Department of Pharmacokinetics and Pharmacodynamics and Global Center of Excellence (COE) Program, School of Pharmaceutical Sciences, University of Shizuoka, Suruga-ku, Shizuoka, Japan.
Peptides. 2010 Jan;31(1):72-8. doi: 10.1016/j.peptides.2009.09.032. Epub 2009 Oct 4.
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(15,20,21), 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 EPO, 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.
血管活性肠肽 (VIP) 通过其特定的受体，如 VPAC1 和 2 受体，发挥免疫调节和抗炎作用。此前，一种稳定的 VIP 衍生物，[R(15,20,21), L(17)]-VIP-GRR (IK312532)，被提议作为一种抗哮喘药物候选物，并且还开发了一种 IK312532 的干粉吸入器系统，用于通过最小的全身副作用进行吸入治疗。在本研究中，使用新开发的卵清蛋白 (OVA)-RP 进行肺部炎症研究，表征了 IK312532 可吸入粉末 (RP) 在哮喘/COPD 样动物模型中的抗炎特性。在 OVA-RP 挑战后，大鼠肺部观察到明显的炎症事件，这表现为炎症生物标志物如嗜酸性过氧化物酶 (EPO)、髓过氧化物酶 (MPO) 和乳酸脱氢酶 (LDH) 的显著增加。然而，气管内给予 IK312532-RP 导致血浆 EPO、MPO 和 LDH 活性显著减弱，BALF 中募集的炎症细胞显著减少，尤其是巨噬细胞和嗜酸性粒细胞。在 IK312532-RP 预处理的大鼠中，组织化学检查显示，浸润到肺部的炎症细胞和上皮壁厚度分别显著减少了 85%和 58%。因此，可吸入的 IK312532 粉末制剂通过抑制粒细胞向肺部募集和上皮细胞增生来发挥抗炎作用，随后减少细胞毒性过氧化物酶。
