Bronchoalveolar lavage fluid from preterm infants with chorioamnionitis inhibits alveolar epithelial repair.
BACKGROUND
Preterm infants are highly susceptible to lung injury. While both chorioamnionitis and antenatal steroids induce lung maturation, chorioamnionitis is also associated with adverse lung development. We investigated the ability of bronchoalveolar lavage fluid (BALF) from ventilated preterm infants to restore alveolar epithelial integrity after injury in vitro, depending on whether or not they were exposed to chorioamnionitis or antenatal steroids. For this purpose, a translational model for alveolar epithelial repair was developed and characterised.


METHODS
BALF was added to mechanically wounded monolayers of A549 cells. Wound closure was quantified over time and compared between preterm infants (gestational age < 32 wks) exposed or not exposed to chorioamnionitis and antenatal steroids (>or= 1 dose). Furthermore, keratinocyte growth factor (KGF) and vascular endothelial growth factor (VEGF) were quantified in BALF, and their ability to induce alveolar epithelial repair was evaluated in the model.


RESULTS
On day 0/1, BALF from infants exposed to antenatal steroids significantly increased epithelial repair (40.3 +/- 35.5 vs. -6.3 +/- 75.0% above control/mg protein), while chorioamnionitis decreased wound-healing capacity of BALF (-2.9 +/- 87.1 vs. 40.2 +/- 36.9% above control/mg protein). BALF from patients with chorioamnionitis contained less KGF (11 (0-27) vs. 0 (0-4) pg/ml) and less detectable VEGF (66 vs. 95%) on day 0. BALF levels of VEGF and KGF correlated with its ability to induce wound repair. Moreover, KGF stimulated epithelial repair dose-dependently, although the low levels in BALF suggest KGF is not a major modulator of BALF-induced wound repair. VEGF also stimulated alveolar epithelial repair, an effect that was blocked by addition of soluble VEGF receptor-1 (sVEGFr1/Flt-1). However, BALF-induced wound repair was not significantly affected by addition of sVEGFr1.


CONCLUSIONS
Antenatal steroids improve the ability of BALF derived from preterm infants to stimulate alveolar epithelial repair in vitro. Conversely, chorioamnionitis is associated with decreased wound-healing capacity of BALF. A definite role for KGF and VEGF in either process could not be established. Decreased ability to induce alveolar epithelial repair after injury may contribute to the association between chorioamnionitis and adverse lung development in mechanically ventilated preterm infants.
Been
Jasper V
JV
Department of Paediatrics, School for Oncology and Developmental Biology (GROW), Maastricht University Medical Centre, PO Box 5800, 6202 AZ Maastricht, the Netherlands. jasper.been@mumc.nl
Zimmermann
Luc J I
LJ
Debeer
Anne
A
Kloosterboer
Nico
N
van Iwaarden
J Freek
JF
D000418:Albumins / Q000378:metabolism; D017209:Apoptosis; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D002821:Chorioamnionitis / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D005260:Female; D051523:Fibroblast Growth Factor 7 / Q000378:metabolism; D005865:Gestational Age; D006801:Humans; D007231:Infant, Newborn; D007234:Infant, Premature; D011247:Pregnancy; D011650:Pulmonary Alveoli / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D012121:Respiration, Artificial; D012127:Respiratory Distress Syndrome, Newborn / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D013256:Steroids / Q000627:therapeutic use; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism; D014945:Wound Healing / Q000187:drug effects
D000418:Albumins; C496453:FGF7 protein, human; D013256:Steroids; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D051523:Fibroblast Growth Factor 7; D040281:Vascular Endothelial Growth Factor Receptor-1