Epithelial Lining Fluid Neutrophil-Gelatinase-Associated Lipocalin Levels in Premature Newborns with Bronchopulmonary Dysplasia and Patency of Ductus Arteriosus

Abstract

Patency of the ductus arteriosus (PDA) and bronchopulmonary dysplasia (BPD) development represent severe affections for premature newborns, therefore the research of early markers for these two conditions is really important. The aim of this study is to analyze epithelial lining fluid (ELF) Neutrophil-gelatinase-associated lipocalin (NGAL) levels for prediction of lung injury or possible involvement of this molecule in PDA. Only scarce and contrasting results have previously been published in this field. In contrast, this molecule, included in a large macromolecular complex together with matrix metalloproteinase-9 (MMP-9), is considered an acceptable marker of infectious/inflammatory processes, cancer monitoring and induction of apoptotic pathway. NGAL was detected in 28 pre-term newborns by means of a commercially available kit in bronchoalveolar lavage fluid (BALF). The results have been corrected to ELF levels, by the urea method, to eliminate bias due to BALF collection. ELF NGAL levels were found significantly increased both in infants developing BPD or in those affected by PDA. By means of multivariate logistic regression analysis the significances were confirmed after adjusting for possible interfering variables such as gestational age and concomitant presence of both PDA and BPD. Our results stress the involvement of NGAL in the mechanisms leading to BPD and also suggest a possible association with PDA, which is often linked to prematurity and BPD development, probably due to the involvement of inflammatory and angiogenetic processes in both pathologies.

Keywords

NGAL BPD MMP-9 prematurity

References

Kjeldsen

Johnsen

A.H.

Sengelov

and Borregaard

. 1993. Isolation and primary structure of NGAL, a novel protein associated with human neutrophil gelatinase. J. Biol. Chem. 268:10425.

Mori

and Nakao

. 2007. Neutrophil gelatinase-associated lipocalin as the real-time indicator of active kidney damage. Kidney Int. 71:96.

Goetz

D.H.

Willie

S.T.

Armen

R.S.

Bratt

Borregaard

and Strong

R.K.

. 2000. Ligand preference inferred from the structure of neutrophil gelatinase associated lipocalin. Biochemistry 29:1935.

Page-McCaw

Ewald

A.J.

and Werb

. 2007. Matrix metalloproteinases and the regulation of tissue remodelling. Nat. Rev. Mol. Cell Biol. 8:221.

D.X.

Hemdahl

A.L.

Gabrielsen

Fuxe

Zhu

Eriksson

and Yan

Z.Q.

. 2006. Induction of neutrophil gelatinase-associated lipocalin in vascular injury via activation of nuclear factor-kappaB. Am. J. Pathol. 169:2245.

Bachorzewska-Gajewska

Malyszko

Sitniewska

Malyszko

J.S.

and Dobrzycki

. 2006. Neutrophil-gelatinase-associated lipocalin and renal function after percutaneous coronary interventions. Am. J. Nephrol. 26:287.

Cowland

J.B.

Muta

and Borregaard

. 2006. IL-1beta-specific up-regulation of neutrophil gelatinase-associated lipocalin is controlled by IkappaB-zeta. J. Immunol. 176:5559.

Dik

W.A.

van Kaam

A.H.

Dekker

Naber

B.A.

Janssen

D.J.

Kroon

A.A.

Zimmermann

L.J.

Versnel

M.A.

and Lutter

. 2006. Early increased levels of matrix metalloproteinase-9 in neonates recovering from respiratory distress syndrome. Biol. Neonate 89:6.

Smith

G.C.S.

1998. The pharmacology of the ductus arteriosus. Pharmacolog. Rev. 50:34.

10.

Fortson

Beharry

K.D.

Nageotte

Sills

J.H.

Stavitsky

Asrat

and Modanlou

H.D.

. 2006. Vaginal versus oral indomethacin in a rabbit model for non-infection-mediated preterm birth: an alternate tocolytic approach. Am. J. Obstet. Gynecol. 195:1058.

11.

Ulug

Goldman

Ben-Shlomo

and Shalev

. 2001. Matrix metalloproteinase (MMP)-2 and MMP-9 and their inhibitor, TIMP-1, in human term decidua and fetal membranes: the effect of prostaglandin F(2alpha) and indomethacin. Mol. Hum. Reprod. 7:1187.

12.

Buller

K.M.

and Day

T.A.

. 1998. Indomethacin attenuates oxytocin and hypothalamic-pituitary-adrenal axis responses to systemic interleukin-1 beta. J. Neuroendocrinal. 1:519.

13.

Garay-Rojas

Harper

Hraba-Renevey

and Kress

. 1996. An apparent autocrine mechanism amplifies the dexamethasone- and retinoic acid-induced expression of mouse lipocalin-encoding gene 24p3. Gene 8:173.

14.

Roudkenar

M.H.

Kuwahara

Baba

Roushandeh

A.M.

Ebishima

Abe

Ohkubo

and Fukumoto

M.J.

. 2007. Oxidative stress induced lipocalin 2 gene expression: addressing its expression under the harmful conditions. Radiat. Res. (Tokyo) 48:39.

15.

Tong

Ovcharenko

Zhu

Chen

C.S.

and Kehrer

J.P.

. 2005. Neutrophil gelatinase-associated lipocalin as a survival factor. Biochem. J. 151:441.

16.

Sveger

Ohlsson

Morse

Polberger

and Laurin

. 2003. Plasma neutrophil lipocalin, elastase-alpha1-antitrypsin complex and neutrophil protease 4 in preterm infants with respiratory distress syndrome. Scand. J. Clin. Lab. Invest. 63:89.

17.

Tambunting

Beharry

K.D.

Hartleroad

Waltzman

Stavitsky

and Modanlou

H.D.

. 2005. Increased lung matrix metalloproteinase-9 levels in extremely premature baboons with bronchopulmonary dysplasia. Pediatr. Pulmonol. 39:5.

18.

Sweet

D.G.

Curley

A.E.

Chesshyre

Pizzotti

Wilbourn

M.S.

Halliday

H.L.

and Warner

J.A.

. 2004. The role of matrix metalloproteinases -9 and -2 in development of neonatal chronic lung disease. Acta Paediatr. 93:791.

19.

Ekekezie

I.I.

Thibeault

D.W.

Simon

S.D.

Norberg

Merrill

J.D.

Ballard

R.A.

Ballard

P.L.

and Truog

W.E.

. 2004. Low levels of tissue inhibitors of metalloproteinases with a high matrix metalloproteinase-9/tissue inhibitor of metalloproteinase-1 ratio are present in tracheal aspirate fluids of infants who develop chronic lung disease. Pediatrics 113:1709.

20.

Vento

Matassa

P.G.

Ameglio

Capoluongo

Zecca

Tortorolo

Martelli

and Romagnoli

. 2005. HFOV in premature neonates: effects on pulmonary mechanics and epithelial lining fluid cytokines. A randomized controlled trial. Intensive Care Med. 31:463.

21.

Rennard

S.I.

Basset

Lecossier

O'Donnell

K.M.

Pinkston

and Martin

P.G.

. 1986. Estimation of volume of epithelial lining fluid recovered by lavage using urea as marker of dilution. J. Appl. Physiol. 60:532.

22.

De Carolis

M.P.

Romagnoli

Polimeni

Piersigilli

Zecca

Papacci

Delogu

and Tortorolo

. 2000. Prophylactic ibuprofen therapy of patent ductus arteriosus in preterm infants. Eur. J. Pediatr. 159:364.

23.

Shennan

A.T.

Dunn

M.S.

Ohlsson

Lennox

and Hoskins

E.M.

. 1988. Abnormal pulmonary outcomes in premature infants: prediction from oxygen requirement in the neonatal period. Pediatrics 82:527.

24.

Asikainen

T.M.

Ahmad

Schneider

B.K.

and White

C.W.

. 2005. Effect of preterm birth on hypoxia-inducible factors and vascular endothelial growth factor in primate lungs. Pediatr. Pulmonol. 40:538.

25.

Asikainen

T.M.

Chang

L.Y.

Coalson

J.J.

Schneider

B.K.

Waleh

N.S.

Ikegami

Shannon

J.M.

Winter

V.T.

Grubb

Clyman

R.I.

Yoder

B.A.

Crapo

J.D.

and White

C.W.

. 2006. Improved lung growth and function through hypoxia-inducible factor in primate chronic lung disease of prematurity. FASEB J. 20:986.

26.

Capoluongo

Vento

Ameglio

Lulli

Matassa

P.G.

Carrozza

Santini

S.A.

Antenucci

Castagnola

Giardina

Romagnoli

and Zuppi

. 2006. Increased levels of IGF-1 and beta2-microglobulin in epithelial lining fluid of preterm newborns developing chronic lung disease, effects of rhG-CSF. Int. J. Immunopathol. Pharmacol. 19:57.