支气管上皮衍生舒张因子对肺动脉舒张影响及传导途径研究
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摘要
一氧化氮(NO)生物学领域出生于1987年,NO-血红蛋白通过鸟苷酸环化酶中反应的重要性的认识是在1998年获得诺贝尔生理学和医学奖。关于NO对呼吸的作用不仅局限于呼吸循环,在靶蛋白质中NO与过渡金属的反应作为NO信号的主要机制是迄今为止最受关注的,尽管如此,半胱氨酸蛋白质残基的S-亚硝基化的重要性研究迅速转移到中心舞台。在脑、神经等众多NO调节呼吸的研究工作令人振奋。Sci. STKE编辑做出NO,而不量O2在调节呼吸的综述报告。
经典的由一氧化氮合成酶(NOSs)家族在L-精氨酸与氧产生NO途径更成为必不可少的研究工作武器。NOSs是一个不同基因分别编码的酶家族。在生物学中,NOS是一种最有调节性的酶。有三个已知的异构体,两个为构成型表达(constitutive NOS,cNOS),第三个是诱导型(inducible NOS,iNOS)。一氧化氮合酶基因的克隆酶表明,原生型包括脑构成型(即神经元型nNOS,NOS1)和内皮构成型(eNOS,NOS3),第三个是诱导型(iNOS ,NOS2)基因。心肌、血管中eNOS的研究发现其磷酸化激活位点。iNOS在免疫、感染中的作用研究进展很快。而关于肺血管中NOS作用与支气管关系的的研究,尤其是神经元型NOS(nNOS)研究未能引起重视。
肺动脉与支气管胚胎来源、解剖学关系密切,构成它们之间生物信号传导的基础。Flavahan等首先报道了气道上皮细胞衍生因子能够使犬支气管平滑肌舒张,戈尔迪霍恩等假设,这个因素对支气管血管有血管扩张作用,但从来没有进行评估。Belik首次研究证实,这是支气管分泌一种可溶性因子,它对邻近肺动脉有一个重要的信号调节作用。乙酰甲胆碱(methacholine, Mch)是一个类似乙酰胆碱的受体激动剂,它可能通过刺激毒蕈碱受体的M1受体诱使收缩气道平滑肌收缩。类似乙酰胆碱,Mch也可以通过刺激内皮依赖的毒蕈碱M1或M3类型的受体,舒张成年大鼠肺动脉。通过它与NOSs抑制剂结合有可能探讨NOSs的作用。
PI3-激酶是一个多功能二聚体酶,包括分解、调节亚群。PI3-激酶家族分为Ⅰ、Ⅱ、Ⅲ三种类型,其中PI-3激酶Ⅰ可分成α-,β-,γ-三个亚单位,存在于平滑肌细胞。而γ-亚单位为分解亚单位,Wormannin和LY294002通过抑制p110-γ分解亚单位使之失活。而NO激活鸟苷酸环化酶,这引起平滑肌松弛:增加细胞内cGMP的含量,抑制钙离子进入细胞,并减少细胞内钙离子浓度,激活K+通道,从而导致超极化和松弛。刺激一环鸟苷酸依赖的蛋白激酶激活肌球蛋白轻链磷酸酶,这种酶使肌球蛋白轻链去磷酸化,从而导致平滑肌松弛。ODQ为可溶性鸟苷酸环化酶抑制剂,抑制NO-cGMP调节途径。
血栓素A2(TXA2)类似物U46619可诱导肺动脉收缩。本实验利用U46619刺激与去除支气管上皮结合/不结合的肺动脉对照分析,并随后利用Mch刺激结合/不结合支气管的肺动脉(并加入/不加入各种抑制剂)对照分析以说明BrEpDRF是否存在。
本实验中用不同NOS抑制剂及LY209442、ODQ抑制新生大鼠Mch舒张结合支气管的肺动脉,以说明对肺动脉舒张作用、NOS异形体作用,及信号传导途径。支持如下假说:刺激新生大鼠引起BrEpDRF释放,作用于肺动脉,通过PI3-激酶/Akt途径磷酸化激活,在eNOS、nNOS磷酸化激活作用下,通过NO-cGMP释放引起平滑肌舒张。本实验有助于进一步研究肺动脉高压及移植缺血再灌注损伤。
本文首次用LY204002为BrEpDFR依赖PI-3激酶/Akt介导肺动脉舒张提供证据。
Pulmonary artery and bronchus has the same origin during embryogenesis; anatomically, they are close, this lay the foundation of signal transduction. Pulmonary vessel resistance control is a complex and unclear process. Although the relationship between airway and pulmonary vessel bed is reported, the bronchial signal transduction and the mechanism of its effect on pulmonary artery are rarely studied. It is reported about trachea effect on pulmonary artery which indicated that smooth muscle of pulmonary artery relaxes likely through nitric oxide (NO) release. There are three know niitric oxide synthase (NOS), includes endothelial NOS (eNOS), neuronal NOS (nNOS) and inducible NOS (iNOS). The three isoforms of NOS are abundantly present in the lung. In pulmonary vasulature, eNOS is presented soley in the endothelial cells. Smooth muscle cells express nNOS constitutively, and iNOS is only expressed following stimulation (e.g. cytokines). It is proved that eNOS can phosphorylate phosphatidylinositol 3-kinase (PI3-kinase) through which produce amount of NO, and NO is expired by neonate is reported, too. But under physical condition, bronchial epithelium derived relaxing factor (BrEpDRF) can relaxes pulmonary artery and the effect of nNOS on NO synthesis during this process is rarely reported.
PI3-kinase is a multifunctional, hereodimer enzyme composed of a catalytic and a regulatory subunit. The PI3-kinase family is subdivided into three classes. ClassⅠPI3-kinases consist of either aα-,β- orγ-catalytic subunit. This class is present in smooth muscle cells and through which to modulate contraction. Inhibitors of PI30kinase (Wotmannin and LY294002) work predominantly by inhibiting the p110γ-catalytic subunit. Akt (protein kinase B) is a known effector signaling by factors that activate the PI3-kinase. Three Akt isoforms are known: Akt1, Akt2, Akt3. All 3 isofroms are widely expressed in various tissues, but Akt1 is the one most abundant in the lung. In ustimulated cell, Akt protein exists in cytoplasm and the tow regulatory phosphorylation sites at threonine at 308 and serine at 473 are in an unphosphorylated state. Following stimulation, Akt is reruited to plasma membrane and sequentially phosphoralated at T308 and S 473 by upstream kinases referred to as 3-PI-dependent protein kinase 1 (PKD1) and PKD2, respectively, to yield a fully activated kinase. This pathway can be activated by growth and other tissue secreted factors. Activation of Akt can directly phospholate guanylate cyclase inhibitor ODQ through which improve NO production. Rarely known function of nNOS, but its isoforms is activated by PI3-kinase/Akt pathway.
Methacholine (Mch) is an agonist of Ach which can stimulate M1 subtype of muscarinic receptor via which to induce smooth muscle contraction of airway. Similar to Mch can also relax pulmonary artery of adult rat through stimulating M1, M3 phenotype of muscarinic receptor which is endothelium dependent. It is reported firstly by Flavahan et al. that airway epithelium derived relaxing factor is capable of relaxing of bronchus smooth muscle in cyon, in that Mch or histamine relaxes aorta smooth muscle in endothelial denuded adult rat, which a proved observation on basis of the existence of airway epithelium later.
U466196 is an analogue of thromboxane A2 (TXA2) which can produce smooth muscle contraction; and methacholine (Mch) can relaxes smooth muscle of pulmonary artery; L-NIO, 7NINA and 400W are inhibitor of eNOS, nNOS and iNOS; LY294002 is a PI3-kinnase inhibitor and ODQ is a NO-cGMP pathway inhibitor, respectively. To study on BrEpDRF and the way of synthesis of NO and the signal pathway in neonate rat, we employed male Sprague-Dawley of 4-8 days. After sacrifice them by pentobarbital overdose i.p. injection, free stage 4 pulmonary artery with/without bronchi attach. Measure contractile force of pulmonary artery attached epithelium denuded bronchi is stimulated by U46619; observe vessel relaxation rate of pulmonary artery with bronchus attached stimulated by Mch under different types of NOS inhibitors, L-NIO, 7NINA and 1400W after pre–stimulated by U46619 to study function of different NOS during the process of NO production. Inhibit relaxation effect of Mch by LY294002 and ODQ is employed to observe if signal is conducted by PI3-kinase/Akt and NO-cGMP pathway. To observe their inhibitory effect, Wormannin, LY294002 and ODQ with Mch are stainned by DAF to compare with the function of Mch alone.
Results: Stimulated by U46619, pulmonary artery with epithelium denuded bronchus contract force is averagely 0.36 mN/mm2,artery alone is averagely 1.89 mN/mm2 under stimulation, (p<0.01). After stimulated by U46619, the relax rate of pulmonary artey with bronchus attached is 40.04% stimulated by Mch, and the relax rate is 23.30% stimulated by Mch with eNOS and nNOS inhibitors, (p<0.01); the relax rate is 38.59% stimulated by Mch with eNOS inhibitor, which is higher than that of caused by Mch with both inhibitors (p<0.01); the relax rate is 37.63% stimulated by Mch with iNOS and eNOS inhibitor together, which is not less than that of stimulated by Mch alone, (p>0.01), respectively. After stimulated by U46619, the relax rate of pulmonary artery with bronchus attached is 39.37% stimulated by Mch, and the relax rate is 11.72% stimulated by Mch with PI3/Akt inhibitor LY294002, compared significantly (p<0.01); the relax rate is 2.15% stimulated by Mch with NO-GMP inhibitor ODQ, which is less than that of stimulated by Mch alone statistically (p<0.01), respectively. Both are stained to observe. U46619, an analogue of thromboxane A2, stimulates pulmonary artery bronchus epithelium denuded/intact group differed significantly implicate that BrEpDRF is associated with pulmonary relaxation under physiological condition, which supports the existence of BrEpDRF. It is found in this study that this effect abolished when the epithelium of bronchus was denuded. It is found this is true even when bronchus floated in Kresb-Henseleit buffer and is nNOS independent by others. Thus implicate BrEpDRF is soluble.
Mch decreases relax effect of Pulmonary artery when inhibit by L-NINO and 7NINA, a inhibitor of eNOS and nNOS respectively, indicateds endothelial and neuronal phenotype acted. Inhibitory effect of both is compared with eNOS alone, which shows nNOS is required, and Mch is eNOS independent, and iNOS do not participate in NO synthesis under physiological condition, which is different from inhibitory effect by others, but supports no changes in pulmonary smooth muscle contaction. L-NINO and 1400W cannot inhibit relaxation of pulmonary artery by Mch denotes effect of nNOS again.
Activation of Akt phosphorates eNOS directly enhances NO production. Isoforms of NOS is presumably activated by PI3/Akt pathway, which is inhibited by LY294002. LY294002 and ODQ inhibits pulmonary artery relaxation induced by Mch in this study, respectively, implicates BrEpDRF is regulated by PI3-kinase and NO-cGMP pathway.
This study denotes bronchial epithelium is associated with pulmonary artery relaxation, supports BrEpDRF exists. BrEpDRF is associated with relaxation via NO synthesis; eNOS and nNOS participate in NO synthesis, but iNOS did not found functional; under Mch stimulation, BrEpDRF is PI3-kinase/Akt pathway dependent and regulated via NO-cGMP pathway.
LY294002, a PI-3 kinase inhibitor, is first employed to show BrEpDRF decreases note to adjacent pulmonary artery smooth muscle via NOS phosphoralation mechanism. We concluded in this study after compared different groups, that bronchus promotes pulmonary relaxation; approve NO production is participated by nNOS; BrEpDRF is possibly exist through which relax pulmonary dilation via NO production. These contribute to further research on pulmonary hypertension and ischemia-reperfuse injury in transplantation. BrEpDRF is signaled by PI3-kinase/Akt pathway and NO-cGMP pathway. The nature of BrEpDRF is to be further evaluated.
经典的由一氧化氮合成酶(NOSs)家族在L-精氨酸与氧产生NO途径更成为必不可少的研究工作武器。NOSs是一个不同基因分别编码的酶家族。在生物学中,NOS是一种最有调节性的酶。有三个已知的异构体,两个为构成型表达(constitutive NOS,cNOS),第三个是诱导型(inducible NOS,iNOS)。一氧化氮合酶基因的克隆酶表明,原生型包括脑构成型(即神经元型nNOS,NOS1)和内皮构成型(eNOS,NOS3),第三个是诱导型(iNOS ,NOS2)基因。心肌、血管中eNOS的研究发现其磷酸化激活位点。iNOS在免疫、感染中的作用研究进展很快。而关于肺血管中NOS作用与支气管关系的的研究,尤其是神经元型NOS(nNOS)研究未能引起重视。
肺动脉与支气管胚胎来源、解剖学关系密切,构成它们之间生物信号传导的基础。Flavahan等首先报道了气道上皮细胞衍生因子能够使犬支气管平滑肌舒张,戈尔迪霍恩等假设,这个因素对支气管血管有血管扩张作用,但从来没有进行评估。Belik首次研究证实,这是支气管分泌一种可溶性因子,它对邻近肺动脉有一个重要的信号调节作用。乙酰甲胆碱(methacholine, Mch)是一个类似乙酰胆碱的受体激动剂,它可能通过刺激毒蕈碱受体的M1受体诱使收缩气道平滑肌收缩。类似乙酰胆碱,Mch也可以通过刺激内皮依赖的毒蕈碱M1或M3类型的受体,舒张成年大鼠肺动脉。通过它与NOSs抑制剂结合有可能探讨NOSs的作用。
PI3-激酶是一个多功能二聚体酶,包括分解、调节亚群。PI3-激酶家族分为Ⅰ、Ⅱ、Ⅲ三种类型,其中PI-3激酶Ⅰ可分成α-,β-,γ-三个亚单位,存在于平滑肌细胞。而γ-亚单位为分解亚单位,Wormannin和LY294002通过抑制p110-γ分解亚单位使之失活。而NO激活鸟苷酸环化酶,这引起平滑肌松弛:增加细胞内cGMP的含量,抑制钙离子进入细胞,并减少细胞内钙离子浓度,激活K+通道,从而导致超极化和松弛。刺激一环鸟苷酸依赖的蛋白激酶激活肌球蛋白轻链磷酸酶,这种酶使肌球蛋白轻链去磷酸化,从而导致平滑肌松弛。ODQ为可溶性鸟苷酸环化酶抑制剂,抑制NO-cGMP调节途径。
血栓素A2(TXA2)类似物U46619可诱导肺动脉收缩。本实验利用U46619刺激与去除支气管上皮结合/不结合的肺动脉对照分析,并随后利用Mch刺激结合/不结合支气管的肺动脉(并加入/不加入各种抑制剂)对照分析以说明BrEpDRF是否存在。
本实验中用不同NOS抑制剂及LY209442、ODQ抑制新生大鼠Mch舒张结合支气管的肺动脉,以说明对肺动脉舒张作用、NOS异形体作用,及信号传导途径。支持如下假说:刺激新生大鼠引起BrEpDRF释放,作用于肺动脉,通过PI3-激酶/Akt途径磷酸化激活,在eNOS、nNOS磷酸化激活作用下,通过NO-cGMP释放引起平滑肌舒张。本实验有助于进一步研究肺动脉高压及移植缺血再灌注损伤。
本文首次用LY204002为BrEpDFR依赖PI-3激酶/Akt介导肺动脉舒张提供证据。
Pulmonary artery and bronchus has the same origin during embryogenesis; anatomically, they are close, this lay the foundation of signal transduction. Pulmonary vessel resistance control is a complex and unclear process. Although the relationship between airway and pulmonary vessel bed is reported, the bronchial signal transduction and the mechanism of its effect on pulmonary artery are rarely studied. It is reported about trachea effect on pulmonary artery which indicated that smooth muscle of pulmonary artery relaxes likely through nitric oxide (NO) release. There are three know niitric oxide synthase (NOS), includes endothelial NOS (eNOS), neuronal NOS (nNOS) and inducible NOS (iNOS). The three isoforms of NOS are abundantly present in the lung. In pulmonary vasulature, eNOS is presented soley in the endothelial cells. Smooth muscle cells express nNOS constitutively, and iNOS is only expressed following stimulation (e.g. cytokines). It is proved that eNOS can phosphorylate phosphatidylinositol 3-kinase (PI3-kinase) through which produce amount of NO, and NO is expired by neonate is reported, too. But under physical condition, bronchial epithelium derived relaxing factor (BrEpDRF) can relaxes pulmonary artery and the effect of nNOS on NO synthesis during this process is rarely reported.
PI3-kinase is a multifunctional, hereodimer enzyme composed of a catalytic and a regulatory subunit. The PI3-kinase family is subdivided into three classes. ClassⅠPI3-kinases consist of either aα-,β- orγ-catalytic subunit. This class is present in smooth muscle cells and through which to modulate contraction. Inhibitors of PI30kinase (Wotmannin and LY294002) work predominantly by inhibiting the p110γ-catalytic subunit. Akt (protein kinase B) is a known effector signaling by factors that activate the PI3-kinase. Three Akt isoforms are known: Akt1, Akt2, Akt3. All 3 isofroms are widely expressed in various tissues, but Akt1 is the one most abundant in the lung. In ustimulated cell, Akt protein exists in cytoplasm and the tow regulatory phosphorylation sites at threonine at 308 and serine at 473 are in an unphosphorylated state. Following stimulation, Akt is reruited to plasma membrane and sequentially phosphoralated at T308 and S 473 by upstream kinases referred to as 3-PI-dependent protein kinase 1 (PKD1) and PKD2, respectively, to yield a fully activated kinase. This pathway can be activated by growth and other tissue secreted factors. Activation of Akt can directly phospholate guanylate cyclase inhibitor ODQ through which improve NO production. Rarely known function of nNOS, but its isoforms is activated by PI3-kinase/Akt pathway.
Methacholine (Mch) is an agonist of Ach which can stimulate M1 subtype of muscarinic receptor via which to induce smooth muscle contraction of airway. Similar to Mch can also relax pulmonary artery of adult rat through stimulating M1, M3 phenotype of muscarinic receptor which is endothelium dependent. It is reported firstly by Flavahan et al. that airway epithelium derived relaxing factor is capable of relaxing of bronchus smooth muscle in cyon, in that Mch or histamine relaxes aorta smooth muscle in endothelial denuded adult rat, which a proved observation on basis of the existence of airway epithelium later.
U466196 is an analogue of thromboxane A2 (TXA2) which can produce smooth muscle contraction; and methacholine (Mch) can relaxes smooth muscle of pulmonary artery; L-NIO, 7NINA and 400W are inhibitor of eNOS, nNOS and iNOS; LY294002 is a PI3-kinnase inhibitor and ODQ is a NO-cGMP pathway inhibitor, respectively. To study on BrEpDRF and the way of synthesis of NO and the signal pathway in neonate rat, we employed male Sprague-Dawley of 4-8 days. After sacrifice them by pentobarbital overdose i.p. injection, free stage 4 pulmonary artery with/without bronchi attach. Measure contractile force of pulmonary artery attached epithelium denuded bronchi is stimulated by U46619; observe vessel relaxation rate of pulmonary artery with bronchus attached stimulated by Mch under different types of NOS inhibitors, L-NIO, 7NINA and 1400W after pre–stimulated by U46619 to study function of different NOS during the process of NO production. Inhibit relaxation effect of Mch by LY294002 and ODQ is employed to observe if signal is conducted by PI3-kinase/Akt and NO-cGMP pathway. To observe their inhibitory effect, Wormannin, LY294002 and ODQ with Mch are stainned by DAF to compare with the function of Mch alone.
Results: Stimulated by U46619, pulmonary artery with epithelium denuded bronchus contract force is averagely 0.36 mN/mm2,artery alone is averagely 1.89 mN/mm2 under stimulation, (p<0.01). After stimulated by U46619, the relax rate of pulmonary artey with bronchus attached is 40.04% stimulated by Mch, and the relax rate is 23.30% stimulated by Mch with eNOS and nNOS inhibitors, (p<0.01); the relax rate is 38.59% stimulated by Mch with eNOS inhibitor, which is higher than that of caused by Mch with both inhibitors (p<0.01); the relax rate is 37.63% stimulated by Mch with iNOS and eNOS inhibitor together, which is not less than that of stimulated by Mch alone, (p>0.01), respectively. After stimulated by U46619, the relax rate of pulmonary artery with bronchus attached is 39.37% stimulated by Mch, and the relax rate is 11.72% stimulated by Mch with PI3/Akt inhibitor LY294002, compared significantly (p<0.01); the relax rate is 2.15% stimulated by Mch with NO-GMP inhibitor ODQ, which is less than that of stimulated by Mch alone statistically (p<0.01), respectively. Both are stained to observe. U46619, an analogue of thromboxane A2, stimulates pulmonary artery bronchus epithelium denuded/intact group differed significantly implicate that BrEpDRF is associated with pulmonary relaxation under physiological condition, which supports the existence of BrEpDRF. It is found in this study that this effect abolished when the epithelium of bronchus was denuded. It is found this is true even when bronchus floated in Kresb-Henseleit buffer and is nNOS independent by others. Thus implicate BrEpDRF is soluble.
Mch decreases relax effect of Pulmonary artery when inhibit by L-NINO and 7NINA, a inhibitor of eNOS and nNOS respectively, indicateds endothelial and neuronal phenotype acted. Inhibitory effect of both is compared with eNOS alone, which shows nNOS is required, and Mch is eNOS independent, and iNOS do not participate in NO synthesis under physiological condition, which is different from inhibitory effect by others, but supports no changes in pulmonary smooth muscle contaction. L-NINO and 1400W cannot inhibit relaxation of pulmonary artery by Mch denotes effect of nNOS again.
Activation of Akt phosphorates eNOS directly enhances NO production. Isoforms of NOS is presumably activated by PI3/Akt pathway, which is inhibited by LY294002. LY294002 and ODQ inhibits pulmonary artery relaxation induced by Mch in this study, respectively, implicates BrEpDRF is regulated by PI3-kinase and NO-cGMP pathway.
This study denotes bronchial epithelium is associated with pulmonary artery relaxation, supports BrEpDRF exists. BrEpDRF is associated with relaxation via NO synthesis; eNOS and nNOS participate in NO synthesis, but iNOS did not found functional; under Mch stimulation, BrEpDRF is PI3-kinase/Akt pathway dependent and regulated via NO-cGMP pathway.
LY294002, a PI-3 kinase inhibitor, is first employed to show BrEpDRF decreases note to adjacent pulmonary artery smooth muscle via NOS phosphoralation mechanism. We concluded in this study after compared different groups, that bronchus promotes pulmonary relaxation; approve NO production is participated by nNOS; BrEpDRF is possibly exist through which relax pulmonary dilation via NO production. These contribute to further research on pulmonary hypertension and ischemia-reperfuse injury in transplantation. BrEpDRF is signaled by PI3-kinase/Akt pathway and NO-cGMP pathway. The nature of BrEpDRF is to be further evaluated.
引文
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