Abstract
Matrix metalloproteinases (MMPs) and chemokines seem to be induced by hyperoxia in preclinical studies. We hypothesized that O2 exposure immediately after birth is associated with altered blood spot MMP 9 and β chemokine concentrations. The following analytes were measured on blood spots on d 1 and 3 of life, using luminex technology in 1059 infants (birth weights <1000 g) in the NICHD Neonatal Research Network: MMP 9, monocyte chemoattractant protein 1 (MCP 1), macrophage inflammatory proteins (1α and β), and regulated upon activation, normal t cell expressed and secreted (RANTES). Infants administered O2 continually from 6 to 24 h of life (n = 729), when compared with those with <6 h exposure (n = 330), had significantly lower mean birth weight and higher rate of respiratory distress syndrome (p < 0.002). On d 3, MCP 1 was higher and RANTES lower among infants with early prolonged O2 exposure. After adjusting for covariates, prolonged early O2 exposure retained a statistically significant association with higher MCP 1 on d 3 (p = 0.003). The consistent association between O2 exposure and MCP 1 among extremely preterm infants suggests that further investigation of its role in oxidative injury is warranted.
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Abbreviations
- FiO2:
-
fractional inspired oxygen
- MCP 1:
-
monocyte chemoattractant protein 1
- MIP:
-
macrophage inflammatory proteins
- MMP:
-
matrix metalloproteinase
- RANTES:
-
regulated upon activation, normal T-cell expressed and secreted
References
Haynes RL, Baud O, Li J, Kinney HC, Volpe JJ, Folkerth DR 2005 Oxidative and nitrative injury in periventricular leukomalacia: a review. Brain Pathol 15: 225–233
Saugstad OD 1997 Bronchopulmonary dysplasia and oxidative stress: are we closer to an understanding of the pathogenesis of BPD?. Acta Paediatr 86: 1277–1282
Tin W, Milligan DW, Pennefather P, Hey E 2001 Pulse oximetry, severe retinopathy, and outcome at one year in babies of less than 28 weeks gestation. Arch Dis Child Fetal Neonatal Ed 84: F106–F110
Bashiri A, Burstein E, Mazor M 2006 Cerebral palsy and fetal inflammatory response syndrome: a review. J Perinat Med 34: 5–12
Speer CP 2003 Inflammation and bronchopulmonary dysplasia. Semin Neonatol 8: 29–38
Speer CP 2006 Inflammation and bronchopulmonary dysplasia: a continuing story. Semin Fetal Neonatal Med 11: 354–362
Saugstad OD 2005 Oxidative stress in the newborn—a 30-year perspective. Biol Neonate 88: 228–236
Markus T, Hansson S, Amer-Wahlin I, Hellstrom-Westas L, Saugstad OD, Ley D 2007 Cerebral inflammatory response after fetal asphyxia and hyperoxic resuscitation in newborn sheep. Pediatr Res 62: 71–77
Bhandari V, Elias JA 2006 Cytokines in tolerance to hyperoxia-induced injury in the developing and adult lung. Free Radic Biol Med 41: 4–18
Legrand C, Gilles C, Zahm JM, Polette M, Buisson AC, Kaplan H, Birembaut P, Tournier JM 1999 Airway epithelial cell migration dynamics. MMP-9 role in cell-extracellular matrix remodeling. J Cell Biol 146: 517–529
Spinale FG 2002 Matrix metalloproteinases: regulation and dysregulation in the failing heart. Circ Res 90: 520–530
Okamoto T, Akaike T, Sawa T, Miyamoto Y, van der Vliet A, Maeda H 2001 Activation of matrix metalloproteinases by peroxynitrite-induced protein S-glutathiolation via disulfide S-oxide formation. J Biol Chem 276: 29596–29602
Munkeby BH, Borke WB, Bjornland K, Sikkeland LI, Borge GI, Lomo J, Rivera S, Khrestchatisky M, Halvorsen B, Saugstad OD 2005 Resuscitation of hypoxic piglets with 100% O2 increases pulmonary metalloproteinases and IL-8. Pediatr Res 58: 542–548
Gushima Y, Ichikado K, Suga M, Okamoto T, Iyonaga K, Sato K, Miyakawa H, Ando M 2001 Expression of matrix metalloproteinases in pigs with hyperoxia-induced acute lung injury. Eur Respir J 18: 827–837
Schock BC, Sweet DG, Ennis M, Warner JA, Young IS, Halliday HL 2001 Oxidative stress and increased type-IV collagenase levels in bronchoalveolar lavage fluid from newborn babies. Pediatr Res 50: 29–33
D'Angio CT, LoMonaco MB, Chaudhry SA, Paxhia A, Ryan RM 1999 Discordant pulmonary proinflammatory cytokine expression during acute hyperoxia in the newborn rabbit. Exp Lung Res 25: 443–465
D'Angio CT, Sinkin RA, LoMonaco MB, Finkelstein JN 1995 Interleukin-8 and monocyte chemoattractant protein-1 mRNAs in oxygen-injured rabbit lung. Am J Physiol 268: L826–L831
Pawlak K, Pawlak D, Mysliwiec M 2005 Circulating beta-chemokines and matrix metalloproteinase-9/tissue inhibitor of metalloproteinase-1 system in hemodialyzed patients—role of oxidative stress. Cytokine 31: 18–24
Deng H, Mason SN, Auten RL Jr 2000 Lung inflammation in hyperoxia can be prevented by antichemokine treatment in newborn rats. Am J Respir Crit Care Med 162: 2316–2323
Vozzelli MA, Mason SN, Whorton MH, Auten RL Jr 2004 Antimacrophage chemokine treatment prevents neutrophil and macrophage influx in hyperoxia-exposed newborn rat lung. Am J Physiol Lung Cell Mol Physiol 286: L488–L493
Skogstrand K, Thorsen P, Norgaard-Pedersen P, Schendel DE, Sorensen LC, Hougaard DM 2005 Simultaneous determination of 25 inflammatory markers and neurotrophins in neonatal dried blood spots by immunoassay xMAP technology. Clin Chem 51: 1854–1866
Sullivan SE, Staba SL, Gersting JA, Hutson AD, Theriaque D, Christensen RD, Calhoun DA 2002 Circulating concentrations of chemokines in cord blood, neonates, and adults. Pediatr Res 51: 653–657
Glowinska-Olszewska B, Urban M 2007 Elevated matrix metalloproteinase 9 and tissue inhibitor of metalloproteinase 1 in obese children and adolescents. Metabolism 56: 799–805
Romero R, Chaiworapongsa T, Espinoza J, Gomez R, Yoon BH, Edwin S, Mazor M, Maymon E, Berry S 2002 Fetal plasma MMP-9 concentrations are elevated in preterm premature rupture of the membranes. Am J Obstet Gynecol 187: 1125–1130
Schulz CG, Sawicki G, Lemke RP, Roeten BM, Schulz R, Cheung PY 2004 MMP-2 and MMP-9 and their tissue inhibitors in the plasma of preterm and term neonates. Pediatr Res 55: 794–801
Cockle JV, Gopichandran N, Walker JJ, Levene MI, Orsi NM 2007 Matrix metalloproteinases and their tissue inhibitors in preterm perinatal complications. Reprod Sci 14: 629–645
Fotopoulos S, Mouchtouri A, Xanthou G, Lipsou N, Petrakou E, Xanthou M 2005 Inflammatory chemokine expression in the peripheral blood of neonates with perinatal asphyxia and perinatal or nosocomial infections. Acta Paediatr 94: 800–806
Dammann O, Phillips TM, Allred EN, O'shea TM, Paneth N, Van Marter LJ, Bose C, Ehrenkranz RA, Bednarek FJ, Naples M, Leviton A, ELGAN Study Investigators 2001 Mediators of fetal inflammation in extremely low gestational age newborns. Cytokine 13: 234–239
Ng PC, Li K, Chui KM, Leung TF, Wong RP, Chu WC, Wong E, Fok TF 2007 IP-10 is an early diagnostic marker for identification of late-onset bacterial infection in preterm infants. Pediatr Res 61: 93–98
Ng PC, Li K, Leung TF, Wong RP, Li G, Chui KM, Wong E, Cheng FW, Fok TF 2006 Early prediction of sepsis-induced disseminated intravascular coagulation with interleukin-10, interleukin-6, and RANTES in preterm infants. Clin Chem 52: 1181–1189
Cavaillon JM, Adib-Conquy M, Fitting C, Adrie C, Payen D 2003 Cytokine cascade in sepsis. Scand J Infect Dis 35: 535–544
Pawlak K, Pawlak D, Mysliwiec M 2004 Oxidative stress influences CC-chemokine levels in hemodialyzed patients. Nephron Physiol 96: p105–p112
Baier RJ, Loggins J, Kruger TE 2001 Monocyte chemoattractant protein 1 and interleukin 8 are increased in bronchopulmonary dysplasia: relation to isolation of Ureaplasma urealyticum. J Investig Med 49: 362–369
Baier RJ, Majid A, Parupia H, Loggins J, Kruger TE 2004 CC chemokine concentrations increase in respiratory distress syndrome and correlate with development of bronchopulmonary dysplasia. Pediatr Pulmonol 37: 137–148
Baier RJ, Loggins J, Kruger TE 2002 Increased interleukin 8 and monocyte chemoattractant protein 1 concentrations in mechanically ventilated preterm infants with pulmonary hemorrhage. Pediatr Pulmonol 34: 131–137
Galasso JM, Liu Y, Szaflarski J, Warren JS, Silverstein FS 2000 Monocyte chemoattractant protein 1 is a mediator of acute excitotoxic injury in neonatal rat brain. Neuroscience 101: 737–744
Paananen R, Husa AK, Vuolteenaho R, Herva R, Kaukola T, Hallman M 2009 Blood cytokines during the perinatal period in very preterm infants: relationship of inflammatory response and bronchopulmonary dysplasia. J Pediatr 154: 39–43
Kramer BW 2008 Antenatal inflammation and lung injury: prenatal origin of neonatal disease. J Perinatol 28: S21–S27
Curley AE, Sweet DG, Thornton CM, O'Hara MD, Chesshyre E, Pizzotti J, Wilbourn MS, Halliday HL, Warner JA 2003 Chorioamnionitis and increased neonatal lung lavage fluid matrix metalloproteinase-9 levels: implications for antenatal origins of chronic lung disease. Am J Obstet Gynecol 188: 871–875
Gupta M, Mestan KK, Martin CR, Pearson C, Ortiz K, Fu L, Stubblefield P, Cerda S, Kasznica JM, Wang X 2007 Impact of clinical and histologic correlates of maternal and fetal inflammatory response on gestational age in preterm births. J Matern Fetal Neonatal Med 20: 39–46
Watterberg KL, Demers LM, Scott SM, Murphy S 1996 Chorioamnionitis and early lung inflammation in infants in whom bronchopulmonary dysplasia develops. Pediatrics 97: 210–215
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We thank our medical and nursing colleagues, the infants, and their parents who agreed to take part in this study.
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Supported by Eunice Kennedy Shriver National Institute of Child Health and Human Development and the Department of Health and Human Services Grants U10 HD21385, U10 HD40689, U10 HD27871, U10 HD21373, U10 HD36790, U10 HD40461, U10 HD34216, U10 HD21397, U10 HD27904, U10 HD40492, U10 HD27856, U10 HD40521, U10 HD27853, U10 HD27880, U10 HD27851, and R03 HD054420 and National Institutes of Health Grants GCRC M01 RR 08084, M01 RR 00125, M01 RR 00750, M01 RR 00070, M01 RR 0039-43, M01 RR 00039, and 5 M01 RR00044.
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Natarajan, G., Shankaran, S., McDonald, S. et al. Circulating β Chemokine and MMP 9 as Markers of Oxidative Injury in Extremely Low Birth Weight Infants. Pediatr Res 67, 77–82 (2010). https://doi.org/10.1203/PDR.0b013e3181c0b16c
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DOI: https://doi.org/10.1203/PDR.0b013e3181c0b16c
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