Inhaled tolafentrine reverses pulmonary vascular remodeling via inhibition of smooth muscle cell migration.
Inhaled tolafentrine reverses pulmonary vascular remodeling via inhibition of smooth muscle cell migration.
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DOI：
10.1186/1465-9921-6-128
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发表时间：
2005-11-01
影响因子：
5.8
通讯作者：
Schermuly RT
中科院分区：
文献类型：
--
作者：
Pullamsetti S;Krick S;Yilmaz H;Ghofrani HA;Schudt C;Weissmann N;Fuchs B;Seeger W;Grimminger F;Schermuly RT
该研究的目的是评估在野百合碱诱导的大鼠肺动脉高压（PAH）期间吸入联合磷酸二酯酶3/4抑制剂托拉芬特林的慢性影响。CD大鼠单次皮下注射野百合碱诱导PAH。四周后，大鼠在无限制的全身气雾剂暴露系统中吸入托拉芬群或假雾化。在这些动物中，检查了（i）吸入托拉芬群的急性肺血管舒张功效（ii）长期吸入托拉芬群的抗重塑作用（iii）托拉芬群对编码细胞粘附和细胞外基质调节的96个基因的表达谱的影响。此外，还研究了托拉芬特林对离体肺动脉平滑肌细胞迁移的抑制作用。野百合碱注射引起严重PAH（右心室收缩压从25.9 ± 4.0增加到4周后的68.9 ± 3.2和6周后的74.9 ± 5.1 mmHg）、心输出量降低和右心肥大。肺动脉中膜厚度和毛细血管前小阻力血管肌化比例明显增加，离体肺动脉平滑肌细胞（PASMC）迁移反应增强。微阵列和随后的真实的时间PCR证实了几种细胞外基质调节和粘附基因的上调，例如基质金属蛋白酶（MMP）2、8、9、10、11、12、20、Icam、Itgax、Plat和serpinb 2。当从第28天至第42天（每天12次气雾剂操作）长期雾化时，在完全建立重度肺动脉高压后，托拉芬群逆转了约60%的所有血液动力学异常、右心肥大和野百合碱诱导的结构性肺血管变化，包括肺动脉肌化的比例。吸入托拉芬特林后，细胞外基质调节和粘附基因的上调减少了近80%。当在体外评估时，托拉芬群阻断增强的PASMC迁移反应。总之，我们第一次证明了吸入组合PDE 3/4抑制剂逆转肺动脉高压充分发展的反应野百合碱在大鼠中。这种“逆向重塑”效应包括肺血管壁的结构变化和基质调节的关键分子途径，伴随着60%的血流动力学正常化。
The aim of the study was to assess the chronic effects of combined phosphodiesterase 3/4 inhibitor tolafentrine, administered by inhalation, during monocrotaline-induced pulmonary arterial hypertension (PAH) in rats. CD rats were given a single subcutaneous injection of monocrotaline to induce PAH. Four weeks after, rats were subjected to inhalation of tolafentrine or sham nebulization in an unrestrained, whole body aerosol exposure system. In these animals (i) the acute pulmonary vasodilatory efficacy of inhaled tolafentrine (ii) the anti-remodeling effect of long-term inhalation of tolafentrine (iii) the effects of tolafentrine on the expression profile of 96 genes encoding cell adhesion and extracellular matrix regulation were examined. In addition, the inhibitory effect of tolafentrine on ex vivo isolated pulmonary artery SMC cell migration was also investigated. Monocrotaline injection provoked severe PAH (right ventricular systolic pressure increased from 25.9 ± 4.0 to 68.9 ± 3.2 after 4 weeks and 74.9 ± 5.1 mmHg after 6 weeks), cardiac output depression and right heart hypertrophy. The media thickness of the pulmonary arteries and the proportion of muscularization of small precapillary resistance vessels increased dramatically, and the migratory response of ex-vivo isolated pulmonary artery smooth muscle cells (PASMC) was increased. Micro-arrays and subsequent confirmation with real time PCR demonstrated upregulation of several extracellular matrix regulation and adhesion genes, such as matrixmetalloproteases (MMP) 2, 8, 9, 10, 11, 12, 20, Icam, Itgax, Plat and serpinb2. When chronically nebulized from day 28 to 42 (12 daily aerosol maneuvers), after full establishment of severe pulmonary hypertension, tolafentrine reversed about 60% of all hemodynamic abnormalities, right heart hypertrophy and monocrotaline-induced structural lung vascular changes, including the proportion of pulmonary artery muscularization. The upregulation of extracellular matrix regulation and adhesion genes was reduced by nearly 80% by inhalation of the tolafentrine. When assessed in vitro, tolafentrine blocked the enhanced PASMC migratory response. In conclusion, we demonstrate for the first time that inhalation of combined PDE3/4 inhibitor reverses pulmonary hypertension fully developed in response to monocrotaline in rats. This "reverse-remodeling" effect includes structural changes in the lung vascular wall and key molecular pathways of matrix regulation, concomitant with 60% normalization of hemodynamics.
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影响因子：
82.9
作者：
Fink, L;Seeger, W;Bohle, RM
通讯作者：
Bohle, RM
影响因子：
20.1
作者：
BENDECK, MP;ZEMPO, N;REIDY, MA
通讯作者：
REIDY, MA
DOI：
10.1073/pnas.90.21.10300
发表时间：
1993-11-01
影响因子：
11.1
作者：
GRAVES, LM;BORNFELDT, KE;KREBS, EG
通讯作者：
KREBS, EG
DOI：
10.1152/ajpheart.00548.2002
发表时间：
2003-11-01
影响因子：
4.8
作者：
Nagaya, N;Okumura, H;Kangawa, K
通讯作者：
Kangawa, K
DOI：
10.1164/ajrccm.156.2.9609092
发表时间：
1997-08-01
影响因子：
24.7
作者：
Schermuly, R;Schmehl, T;Walmrath, D
通讯作者：
Walmrath, D