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

Abstract

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 μg, 10 μg, and 30 μg 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-α level and cAMP-PDE, PDE4 activity in lung homogenate raised significantly. P aO 2, P aCO 2 and PH value in peripheral arterial blood also changed obviously, P aO 2 and PH value dropped slightly and P aCO 2 increased significantly in LPS group. ZL-n-91 (3 μg, 10 μg, 30 μg kg − 1 ) dose-dependently reduced the total leukocyte number, neutrophil number and total protein content in BALF, MPO activity, TNF-α 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 aO 2 and P aCO 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 μg kg − 1 group, while Dex group was similar with saline group. The present study confirms that the inhibitory effect of ZL-n-91(30 μg 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.