Abstract
Aspiration of meconium produces an inflammatory reaction resulting in necrotic changes in lung tissue. To further investigate the mechanisms of the meconium-induced early pulmonary injury, twenty 10–12-d-old piglets were studied for lung tissue ultrastructural and apoptotic changes and phospholipase A2 activity. Twelve piglets received an intratracheal bolus (3 mL/kg) of a 20-mg/mL (thin, n= 6) or 65-mg/mL (thick, n= 6) mixture of human meconium, and control piglets (n= 5) received the same amount of intratracheal saline. Three ventilated piglets with no aspiration were also studied. Pulmonary hemodynamics and systemic oxygenation were followed for 6 h after meconium or saline insufflation. In the control groups, the pulmonary tissue showed open alveolar spaces and intact vascular walls, whereas meconium administration resulted in severe pneumonitis, with alveolar spaces filled with inflammatory exudate. Meconium instillation additionally resulted in edematous changes in the vascular walls and alveolar epithelium, whereas type II pneumocytes were intact. The amount of apoptotic cells was increased, especially in the respiratory epithelium, and the catalytic activity of phospholipase A2 in lung tissue samples was significantly elevated after thick meconium instillation. This activity rise proved to be mainly because of human group I phospholipase A2, introduced by meconium. Our data thus show that aspiration of meconium leads to severe lung tissue inflammation with early ultrastructural changes in the pulmonary alveolar walls and is associated with apoptotic cell death in the epithelium, already during the first hours after the insult. These results further suggest that high phospholipase A2 activity, mainly introduced into the lungs within the meconium, may have an important role in the initiation of these alterations in neonatal lungs.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
Abbreviations
- MPO:
-
myeloperoxidase
- PLA2:
-
phospholipase A2
- H&E:
-
hematoxylin and eosin
References
Tyler DC, Murphy J, Cheney FW 1978 Mechanical and chemical damage to lung tissue caused by meconium aspiration. Pediatrics 62: 454–459
Wiswell TE, Bent RC 1993 Meconium staining and the meconium aspiration syndrome. Pediatr Clin North Am 40: 955–981
Kojima T, Hattori K, Fujiwara T, Sasai-Takedatsu M, Kobayashi Y 1994 Meconium-induced lung injury mediated by activation of alveolar macrophages. Life Sci 54: 1559–1562
Davey AM, Becker JD, Davis JM 1993 Meconium aspiration syndrome: physiological and inflammatory changes in a newborn piglet model. Pediatr Pulmonol 16: 101–108
Arbibe L, Koumanov K, Vial D, Rougeot C, Faure G, Havet N, Longacre S, Vargaftig BB, Bereziat G, Voelker DR, Wolf C, Touqui L 1998 Generation of lysophospholipids from surfactant in acute lung injury is mediated by type-II phospholipase A2 and inhibited by a direct surfactant protein A-phospholipase A2 protein interaction. J Clin Invest 102: 1152–1160
Liu L-Y, Sun B, Tian Y, Lu B-Z, Wang J 1993 Changes of pulmonary glucocorticoid receptor and phospholipase A2 in sheep with acute lung injury after high dose endotoxin infusion. Am Rev Respir Dis 148: 878–881
Niewoehner DE, Rice K, Duane P, Sinha AA, Gebhard R, Wangensteen D 1989 Induction of alveolar epithelial injury by phospholipase A2 . J Appl Physiol 66: 261–267
Holm BA, Keicher L, Liu M, Sokolowski J, Enhorning G 1991 Inhibition of pulmonary surfactant function by phospholipases. J Appl Physiol 71: 317–321
Durham SK, Selig WM 1990 Phospholipase A2-induced pathophysiologic changes in the guinea pig lung. Am J Pathol 136: 1283–1291
Vadas P, Pruzanski W 1986 Role of secretory phospholipase A2 in the pathobiology of disease. Lab Invest 55: 391–404
Kim DK, Fukuda T, Thompson BT, Cockrill B, Hales C, Bonventre JV 1995 Bronchoalveolar lavage fluid phospholipase A2 activities are increased in human adult respiratory distress syndrome. Am J Physiol 269:L109–L118
Vadas P 1984 Elevated plasma phospholipase A2 levels: correlation with the hemodynamic and pulmonary changes in Gram-negative septic shock. J Lab Clin Med 104: 873–881
Pulkkinen MO, Eskola J, Kleimola V, Simberg NH, Thuren T 1990 Pancreatic and catalytic phospholipase A2 in relation to pregnancy, labor and fetal outcome. Gynecol Obstet Invest 29: 104–107
Wissing D, Mouritzen H, Egeblad M, Poirier GG, Jäättelä M 1997 Involvement of caspase-dependent activation of cytosolic phospholipase A2 in tumor necrosis factor-induced apoptosis. Proc Natl Acad Sci USA 94: 5073–5077
Haworth SG, Hislop AA 1981 Adaptation of the pulmonary circulation to extra-uterine life in the pig and its relevance to the human infant. Cardiovasc Res 15: 108–119
Holopainen R, Soukka H, Halkola L, Kääpä P 1997 Meconium aspiration induces a concentration-dependent pulmonary hypertensive response in newborn piglets. Pediatr Pulmonol 25: 107–113
Laine VJO, Numan KM, Peuravuori HJ, Henriksen K, Parvinen M, Nevalainen TJ 1996 Lipopolysaccharide induced apoptosis of rat pancreatic acinar cells. Gut 38: 747–752
Schädlich HR, Buchler M, Beger HG 1987 Improved method for the determination of phospholipase A2 catalytic activity concentration in human serum and ascites. J Clin Chem Clin Biochem 25: 505–550
Santavuori SA, Kortesuo PT, Eskola JU, Nevalainen TJ 1991 Application of a new monoclonal antibody for time-resolved fluoroimmunoassay of human pancreatic phospholipase A2 . Eur J Clin Chem Clin Biochem 29: 819–826
Nevalainen TJ, Kortesuo PT, Rintala E, Märki F 1992 Immunochemical detection of group I and group II phospholipase A2 in human serum. Clin Chem 38: 1824–1829
Grisham MB, Benoit JN, Granger DN 1990 Assessment of leukocyte involvement during ischemia and reperfusion of intestine. Methods Enzymol 186: 729–742
Hsu SM, Raine L, Fanger H 1981 The use of avidin-biotin-peroxidase complex (ABO) in immunoperoxidase techniques: a comparison between ABC and unlabeled antibody (PAP) procedures. J Histochem Cytochem 29: 577–580
Jones CA, Cayabyab RG, Kwong KYC, Stotts C, Wong B, Hamdan H, Minoo P, DeLemos RA 1996 Undetectable interleukin (IL)-10 and persistent IL-8 expression early in hyaline membrane disease: a possible developmental basis for the predisposition to chronic lung inflammation in preterm newborns. Pediatr Res 39: 966–975
Strieter RM 1994 Acute lung injury: the role of cytokines in the elicitation of neutrophils. J Invest Med 42: 640–651
Arbibe L, Vial D, Rosinski-Chupin I, Havet N, Huerre M, Vargaftig BB, Touqui L 1997 Endotoxin induces expression of type II phospholipase A2 in macrophages during acute lung injury in guinea pigs. J Immunol 159: 391–400
Hoeck WG, Ramesha CS, Chang DJ, Fan N, Heller RA 1993 Cytoplasmic phospholipase A2 activity and gene expression are stimulated by tumor necrosis factor: dexamethasone blocks the induced synthesis. Proc Natl Acad Sci USA 90: 4475–4479
Oelberg DG, Downey SA, Flynn MM 1990 Bile salt-induced intracellular Ca++ accumulation in type II pneumocytes. Lung 168: 297–308
Higgins ST, Wu A-M, Sen N, Spritzer AR, Chander A 1996 Meconium increases surfactant secretion in isolated rat alveolar type II cells. Pediatr Res 39: 443–447
Sun B, Curstedt T, Robertson B 1993 Surfactant inhibition in experimental meconium aspiration. Acta Paediatr 82: 182–189
Perlman EJ, Moore GW, Hutchins GM 1989 The pulmonary vasculature in meconium aspiration. Hum Pathol 20: 701–706
Selig WM, Durham SK, Welton AF 1989 Pulmonary responses to phospholipase A2 in the perfused guinea pig lung. J Appl Physiol 67: 2495–2503
Soukka H, Halkola L, Aho H, Rautanen M, Kero P, Kääpä P 1997 Methylprednisolone attenuates the pulmonary hypertensive response in porcine meconium aspiration. Pediatr Res 42: 145–150
Savill J 1994 Apoptosis in disease. Eur J Clin Invest 24: 715–723
Kazzaz JA, Xu J, Palaia TA, Mantell L, Fein AM, Horowitz S 1996 Cellular oxygen toxicity: oxidant injury without apoptosis. J Biol Chem 271: 15182–15186
Kääpä P, Kytölä J, Soukka H, Ahotupa M 1997 Human meconium has potent antioxidative properties. Biol Neonate 72: 71–75
Haimovitz-Friedman A, Cordon-Cardo C, Bayoumy S, Garzotto M, McLoughlin M, Gallily R, Edwards CK, Schuhman EH, Fuks Z, Kolesnick R 1997 Lipopolysaccharide induces disseminated endothelial apoptosis requiring ceramide generation. J Exp Med 186: 1831–1841
Author information
Authors and Affiliations
Additional information
This study was financially supported by the Finnish Heart Association and the Sigrid Juselius Foundation.
Rights and permissions
About this article
Cite this article
Holopainen, R., Aho, H., Laine, J. et al. Human Meconium Has High Phospholipase A2 Activity and Induces Cellular Injury and Apoptosis in Piglet Lungs. Pediatr Res 46, 626 (1999). https://doi.org/10.1203/00006450-199911000-00022
Received:
Accepted:
Issue date:
DOI: https://doi.org/10.1203/00006450-199911000-00022
This article is cited by
-
Meconium-induced inflammation and surfactant inactivation: specifics of molecular mechanisms
Pediatric Research (2016)
-
Glucocorticoids in the treatment of neonatal meconium aspiration syndrome
European Journal of Pediatrics (2011)
-
Phospholipase A2 in meconium-induced lung injury
Journal of Perinatology (2008)
-
The role of complement in meconium aspiration syndrome
Journal of Perinatology (2008)
-
Intracellular and extracellular serpins modulate lung disease
Journal of Perinatology (2008)


