Published ahead of print on August 18, 2005, doi:10.1164/rccm.200506-1007OC Am. J. Respir. Crit. Care Med., Volume 172, Number 10, November 2005, 1315-1321 A more recent version of this article appeared on November 15, 2005
Submitted on June 30, 2005 Recruited Inflammatory Cells Mediate Endotoxin Induced Lung Maturation in Preterm Fetal LambsSuhas G Kallapur1*,1 Divison of Pulmonary Biology and Neonatology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA, 2 University of Western Australia, School of Women's and Infants' Health, Perth, W. Australia, Australia, 3 ICOS Corporation, Bothell, WA, USA * To whom correspondence should be addressed. E-mail: suhas.kallapur{at}cchmc.org.
Rationale: Chorioamnionitis is paradoxically associated with a decreased incidence of respiratory distress syndrome in preterm infants. In preterm lambs, intra-amniotic endotoxin and interleukin-1 induce lung inflammation followed by lung maturation. Objective: To test if inflammatory cells are required to mediate induced lung maturation. Methods: Lung inflammation was induced by intra-amniotic injection of endotoxin or IL-1. Inflammatory cell recruitment to the lung was inhibited by an anti-CD18 blocking antibody given intra-muscular to the fetus. Preterm lambs were delivered at 124d gestation (term=150d) 2 days or 7 days after exposure to endotoxin/IL-1 or endotoxin/IL-1+anti-CD18 antibody. Measurements: Lung inflammation was measured by bronchoalveolar lavage fluid cell count, inflammatory scoring of lung parenchyma, expression of pro-inflammatory cytokines and inducible nitric oxide synthase. Lung maturation was quantitated by surfactant protein mRNA expression, saturated phosphatidyl choline pool size and pressure-volume curves. Main results: Inhibition of CD18 significantly reduced endotoxin induced but not IL-1 induced fetal lung inflammatory cell recruitment and activation as well as expression of pro-inflammatory cytokines. Compared with controls, both endotoxin and IL-1 induced lung maturation. Anti CD18 antibody administration inhibited only endotoxin induced but not IL-1 induced increases in surfactant protein mRNA and surfactant saturated phospatidylcholine. Exposure to anti-CD18 antibody moderated endotoxin induced increases in lung volumes but had no effect on IL-1 induced increases in lung volumes. Conclusions: i) Endotoxin but not IL-1 induced inflammatory cell recruitment in the preterm fetal lamb lung is CD18 dependent. ii) Recruited inflammatory cells mediate some aspects of fetal lung maturation. Key words: Respiratory distress syndrome, surfactant, chorio-amnionitis, BPD, CD18
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