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IL-8 signaling does not mediate intra-amniotic LPS-induced inflammation and maturation in preterm fetal lamb lung.

Abstract
Preterm infants exposed to chorioamnionitis and preterm sheep fetuses exposed to intra-amniotic (IA) LPS have lung inflammation, increased IL-8 levels, and lung maturation. We tested the hypothesis that IL-8 signaling mediates IA LPS-induced lung inflammation and lung maturation. Two strategies were used: 1) we tested if IA injection of recombinant sheep IL-8 (rsIL-8) induced fetal inflammation and 2) if IL-8 signaling was blocked by a novel CXCR2 receptor blocker, nicotinanilide thioglycolate methyl ester (NTME). To test effects of IL-8 in the fetus, rsIL-8 was given intravascularly (50 microg) at 124 +/- 1 day of gestation (term = 150 days). A separate group of sheep was given IA rsIL-8 (100 microg) and delivered 5 h to 7 days later at 124 +/- 1 day of gestation. After confirming efficacy of the CXCR2 inhibitor, effects of IL-8 blockade were tested by injecting fetal sheep intramuscularly with NTME (10 mg) before IA injection of Escherichia coli LPS (10 mg). Sheep fetuses were delivered 1 or 7 days after injections at 124 +/- 1 day of gestation. IA rsIL-8 induced a modest fivefold increase in bronchoalveolar lavage (BAL) monocytes and neutrophils and increased lung monocyte hydrogen peroxide generation. However, rsIL-8 did not induce lung maturation. Intravascular rsIL-8 did not change fetal cardiovascular variables, blood pH, or blood leukocyte counts. Inhibition of CXCR2 decreased IA LPS-induced increases in BAL proteins at 1 day but not at 7 days. NTME did not significantly decrease IA LPS-induced BAL leukocyte influx and lung cytokine mRNA expression. Inhibition of CXCR2 did not change IA LPS-induced lung maturation. IL-8 signaling does not mediate LPS-induced lung inflammation and lung maturation.
AuthorsSuhas G Kallapur, Timothy J M Moss, Richard L Auten Jr, Ilias Nitsos, J Jane Pillow, Boris W Kramer, Dean Y Maeda, John P Newnham, Machiko Ikegami, Alan H Jobe
JournalAmerican journal of physiology. Lung cellular and molecular physiology (Am J Physiol Lung Cell Mol Physiol) Vol. 297 Issue 3 Pg. L512-9 (Sep 2009) ISSN: 1522-1504 [Electronic] United States
PMID19574422 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Esters
  • Interleukin-8
  • Lipopolysaccharides
  • Receptors, Interleukin-8B
  • Recombinant Proteins
Topics
  • Amnion (drug effects)
  • Animals
  • Drug Administration Routes
  • Esters (pharmacology)
  • Female
  • Fetus (drug effects, pathology)
  • Inflammation (chemically induced, metabolism)
  • Interleukin-8 (metabolism)
  • Leukocyte Count
  • Lipopolysaccharides (administration & dosage, pharmacology)
  • Lung (drug effects, pathology)
  • Pregnancy
  • Premature Birth (pathology)
  • Receptors, Interleukin-8B (antagonists & inhibitors)
  • Recombinant Proteins (pharmacology)
  • Reproducibility of Results
  • Sheep
  • Signal Transduction (drug effects)

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