A3 adenosine receptors and mitogen-activated protein kinases in lung injury following in vivo reperfusion.
A3 adenosine receptors and mitogen-activated protein kinases in lung injury following in vivo reperfusion.
复制标题
体内再灌注后，A3腺苷受体和有丝分裂原激活的蛋白激酶在肺损伤中。
DOI：
10.1186/cc4893
复制
发表时间：
2006
期刊：
影响因子：
15.1
通讯作者：
Jacobson, Kenneth A.
中科院分区：
文献类型：
--
作者：
Matot, Idit;Weiniger, Carolyn F.;Zeira, Evelyne;Galun, Eithan;Joshi, Bhalchandra V.;Jacobson, Kenneth A.
虽然A3腺苷受体的激活可以减轻再灌注肺损伤和相关的细胞凋亡，但介导这种保护的信号通路尚不清楚。腺苷激动剂可激活丝裂原活化的蛋白激酶，这些激酶与缺血/再灌注损伤有关；因此，本研究的目的是确定再灌注刺激A3腺苷受体是否会调节不同丝裂原活化蛋白激酶的表达。此外，我们比较了A3腺苷激动剂IB-MECA与新合成的高选择性A3腺苷受体激动剂MRS3558对再灌注肺损伤的影响。研究采用在体自发呼吸猫模型，分离左肺下叶，缺血2小时，再灌注3小时。再灌注前给予选择性A3腺苷受体激动剂IB-MECA （0.05 mg/kg、0.1 mg/kg或0.3 mg/kg）和MRS3558 （0.05 mg/kg或0.1 mg/kg）。再灌注前使用的两种A3腺苷受体激动剂均显著（P < 0.01）降低了损伤和凋亡指标，包括损伤肺泡百分比、湿/干重比、髓过氧化物酶活性、TUNEL（原位tdt介导的dUTP缺口末端标记）阳性细胞、caspase 3活性和表达。低剂量MRS3558的效果更明显。再灌注结束时，与对照组相比，磷酸化的c-Jun氨基末端蛋白激酶（JNK）、p38和细胞外信号调节激酶（ERK）1/2水平升高。A3激动剂预处理上调磷酸化的ERK1/2水平，但未改变磷酸化的JNK和p38水平。A3腺苷受体激活的保护作用部分是通过上调磷酸化的ERK介导的。此外，MRS3558在减轻再灌注肺损伤方面比IB-MECA更有效。结果表明，增强ERK通路不仅可能使细胞死亡和存活之间的平衡转向细胞存活，而且A3激动剂有可能作为缺血/再灌注诱导的肺损伤的有效治疗方法。
Although activation of A3 adenosine receptors attenuates reperfusion lung injury and associated apoptosis, the signaling pathway that mediates this protection remains unclear. Adenosine agonists activate mitogen-activated protein kinases, and these kinases have been implicated in ischemia/reperfusion injury; the purpose of this study was therefore to determine whether A3 adenosine receptor stimulation with reperfusion modulates expression of the different mitogen-activated protein kinases. In addition, we compared the effect of the A3 adenosine agonist IB-MECA with the newly synthesized, highly selective A3 adenosine receptor agonist MRS3558 on injury in reperfused lung. Studies were performed in an in vivo spontaneously breathing cat model, in which the left lower lobe of the lung was isolated and subjected to 2 hours of ischemia and 3 hours of reperfusion. The selective A3 adenosine receptor agonists IB-MECA (0.05 mg/kg, 0.1 mg/kg, or 0.3 mg/kg) and MRS3558 (0.05 mg/kg or 0.1 mg/kg) were administered before reperfusion. Both A3 adenosine receptor agonists administered before reperfusion markedly (P < 0.01) attenuated indices of injury and apoptosis, including the percentage of injured alveoli, wet/dry weight ratio, myeloperoxidase activity, TUNEL (in situ TdT-mediated dUTP nick end labeling)-positive cells, and caspase 3 activity and expression. The more pronounced effects at low doses were observed with MRS3558. Increases in phosphorylated c-Jun amino-terminal protein kinase (JNK), p38, and extracellular signal-regulated kinase (ERK)1/2 levels were observed by the end of reperfusion compared with controls. Pretreatment with the A3 agonists upregulated phosphorylated ERK1/2 levels but did not modify phosphorylated JNK and p38 levels. The protective effects of A3 adenosine receptor activation are mediated in part through upregulation of phosphorylated ERK. Also, MRS3558 was found to be more potent than IB-MECA in attenuating reperfusion lung injury. The results suggest not only that enhancement of the ERK pathway may shift the balance between cell death and survival toward cell survival, but also that A3 agonists have potential as an effective therapy for ischemia/reperfusion-induced lung injury.
登录
查看更多内容
DOI：
10.1016/j.jtcvs.2003.04.001
发表时间：
2004-03-01
影响因子：
6
作者：
Khan, TA;Bianchi, C;Sellke, FW
通讯作者：
Sellke, FW
DOI：
10.1152/ajpheart.01008.2004
发表时间：
2005-08-01
影响因子：
4.8
作者：
Lasley, RD;Keith, BJ;Mentzer, RM
通讯作者：
Mentzer, RM
影响因子：
4
作者：
Fedorova, IM;Jacobson, MA;Jacobson, KA
通讯作者：
Jacobson, KA
影响因子：
64.8
作者：
Chang, LF;Karin, M
通讯作者：
Karin, M
DOI：
10.1152/ajpheart.01006.2004
发表时间：
2005-03-01
影响因子：
4.8
作者：
Ballard-Croft, C;Kristo, G;Lasley, RD
通讯作者：
Lasley, RD