Long-acting analogue of vasoactive intestinal peptide, [R15,20,21, L17]-VIP-GRR (IK312532), protects rat alveolar L2 cells from the cytotoxicity of cigarette smoke
Long-acting analogue of vasoactive intestinal peptide, [R15,20,21, L17]-VIP-GRR (IK312532), protects rat alveolar L2 cells from the cytotoxicity of cigarette smoke
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DOI：
10.1016/j.regpep.2004.04.025
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发表时间：
2004-12-15
影响因子：
--
通讯作者：
Kashimoto, K
中科院分区：
文献类型：
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作者：
Onoue, S;Endo, K;Kashimoto, K
血管活性肠肽（VIP）和垂体腺苷酸环化酶激活肽（PACAP）在许多生物反应中作为神经递质发挥作用。我们先前报道了VIP（IK 312532; [Arg，（15，20，21），Leu（17）]-VIP）中的Lys被Arg取代，Met被Leu取代，导致代谢稳定性和生物活性的显著改善。在本研究中，我们研究了VIP及其相关肽，包括长效VIP衍生物（IK 312532）和PACAP 27对香烟烟雾提取物（CSE），慢性阻塞性肺疾病（COPD）的致病因素，在大鼠肺泡L2细胞的细胞毒性的影响。RT-PCR显示VIP特异性VPAC 2受体mRNA在L2细胞中的优势表达，VIP及其相关肽具有特异性结合活性和对腺苷酸环化酶的强刺激作用。浓度为0.1%或更高的CSE诱导L2细胞的显著凋亡性死亡。有趣的是，在具有CSE（0.25%）的L2细胞中添加浓度为10（-11）M或更高的神经肽导致细胞死亡的显著减弱，同时CSE诱发的胱天蛋白酶-3活性失活。与VIP相比，IK 312532对酶消化更稳定，并且IK 312532的保护作用比VIP高1.6倍。结合我们先前的报告显示IK 312532在肺中具有长效松弛活性，IK 312532可能是治疗哮喘和COPD的潜在候选药物。(C)2004 Elsevier B. V.保留所有权利。
Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) act as neurotransmitters in numerous biological responses. We previously reported that the replacement of Lys by Arg, and Met by Leu in VIP (IK312532; [Arg,(15,20,21), Leu(17)]-VIP) resulted in a significant improvement in metabolic stability and biological activity. In the present study, we investigated the effect of VIP and its related peptides including long-acting VIP derivative (IK312532) and PACAP27 on the cytotoxicity of cigarette smoke extract (CSE), a causative factor of chronic obstructive pulmonary disease (COPD), in rat alveolar L2 cells. RT-PCR displayed the dominant expression of mRNA for the VIP-specific VPAC2 receptor in L2 cells, and VIP and the related peptides showed the specific binding activity and potent stimulation of adenylate cyclase. CSE at a concentration of 0.1% or higher induced significant apoptotic death of L2 cells. Interestingly, the addition of neuropeptides at a concentration of 10(-11) M or higher in L2 cells with CSE (0.25%) resulted in significant attenuation of cell death with the deactivation of CSE-evoked caspase-3 activity. IK312532 was much stable against the enzymatic digestion compared to VIP, and the protective effect of IK312532 was 1.6-fold higher than that of VIP. Taken together with our previous report showing that IK312532 has long-acting relaxant activity in the lung, IK312532 may be a potential candidate for drug treatment of asthma and COPD. (C) 2004 Elsevier B.V. All rights reserved.