Effect of the inhibition of PLA 2 on oxidative lung injury induced by interleukin-1alpha.
- Author:
Young Man LEE
1
;
Hyun Gug CHO
;
Yoon Yub PARK
;
Jong Ki KIM
;
Yoon Jeong LEE
;
Won Hark PARK
;
Teoan KIM
Author Information
1. Department of Physiology, School of Medicine Catholic University of Taegu-Hyosung, Taegu 705-034, Korea.
- Publication Type:Original Article
- Keywords:
Acute lung injury;
Neutrophils;
Oxidative stress;
PLA2;
Alveolar barrier
- MeSH:
Acute Lung Injury;
Animals;
Bronchoalveolar Lavage;
Bronchoalveolar Lavage Fluid;
Cytokines;
Cytoplasm;
Endothelial Cells;
gamma-Glutamyltransferase;
Insufflation;
Interleukin-1;
Interleukin-1alpha*;
Leukotriene C4;
Lung Injury*;
Lung*;
Microscopy, Electron;
Necrosis;
Neutrophils;
Oxidants;
Oxidative Stress;
Phospholipases A2;
Pneumocytes;
Pulmonary Surfactants;
Quinacrine;
Rats;
Reactive Oxygen Species;
Respiratory Burst;
Respiratory Distress Syndrome, Adult;
Trachea;
Tumor Necrosis Factor-alpha
- From:The Korean Journal of Physiology and Pharmacology
1998;2(5):617-628
- CountryRepublic of Korea
- Language:English
-
Abstract:
In order to understand the pathogenetic mechanism of adult respiratory distress syndrome (ARDS), the role of phospholipase A2 (PLA2) in association with oxidative stress was investigated in rats. Interleukin-1alpha (IL-1, 50 mug/rat) was used to induce acute lung injury by neutrophilic respiratory burst. Five hours after IL-1 insufflation into trachea, microvascular integrity was disrupted, and protein leakage into the alveolar lumen was followed. An infiltration of neutrophils was clearly observed after IL-1 treatment. It was the origin of the generation of oxygen radicals causing oxidative stress in the lung. IL-1 increased tumor necrosis factor (TNF) and cytokine-induced neutrophil chemoattractant (CINC) in the bronchoalveolar lavage fluid, but mepacrine, a PLA2 inhibitor, did not change the levels of these cytokines. Although IL-1 increased PLA2 activity time-dependently, mepacrine inhibited the activity almost completely. Activation of PLA2 elevated leukotriene C4 and B4 (LTC4 and LTB4), and 6-keto-prostaglandin F2alpha (6-keto-PGF2alpha) was consumed completely by respiratory burst induced by IL-1. Mepacrine did not alter these changes in the contents of lipid mediators. To estimate the functional changes of alveolar barrier during the oxidative stress, quantitative changes of pulmonary surfactant, activity of gamma glutamyltransferase (GGT), and ultrastructural changes were examined. IL-1 increased the level of phospholipid in the bronchoalveolar lavage (BAL) fluid, which seemed to be caused by abnormal, pathological release of lamellar bodies into the alveolar lumen. Mepacrine recovered the amount of surfactant up to control level. IL-1 decreased GGT activity, while mepacrine restored it. In ultrastructural study, when treated with IL-1, marked necroses of endothelial cells and type II pneumocytes were observed, while mepacrine inhibited these pathological changes. In histochemical electron microscopy, increased generation of oxidants was identified around neutrophils and in the cytoplasm of type II pneumocytes. Mepacrine reduced the generation of oxidants in the tissue produced by neutrophilic respiratory burst. In immunoelectron microscopic study, PLA2 was identified in the cytoplasm of the type II pneumocytes after IL-1 treatment, but mepacrine diminished PLA2 particles in the cytoplasm of the type II pneumocyte. Based on these experimental results, it is suggested that PLA2 plays a pivotal role in inducing acute lung injury mediated by IL-1 through the oxidative stress by neutrophils. By causing endothelial damage, functional changes of pulmonary surfactant and alveolar type I pneumocyte, oxidative stress disrupts microvascular integrity and alveolar barrier.
