Uterine overdistention induces preterm labor mediated by inflammation: observations in pregnant women and nonhuman primates - 02/12/15
, Natasha Singh, MBBS, MRCOG, BSCCP i, Aarthi R. Mohan, MD, PhD j, Roger C. Young, MD, PhD l, Lisa Ngo, BS g, Ananya Das, MSc j, Jesse Tsai, BS b, Aasthaa Bansal, PhD d, Louis Paolella, BS e, Bronwen R. Herbert, BSc, PhD j, Suren R. Sooranna, PhD j, G. Michael Gough, MSc f, Cliff Astley, MS f, Keith Vogel, DVM f, Audrey E. Baldessari, DVM f, Theodor K. Bammler, PhD b, James MacDonald, MSc b, Michael G. Gravett, MD a, h, Lakshmi Rajagopal, PhD c, g, Mark R. Johnson, MD, PhD kAbstract |
Objective |
Uterine overdistention is thought to induce preterm labor in women with twin and multiple pregnancies, but the pathophysiology remains unclear. We investigated for the first time the pathogenesis of preterm birth associated with rapid uterine distention in a pregnant nonhuman primate model.
Study Design |
A nonhuman primate model of uterine overdistention was created using preterm chronically catheterized pregnant pigtail macaques (Macaca nemestrina) by inflation of intraamniotic balloons (N = 6), which were compared to saline controls (N = 5). Cesarean delivery was performed due to preterm labor or at experimental end. Microarray, quantitative reverse transcriptase polymerase chain reaction, Luminex (Austin, TX), and enzyme-linked immunosorbent assay were used to measure messenger RNA (mRNA) and/or protein levels from monkey (amniotic fluid, myometrium, maternal plasma) and human (amniocytes, amnion, myometrium) tissues. Statistical analysis employed analysis of covariance and Wilcoxon rank sum. Biomechanical forces were calculated using the law of Laplace.
Results |
Preterm labor occurred in 3 of 6 animals after balloon inflation and correlated with greater balloon volume and uterine wall stress. Significant elevations of inflammatory cytokines and prostaglandins occurred following uterine overdistention in an “inflammatory pulse” that correlated with preterm labor (interleukin [IL]-1β, tumor necrosis factor [TNF]-α, IL-6, IL-8, CCL2, prostaglandin E2, prostaglandin F2α, all P < .05). A similar inflammatory response was observed in amniocytes in vitro following mechanical stretch (IL1β, IL6, and IL8 mRNA multiple time points, P < .05), in amnion of women with polyhydramnios (IL6 and TNF mRNA, P < .05) and in amnion (TNF-α) and myometrium of women with twins in early labor (IL6, IL8, CCL2, all P < .05). Genes differentially expressed in the nonhuman primate after balloon inflation and in women with polyhydramnios and twins are involved in tissue remodeling and muscle growth.
Conclusion |
Uterine overdistention by inflation of an intraamniotic balloon is associated with an inflammatory pulse that precedes and correlates with preterm labor. Our results indicate that inflammation is an early event after a mechanical stress on the uterus and leads to preterm labor when the stress is sufficiently great. Further, we find evidence of uterine tissue remodeling and muscle growth as a common, perhaps compensatory, response to uterine distension.
Le texte complet de cet article est disponible en PDF.Key words : amniocyte, amnion, chemokine (C-C motif) ligand 2, choriodecidua, cytokines, interleukin-1, interleukin-8, Macaca nemestrina, monocyte chemotactic protein 1, myometrium, pregnancy, preterm labor, prostaglandin E2, prostaglandin F2α, tumor necrosis factor, uterine stress, uterine stretch
Plan
| Research reported in this publication was supported by the March of Dimes (21-FY08-562), National Institute of Allergy and Infectious Diseases and the Eunice Kennedy Shriver National Institute for Child Health and Human Development of the National Institute of Health (NIH) (grant numbers R01AI100989, R21AI09222, R01AI112619, K08AI067910, P30HD002274, U54 HD083091), and the Global Alliance for the Prevention of Prematurity and Stillbirth (GAPPS 12007) in partnership with the Bill and Melinda Gates Foundation. This project was also supported by the Office of Research Infrastructure Programs of the NIH (P51OD010425) through the Washington National Primate Research Center. |
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| The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or other funders. The sponsors had no role in the study design, collection, analysis, and interpretation of the data; writing of the report; or decision to submit the article for publication. |
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| The authors report no conflict of interest. |
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| Cite this article as: Adams Waldorf KM, Singh N, Mohan AR, et al. Uterine overdistention induces preterm labor mediated by inflammation: observations in pregnant women and nonhuman primates. Am J Obstet Gynecol 2015;213:830.e1-19. |
Vol 213 - N° 6
P. 830.e1-830.e19 - décembre 2015 Retour au numéro
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