The impact of antisense NF-kappaB on monocrotaline-induced pulmonary hypertension in pneumonectomized mice

反义NF-κB对野百合碱诱导的肺切除小鼠肺动脉高压的影响

• 批准号: 13671617
• 负责人: UEZONO Shoichi
• 金额: $ 1.98万
• 依托单位: Tokyo Women's Medical University
• 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-13671617/
• 关键词: pulmonary hypertension; monocrotaline; MF-KB; rat; mouse; pneumonectomy; antisense; アンチセンス

The purpose of this project is to develop an animal model to produce certain pathological changes that resemble those seen in humans with primary pulmonary hypertension. Initially, this study was targeted for mice ; however, monocrotaline was found to have little effects on pulmonary vasculature. Therefore, monocrotaline was administered in pneumonectomized rats to induce proliferations of pulmonary vascular endothelial cells, which successfully lead to pulmonary arterial hypertension and pulmonary arterial neointimal formation. We then characterized physiological and pathological findings in this newly developed pulmonary hypertension model. Of note, mean pulmonary pressure rose to over 40 mmHg over three weeks following monocrotaline administration, which was markedly enhanced by nearly two-fold compared to when monocrotaline was administered alone. Using this model, rats with pulmonary hypertension were treated with antisense oligonucleotide NF-kappaB. Due to poor absorption into pulmonary vasculature when nucleotides were given intraperitoneally, this antisense failed to attenuate the development of pulmonary hypertension. Transtracheal injection of these antisense oligonucleotides is currently under investigation to maximize its therapeutic effects on pulmonary hypertension.

该项目的目的是开发一种动物模型，以产生类似于人类原发性肺动脉高压的某些病理变化。最初，这项研究的目标是小鼠;然而，野百合碱被发现对肺血管系统的影响很小。因此，野百合碱给药在肺切除大鼠诱导肺血管内皮细胞增殖，这成功地导致肺动脉高压和肺动脉新生内膜形成。然后，我们在这个新开发的肺动脉高压模型的生理和病理结果的特点。值得注意的是，单百合碱给药后三周平均肺压上升至40 mmHg以上，与单百合碱单独给药相比，肺压明显增加近两倍。利用该模型，用反义寡核苷酸NF-κ B治疗肺动脉高压大鼠。由于当腹腔内给予核苷酸时肺血管吸收不良，该反义核酸未能减弱肺动脉高压的发展。目前正在研究经气管注射这些反义寡核苷酸以最大化其对肺动脉高压的治疗效果。

项目成果

Makiko Komori: "Urinary trypsin inhibitor improves microcirculation bronchospasm, and survival during systemic anaphylaxis in rabbits"Anesthesiology. 96. A414 (2002)

Makiko Komori：“尿胰蛋白酶抑制剂可改善微循环支气管痉挛，并提高兔子全身过敏反应期间的生存率”麻醉学。

Makiko Komori: "Urinary trypsin inhibitor improves microcirculation and bronchospasm associated with systemic anaphylaxis in rabbits in vivo"Shock. (発売予定).

小森真纪子：“尿胰蛋白酶抑制剂可改善与体内兔子全身性过敏反应相关的微循环和支气管痉挛”休克（待发布）。

Makiko Komori: "Urinary trypsin inhibitor improves microcirculation, bronchospasm, and survival during systemic anaphylaxis in rabbits"Anesthesiology. 96. A414 (2002)

Makiko Komori：“尿胰蛋白酶抑制剂可改善兔子全身过敏反应期间的微循环、支气管痉挛和存活率”麻醉学。

Makiko Komori: "Urinary trypsin inhibitor improves microcirculation and bronchospasm associated with systemic anaphylaxis in rabbits in vivo"Shock. (発表予定).

Makiko Komori：“尿胰蛋白酶抑制剂可改善与体内兔子全身过敏反应相关的微循环和支气管痉挛”休克（待提交）。

Makiko Komori: "Urinary trypsin inhibitor improves microcirculation and bronchospasm associated with systemic anaphylaxis in rabbits in vivo"Shock. (in press).

小森真纪子：“尿胰蛋白酶抑制剂可改善与兔子体内全身性过敏反应相关的微循环和支气管痉挛”休克。