The fetal maturational and inflammatory responses to different routes of endotoxin infusion in sheep.
OBJECTIVE
In clinical practice, chorioamnionitis has been observed to enhance fetal lung maturation in the short term but may predispose to chronic lung disease thereafter. Using the sheep model, we have previously shown that injection of endotoxin into the amniotic cavity results in inflammatory responses and profoundly enhances newborn lung function after preterm birth. The fetus tolerates intra-amniotic doses of endotoxin considerably greater than those that are lethal if given intramuscularly. This study aimed to explore the mechanisms by which endotoxin matures the lungs by determining whether the route of administration influenced the maturational responses of the fetus.


METHODS
Date-mated ewes at 118 days of pregnancy were allocated at random to receive endotoxin (Escherichia coli lipopolysaccharide 055;B5) directly into the trachea (n = 7), stomach (n = 6), amniotic cavity (n = 7), or peritoneal cavity (n = 4) of the fetal lamb by surgical implantation of an osmotic pump delivering 1 mg of endotoxin over a 24-hour period. Results were compared with those obtained in saline solution-infused controls (n = 9). The lambs were delivered by cesarean section at 125 days' gestation (term is 150 days).


RESULTS
Endotoxin infusion into the trachea, stomach, and amniotic cavity each resulted in inflammatory responses in lung fluid and improved postnatal lung function, and effects were similar for each route of administration. These effects occurred with minimal features of systemic inflammation. Intraperitoneal infusion resulted in severe fetal acidosis or death.


CONCLUSIONS
These findings provide further evidence that the lung-maturing effects of intra-amniotic endotoxin are mediated by local factors in the respiratory system rather than by systemic inflammatory responses. Chorioamnionitis may alter lung function and possibly lead to chronic injury without clinical features of systemic inflammation or compromise.
Newnham
John P
JP
Department of Obstetrics and Gynaecology, University of Western Australia at King Edward Memorial Hospital, Subiaco, Perth, Australia.
Moss
Timothy J M
TJ
Kramer
Boris W
BW
Nitsos
Ilias
I
Ikegami
Machiko
M
Jobe
Alan H
AH
D000138:Acidosis / Q000139:chemically induced; D000653:Amniotic Fluid / Q000166:cytology / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn / Q000502:physiology; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D002821:Chorioamnionitis / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D005314:Embryonic and Fetal Development / Q000187:drug effects*; D004731:Endotoxins / Q000008:administration & dosage* / Q000494:pharmacology; D004926:Escherichia coli; D005260:Female; D005313:Fetal Death / Q000139:chemically induced; D007260:Infusion Pumps; D007274:Injections, Intraperitoneal / Q000009:adverse effects; D007958:Leukocyte Count; D008168:Lung / Q000187:drug effects / Q000502:physiology; D009504:Neutrophils / Q000473:pathology; D010713:Phosphatidylcholines / Q000378:metabolism; D011247:Pregnancy; D012756:Sheep / Q000196:embryology; D013270:Stomach; D014132:Trachea
D004731:Endotoxins; D010713:Phosphatidylcholines