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Action of a Novel PDE4 inhibitor ZL-n-91 on lipopolysaccharide-induced acute lung injury
- Source :
- International Immunopharmacology. 10:406-411
- Publication Year :
- 2010
- Publisher :
- Elsevier BV, 2010.
-
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 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.
- Subjects :
- Lipopolysaccharides
Male
Xylazine
medicine.medical_specialty
Phosphodiesterase Inhibitors
medicine.medical_treatment
Acute Lung Injury
Immunology
Anti-Inflammatory Agents
Lung injury
Dexamethasone
Mice
Internal medicine
Intubation, Intratracheal
medicine
Animals
Immunology and Allergy
Respiratory system
Furans
Saline
Rolipram
Anesthetics
Peroxidase
Pharmacology
Mice, Inbred ICR
Lung
medicine.diagnostic_test
Tumor Necrosis Factor-alpha
business.industry
Phenyl Ethers
Cyclic Nucleotide Phosphodiesterases, Type 4
Bronchoalveolar lavage
medicine.anatomical_structure
Endocrinology
3',5'-Cyclic-AMP Phosphodiesterases
Toxicity
Ketamine
Phosphodiesterase 4 Inhibitors
Blood Gas Analysis
business
Bronchoalveolar Lavage Fluid
medicine.drug
Subjects
Details
- ISSN :
- 15675769
- Volume :
- 10
- Database :
- OpenAIRE
- Journal :
- International Immunopharmacology
- Accession number :
- edsair.doi.dedup.....f62413da6d8a4c2d1dfb3f96f56442c6