Sergejeva Svetlana, Hoshino Hiroshi, Yoshihara Shigemi, Kashimoto Kazuhiza, Lötvall Jan, Lindén Anders
Lung Pharmacology Group, Department of Respiratory Medicine and Allergology, Göteborg University, Guldhedsgatan 10A, SE 41346 Gothenburg, Sweden.
Regul Pept. 2004 Feb 15;117(2):149-54. doi: 10.1016/j.regpep.2003.10.002.
Currently, there is no effective pharmacotherapy against exaggerated mobilisation of neutrophils in human airway diseases such as chronic obstructive pulmonary disease and asthma. We evaluated the effect of two synthetic vasoactive intestinal peptide (VIP)-like analogues on cytokine-induced neutrophil recruitment in airways in vivo. Recombinant interleukin (IL)-1 beta was administered intratracheally (i.t.) to intubated, spontaneously breathing Sprague-Dawley rats. The rats were pretreated either with a VIP synthetic peptide analogue, a pituitary adenylate cyclase-activating peptide (PACAP)-1-27 synthetic analogue, the beta(2)-adrenoceptor agonist salbutamol or vehicle, systemically or locally. Differential cell counts were performed on bronchoalveolar lavage fluid (BALf) cytospins. Effects on mean arterial blood pressure (MAP) were monitored in separate experiments. Systemic administration of the VIP analogue, the PACAP analogue and salbutamol attenuated the cytokine-induced increase in BALf neutrophil number. Local administration of the VIP analogue and salbutamol, but not the PACAP analogue, also decreased the neutrophil number in BALf. Local administration of the VIP analogue and salbutamol caused a transient decrease in MAP. Systemic or local administration of a synthetic VIP peptide analogue inhibits cytokine-induced neutrophil recruitment in airways in vivo. This action is exerted without severe, sustained cardiovascular side effects, and deserves to be further evaluated in obstructive pulmonary diseases in human.
目前，针对慢性阻塞性肺疾病和哮喘等人类气道疾病中嗜中性粒细胞过度动员，尚无有效的药物疗法。我们评估了两种合成的血管活性肠肽（VIP）类似物对体内气道中细胞因子诱导的嗜中性粒细胞募集的影响。将重组白细胞介素（IL）-1β经气管内（i.t.）给予插管的、自主呼吸的Sprague-Dawley大鼠。大鼠分别全身或局部用VIP合成肽类似物、垂体腺苷酸环化酶激活肽（PACAP）-1-27合成类似物、β₂肾上腺素能受体激动剂沙丁胺醇或赋形剂进行预处理。对支气管肺泡灌洗液（BALf）细胞涂片进行细胞分类计数。在单独的实验中监测对平均动脉血压（MAP）的影响。VIP类似物、PACAP类似物和沙丁胺醇的全身给药减轻了细胞因子诱导的BALf嗜中性粒细胞数量增加。VIP类似物和沙丁胺醇的局部给药，但不是PACAP类似物，也减少了BALf中的嗜中性粒细胞数量。VIP类似物和沙丁胺醇的局部给药导致MAP短暂下降。合成VIP肽类似物的全身或局部给药在体内抑制气道中细胞因子诱导的嗜中性粒细胞募集。这种作用在没有严重、持续的心血管副作用的情况下发挥，值得在人类阻塞性肺疾病中进一步评估。
