Zhejiang Respiratory Drugs Research Laboratory of State Foods & Drugs Administration of China, Medical School of Zhejiang University, Hangzhou 310058, China.
Int Immunopharmacol. 2010 Apr;10(4):406-11. doi: 10.1016/j.intimp.2010.01.003. Epub 2010 Jan 13.
In the present study, we investigated the effect of classic PDE4 inhibitor rolipram and novel PDE4 inhibitor ZL-n-91 on LPS-induced acute lung injury (ALI) in mice and its mechanism. ALI was induced in ICR mice by instilling intratracheally with LPS, and mice were divided into seven groups: control (Saline), LPS group, ZL-n-91 (3 microg, 10 microg, and 30 microg kg(-1), ip), Rolipram (1.0 mg kg(-1), ip) and dexamethasone (0.5 mg kg(-1), ip). After the 6h of instilling intratracheally with LPS in mice, total leukocyte number, neutrophil number and protein content in BALF increased rapidly, a large number of neutrophil infiltration around the pulmonary vessel and airway, the lung wet weight/dry weight (w/d)ratio raised significantly. MPO activity, TNF-alpha level and cAMP-PDE, PDE4 activity in lung homogenate raised significantly. P(a)O(2), P(a)CO(2) and PH value in peripheral arterial blood also changed obviously, P(a)O(2) and PH value dropped slightly and P(a)CO(2) increased significantly in LPS group. ZL-n-91 (3 microg, 10 microg, 30 microg kg(-1)) dose-dependently reduced the total leukocyte number, neutrophil number and total protein content in BALF, MPO activity, TNF-alpha level and cAMP-PDE, PDE4 activity in lung homogenate, but the effect of ZL-n-91 in pathological changes and lung wet w/d ratio is slight; Rol and Dex significantly reduced lung wet w/d ratio and improved pathological changes, neutrophil around the pulmonary vessel and airway significantly reduced, symptoms of lung edema relieved; The PH value, P(a)O(2) and P(a)CO(2) in ZL-n-91 high dosage group and Rol group had changes, but there was no significant difference compared with LPS group or saline group; After the administration, the righting reflex recovery time significantly shorten in every group of ZL-n-91. the righting reflex recovery time of Rol group was similar with ZL-n-91 30 microg kg(-1) group, while Dex group was similar with saline group. The present study confirms that the inhibitory effect of ZL-n-91(30 microg kg(-1)) on the inflammatory reactivity, including inhibition of inflammatory cell and protein exudation, MPO and PDE4 activity, improvement of the blood gas, those effects were equivalent with rolipram 1 mg kg(-1), and suggested that ZL-n-91 was stronger than rolipram in PDE4 inhibition. So we speculated that ZL-n-91 may have stronger therapeutic potential for treatment of inflammatory disease than rolipram, meantime have stronger nervous system effect than rolipram.
在本研究中，我们研究了经典 PDE4 抑制剂罗利普兰和新型 PDE4 抑制剂 ZL-n-91 对 LPS 诱导的小鼠急性肺损伤 (ALI) 的影响及其机制。通过气管内滴注 LPS 诱导 ICR 小鼠发生 ALI，将小鼠分为 7 组：对照组（生理盐水）、LPS 组、ZL-n-91（3μg、10μg 和 30μg/kg，ip）、罗利普兰（1.0mg/kg，ip）和地塞米松（0.5mg/kg，ip）。在 LPS 气管内滴注后 6 小时，总白细胞数、中性粒细胞数和 BALF 中的蛋白含量迅速增加，大量中性粒细胞浸润肺血管和气道周围，肺湿重/干重（w/d）比值显著升高。肺组织匀浆中的 MPO 活性、TNF-α 水平和 cAMP-PDE、PDE4 活性也显著升高。外周动脉血中的 PaO2、PaCO2 和 pH 值也明显改变，LPS 组 PaO2 和 pH 值略有下降，PaCO2 明显升高。ZL-n-91（3μg、10μg、30μg/kg）剂量依赖性降低 BALF 中的总白细胞数、中性粒细胞数和总蛋白含量、肺组织匀浆中的 MPO 活性、TNF-α 水平和 cAMP-PDE、PDE4 活性，但对 ZL-n-91 的病理变化和肺湿 w/d 比值的影响较小；罗利和地塞米松显著降低肺湿 w/d 比值，改善病理变化，显著减少肺血管和气道周围的中性粒细胞，减轻肺水肿症状；ZL-n-91 高剂量组和罗利组的 pH 值、PaO2 和 PaCO2 发生变化，但与 LPS 组或生理盐水组相比无显著差异；给药后，ZL-n-91 各给药组的翻正反射恢复时间明显缩短，罗利组的翻正反射恢复时间与 ZL-n-91 30μg/kg 组相似，而地塞米松组与生理盐水组相似。本研究证实，ZL-n-91（30μg/kg）对炎症反应的抑制作用，包括抑制炎症细胞和蛋白渗出、MPO 和 PDE4 活性、改善血气，这些作用与罗利普兰 1mg/kg 相似，提示 ZL-n-91 在 PDE4 抑制方面比罗利普兰更强。因此，我们推测 ZL-n-91 治疗炎症性疾病的治疗潜力可能强于罗利普兰，同时对神经系统的影响也强于罗利普兰。
