Angiotensin II Receptor Blockade Inhibits Pneumocyte Apoptosis in Experimental Meconium Aspiration

Abstract

Lung tissue inflammation and apoptosis are implicated in the pathogenesis of meconium aspiration-induced lung injury in the newborn, but the mechanisms of these reactions are still poorly known. We investigated the time-dependent leukocyte influx and appearance of apoptosis, as well as the contribution of angiotensin (ANG) II receptor action on these processes in the meconium-induced lung injury. Experimental meconium aspiration was induced by intratracheal instillation of human meconium in 18 rats, and eight rats were further pretreated with an unspecific ANG II receptor inhibitor saralasin. Rats were ventilated with 60% oxygen for 1, 3, or 5 h, and the lungs were then studied histologically for tissue injury and with DNA nick-end labeling and electron microscopy for apoptotic cell death. Lung tissue myeloperoxidase activity and expression of angiotensinogen mRNA and endothelial monocyte-activating polypeptide (EMAP) II protein were also analyzed. The meconium-instilled lungs showed increasing neutrophil migration and histologic injury after the first hour, whereas the number of epithelial apoptotic cells was elevated from the control level throughout the study. Myeloperoxidase activity was high, and the angiotensinogen mRNA and EMAP II protein was up-regulated at 5 h after the meconium insult. Pretreatment with saralasin significantly prevented the increase in lung tissue myeloperoxidase activity, EMAP II, and lung epithelial apoptosis. The results suggest that pulmonary meconium insult rapidly results in epithelial apoptosis, before significant neutrophil sequestration into the lungs. Perinatal aspiration of meconium frequently results in severe pulmonary failure with ventilation-perfusion mismatching in the lungs, hypoxemia, and increase in pulmonary vascular resistance, associated with high morbidity and mortality in fullor postterm newborn infants. The pathophysiology of the neonatal meconium aspiration syndrome (MAS) is complex, but inflammation with accumulation of polymorphonuclear leukocytes in the pulmonary tissue is believed to be a central event in the development of acute tissue damage (1, 2). This inflammatory reaction is associated with increased pulmonary vascular permeability leading to proteinaceous exudation into the alveolar spaces and inactivation of the pulmonary surfactant and may together with direct toxic effects of meconium significantly contribute to the lung injury process (1, 2). Still, the clinical effects of anti-inflammatory therapeutic approaches and surfactant replacement treatment have often been unsatisfactory and have not consistently improved the outcome of severe complications of this disease (1-3). New advances in the pathophysiology of MAS therefore are needed.Apoptosis, programmed cell death, is usually regarded as a physiologic mechanism in organ remodeling (4) but has been

Angiotensin II in apoptotic lung injury: potential role in meconium aspiration syndrome

“…In a similar study of rats, Lukkarinen et al 69 showed that pretreatement of rats with the nonselective ANG receptor blocker saralasin, given intraperitoneally before meconium instillation, prevented AEC apoptosis detected by both DNA fragmentation assay and electron microscopy. The meconium increase AGT mRNA in the lungs, suggesting apoptosis-induced upregulation of AGT in AECs.…”

Pancreatic Phospholipase A2 Contributes to Lung Injury in Experimental Meconium Aspiration

“…Previous studies in our laboratory in fact demonstrate that human meconium contains high amount of PLA 2 -I and that the PLA 2 activity and concentration of PLA 2 -I in the meconium-contaminated lung tissue is high (3). Although these results connected intra-tracheal insufflation of particulate meconium with pulmonary inflammation, there are also data suggesting an important role for the soluble fraction of human meconium in the initiation of acute inflammatory response in the insulted lungs (3,4). We hypothesized that PLA 2 -I is present in both particulate and soluble fraction of meconium and that it contributes to the inflammatory and apoptotic lung injury induced by meconium aspiration, and therefore decided to investigate the pulmonary effects of meconium before and after extraction of PLA 2 -I, and also the direct effects of intra-tracheal PLA 2 -I.…”

“…The pathophysiology of the neonatal meconium aspiration syndrome (MAS) is complex, but inflammation with pulmonary surge of cytokines, possibly through activation of alveolar macrophages, and accumulation of polymorphonuclear leukocytes in the pulmonary tissue is believed to be a central event in the development of acute tissue damage (1,2). This inflammatory reaction is connected with increased lung epithelial cell apoptosis, which may together with inactivation of the pulmonary surfactant and direct toxic effects of meconium significantly contribute to the lung injury process (1,3,4). Still, the clinical effects of anti-inflammatory therapeutic approaches are unsatisfactory and do not consistently improve the outcome of severe complications of this disease (1).…”

The role of complement in meconium aspiration syndrome

“…24 In addition, meconium has been shown capable of upregulating cyclooxygenase-2 mRNA expression in rat lungs, a process that is inhibited by dexamethasone, but not indomethacin 25 and enhance the release of thromboxane-A 2 in human airway epithelial cells. 26 Finally, apoptosis associated with meconium 22,27,28 could be inhibited by angiotensin II receptor blockade. 27 The effect of meconium on oxidative burst (release of reactive oxygen species) has been difficult to interpret.…”

“…26 Finally, apoptosis associated with meconium 22,27,28 could be inhibited by angiotensin II receptor blockade. 27 The effect of meconium on oxidative burst (release of reactive oxygen species) has been difficult to interpret. Although one study showed that meconium stimulated alveolar macrophages to produce superoxide anion, 29 another study showed that light and very light meconium inhibited neutrophil oxidative burst.…”