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Cord blood Clara cell protein CC16 predicts the development of bronchopulmonary dysplasia

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Abstract

Clara cell protein (CC16) is an anti-inflammatory protein and a biomarker of pulmonary epithelial cells and alveolocapillary membrane injury in adults. We investigated whether low cord blood concentrations of CC16 are associated with the development of respiratory distress syndrome (RDS) and bronchopulmonary dysplasia (BPD) in preterm infants and the relationship between CC16 and its pro-inflammatory counterpart, the secretory phospholipase A2 (sPLA2) enzyme. CC16 concentration, sPLA2 activity and IL-6 concentration were measured in cord blood plasma from 79 preterm infants (25 controls, 37 infants who developed RDS and 17 infants who developed BPD). After adjustment for gestational age and Apgar score at 5 min, the CC16 concentration was lower in BPD infants than in preterm controls (p<0.01). sPLA2 activity was similar in all groups and the IL-6 concentrations were increased in both RDS and BPD infants (p<0.01 and p<0.05, respectively, vs. controls). We conclude that low cord blood CC16 concentrations in preterm infants independently predict the development of BPD. Low CC16 levels may reflect early lung injury, which contributes to the severity of RDS and progress towards BPD. Future studies are needed to assess whether the early administration of recombinant human CC16 in preterm infants with low cord blood CC16 prevents the development of BPD.

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Abbreviations

ARDS:

Acute respiratory distress syndrome

AUC:

Area under the curve

BPD:

Bronchopulmonary dysplasia

CC16:

Clara cell protein

COPD:

Chronic obstructive pulmonary diseases

CPAP:

Continuous positive airway pressure

IL-6:

Interleukin-6

IVH:

Intraventricular haemorrhage

PDA:

Patent ductus arteriosus

PVL:

Periventricular leucomalacia

RDS:

Respiratory distress syndrome

ROC:

Receiver operating characteristic

ROP:

Retinopathy of prematurity

sPLA2 :

Secretory phospholipase A2

References

  1. Bernard A, Thielemans N, Lauwerys R, Langhendries JP, Van Lierde M, Freund MM (1994) Clara cell protein in human amniotic fluid: a potential marker of fetal lung growth. Pediatr Res 36:771–775

    Article  PubMed  CAS  Google Scholar 

  2. Bland RD (1972) Cord-blood total protein level as a screening aid for the idiopathic respiratory-distress syndrome. N Engl J Med 287:9–13

    PubMed  CAS  Google Scholar 

  3. Broeckaert F, Clippe A, Knoops B, Hermans C, Bernard A (2000) Clara cell secretory protein (CC16): features as a peripheral lung biomarker. Ann N Y Acad Sci 923:68–77

    Article  PubMed  CAS  Google Scholar 

  4. Brus F, van Oeveren W, Okken A, Oetomo SB (1997) Number and activation of circulating polymorphonuclear leukocytes and platelets are associated with neonatal respiratory distress syndrome severity. Pediatrics 99:672–680

    Article  PubMed  CAS  Google Scholar 

  5. Chandra S, Davis JM, Drexler S, Kowalewska J, Chester D, Koo HC, Pollack S, Welch R, Pilon A, Levine CR (2003) Safety and efficacy of intratracheal recombinant human Clara cell protein in a newborn piglet model of acute lung injury. Pediatr Res 54:509–515

    Article  PubMed  CAS  Google Scholar 

  6. Crowl RM, Stoller TJ, Conroy RR, Stoner CR (1991) Induction of phospholipase A2 gene expression in human hepatoma cells by mediators of the acute phase response. J Biol Chem 266:2647–2651

    PubMed  CAS  Google Scholar 

  7. Dhanireddy R, Kikukawa T, Mukherjee AB (1988) Detection of a rabbit uteroglobin-like protein in human neonatal tracheobronchial washings. Biochem Biophys Res Commun 152:1447–1454

    Article  PubMed  CAS  Google Scholar 

  8. Ferreira PJ, Bunch TJ, Albertine KH, Carlton DP (2000) Circulating neutrophil concentration and respiratory distress in premature infants. J Pediatr 136:466–472

    Article  PubMed  CAS  Google Scholar 

  9. Furue S, Mikawa K, Nishina K, Shiga M, Ueno M, Tomita Y, Kuwabara K, Teshirogi I, Ono T, Hori Y, Matsukawa A, Yoshinaga M, Obara H (2001) Therapeutic time-window of a group IIA phospholipase A2 inhibitor in rabbit acute lung injury: correlation with lung surfactant protection. Crit Care Med 29:719–727

    Article  PubMed  CAS  Google Scholar 

  10. Gioldassi XM, Papadimitriou H, Mikraki V, Karamanos NK (2004) Clara cell secretory protein: determination of serum levels by an enzyme immunoassay and its importance as an indicator of bronchial asthma in children. J Pharm Biomed Anal 34:823–826

    Article  PubMed  CAS  Google Scholar 

  11. Groneck P, Götze-Speer B, Oppermann M, Eiffert H, Speer CP (1994) Association of pulmonary inflammation and increased microvascular permeability during the development of bronchopulmonary dysplasia: a sequential analysis of inflammatory mediators in respiratory fluids of high-risk preterm neonates. Pediatrics 93:712–718

    PubMed  CAS  Google Scholar 

  12. Halatek T, Hermans C, Broeckaert F, Wattiez R, Wiedig M, Toubeau G, Falmagne P, Bernard A (1998) Quantification of Clara cell protein in rat and mouse biological fluids using a sensitive immunoassay. Eur Respir J 11:726–733

    PubMed  CAS  Google Scholar 

  13. Harrod KS, Mounday AD, Stripp BR, Whitsett JA (1998) Clara cell secretory protein decreases lung inflammation after acute virus infection. Am J Physiol 275:L924–930

    PubMed  CAS  Google Scholar 

  14. Hermans C, Bernard A (1999) Lung epithelium-specific proteins: characteristics and potential applications as markers. Am J Respir Crit Care Med 159:646–678

    PubMed  CAS  Google Scholar 

  15. Hermans C, Knoops B, Wiedig M, Arsalane K, Toubeau G, Falmagne P, Bernard A (1999) Clara cell protein as a marker of Clara cell damage and bronchoalveolar blood barrier permeability. Eur Respir J 13:1014–1021

    Article  PubMed  CAS  Google Scholar 

  16. Hermans C, Petrek M, Kolek V, Weynand B, Pieters T, Lambert M, Bernard A (2001) Serum Clara cell protein (CC16), a marker of the integrity of the air–blood barrier in sarcoidosis. Eur Respir J 18:507–514

    Article  PubMed  CAS  Google Scholar 

  17. Jacobs RF, Wilson CB, Palmer S, Springmeyer SC, Henderson WR, Glover DM, Kessler DL Jr, Murphy JH, Hughes JP, van Belle G, Chi EY, Hodson WA (1985) Factors related to the appearance of alveolar macrophages in the developing lung. Am Rev Respir Dis 131:548–553

    PubMed  CAS  Google Scholar 

  18. Jobe AH (2003) Antenatal factors and the development of bronchopulmonary dysplasia. Semin Neonatol 8:9–17

    Article  PubMed  Google Scholar 

  19. Johnston CJ, Mango GW, Finkelstein JN, Stripp BR (1997) Altered pulmonary response to hyperoxia in Clara cell secretory protein deficient mice. Am J Respir Cell Mol Biol 17:147–155

    PubMed  CAS  Google Scholar 

  20. Jorens PG, Sibille Y, Goulding NJ, van Overveld FJ, Herman AG, Bossaert L, De Backer WA, Lauwerys R, Flower RJ, Bernard A (1995) Potential role of Clara cell protein, an endogenous phospholipase A2 inhibitor, in acute lung injury. Eur Respir J 8:1647–1653

    Article  PubMed  CAS  Google Scholar 

  21. Lassus P, Nevalainen TJ, Eskola JU, Andersson S (2000) Clara-cell secretory protein in preterm infants’ tracheal aspirates correlates with maturity and increases in infection. Pediatr Pulmonol 30:466–469

    Article  PubMed  CAS  Google Scholar 

  22. Levine CR, Gewolb IH, Allen K, Welch RW, Melby JM, Pollack S, Shaffer T, Pilon AL, Davis JM (2005) The safety, pharmacokinetics, and anti-inflammatory effects of intratracheal recombinant human Clara cell protein in premature infants with respiratory distress syndrome. Pediatr Res 58:15–21

    Article  PubMed  CAS  Google Scholar 

  23. Loughran-Fowlds A, Oei J, Wang H, Xu H, Wimalasundera N, Egan C, Henry R, Lui K (2006) The influence of gestation and mechanical ventilation on serum clara cell secretory protein (CC10) concentrations in ventilated and nonventilated newborn infants. Pediatr Res 60:103–108

    Article  PubMed  Google Scholar 

  24. Markarian M, Jackson JJ, Bannon AE (1966) Serial serum total protein values in premature infants with and without the respiratory distress syndrome. J Pediatr 69:1046–1053

    Article  PubMed  CAS  Google Scholar 

  25. Merritt TA, Puccia JM, Stuard ID (1981) Cytologic evaluation of pulmonary effluent in neonates with respiratory distress syndrome and bronchopulmonary dysplasia. Acta Cytol 25:631–639

    PubMed  CAS  Google Scholar 

  26. Miller TL, Shashikant BN, Melby JM, Pilon AL, Shaffer TH, Wolfson MR (2005) Recombinant human Clara cell secretory protein in acute lung injury of the rabbit: effect of route of administration. Pediatr Crit Care Med 6:698–706

    Article  PubMed  Google Scholar 

  27. Miller TL, Shashikant BN, Pilon AL, Pierce RA, Shaffer TH, Wolfson MR (2006) Effects of an intratracheally delivered anti-inflammatory protein (rhCC10) on physiological and lung structural indices in a juvenile model of acute lung injury. Biol Neonate 89:159–170

    Article  PubMed  CAS  Google Scholar 

  28. Ramsay PL, DeMayo FJ, Hegemier SE, Wearden ME, Smith CV, Welty SE (2001) Clara cell secretory protein oxidation and expression in premature infants who develop bronchopulmonary dysplasia. Am J Respir Crit Care Med 164:155–161

    PubMed  CAS  Google Scholar 

  29. 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

    Article  PubMed  CAS  Google Scholar 

  30. Touqui L, Arbibe L (1999) A role for phospholipase A2 in ARDS pathogenesis. Mol Med Today 5:244–249

    Article  PubMed  CAS  Google Scholar 

  31. Walsh MC, Szefler S, Davis J, Allen M, Van Marter L, Abman S, Blackmon L, Jobe A (2006) Summary proceedings from the bronchopulmonary dysplasia group. Pediatrics 117:S52–S56

    PubMed  Google Scholar 

  32. Welty SE (2005) CC10 administration to premature infants: in search of the “silver bullet” to prevent lung inflammation. Pediatr Res 58:7–9

    Article  PubMed  Google Scholar 

  33. Yedgar S, Cohen Y, Shoseyov D (2006) Control of phospholipase A2 activities for the treatment of inflammatory conditions. Biochim Biophys Acta 1761:1373–1382

    PubMed  CAS  Google Scholar 

  34. Yoon BH, Romero R, Jun JK, Park KH, Park JD, Ghezzi F, Kim BI (1997) Amniotic fluid cytokines (interleukin-6, tumor necrosis factor-alpha, interleukin-1 beta, and interleukin-8) and the risk for the development of bronchopulmonary dysplasia. Am J Obstet Gynecol 177:825–830

    Article  PubMed  CAS  Google Scholar 

  35. Zhang Z, Kundu GC, Yuan CJ, Ward JM, Lee EJ, DeMayo F, Westphal H, Mukherjee AB (1997) Severe fibronectin-deposit renal glomerular disease in mice lacking uteroglobin. Science 276:1408–1412

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

The authors thank J. Geerdink for technical assistance, R. Munneke for assistance in the collection of cord blood samples, the nurses and midwives from the delivery room for the collection of cord blood and M. Mietes for assistance with the collection and review of the literature.

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Authors and Affiliations

  1. Neonatal Center, Department of Pediatrics, Leiden University Medical Center, J6-S, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands

    Alexandra J. J. Schrama, Howard M. Berger & Frans J. Walther

  2. Unit of Industrial Toxicology and Occupational Medicine, Faculty of Medicine, Catholic University of Louvain, 30.54 Clos Chapelle-aux-Champs, 1200, Brussels, Belgium

    Alfred Bernard

  3. Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ, Amsterdam, The Netherlands

    Ben J. H. M. Poorthuis

  4. Department of Medical Statistics, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands

    Aeilko H. Zwinderman

Authors
  1. Alexandra J. J. Schrama
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  2. Alfred Bernard
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  3. Ben J. H. M. Poorthuis
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  4. Aeilko H. Zwinderman
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  5. Howard M. Berger
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  6. Frans J. Walther
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Corresponding author

Correspondence to Frans J. Walther.

Additional information

This study was supported by grant 920-03-083 from the Netherlands Organisation for Scientific Research (NWO).

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Schrama, A.J.J., Bernard, A., Poorthuis, B.J.H.M. et al. Cord blood Clara cell protein CC16 predicts the development of bronchopulmonary dysplasia. Eur J Pediatr 167, 1305–1312 (2008). https://doi.org/10.1007/s00431-008-0713-2

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  • DOI: https://doi.org/10.1007/s00431-008-0713-2

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