Inhalable powder formulation of a stabilized vasoactive intestinal peptide (VIP) derivative: Anti-inflammatory effect in experimental asthmatic rats
Inhalable powder formulation of a stabilized vasoactive intestinal peptide (VIP) derivative: Anti-inflammatory effect in experimental asthmatic rats
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DOI：
10.1016/j.peptides.2009.09.032
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发表时间：
2010-01-01
期刊：
影响因子：
3
通讯作者：
Yamada, Shizuo
中科院分区：
文献类型：
--
作者：
Misaka, Shingen;Aoki, Yosuke;Yamada, Shizuo
血管活性肠肽（VIP）通过其特异性受体如VPAC 1和2受体发挥免疫调节和抗炎作用。以前，稳定的VIP衍生物，[R-15，R-20，R-21，L-17]-VIP-GRR（IK 312532）被提议作为抗哮喘药物的候选物，并且还开发了具有最小全身副作用的（IK 312532）的干粉吸入器系统用于吸入治疗。在本研究中，IK 312532可吸入粉末（RP）的抗炎特性在哮喘/COPD样动物模型中进行了表征，使用新开发的卵清蛋白（OVA）-RP治疗肺部炎症。OVA-RP攻击后，大鼠肺中观察到明显的炎症事件，如嗜酸性粒细胞过氧化物酶（EPO）、髓过氧化物酶（MPO）和乳酸脱氢酶（LDH）等炎症生物标志物的显著增加所证明的。然而，动脉内给予IK 312532-RP导致血浆EPC、MPO和LDH活性显著减弱，以及BALF中募集的炎性细胞显著减少，尤其是巨噬细胞和嗜酸性粒细胞。在IK 312532-RP预处理的大鼠中，组织化学检查显示浸润到肺的炎性细胞和上皮壁厚度分别显著减少85%和58%。因此，IK 312532的可吸入粉末制剂通过抑制粒细胞向肺的募集和上皮增生，随后减少细胞毒性过氧化物酶来发挥其抗炎活性。(C)2009 Elsevier Inc. All rights reserved.
Vasoactive intestinal peptide (VIP) exerts immunomodulating and anti-inflammatory activities through its specific receptors, such as VPAC1 and 2 receptors. Previously, a stabilized VIP derivative, [R-15,R-20,R-21, L-17]-VIP-GRR (IK312532), was proposed as a candidate of anti-asthma drug, and a dry powder inhaler system of (IK312532 was also developed for inhalation therapy with minimal systemic side-effects. In the present study, the anti-inflammatory properties of IK312532 respirable powder (RP) were characterized in an asthma/COPD-like animal model, with the use of newly developed ovalbumin (OVA)-RP for lung inflammation. Marked inflammatory events in the lung were observed after OVA-RP challenge in rats as evidenced by significant increase of inflammatory biomarkers such as eosinophil peroxidase (EPO), myeloperoxidase (MPO) and lactate dehydrogenase (LDH). However, intratracheal administration of IK312532-RP led to significant attenuation of plasma EPC, MPO and LDH activities, as well as significant reduction of recruited inflammatory cells in BALF, especially macrophages and eosinophils. In the rats pretreated with IK312532-RP, histochemical examinations revealed that the inflammatory cells infiltrating to the lung and the epithelial wall thickness decreased significantly by 85% and 58%, respectively. Thus, inhalable powder formulation of IK312532 exerts its anti-inflammatory activity by suppressing granulocyte recruitment to the lung and epithelial hyperplasia, followed by the reduction of cytotoxic peroxidases. (C) 2009 Elsevier Inc. All rights reserved.