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Objective To investigate the role of polymorphonuclear leukocytes (PMNs) in a mouse model of E. coli-induced labor. Study Design Intraperitoneal injection of rabbit anti-mouse PMN antiserum or control was performed in CD-1 mice 29 hours and 5 hours prior to laparotomy and intrauterine injection of either killed E. coli or phosphate buffered saline on Day 14.5 of pregnancy. Preterm delivery was defined as delivery of at least one pup within 48 hours. Circulating leukocyte counts were determined manually or by flow cytometry at the time of surgery and 8, 24 and 48 hours afterwards. Maternal and fetal tissues were analyzed in a separate group of animals 8 hours after surgery. Results Pre-treatment with anti-PMN antiserum significantly decreased the numbers of circulating leukocytes and the proportion of neutrophils among all leukocytes by 70–80% at surgery and at least 8 hours thereafter. Neutrophil depletion significantly reduced two markers of neutrophil activation in uterus and placenta (neutrophil elastase and myeloperoxidase activity) and neutrophil infiltration into gestational tissues in bacterially treated animals to baseline (control) levels, but did not affect preterm birth rates. The large E. coli-induced increases in uterine inflammatory markers (interleukin 1β, tumor necrosis factor, CCL5, cyclooxygenase 2) were not affected or were only minimally affected by neutrophil depletion. Conclusions Although PMN antiserum reduces both neutrophil number and activity, it does not diminish sensitivity to bacterially induced delivery or meaningfully alter the expression of inflammatory markers in the mouse model. Preterm birth and inflammation in this model are not likely to depend on neutrophil function.

BACKGROUND The relative roles of the mother and fetus in signaling for labor remain poorly understood. OBJECTIVE We previously demonstrated using gene-knockout (KO) mice that E. coli-induced preterm delivery is completely dependent upon MyD88, a toll-like receptor adaptor protein. Here, we leveraged this finding to conduct a genetic experiment testing whether the mother, the fetus, or both signal for parturition in bacterially induced labor. STUDY DESIGN Six different maternal/fetal genotype combinations for MyD88 were studied: Wild-type (WT) dams carrying either (1) WT or (2) MyD88 heterozygous (het) fetuses (generated by mating WT females with WT or MyD88-KO males, respectively); (3) WT dams carrying MyD88-KO fetuses (generated by replacing the ovaries of WT females with MyD88-KO ovaries, followed by mating with MyD88-KO males). A similar strategy was used to generate MyD88-KO dams carrying (4) MyD88-KO, (5) MyD88 het or (6) WT fetuses. On day 14.5 of gestation, mice received intrauterine injections of either 1 × 109 killed E. coli or sterile medium. Delivery of ≥1 fetus within 48h was considered preterm. A separate group of similarly treated pregnant mice was euthanized 5 hours after surgery for gene expression and tissue analysis. RESULTS E. coli-induced preterm delivery is dependent upon maternal and not fetal genotype: >95% of WT and < 5% of MyD88-KO dams deliver prematurely regardless of fetal genotype (p=0.0001). In contrast, fetal survival in utero is influenced by fetal genotype: in MyD88-KO dams, in which premature birth rarely occurs, only 81% of WT and 86% of MyD88-heterozygous fetuses were alive 48 hours after surgery compared to 100% of MyD88-KO fetuses (p < 0.01). mRNAs for the inflammatory mediators IL-1β, TNF, IL-6 and COX-2 were elevated in uterine tissues only in WT mothers treated with E. coli, and were low or undetectable in the uteri of KO mothers or in animals treated with saline. Serum progesterone levels were lower in KO mothers with WT ovaries than in WT mothers with KO ovaries, but bacterial exposure did not impact these levels. CONCLUSIONS In the murine E. coli-induced labor model, preterm delivery and uterine expression of inflammatory mediators is determined by the mother and not the fetus, and is not attributable to a decline in serum progesterone.

Background: We sought to develop a model of bacterially induced preterm delivery in rats to parallel similar models in mice.