Rats -Especially in the Effect on Epithelium by Steroid Hormone at Onset

自发性高血压大鼠股骨头缺血性坏死的病理药理学研究——特别是发病时类固醇激素对上皮细胞的影响

• 批准号: 13671519
• 负责人: KUMAGAI Kenji
• 金额: $ 2.3万
• 依托单位: Nagasaki University Hospital
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13671519/
• 关键词: stroke-prone spontaneously hypertensive rats; Osteonecrosis of the femoral head; Endothelium; NOS inhibitor; Steroid horumone; Hyperlipemia; 自然発症高血圧ラット; SHRSP

Stroke-prone spontaneously hypertensive rats (SHRSP) are thought to be an animal model of osteonecrosis of the femoral head (ONFH). Studies for human ONFH and animal models have indicated that steroid hormone-induced hyperlipemia causing swollened adipocyts and endothelium dysfunctions is related to the etiology of this necrosis. Human ONFH, complicated by a high dose of steroid hormone-therapy, is a major side effect of organ transplantation. Our previous studies revealed that ONFH was observed in SHRSP at 15 to 20 weeks of age, and chronic ingestion of an NOS inhibitor inhibited the onset of the disease. To clarify the participation of hyperlipemia as an etiological factor in the disease, we examined the onset of ONFH in a new animal model of SHRSP fed a high fat and high cholesterol diet (HFC) containing N^G-nitro-L-arginine (L-NNA), as an NOS inhibitor. SHRSP with an administration of steroid hormone was used for the purpose of comparison.Male SHRSP/Nagasaki, maintained and bred at … More the Laboratory Animal Center for Biomedical Research, Nagasaki University School of Medicine were used. At 15 weeks of age, rats were put at random into groups of 30, 25 and 24. The first group of 30 rats were fed the HFC diet containing L-NNA in a dose of 0.006% (HFC-NNA group). The second group of 25 was fed the SP diet (Funabashi Farm Co., Chiba, Japan), and at 17 weeks of age, 5 or 10 mg of methylpredonisolone was subcuatneously injected into the second group of rats (Steroid group). The third group of 24 rats, given the SP diet with no drug, served as controls. The rats were decapitated at 19 weeks of age.The incidence of ONFH in the Steroid group was 50%, but it was lower in the HFC-NNA group and the control SHRSP. Numerous adipocytes in the metaphysial bone marrow of the HFC-NNA group and the Steroid group was observed microscopically. In the Steroid group, we noted the epiphysial bone marrow was filled with massive swollen adipocytes. In addition, there was a migration of swollen fatty cells into the necrotic area in the epiphysial bone marrow of the Steroid group. 94.0% of this group also demonstrated osteonecrosis and/or swollen adipocytes.Epidemiological investigations for human ONFH has suggested that steroid hormone and alcohol intake are etiological factors related to the avascular necrosis of femoral head. We observed here the highest incidence of ONFH in the Steroid group. A hyperlipemia-induced increase in the number and invasion to necrotic areas of adipocytes seems to be an etiological factor, however, a lower incidense was observed in the HFC-NNA group with hypercholesterolemia. We admit that other mechanisms may be operative in the experimental model of femoral head avascular necrosis. Less

卒中易发自发性高血压大鼠（SHRSP）被认为是股骨头骨坏死（ONFH）的动物模型。对人类ONFH和动物模型的研究表明，类固醇激素诱导的高脂血症引起的脂肪细胞肿胀和内皮细胞功能障碍与这种坏死的病因有关。人类ONFH，伴随高剂量类固醇激素治疗，是器官移植的主要副作用。我们之前的研究显示，在15至20周龄的SHRSP中观察到ONFH，慢性摄入NOS抑制剂可以抑制疾病的发作。为了阐明高脂血症作为该疾病的一个病因因素的参与，我们在一种新的SHRSP动物模型中研究了ONFH的发病情况，该动物模型喂食含有N^ g -硝基- l -精氨酸（L-NNA）作为NOS抑制剂的高脂肪高胆固醇饮食（HFC）。SHRSP与类固醇激素的管理是为了进行比较。雄性SHRSP/长崎，在长崎大学医学院生物医学研究实验动物中心饲养和繁殖。15周龄时，将大鼠随机分为30、25、24组。第一组30只大鼠饲喂含L-NNA剂量为0.006%的HFC饲料（HFC- nna组）。第二组25只，饲喂日本千叶船桥农场公司SP日粮，17周龄时皮下注射甲基强的松龙5、10 mg（类固醇组）。第三组24只大鼠，给予不含药物的SP饮食作为对照。这些大鼠在19周龄时被斩首。类固醇组ONFH发生率为50%，HFC-NNA组和对照SHRSP组发生率较低。显微镜下观察到HFC-NNA组和类固醇组骨髓骺端有大量脂肪细胞。在类固醇组，我们注意到骨髓上皮充满了大量肿胀的脂肪细胞。此外，类固醇组肿胀的脂肪细胞迁移到骨髓骺端坏死区域。94.0%的患者还表现为骨坏死和/或脂肪细胞肿胀。人类ONFH的流行病学调查表明，类固醇激素和酒精摄入是与股骨头缺血性坏死相关的病因。我们观察到类固醇组的ONFH发生率最高。高脂血症诱导的脂肪细胞数量的增加和对坏死区域的侵袭似乎是一个病因，然而，在高胆固醇血症的HFC-NNA组中观察到的发病率较低。我们承认在股骨头缺血性坏死的实验模型中可能存在其他机制。少

项目成果

Kenji Kumagai, Masahiro Wada, Masami Niwa et al.: "Osteonecrosis of the Femoral Head in Spontaneously Hypertensive Rat (SHR) Strains"Clinical and Experimental Hypertention. 23・5. 408 (2001)

Kenji Kumagai、Masahiro Wada、Masami Niwa 等：“自发性高血压大鼠 (SHR) 株的股骨头坏死”临床和实验性高血压 23・5。

Kis B, Niwa M, et al.: "Cerebral endothelial cells are a major source of adrenomedullin"J Neuroendocrinol.. 14・4. 283-293 (2002)

Kis B、Niwa M 等：“脑内皮细胞是肾上腺髓质素的主要来源”J Neuroendocrinol.. 14・4 (2002)。

熊谷 謙治, 丹羽 正美: "SHR大腿骨頭壊死モデルに於けるNOS inhibitorの影響"厚生労働省特定疾患対策研究事業 骨・関節系調査研究班 特発性大腿骨頭壊死症調査研究分科会 平成13年度研究報告書. 76-79 (2001)

Kenji Kumagai、Masami Niwa：“NOS抑制剂对SHR股骨头坏死模型的影响”厚生劳动省，特定疾病控制研究项目，骨和关节系统研究组，特发性股骨头坏死研究小组，2001年研究报告.76-79 (2001)

Kenji Kumagai, Masami Niwa, et al.: "Osteonecrosis of Femoral Head in the Stroke Prone Spontaneously Hypertensive Rats"Clinical and Experimental Hypertention. 24・5. 477-478 (2002)

Kenji Kumagai、Masami Niwa 等：“易发生中风的自发性高血压大鼠的股骨头坏死”《临床和实验高血压》24・5。

Abraham CS, Harada N, Deli MA, Niwa M.: "Transient forebrain ischemia increases the blood-brain barrier permeability for albumin in stroke-prone spontaneously hypertensive rats"Cell Mol Neurobiol.. 22・4. 455-462 (2002)

Abraham CS、Harada N、Deli MA、Niwa M.：“短暂的前脑缺血增加了易发生中风的自发性高血压大鼠的血脑屏障对白蛋白的渗透性”Cell Mol Neurobiol.. 22・4（2002）。