IL-8 signaling does not mediate intra-amniotic LPS-induced inflammation and maturation in preterm fetal lamb lung.
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.
Kallapur
Suhas G
SG
Cincinnati Children's Hospital Medical Center, University of Cincinnati, Division of Pulmonary Biology, 3333 Burnet Ave., Cincinnati, OH 45229-3039, USA. suhas.kallapur@cchmc.org
Moss
Timothy J M
TJ
Auten
Richard L
RL
Nitsos
Ilias
I
Pillow
J Jane
JJ
Kramer
Boris W
BW
Maeda
Dean Y
DY
Newnham
John P
JP
Ikegami
Machiko
M
Jobe
Alan H
AH
D000650:Amnion / Q000187:drug effects; D000818:Animals; D004333:Drug Administration Routes; D004952:Esters / Q000494:pharmacology; D005260:Female; D005333:Fetus / Q000187:drug effects / Q000473:pathology*; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism*; D016209:Interleukin-8 / Q000378:metabolism*; D007958:Leukocyte Count; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000494:pharmacology*; D008168:Lung / Q000187:drug effects / Q000473:pathology*; D011247:Pregnancy; D047928:Premature Birth / Q000473:pathology*; D023063:Receptors, Interleukin-8B / Q000037:antagonists & inhibitors; D011994:Recombinant Proteins / Q000494:pharmacology; D015203:Reproducibility of Results; D012756:Sheep; D015398:Signal Transduction / Q000187:drug effects*
D004952:Esters; D016209:Interleukin-8; D008070:Lipopolysaccharides; D023063:Receptors, Interleukin-8B; D011994:Recombinant Proteins