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B Inhibitor1
*Liggins Institute and
National Research Centre for Growth and Development, University of Auckland, Auckland, New Zealand; and
School of Women’s and Infants’ Health, University of Western Australia, Perth, Western Australia, Australia
Intrauterine inflammation plays a major role in the etiology of preterm labor and birth. We established an ex vivo model employing perfused full-thickness term gestational membranes to study membrane transport, function, and inflammatory responses. Exposure of the maternal (decidual) face of the membranes to LPS (5 µg/ml) resulted in increased accumulation of proinflammatory cytokines in the maternal compartment within 4 h, followed by a response in the fetal (amniotic) compartment. Using cytokine arrays, exposure to LPS was found to result in increased secretion of a large number of cytokines and chemokines in both compartments, most notably IL-5, IL-6, IL-7, MDC (macrophage-derived chemokine), MIG (monokine induced by IFN-
), TARC (thymus and activation-regulated chemokine), TGF-β, and TNF-
. PGE2 accumulation also increased in response to LPS, particularly in the fetal compartment. Cotreatment with sulfasalazine, which inhibited nuclear translocation of NF-
B p65, had a rapid and marked inhibitory effect on the rate of cytokine accumulation in the maternal compartment, with lesser but significant effects observed in the fetal compartment. While membrane integrity was not discernibly impaired with LPS or sulfasalazine exposure, rates of chorionic apoptosis after 20 h were doubled in sulfasalazine-treated tissues. We conclude that the system described provides a means of accurately modeling human gestational membrane functions and inflammatory activation ex vivo. Decidual LPS exposure was shown to elicit a robust inflammatory response in both the maternal and fetal compartments. Sulfasalazine was an effective antiinflammatory agent in this model, but also exerted proapoptotic effects that raise concerns regarding its placental effects when administered in pregnancy.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported in part by a Prematurity Initiative Program Grant No. 21-FY05-1247 from the March of Dimes Foundation, the Health Research Council of New Zealand, the Maurice and Phyllis Paykel Trust, and the National Research Centre for Growth and Development (New Zealand). J.A.K. is supported by the Women and Infants Research Foundation (Western Australia); M.D.M. is supported by a James Cook Research Fellowship funded by the Royal Society of New Zealand.
2 Address correspondence and reprint requests to Dr. Jeffrey A. Keelan, School of Women’s and Infants’ Health, University of Western Australia, King Edward Memorial Hospital, 374 Bagot Road, Subiaco, Perth, Western Australia 6008, Australia. E-mail address: jeff.keelan{at}uwa.edu.au
3 Abbreviations used in this paper: MMP, matrix metalloprotease; CV, coefficient of variation; FITC-Dx, FITC-coupled dextran; LDH, lactate dehydrogenase; MDC, macrophage-derived chemokine; MIG, monokine induced by IFN-; SSZ, sulfasalazine; TARC, thymus and activation-regulated chemokine.
4 The online version of this article contains supplemental material.
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