Action of a Novel PDE4 inhibitor ZL-n-91 on lipopolysaccharide-induced acute lung injury.
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.
Tang
Hui-Fang
HF
Zhejiang Respiratory Drugs Research Laboratory of State Foods & Drugs Administration of China, Medical School of Zhejiang University, Hangzhou 310058, China.
Lu
Jian-Ju
JJ
Tang
Jin-Fei
JF
Zheng
Xiang
X
Liang
Ya-Qin
YQ
Wang
Xue-Feng
XF
Wang
Ya-Juan
YJ
Mao
Lian-Gen
LG
Chen
Ji-Qiang
JQ
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000378:metabolism; D055371:Acute Lung Injury / Q000139:chemically induced / Q000188:drug therapy*; D000777:Anesthetics / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D001784:Blood Gas Analysis; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism; D003907:Dexamethasone / Q000627:therapeutic use; D005663:Furans / Q000037:antagonists & inhibitors / Q000627:therapeutic use*; D007442:Intubation, Intratracheal; D007649:Ketamine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009195:Peroxidase / Q000378:metabolism; D010647:Phenyl Ethers / Q000037:antagonists & inhibitors / Q000627:therapeutic use*; D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors / Q000627:therapeutic use*; D020889:Rolipram / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014991:Xylazine / Q000037:antagonists & inhibitors / Q000494:pharmacology
D000777:Anesthetics; D000893:Anti-Inflammatory Agents; D005663:Furans; D008070:Lipopolysaccharides; D010647:Phenyl Ethers; D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors; D014409:Tumor Necrosis Factor-alpha; C548712:Zl-n-91 compound; D014991:Xylazine; D007649:Ketamine; D003907:Dexamethasone; D009195:Peroxidase; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D020889:Rolipram