Abstract
Inflammation plays an important role in the pathogenesis of meconium aspiration syndrome, and pneumonitis is one of the major characteristics. We have previously shown that meconium has chemotactic properties because of the presence of IL-8. We hypothesize that IL-8 and other proinflammatory substances in meconium may amplify inflammation in meconium aspiration syndrome, inducing endogenous cytokine production by lung epithelial cells. We measured proinflammatory substances in first-pass meconium from healthy newborns and evaluated the effect of sterile meconium on cytokine production in cultured A549 alveolar epithelial cells in vitro. IL-1β, IL-6, IL-8, and tumor necrosis factor-α were measured by ELISA, and heme was measured spectrophotometrically. After incubation of meconium samples with A549 cells, cytokine concentrations in the supernatant were measured. Meconium samples contained variable amounts of IL-1β, IL-6, IL-8, tumor necrosis factor-α, and heme. On stimulation of A549 cells with meconium, the IL-8 concentration in the culture supernatant significantly increased above baseline measurements, whereas tumor necrosis factor-α showed a variable pattern and IL-1β or IL-6 remained unchanged. There was no quantitative relationship between the concentration of the measured cytokines and heme in meconium and cytokine release by the A549 cells after meconium exposure. Meconium contains proinflammatory substances. All samples induced IL-8 release and some induced tumor necrosis factor-α release in cultured A549 epithelial cells. We speculate that proinflammatory substances in meconium can induce lung inflammation in meconium aspiration syndrome in two ways: directly via cytokines and heme present in meconium and indirectly by inducing cytokine release by the epithelial lung cells.
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Abbreviations
- MAS:
-
meconium aspiration syndrome
- MSAF:
-
meconium-stained amniotic fluid
- TNF-α:
-
tumor necrosis factor-α
- TMB:
-
3,5,3′,5′-tetramethyl benzidine
References
Cleary GM, Wiswell TE 1998 Meconium-stained amniotic fluid and the meconium aspiration syndrome. An update. Pediatr Clin North Am 45: 511–529
Burgess AM, Hutchins GM 1996 Inflammation of the lungs, umbilical cord and placenta associated with meconium passage in utero. Review of 123 autopsied cases. Pathol Res Pract 192: 1121–1128
Kytola J, Uotila P, Kaapa P 1999 Meconium stimulates cyclooxygenase-2 expression in rat lungs. Prostaglandins Leukot Essent Fatty Acids 60: 107–110
de Beaufort AJ, Pelikan DM, Elferink JG, Berger HM 1998 Effect of interleukin 8 in meconium on in-vitro neutrophil chemotaxis. Lancet 352: 102–105
Yamada T, Matsubara S, Minakami H, Kohmura Y, Hiratsuka M, Sato I 2000 Chemotactic activity for polymorphonuclear leukocytes: meconium versus meconium-stained amniotic fluid. Am J Reprod Immunol 44: 275–278
Wagener FA, Eggert A, Boerman OC, Oyen WJ, Verhofstad A, Abraham NG, Adema G, van Kooyk Y, de Witte T, Figdor CG 2001 Heme is a potent inducer of inflammation in mice and is counteracted by heme oxygenase. Blood 98: 1802–1811
Zagariya A, Bhat R, Uhal B, Navale S, Freidine M, Vidyasagar D 2000 Cell death and lung cell histology in meconium aspirated newborn rabbit lung. Eur J Pediatr 159: 819–826
Keski-Nisula L, Aalto ML, Katila ML, Kirkinen P 2000 Intrauterine inflammation at term: a histopathologic study. Hum Pathol 31: 841–846
Lally KP, Mehall JR, Xue H, Thompson J 1999 Meconium stimulates a pro-inflammatory response in peritoneal macrophages: implications for meconium peritonitis. J Pediatr Surg 34: 214–217
Wiswell TE 2001 Advances in the treatment of the meconium aspiration syndrome. Acta Paediatr Suppl 90: 28–30
Ekekezie II, Thibeault DW, Zwick DL, Rezaiekhaligh MH, Mabry SM, Morgan RE, Norberg M, Truog WE 2000 Independent and combined effects of prolonged inhaled nitric oxide and oxygen on lung inflammation in newborn piglets. Biol Neonate 77: 37–44
Kinsella JP, Parker TA, Galan H, Sheridan BC, Abman SH 1999 Independent and combined effects of inhaled nitric oxide, liquid perfluorochemical, and high-frequency oscillatory ventilation in premature lambs with respiratory distress syndrome. Am J Respir Crit Care Med 159: 1220–1227
Martinez-Burnes J, Lopez A, Horney B, MacKenzie A, Brimacombe M 2001 Cytologic and biochemical changes associated with inoculation of amniotic fluid and meconium into lungs of neonatal rats. Am J Vet Res 62: 1636–1641
Schrama AJ, de Beaufort AJ, Sukul YR, Jansen SM, Poorthuis BJ, Berger HM 2001 Phospholipase A2 is present in meconium and inhibits the activity of pulmonary surfactant: an in vitro study. Acta Paediatr 90: 412–416
Holopainen R, Aho H, Laine J, Peuravuori H, Soukka H, Kaapa P 1999 Human meconium has high phospholipase A2 activity and induces cellular injury and apoptosis in piglet lungs. Pediatr Res 46: 626–632
Oleksy A, Banbula A, Bugno M, Travis J, Potempa J 2002 Proteolysis of interleukin-6 receptor (IL-6R) by Porphyromonas gingivalis cysteine proteinases (gingipains) inhibits interleukin-6-mediated cell activation. Microb Pathog 32: 173–181
Doran KS, Chang JC, Benoit VM, Eckmann L, Nizet V 2002 Group B streptococcal beta-hemolysin/cytolysin promotes invasion of human lung epithelial cells and the release of interleukin-8. J Infect Dis 185: 196–203
Larsson BM, Larsson K, Malmberg P, Palmberg L 1999 Gram positive bacteria induce IL-6 and IL-8 production in human alveolar macrophages and epithelial cells. Inflammation 23: 217–230
Speer CP, Groneck P 1998 Oxygen radicals, cytokines, adhesion molecules and lung injury in neonates. Semin Neonatol 3: 219–228
Taylor PC, Williams RO, Maini RN 2001 Immunotherapy for rheumatoid arthritis. Curr Opin Immunol 13: 611–616
van Dullemen HM, Van Deventer SJ, Hommes DW, Bijl HA, Jansen J, Tytgat GN, Woody J 1995 Treatment of Crohn's disease with anti-tumor necrosis factor chimeric monoclonal antibody (cA2). Gastroenterology 109: 129–135
Yang XD, Corvalan JR, Wang P, Roy CM, Davis CG 1999 Fully human anti-interleukin-8 monoclonal antibodies: potential therapeutics for the treatment of inflammatory disease states. J Leukoc Biol 66: 401–410
Carvalho GL, Wakabayashi G, Shimazu M, Karahashi T, Yoshida M, Yamamoto S, Matsushima K, Mukaida N, Clark BD, Takabayashi T, Brandt CT, Kitajima M 1997 Anti-interleukin-8 monoclonal antibody reduces free radical production and improves hemodynamics and survival rate in endotoxic shock in rabbits. Surgery 122: 60–68
Modelska K, Pittet JF, Folkesson HG, Courtney B V, Matthay MA 1999 Acid-induced lung injury: protective effect of anti-interleukin-8 pretreatment on alveolar epithelial barrier function in rabbits. Am J Respir Crit Care Med 160: 1450–1456
Kwon OJ, Au BT, Collins PD, Adcock IM, Mak JC, Robbins RR, Chung KF, Barnes PJ 1994 Tumor necrosis factor-induced interleukin-8 expression in cultured human airway epithelial cells. Am J Physiol 267: L398–L405
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de Beaufort, A., Bakker, A., van Tol, M. et al. Meconium Is a Source of Pro-Inflammatory Substances and Can Induce Cytokine Production in Cultured A549 Epithelial Cells. Pediatr Res 54, 491–495 (2003). https://doi.org/10.1203/01.PDR.0000082017.97479.39
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DOI: https://doi.org/10.1203/01.PDR.0000082017.97479.39
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