Action of a Novel PDE4 inhibitor ZL-n-91 on lipopolysaccharide-induced acute lung injury

作者：Tang, Hui-Fang; Lu, Jian-Ju; Tang, Jin-Fei; Zheng, Xiang; Liang, Ya-qin; Wang, Xue-Feng; Wang, Ya-Juan; Mao, Lian-Gen; Chen, Ji-Qiang^*

来源：International Immunopharmacology, 2010, 10(4): 406-411.

DOI：10.1016/j.intimp.2010.01.003

• ZL-n-91
• Rolipram
• Lipopolysaccharide (LPS)
• Acute lung injury (ALI)
• Bronchoalveolar lavage fluid (BALF)
• Tumor necrosis factor-alpha (TNF-alpha)

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 mu g, 10 mu g, and 30 mu g kg(-1), ip), Rolipram (1.0 mg kg(-1), ip) and dexamethasone (0.5 mg kg(-1), ip). After the 6 h 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. PaO2, PaCO2 and PH value in peripheral arterial blood also changed obviously, PaO2 and PH value dropped slightly and PaCO2 increased significantly in LPS group. ZL-n-91 (3 Kg, 10 mu g, 30 mu g 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, PaO2 and PaCO2 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 mu g kg(-1) group, while Dex group was similar with saline group. The present study confirms that the inhibitory effect of ZL-n-91(30 Kg 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.

• 出版日期2010-4
• 单位浙江大学