Imatinib relaxes the pulmonary venous bed of guinea pigs.
Imatinib relaxes the pulmonary venous bed of guinea pigs.
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DOI：
10.1186/s12931-017-0514-0
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发表时间：
2017-02-08
影响因子：
5.8
通讯作者：
Rieg AD
中科院分区：
文献类型：
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作者：
Maihöfer NA;Suleiman S;Dreymüller D;Manley PW;Rossaint R;Uhlig S;Martin C;Rieg AD
最近，IMPRES研究显示，全身伊马替尼可改善晚期肺动脉高压患者的运动能力。伊马替尼阻断血小板衍生生长因子（PDGF）受体（PDGFR）的酪氨酸激酶活性，起到抗增殖和舒张肺动脉的作用。然而，到目前为止，伊马替尼对肺静脉（PV）和毛细血管后阻力的舒张作用尚不清楚，尽管由于左心脏病（LHD）引起的肺动脉高压（PH）是最常见的，主要影响PV。其次，目前还不清楚PDGFR的激活是否会改变肺静脉张力。由于报告的全身伊马替尼的不良反应，我们评估了雾化伊马替尼对毛细血管后阻力的影响。从豚鼠制备精密切割肺切片（PCLS）。用内皮素-1（ET-1）预收缩肺静脉，并通过视频显微镜研究伊马替尼诱导的舒张作用;同时评价PDGF-BB相关的血管特性。在豚鼠离体灌注肺（IPL）中研究了灌注/雾化伊马替尼对毛细血管后阻力的影响。用ELISA法测定肺静脉细胞内cAMP/cGMP。在PCLS中，伊马替尼（100 μM）使预收缩的肺静脉松弛（126%）。在肺静脉，伊马替尼增加cAMP，但不是cGMP和抑制腺苷酸环化酶或蛋白激酶A减少伊马替尼诱导的松弛。此外，抑制KATP-通道，-通道或KV-通道减少伊马替尼诱导的舒张，而NO-信号的抑制没有效果。在IPL中，灌注或雾化伊马替尼减少ET-1诱导的毛细血管后阻力增加。在PCLS中，PDGF-BB收缩PV，这被伊马替尼和PDGFR-β激酶抑制剂SU 6668阻断，而抑制PDGFR-α（泊那替尼）没有显著影响。相反，PDGFR-β激酶抑制剂（SU 6668/DMPQ）可使ET-1预收缩的肺静脉松弛，与伊马替尼相当，而PDGFR-α激酶抑制剂泊那替尼则不然。伊马替尼诱导的舒张依赖于cAMP和K+通道的激活。灌注或雾化伊马替尼显著降低收缩前（ET-1）肺静脉床的毛细血管后阻力。因此，雾化伊马替尼是可行的，并可能减少全身副作用。相反，PDGF-BB通过激活PDGFR-β收缩PV，表明伊马替尼诱导的舒张依赖于PDGFR-β拮抗作用。伊马替尼结合了短期松弛剂和长期抗增殖作用。因此，伊马替尼可能是一个有前途的治疗PH由于LHD。
Recently, the IMPRES study revealed that systemic imatinib improves exercise capacity in patients with advanced pulmonary arterial hypertension. Imatinib blocks the tyrosine kinase activity of the platelet-derived growth factor (PDGF)-receptor (PDGFR), acts antiproliferative and relaxes pulmonary arteries. However so far, the relaxant effects of imatinib on pulmonary veins (PVs) and on the postcapillary resistance are unknown, although pulmonary hypertension (PH) due to left heart disease (LHD) is most common and primarily affects PVs. Next, it is unknown whether activation of PDGFR alters the pulmonary venous tone. Due to the reported adverse effects of systemic imatinib, we evaluated the effects of nebulized imatinib on the postcapillary resistance. Precision-cut lung slices (PCLS) were prepared from guinea pigs. PVs were pre-constricted with Endothelin-1 (ET-1) and the imatinib-induced relaxation was studied by videomicroscopy; PDGF-BB-related vascular properties were evaluated as well. The effects of perfused/nebulized imatinib on the postcapillary resistance were studied in cavine isolated perfused lungs (IPL). Intracellular cAMP/cGMP was measured by ELISA in PVs. In PCLS, imatinib (100 μM) relaxed pre-constricted PVs (126%). In PVs, imatinib increased cAMP, but not cGMP and inhibition of adenyl cyclase or protein kinase A reduced the imatinib-induced relaxation. Further, inhibition of KATP-channels, -channels or Kv-channels diminished the imatinib-induced relaxation, whereas inhibition of NO-signaling was without effect. In the IPL, perfusion or nebulization of imatinib reduced the ET-1-induced increase of the postcapillary resistance. In PCLS, PDGF-BB contracted PVs, which was blocked by imatinib and by the PDGFR-β kinase inhibitor SU6668, whereas inhibition of PDGFR-α (ponatinib) had no significant effect. Conversely, PDGFR-β kinase inhibitors (SU6668/DMPQ) relaxed PVs pre-constricted with ET-1 comparable to imatinib, whereas the PDGFR-α kinase inhibitor ponatinib did not. Imatinib-induced relaxation depends on cAMP and on the activation of K+-channels. Perfused or nebulized imatinib significantly reduces the postcapillary resistance in the pre-constricted (ET-1) pulmonary venous bed. Hence, nebulization of imatinib is feasible and might reduce systemic side effects. Conversely, PDGF-BB contracts PVs by activation of PDGFR-β suggesting that imatinib-induced relaxation depends on PDGFR-β-antagonism. Imatinib combines short-term relaxant and long-term antiproliferative effects. Thus, imatinib might be a promising therapy for PH due to LHD.