Selective phosphodiesterase 3 inhibitor olprinone attenuates meconium-induced oxidative lung injury

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• 作者：Daniela Mokra^a ; ^{mokra@jfmed.uniba.sk} ; Anna Drgova^b ; Rudolf Pullmann Sr.^c ; Andrea Calkovska^a
• 关键词：Meconium ; Olprinone ; Phosphodiesterase inhibitor ; Oxidation ; Lung injury
• 刊名：Pulmonary Pharmacology & Therapeutics
• 出版年：2012
• 期刊代码：56_10945539
• 类别：pha
• 出版时间：June, 2012
• 卷：25
• 期：3
• 页码：216-222
• 文件大小：820 K

摘要

Since inflammation and oxidation play a key role in the pathophysiology of neonatal meconium aspiration syndrome, various anti-inflammatory drugs have been tested in the treatment. This study evaluated whether the phosphodiesterase (PDE) 3 inhibitor olprinone can alleviate meconium-induced inflammation and oxidative lung injury. Oxygen-ventilated rabbits intratracheally received 4聽ml/kg of meconium (25聽mg/ml) or saline. Thirty minutes after meconium/saline instillation, meconium-instilled animals were treated by intravenous olprinone (0.2聽mg/kg) or were left without treatment. All animals were oxygen-ventilated for an additional 5聽h. A bronchoalveolar lavage (BAL) of the left lungs was performed and differential leukocyte count in the sediment was estimated. The right lungs were used to determine lung edema by wet/dry weight ratio, as well as to detect oxidative damage to the lungs. In the lung tissue homogenate, total antioxidant status (TAS) was determined. In isolated lung mitochondria, the thiol group content, conjugated dienes, thiobarbituric acid-reactive substances (TBARS), dityrosine, lysine-lipid peroxidation products, and activity of cytochrome c oxidase (COX) were estimated. To evaluate the effects of meconium instillation and olprinone treatment on the systemic level, TBARS and TAS were determined in the blood plasma, as well. Meconium instillation increased the relative numbers of neutrophils and eosinophils in the BAL fluid, increased edema formation and concentrations of oxidation markers, and decreased TAS. Treatment with olprinone reduced the numbers of polymorphonuclears in the BAL fluid, decreased the formation of most oxidation markers in the lungs, reduced lung edema and prevented a decrease in TAS in the lung homogenate compared to non-treated animals. In the blood plasma, olprinone decreased TBARS and increased TAS compared to the non-treated group. Conclusion, the selective PDE3 inhibitor olprinone has shown potent antioxidative and anti-inflammatory effects in the meconium-induced oxidative lung injury.