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Phospholipase A2 in Meconium-Induced Lung Injury

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Phospholipase A2 in Meconium-Induced Lung Injury Journal of Perinatology (2008) 28, S120–S122 r 2008 Nature Publishing Group All rights reserved. 0743-8346/08 $30 www.nature.com/jp REVIEW Phospholipase A2 in meconium-induced lung injury PKa¨¨apa¨ and H Soukka Department of Pediatrics, Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland PLA2 may occur as cytosolic (cPLA2) and secretory (sPLA2) Although the triggering mechanisms of tissue inflammation and injury in types, increasing attention has been paid to the role of secretory meconium-contaminated lungs are still unclear, there is increasing 7 PLA2 as an acute phase protein in inflammatory conditions. evidence to suggest a central role for phospholipase A2’s (PLA2). In fact, In this paper, the present understanding of the role of secretory elevated PLA activities together with high enzyme concentrations, especially 2 PLA2 in acute lung injury, specifically when induced by meconium the amount of pancreatic (group I) secretory PLA2 (PLA2-I), have been aspiration, is delineated. A new line of basic and clinical detected in human meconium and in meconium-contaminated lungs. research of MAS, namely the possible contribution of meconium- Recent data from our laboratory further indicate that human pancreatic introduced secretory PLA2 to systemic inflammation, is PLA2, introduced in high amounts within aspirated particulate meconium, also highlighted. is a potent inducer of lung tissue inflammatory injury. Our finding of elevated human PLA2-I concentrations in plasma during the first hours after intratracheal meconium administration in newborn piglets further suggests that intrapulmonary aspiration of meconium could also have PLA and acute lung injury systemic inflammatory and injurious effects. This, however, remains to be 2 studied in further detail. Several lines of clinical and experimental evidence implicate that Journal of Perinatology (2008) 28, S120–S122; doi:10.1038/jp.2008.147 excess pulmonary PLA2 activity, through generation of potent vasoactive and proinflammatory lysophospholipids and eicosanoids,5,6 may contribute to the progression of various inflammatory lung disorders.5–9 In agreement, high blood and pulmonary enzyme activity, correlating with the disease severity, has been found in acute respiratory distress in adults.10 Although Aspiration of meconium is known to initiate a complex cascade of high PLA2 activity in inflammatory lung injuries is commonly pulmonary processes, resulting in progressively increasing connected with increased release of group II secretory PLA2 6,7,11 pulmonary vascular tone and a rapidly developing inflammatory (PLA2-II) from macrophages and platelets, group I PLA2 tissue injury with concomitant surfactant dysfunction in the (PLA2-I), secreted by the pancreas, is also known to be expressed 12 affected lungs.1,2 Although the critical role of pulmonary and to modulate cellular function in human lungs. Mammalian inflammation in the course of neonatal meconium aspiration PLA2-I is in fact able to inactivate pulmonary surfactant concentra- 13 syndrome (MAS) has been emphasized, the triggering tion-dependently through hydrolysis of phosphatidylcholine. mechanisms and the manifold interplay of the injurious mediators PLA2-I may additionally, independent of the enzyme catalytic in MAS are still poorly identified. There is yet evidence that activity, stimulate through specific membrane receptor action human meconium may induce production of proinflammatory neutrophil function and cytokine and eicosanoid production from 7,14 agents within the lungs, and that some proinflammatory pulmonary cells. Moreover, experimental investigations have components of meconium itself, such as cytokines and shown that exogenously administered PLA2-I may induce, most phospholipase A2 (PLA2), may additionally contribute to intense likely through increased pulmonary thromboxane A2 synthesis, 15 inflammation and injury in the meconium-contaminated lung receptor-mediated contractile responses in the airways. It is 3,4 tissue. PLA2 represents a family of ubiquitous enzymes that therefore apparent that PLA2 activity associated with upregulation through cleavage of membrane phospholipids release arachidonic of PLA2-I may be important in the pathogenesis of acute acid, the precursor of proinflammatory eicosanoid.5,6 Although inflammatory lung injury. Still, variations in the tissue expressions of different PLA2 enzyme types in the insulted lungs may also have Correspondence: Dr P Ka¨a¨pa¨, Department of Pediatrics and Research Centre of Applied and consequences in the clinical course and therapeutic approaches Preventive Cardiovascular Medicine, University of Turku, Kiinamyllynkatu 10, Turku, FIN 20520, Finland. (for example, use of specific PLA2 inhibitors) of acute lung injuries 6,7 E-mail: pekka.kaapa@utu.fi from various origin. PLA2 in meconium-injured lungs PKa¨a¨pa¨ and H Soukka S121 The role of PLA2 in meconium-induced lung injury Earlier studies in our laboratory have demonstrated that human meconium has very high catalytic PLA2 activity, mainly (>90%) 4 due to high concentration of human pancreatic PLA2-I. In line with this finding, tissue PLA2 activity and concentration of human pancreatic PLA2 in the meconium-contaminated lungs are concentration-dependently elevated and correlate directly with the severity of the meconium-induced lung injury.4,16,17 In these studies, promotion of lung edema formation and neutrophil influx through insufflated human PLA2-I, either in soluble form or within meconium, further substantiates the central role of pulmonary Figure 1 Serum human pancreatic phospholipase A (PLA ) concentrations at PLA2-I in the development of lung injury after meconium 2 2 aspiration.16,17 High PLA activity in meconium, mainly due to baseline (BL) and during 6 h after meconium aspiration in newborn piglets 2 (n ¼ 5). Mean (s.d.); *P<0.05 vs BL. secretory PLA2-I, is additionally shown to be associated with decreased surfactant biophysical activity in the affected lungs.18 This inactivation could be explained by enzymatic hydrolysis of 23 dipalmitoyl-phosphatidylcholine, the major lipid constituent of in extrapulmonary organs. Intrapulmonary meconium exposure surfactant, but also the produced lyso-phosphatidylcholine may is indeed demonstrated to result in systemic complement have an inhibitory role.19 Although some experimental data activation, cytokine release, and activation of circulating neutrophils with production of a variety of biologically active suggest that type I secretory PLA2 may induce type II PLA2 1,23 20 mediators, including reactive oxygen radicals. In line with these expression, challenge of the lungs with high pancreatic PLA2 activity within aspirated meconium does not seem to influence findings, our recent studies indicate that pancreatic PLA2, 16,17 contained in high amount in meconium and thereby introduced pulmonary PLA2-II production. It is thus conceivable that into the lungs, may be absorbed, at least to some extent, into the exposure of the lungs meconium with high pancreatic PLA2 4,17 activity, specifically through aspiration of thick particulate pulmonary circulation. In fact, we were able to demonstrate meconium, may markedly participate in propagation of the that human pancreatic PLA2 concentrations in plasma are elevated ensuing pulmonary failure.17 Yet, the possible involvement of other during the first hours after intratracheal human meconium phospholipases in the development of meconium-induced lung administration in newborn piglets (Figure 1). Similar PLA2 activation and circulatory release have been recognized in clinical injury remains to be investigated. 24 Although the above considerations may potentially offer new disorders that promote systemic inflammation. Alike, markedly elevated lung and blood PLA2 activity, correlating with the disease ways to treat infants with MAS, most of the current therapies of 10 MAS are symptomatic, and their clinical effects have been severity, has been found in adults with acute respiratory distress. unsatisfactory and often conflicting.1 Accordingly, our earlier data The systemic inflammatory reaction with systemic release of mediators, such as PLA2 and cytokines, is supposed to ultimately indicate that early administration of dexamethasone, known to 24 21 lead to extrapulmonary organ dysfunction and injury. Recent inhibit stimulated PLA2 synthesis, does not reduce lung PLA2 activity or inflammation in experimental meconium aspiration.22 experimental data from our laboratory in fact indicate that severe Alike, some of our preliminary data show that mepacrine, an meconium aspiration itself, without any complicating incidents, may result in brain tissue injury, specifically in the hippocampus.25 unspecific PLA2 inhibitor, does not decrease PLA2 activity or prevent inflammatory injury, but rather tends to elevate tissue enzyme Nevertheless, it still remains undetermined how often and at what activity in the meconium-contaminated lungs (P. Ka¨a¨pa¨, intensity systemic inflammation occurs in connection with unpublished observation). Clearly, more investigations are needed meconium aspiration and what is its significance for the outcome of infants with severe MAS. before the pathophysiological relevance of PLA2 in neonatal MAS is revealed. Conclusions Taken together, there is a bulk of evidence indicating that The role of PLA2 in systemic inflammatory reaction intrapulmonary aspirated meconium, specifically in thick after meconium aspiration particulate form, challenges the lungs with high human pancreatic Recent investigations
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