胆汁性肝硬化大鼠肺组织中ET-1、PGI_2含量及ET-1、COXs蛋白表达的研究
|
摘要
目 的 : 肝 硬 化 终 末 期 患 者 可 并 发 肝 肺 综 合 征
（hepatopulmonary syndrome,HPS），HPS 预后不良。肺内血
管扩张（intrapulmonary vascular dilatation, IPVD）是其特征
性病理改变，循环中或局部扩张/收缩血管物质失衡是 IPVD
发生的原因之一。本课题采用胆总管结扎（common bile duct
ligation, CBDL）制备胆汁性肝硬化模型，检测肝硬化大鼠肺
组织中内皮素-1（endothelin-1，ET-1）、前列环素（prostacyclin，
PGI2）含量及 ET-1、环氧合酶-1（cyclooxygenase-1，COX-1）、
环氧合酶-2（COX-2）蛋白表达水平，并同时检测血浆中ET-1、
PGI2 含量及肝组织 ET-1、COX-1、COX-2 蛋白表达水平作
对比，以探索它们在 IPVD 发生中的作用，并对它们之间的
关系作初步分析。
方法：雄性 SD 大鼠，体重 200-250 克，随机分为 2 组：
实验组、假手术（sham）组。实验组采用 CBDL 制备胆汁性
肝硬化模型，实验组再设 3 个时相组：1wk CBDL 组、2wk
CBDL 组、4wk CBDL 组，分别在手术后 1 周末、2 周末、4
周末活杀取材。sham 组大鼠仅分离出胆总管，不作结扎和剪
断，手术后 4 周末活杀取材。术后第 4 周末模型组大鼠肝组
织病理切片证实有肝硬化存在。各组大鼠麻醉后右心室穿刺
取血，混入抗凝剂后，分离血浆，-20℃保存；取右下肺组织，
制成匀浆，离心后取上清液，-20℃保存。放免法（RIA）同
1
中 文 摘 要
时测定血浆及肺组织ET-1与PGI2的稳定代谢产物6-酮-前列
腺素 F1 （6-keto-PGF1 ）的含量。取大鼠肝脏同一部分、左
α α
肺下叶，用 10％中性福尔马林固定 48 小时，石蜡包埋。肝
组织切片采用常规 HE 染色、Masson 三色染色，肺组织切片
行常规 HE 染色，光镜下观察其病理变化。各组大鼠肝、肺
组织切片行免疫组化 SP 法检测 ET-1、COX-1、COX-2 蛋白
表达水平，病理图象分析系统处理切片染色结果。
结果：1.肝组织病理学表现：大鼠胆总管结扎 1 周末 ，
肝细胞散在变性、坏死，汇管区小胆管增生。2 周末肝细胞
灶状、片状变性、坏死，增生向肝小叶内扩展。4 周末，肝
细胞多萎缩消失，肝小叶中央静脉和肝窦周围出现胶原纤维
沉积，纤维间隔形成，肝小叶结构紊乱。2.肺组织病理学表
现：光镜下所有大鼠肺间质无水肿，肺泡细胞无变性坏死，
肺泡壁无破坏，肺泡形态正常。只有 4wk CBDL 组大鼠肺泡
毛细血管扩张，肺泡间隔增宽。3.血浆和肺组织 ET-1、
6-keto-PGF1 含量：sham 组、1wk CBDL 组、2wk 组、4wk
α
组血浆 ET-1 含量（pg/ml）分别为 119.50±11.69、179±12.67、
259.36±18.91、334.08±33.34，差异有显著性（F=370.79, P
＜0.001），两两比较显示，各时相组均明显高于 sham 组（P
﹤0.05），各时相组之间差异有显著性（P﹤0.05）；血浆
6-K-PGF1α含量（pg/ml）分别为 605.77±29.58、1122.66±
85.89、1686.34±30.09、1686.34±30.09，差异有显著性
（F=631.22, P＜0.001)，各时相组均明显高于 sham 组（P﹤
0.05），各时相组之间差异有显著性（P﹤0.05）；肺组织 ET-1
含量(ng/g)分别为 2.75±0.32、2.99±0.37、2.99±0.51、3.28
±0.49，差异无显著性（F=4.66，P＞0.05）；肺组织
2
中 文 摘 要
6-keto-PGF1 含量（ng/g）分别为 38.78±1.71、42.41±1.62、
α
44.31±1.29、46.41±0.53，差异有显著性 (F=96.86, P﹤
0.001)，各时相组均明显高于 sham 组（P＜0.05)，各时相组
之间差异有显著性（P＜0.05)。4.肺组织 ET-1、COX-1、COX-2
蛋白免疫组化染色：ET-1 蛋白阳性染色位于胞浆内，在 sham
组主要分布于支气管上皮细胞、肺泡动脉内皮细胞、肺泡毛
细血管内皮细胞、肺泡上皮细胞，在实验组上述部位均有表
达；COX-1 蛋白阳性染色位于细胞浆内，在 sham 组主要分
布于支气管上皮细胞、肺门大静脉平滑肌细胞，实验组表达
部位与 sham 组相同；COX-2 蛋白阳性染色位于核膜上，在
sham 组主要分布于支气管周围、血管周围的巨噬细胞，实验
组分布于支气管上皮细胞、肺泡上皮细胞、肺巨噬细胞、血
管内皮细胞。5.肺组织 ET-1、COX-1、COX-2 蛋白表达水平：
sham 组、1wk CBDL 组、2wk 组、4wk 组肺组织 ET-1 蛋白
表达水平（阳性面积% 下同）分别为 10.51±5.70、11.68
±7.54、8.98±4.03、13.37±8.83，差异无显著性（F=0.23, P
＞0.05）；COX-1 蛋白表达水平分别为 20.48±12.81、22.65
±13.36、22.93±11.19、22.41±14.41，差异无显著性（F=0.073,
P＞0.05）；COX-2 蛋白表达水平分别为 6.01±3.03、22.82±
14.89、40.08±14.74、65.86±15.83，差异有显著性（F=70.31,
P＜0.001)。各时相组均明显高于 sham 组（P﹤0.05），各时
相组之间差异有显著性（P﹤0.05）。6.肝组织 ET-1、COX-1、
COX-2 蛋白免疫组化染色：ET-1 蛋白阳性染色位于胞浆内，
在 sham 组主要分布在中央静脉及中央静脉周围的肝细胞胞
浆内，周边逐渐减弱，在实验组上述区域也有染色
Objective:Hepatopulmonary syndrome(HPS) may occur in
some patients with liver cirrhosis.HPS is characterized by
intrapulmonary vascular dilatation(IPVD). Using a rat model of
liver cirrhosis induced by common bile duct ligation(CBDL),we
examined plasma and lung levels of ET-1,PGI2,evaluated
expression of ET-1, cyclooxygenase-1，cyclooxygenase-2 in
lung .
Methods:A total of 24 male Sprague-Dawley rats
weighing 200-250g were randomly divided into 4 grops of 6
each:sham CBDL,1wkCBDL,2wkCBDL,4wkCBDL.Surgery for
common bile duct ligation was carried in 18 rats to induce liver
cirrhosis under sterile conditions.The common bile bile duct was
gently exposed and doubly ligated with silk threads,and excised
completely between the two ties.A sham operation was
performed in 6 rats in a similar manner to that for
CBDL ,involving mobilization of the common bile duct but no
ligation and excision.Histological analysis conforms biliary
cirrhosis by 4 wk after ligation.A blood sample of 6ml was
drawn from the right ventricle, plasma was separated from
blood samples,and was stored at -20℃ until analysis.The right
6
英 文 摘 要
lung was quickly removed , and homogenated with glass
homogenizer. The lung homogenate was centrifugated,and was
stored at -20℃ until analysis.Plasma and lung homogenate
ET-1 and 6-keto-PGF1 concentrations were measured by
α
RIA.Livers and lungs were fixed with 10％ buffered Formalin
for 48h.Small pieces of lung and liver were paraffin embedded.
Paraffin sections 5μm thick serially mounted onto
slides.Hematoxylin and eosin staining was performed on tissue
sections from 18 CBDL rats to assess histological changes to the
lung and liver. Expression of ET-1,COX-1,COX-2 were
examined by immunhistochemistry.
Results:1.Hepatic histological examination: The
macroscopic apprearance of the liver showed the features of
biliary cirrhosis by 4wk after ligation.2. Pulmonary histological
examination:All rats have no inflammation or architectural
distortion,except 4wk CBDL rats have the alveolus capillary
dilatation.3.Plasma and lung homogenate ET-1 and
6-keto-PGF1 concentrations:
α Levels of plasma ET-1
concentrations(pg/ml) from sham,1wk CBDL, 2wk CBDL, 4wk
CBDL rats were 119.50±11.69、179±12.67、259.36±18.91、
334.08±33.34 and significantly increased step by step. Levels
of plasma 6-keto-PGF1 concentrations(pg/ml) from sham,1wk
α
CBDL, 2wk CBDL, 4wk CBDL rats were 605.77±29.58、
1122.66 ± 85.89 、 1686.34 ± 30.09 、 1686.34 ± 30.09 and
significantly increased step by step. Lung homogenate ET-1
levels（ng/g） from sham,1wk CBDL, 2wk CBDL, 4wk CBDL
7
英 文 摘 要
rats were 2.75±0.32、2.99±0.37、2.99±0.51、3.28±0.49 and
there was no significant increase from CBDL rats relative to
sham values. Lung homogenate 6-keto-PGF1 levels（ng/g）from
α
sham,1wk CBDL, 2wk CBDL, 4wk CBDL rats were 38.78±
1.71、42.41±1.62、44.31±1.29、46.41±0.53 and significantly
increased step by step. 4. Lung ET-1 positive staining was
observed in cytosol.In sham CBDL rats they were mainly
located in bronchiolar epithelium,vascular endothelium,alveolar
cell.In CBDL rats they were observed in the same areas. COX-1
positive staining was observed in cytosol. In sham CBDL rats
they were mainly located in the media of large pulmonary veins
and the bronchial epithelium. In CBDL rats they were observed
in the same areas. COX-2 positive staining was observed in
nucleus. In sham CBDL rats they were mainly located in
macropages around the bronchs and vessels. In CBDL rats they
were observed in alveolar macropages and alveolar
capillaries.5.Express of ET-1 protein(positive areas%) in
sham,1wk CBDL, 2wk CBDL, 4wk CBDL rats were 10.51±
5.70、11.68±7.54、8.98±4.03、13.37±8.83 and there was no
significa
（hepatopulmonary syndrome,HPS），HPS 预后不良。肺内血
管扩张（intrapulmonary vascular dilatation, IPVD）是其特征
性病理改变，循环中或局部扩张/收缩血管物质失衡是 IPVD
发生的原因之一。本课题采用胆总管结扎（common bile duct
ligation, CBDL）制备胆汁性肝硬化模型，检测肝硬化大鼠肺
组织中内皮素-1（endothelin-1，ET-1）、前列环素（prostacyclin，
PGI2）含量及 ET-1、环氧合酶-1（cyclooxygenase-1，COX-1）、
环氧合酶-2（COX-2）蛋白表达水平，并同时检测血浆中ET-1、
PGI2 含量及肝组织 ET-1、COX-1、COX-2 蛋白表达水平作
对比，以探索它们在 IPVD 发生中的作用，并对它们之间的
关系作初步分析。
方法：雄性 SD 大鼠，体重 200-250 克，随机分为 2 组：
实验组、假手术（sham）组。实验组采用 CBDL 制备胆汁性
肝硬化模型，实验组再设 3 个时相组：1wk CBDL 组、2wk
CBDL 组、4wk CBDL 组，分别在手术后 1 周末、2 周末、4
周末活杀取材。sham 组大鼠仅分离出胆总管，不作结扎和剪
断，手术后 4 周末活杀取材。术后第 4 周末模型组大鼠肝组
织病理切片证实有肝硬化存在。各组大鼠麻醉后右心室穿刺
取血，混入抗凝剂后，分离血浆，-20℃保存；取右下肺组织，
制成匀浆，离心后取上清液，-20℃保存。放免法（RIA）同
1
中 文 摘 要
时测定血浆及肺组织ET-1与PGI2的稳定代谢产物6-酮-前列
腺素 F1 （6-keto-PGF1 ）的含量。取大鼠肝脏同一部分、左
α α
肺下叶，用 10％中性福尔马林固定 48 小时，石蜡包埋。肝
组织切片采用常规 HE 染色、Masson 三色染色，肺组织切片
行常规 HE 染色，光镜下观察其病理变化。各组大鼠肝、肺
组织切片行免疫组化 SP 法检测 ET-1、COX-1、COX-2 蛋白
表达水平，病理图象分析系统处理切片染色结果。
结果：1.肝组织病理学表现：大鼠胆总管结扎 1 周末 ，
肝细胞散在变性、坏死，汇管区小胆管增生。2 周末肝细胞
灶状、片状变性、坏死，增生向肝小叶内扩展。4 周末，肝
细胞多萎缩消失，肝小叶中央静脉和肝窦周围出现胶原纤维
沉积，纤维间隔形成，肝小叶结构紊乱。2.肺组织病理学表
现：光镜下所有大鼠肺间质无水肿，肺泡细胞无变性坏死，
肺泡壁无破坏，肺泡形态正常。只有 4wk CBDL 组大鼠肺泡
毛细血管扩张，肺泡间隔增宽。3.血浆和肺组织 ET-1、
6-keto-PGF1 含量：sham 组、1wk CBDL 组、2wk 组、4wk
α
组血浆 ET-1 含量（pg/ml）分别为 119.50±11.69、179±12.67、
259.36±18.91、334.08±33.34，差异有显著性（F=370.79, P
＜0.001），两两比较显示，各时相组均明显高于 sham 组（P
﹤0.05），各时相组之间差异有显著性（P﹤0.05）；血浆
6-K-PGF1α含量（pg/ml）分别为 605.77±29.58、1122.66±
85.89、1686.34±30.09、1686.34±30.09，差异有显著性
（F=631.22, P＜0.001)，各时相组均明显高于 sham 组（P﹤
0.05），各时相组之间差异有显著性（P﹤0.05）；肺组织 ET-1
含量(ng/g)分别为 2.75±0.32、2.99±0.37、2.99±0.51、3.28
±0.49，差异无显著性（F=4.66，P＞0.05）；肺组织
2
中 文 摘 要
6-keto-PGF1 含量（ng/g）分别为 38.78±1.71、42.41±1.62、
α
44.31±1.29、46.41±0.53，差异有显著性 (F=96.86, P﹤
0.001)，各时相组均明显高于 sham 组（P＜0.05)，各时相组
之间差异有显著性（P＜0.05)。4.肺组织 ET-1、COX-1、COX-2
蛋白免疫组化染色：ET-1 蛋白阳性染色位于胞浆内，在 sham
组主要分布于支气管上皮细胞、肺泡动脉内皮细胞、肺泡毛
细血管内皮细胞、肺泡上皮细胞，在实验组上述部位均有表
达；COX-1 蛋白阳性染色位于细胞浆内，在 sham 组主要分
布于支气管上皮细胞、肺门大静脉平滑肌细胞，实验组表达
部位与 sham 组相同；COX-2 蛋白阳性染色位于核膜上，在
sham 组主要分布于支气管周围、血管周围的巨噬细胞，实验
组分布于支气管上皮细胞、肺泡上皮细胞、肺巨噬细胞、血
管内皮细胞。5.肺组织 ET-1、COX-1、COX-2 蛋白表达水平：
sham 组、1wk CBDL 组、2wk 组、4wk 组肺组织 ET-1 蛋白
表达水平（阳性面积% 下同）分别为 10.51±5.70、11.68
±7.54、8.98±4.03、13.37±8.83，差异无显著性（F=0.23, P
＞0.05）；COX-1 蛋白表达水平分别为 20.48±12.81、22.65
±13.36、22.93±11.19、22.41±14.41，差异无显著性（F=0.073,
P＞0.05）；COX-2 蛋白表达水平分别为 6.01±3.03、22.82±
14.89、40.08±14.74、65.86±15.83，差异有显著性（F=70.31,
P＜0.001)。各时相组均明显高于 sham 组（P﹤0.05），各时
相组之间差异有显著性（P﹤0.05）。6.肝组织 ET-1、COX-1、
COX-2 蛋白免疫组化染色：ET-1 蛋白阳性染色位于胞浆内，
在 sham 组主要分布在中央静脉及中央静脉周围的肝细胞胞
浆内，周边逐渐减弱，在实验组上述区域也有染色
Objective:Hepatopulmonary syndrome(HPS) may occur in
some patients with liver cirrhosis.HPS is characterized by
intrapulmonary vascular dilatation(IPVD). Using a rat model of
liver cirrhosis induced by common bile duct ligation(CBDL),we
examined plasma and lung levels of ET-1,PGI2,evaluated
expression of ET-1, cyclooxygenase-1，cyclooxygenase-2 in
lung .
Methods:A total of 24 male Sprague-Dawley rats
weighing 200-250g were randomly divided into 4 grops of 6
each:sham CBDL,1wkCBDL,2wkCBDL,4wkCBDL.Surgery for
common bile duct ligation was carried in 18 rats to induce liver
cirrhosis under sterile conditions.The common bile bile duct was
gently exposed and doubly ligated with silk threads,and excised
completely between the two ties.A sham operation was
performed in 6 rats in a similar manner to that for
CBDL ,involving mobilization of the common bile duct but no
ligation and excision.Histological analysis conforms biliary
cirrhosis by 4 wk after ligation.A blood sample of 6ml was
drawn from the right ventricle, plasma was separated from
blood samples,and was stored at -20℃ until analysis.The right
6
英 文 摘 要
lung was quickly removed , and homogenated with glass
homogenizer. The lung homogenate was centrifugated,and was
stored at -20℃ until analysis.Plasma and lung homogenate
ET-1 and 6-keto-PGF1 concentrations were measured by
α
RIA.Livers and lungs were fixed with 10％ buffered Formalin
for 48h.Small pieces of lung and liver were paraffin embedded.
Paraffin sections 5μm thick serially mounted onto
slides.Hematoxylin and eosin staining was performed on tissue
sections from 18 CBDL rats to assess histological changes to the
lung and liver. Expression of ET-1,COX-1,COX-2 were
examined by immunhistochemistry.
Results:1.Hepatic histological examination: The
macroscopic apprearance of the liver showed the features of
biliary cirrhosis by 4wk after ligation.2. Pulmonary histological
examination:All rats have no inflammation or architectural
distortion,except 4wk CBDL rats have the alveolus capillary
dilatation.3.Plasma and lung homogenate ET-1 and
6-keto-PGF1 concentrations:
α Levels of plasma ET-1
concentrations(pg/ml) from sham,1wk CBDL, 2wk CBDL, 4wk
CBDL rats were 119.50±11.69、179±12.67、259.36±18.91、
334.08±33.34 and significantly increased step by step. Levels
of plasma 6-keto-PGF1 concentrations(pg/ml) from sham,1wk
α
CBDL, 2wk CBDL, 4wk CBDL rats were 605.77±29.58、
1122.66 ± 85.89 、 1686.34 ± 30.09 、 1686.34 ± 30.09 and
significantly increased step by step. Lung homogenate ET-1
levels（ng/g） from sham,1wk CBDL, 2wk CBDL, 4wk CBDL
7
英 文 摘 要
rats were 2.75±0.32、2.99±0.37、2.99±0.51、3.28±0.49 and
there was no significant increase from CBDL rats relative to
sham values. Lung homogenate 6-keto-PGF1 levels（ng/g）from
α
sham,1wk CBDL, 2wk CBDL, 4wk CBDL rats were 38.78±
1.71、42.41±1.62、44.31±1.29、46.41±0.53 and significantly
increased step by step. 4. Lung ET-1 positive staining was
observed in cytosol.In sham CBDL rats they were mainly
located in bronchiolar epithelium,vascular endothelium,alveolar
cell.In CBDL rats they were observed in the same areas. COX-1
positive staining was observed in cytosol. In sham CBDL rats
they were mainly located in the media of large pulmonary veins
and the bronchial epithelium. In CBDL rats they were observed
in the same areas. COX-2 positive staining was observed in
nucleus. In sham CBDL rats they were mainly located in
macropages around the bronchs and vessels. In CBDL rats they
were observed in alveolar macropages and alveolar
capillaries.5.Express of ET-1 protein(positive areas%) in
sham,1wk CBDL, 2wk CBDL, 4wk CBDL rats were 10.51±
5.70、11.68±7.54、8.98±4.03、13.37±8.83 and there was no
significa
引文
1 Luo B, Abrams GA, Fallon MB.Endothelin-1 in the rat
bile duct ligation model of hepatopulmonary
syndrome:Correlation with pulmonary dysfunction. J
Hepatol,1998,29:571～578
2 Fallon MB, Abrams GA, Mcgrath JW. Common bile
duct ligation in the rat: a model of intrapulmonary
vasodilatation and hepatopulmonary syndrome.Am J
Physiol,1997, 272: G779～G784
3 病毒性肝炎防治方案（试行）.中华传染病学杂志，1995，
13（4）：241
4 Krowka MJ, Cortese DA. Hepatopulmonary syndrome.
Current comcepts in diagnostic and therapeutic
considerations.Chest, 1994,105:1528～1537
5 Rodriguez-Roisin R, Agusti AG, Roca J. The
hepatopulmonary syndrome: new name, old
complexities.Thorax, 1992,47: 897～902
6 Rydell R, Hoffbauer FW.Multiple pulmonary arteriovenous
fistulas in juvenile cirrhosis. Am J Med ,1956,21:450～459
7 Fallon MB, Abrams GA, Mcgrath JW. Common bile
duct ligation in the rat: a model of intrapulmonary
vasodilatation and hepatopulmonary syndrome.Am J
Physiol,1997, 272: G779～G784
8 Schraufnagel DE, Malik R, Goel V. Lung capillary changes
46
研 究 论 文
in hepatic cirrhosis in rats.Am J Physiol,
1997,272:L139～L147
9 Fallon MB,Abrams GA.Pulmonary dysfunction in chronic
liver disease.Hepatlolgy, 2000,32:859～895
10 Nayler WG,et al.Endothelin : Isoforms, binding sits and
possible implications in pathology.Trends Pharm
Sci,1990,11:69～99
11 Zhang XJ,Katsumi Y,Akimoto T,et al.Intrapulmonary
vascular dilatation and nitric oxide in hypoxemic rats with
chronic bile duct ligation. J Hepatol,2003,39:724～730
12 Liu L,Zhang M, Fallon MB. Hepatology,2001,33(3):722
～727
13 Lumsden AB,Henderson JM, KutnerMH, etal. Endotoxin
levels measured by a chromogenic assay in portal,
hepatic,and peripheral blood in patients with cirrhosis.
Hepatology,1988,8:232～236
14 Hartleb M, Moreau R, Cailmail S, et al Vascular hyporespo
nsiveness to endothelin 1 in rats with cirrhosis.
Gastroenterology, 1994,107(4):1085～1093
15 Highsmith RF, Blackbum K, Schmidt DJ. Endothelin and
calcium dynamics in vascular smooth muscle. Annu Rev
Physiol,1992,54(2):257～277
16 陈美,梁统,周克元.环氧合酶 2 研究的新进展.国外医
学·生理、病理科学与临床分册,2003,23(5):528～531
17 Hamalton G,PhingRCF,Hutton RA.The relationship
between prostacyclinactieity and pressureint
47
研 究 论 文
heportalvein.Hepatology,
1982,12:236～243
18 Sitzmann JV,Campbeiik,Wu YP,et al.prostacylin production
in acute,chronic, and long term experimental portal
hypertension.Surgery, 1994,115:290 294.
19 Hou MC, Cahill PA, Zhang S. Enhanced cyclooxygenase-1
expression within the superior mesenteric artery of portal
hypertensive rats: role in the hyperdynamic circulation.
Hepatology 1998;27:20～27
20 Tsugawa K,Hashizume M, Migou S, et al. A selective
cyclooxygenase-2 inhibitor,NS-398, may improve portal
hypertention without inducing gastric mucosal injury. J
Gastroenterol Hepatol, 1999,14:642-651
21 刘玉军.前列环素与临床.天津科学技术出版社，1987，45
22 Walenga RW,Kester M,Coroneos E, et al. Constitutive
expression of prostagl and in endoperoxideG/Hsynthetase
(PGHS)-2 but not PGHS-1 in human tracheal epithelial
cell sinvitrol.Prostaglandins,1996,52(5):341～359
23 AsanoK, LillyCM,Drazen JM.ProstaglandinG/H synthase-2
is the constitutive and dominant is forming cultured human
lung epithelial cells.AmJPhysiol,1996,271(1):126～131
24 Chen D, Balyakina EV, Lawrence M, Christman BW,
Meyrick BC.yclooxygenase is regulated by ET-1 and
MAPKs in peripheral lung microvascular smooth muscle
cells. Am J Physiol Lung Cell Mol Physiol,2003,
284(4):L614-621
48
研 究 论 文
25 张继锋,李辉,田青,等.前列环素对内皮素生理效应的拮抗
作用.中国病理生理杂志,1994,10(4):339
26 MasakiT,etal. Molecular and cellular mechanism of
endothelin regulation-implication for vascular
function.Circulation,1991,84:1457～1459
bile duct ligation model of hepatopulmonary
syndrome:Correlation with pulmonary dysfunction. J
Hepatol,1998,29:571～578
2 Fallon MB, Abrams GA, Mcgrath JW. Common bile
duct ligation in the rat: a model of intrapulmonary
vasodilatation and hepatopulmonary syndrome.Am J
Physiol,1997, 272: G779～G784
3 病毒性肝炎防治方案（试行）.中华传染病学杂志，1995，
13（4）：241
4 Krowka MJ, Cortese DA. Hepatopulmonary syndrome.
Current comcepts in diagnostic and therapeutic
considerations.Chest, 1994,105:1528～1537
5 Rodriguez-Roisin R, Agusti AG, Roca J. The
hepatopulmonary syndrome: new name, old
complexities.Thorax, 1992,47: 897～902
6 Rydell R, Hoffbauer FW.Multiple pulmonary arteriovenous
fistulas in juvenile cirrhosis. Am J Med ,1956,21:450～459
7 Fallon MB, Abrams GA, Mcgrath JW. Common bile
duct ligation in the rat: a model of intrapulmonary
vasodilatation and hepatopulmonary syndrome.Am J
Physiol,1997, 272: G779～G784
8 Schraufnagel DE, Malik R, Goel V. Lung capillary changes
46
研 究 论 文
in hepatic cirrhosis in rats.Am J Physiol,
1997,272:L139～L147
9 Fallon MB,Abrams GA.Pulmonary dysfunction in chronic
liver disease.Hepatlolgy, 2000,32:859～895
10 Nayler WG,et al.Endothelin : Isoforms, binding sits and
possible implications in pathology.Trends Pharm
Sci,1990,11:69～99
11 Zhang XJ,Katsumi Y,Akimoto T,et al.Intrapulmonary
vascular dilatation and nitric oxide in hypoxemic rats with
chronic bile duct ligation. J Hepatol,2003,39:724～730
12 Liu L,Zhang M, Fallon MB. Hepatology,2001,33(3):722
～727
13 Lumsden AB,Henderson JM, KutnerMH, etal. Endotoxin
levels measured by a chromogenic assay in portal,
hepatic,and peripheral blood in patients with cirrhosis.
Hepatology,1988,8:232～236
14 Hartleb M, Moreau R, Cailmail S, et al Vascular hyporespo
nsiveness to endothelin 1 in rats with cirrhosis.
Gastroenterology, 1994,107(4):1085～1093
15 Highsmith RF, Blackbum K, Schmidt DJ. Endothelin and
calcium dynamics in vascular smooth muscle. Annu Rev
Physiol,1992,54(2):257～277
16 陈美,梁统,周克元.环氧合酶 2 研究的新进展.国外医
学·生理、病理科学与临床分册,2003,23(5):528～531
17 Hamalton G,PhingRCF,Hutton RA.The relationship
between prostacyclinactieity and pressureint
47
研 究 论 文
heportalvein.Hepatology,
1982,12:236～243
18 Sitzmann JV,Campbeiik,Wu YP,et al.prostacylin production
in acute,chronic, and long term experimental portal
hypertension.Surgery, 1994,115:290 294.
19 Hou MC, Cahill PA, Zhang S. Enhanced cyclooxygenase-1
expression within the superior mesenteric artery of portal
hypertensive rats: role in the hyperdynamic circulation.
Hepatology 1998;27:20～27
20 Tsugawa K,Hashizume M, Migou S, et al. A selective
cyclooxygenase-2 inhibitor,NS-398, may improve portal
hypertention without inducing gastric mucosal injury. J
Gastroenterol Hepatol, 1999,14:642-651
21 刘玉军.前列环素与临床.天津科学技术出版社，1987，45
22 Walenga RW,Kester M,Coroneos E, et al. Constitutive
expression of prostagl and in endoperoxideG/Hsynthetase
(PGHS)-2 but not PGHS-1 in human tracheal epithelial
cell sinvitrol.Prostaglandins,1996,52(5):341～359
23 AsanoK, LillyCM,Drazen JM.ProstaglandinG/H synthase-2
is the constitutive and dominant is forming cultured human
lung epithelial cells.AmJPhysiol,1996,271(1):126～131
24 Chen D, Balyakina EV, Lawrence M, Christman BW,
Meyrick BC.yclooxygenase is regulated by ET-1 and
MAPKs in peripheral lung microvascular smooth muscle
cells. Am J Physiol Lung Cell Mol Physiol,2003,
284(4):L614-621
48
研 究 论 文
25 张继锋,李辉,田青,等.前列环素对内皮素生理效应的拮抗
作用.中国病理生理杂志,1994,10(4):339
26 MasakiT,etal. Molecular and cellular mechanism of
endothelin regulation-implication for vascular
function.Circulation,1991,84:1457～1459