Inhalable powder formulation of vasoactive intestinal peptide derivative, [R15,20,21, L17]-VIP-GRR, attenuated neutrophilic airway inflammation in cigarette smoke-exposed rats.
Inhalable powder formulation of vasoactive intestinal peptide derivative, [R15,20,21, L17]-VIP-GRR, attenuated neutrophilic airway inflammation in cigarette smoke-exposed rats.
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DOI：
10.1016/j.ejps.2010.08.007
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发表时间：
2010-11
期刊：
影响因子：
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通讯作者：
S. Onoue;S. Misaka;Yosuke Aoki;Shin-Ichiro Karaki;A. Kuwahara;Asami Ohide;T. Mizumoto;S. Yamada
中科院分区：
文献类型：
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作者：
S. Onoue;S. Misaka;Yosuke Aoki;Shin-Ichiro Karaki;A. Kuwahara;Asami Ohide;T. Mizumoto;S. Yamada
香烟烟雾(CS)已被认为是慢性阻塞性肺疾病(COPD)的主要致病因素，因此CS暴露的COPD啮齿动物模型在基础研究和药物开发方面引起了极大的兴趣和关注。在本研究中，利用实验性COPD模型大鼠，评价了新制备的长效VIP衍生物[Arg15，20，21，Leu17]-VIP-GRR(IK312532)的呼吸粉剂(RP)的治疗潜力，重点观察了促炎生物标志物、形态和组织化学变化以及呼吸系统中的渗透细胞。CS染毒11天后，除嗜酸性粒细胞外，细支气管炎性细胞明显浸润，杯状细胞化生、增生。吸入IK312532-RP(50μg/只)后，大鼠肺泡灌洗液和肺组织中粒细胞募集分别减少74%和71%，杯状细胞减少68%。生物标志物研究表明，吸入IK312532-RP可以抑制CS诱导的血浆和肺组织髓过氧化物酶的升高，分别抑制87%和70%，可能导致对中性粒细胞炎症症状的有效抑制。TUNEL染色结果显示，CS染毒大鼠呼吸道组织出现明显的细胞凋亡损伤，吸入IK312532-RP的CS染毒大鼠肺组织TUNEL阳性细胞明显减少。目前的发现表明，由于IK312532具有强大的免疫调节活性，可吸入制剂IK312532可能对COPD或其他呼吸道炎症疾病有效。
Cigarette smoke (CS) has been identified as a predominant causative factor for chronic obstructive pulmonary disease (COPD), so CS-exposed rodent model of COPD has drawn considerable interest and attention for fundamental study and drug discovery. In the present study, using experimental COPD model rats, the therapeutic potential of a newly prepared respirable powder (RP) formulation of a long-acting VIP derivative, [Arg15,20,21, Leu17]-VIP-GRR (IK312532), was assessed with a focus on pro-inflammatory biomarkers, morphological and histochemical changes, and infiltrated cells in the respiratory system. CS exposure of rats for 11 days led to the marked infiltration of inflammatory cells, except for eosinophils, in bronchiolar epithelium, followed by goblet cell metaplasia and hyperplasia. However, inhalation of IK312532-RP (50μg/rat) in the CS-exposed rats resulted in 74 and 71% reductions of granulocyte recruitment in bronchoalveolar lavage fluids and lung tissues, respectively, with 68% decrease of goblet cells. Biomarker study demonstrated that the inhaled IK312532-RP could suppress the CS-evoked increase of myeloperoxidase in both plasma and lung by 87 and 70%, respectively, possibly leading to potent suppression of neutrophilic inflammatory symptoms. The results from TUNEL staining were indicative of apoptotic damage in respiratory tissues of the CS-exposed rats, and there appeared to be marked decrease of TUNEL-positive cells in the CS-exposed rat with inhaled IK312532-RP. The present findings suggest that an inhalable formulation of IK312532 might be efficacious as a therapy for COPD or other airway inflammatory diseases because of its potent immunomodulating activities.