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Title: Role of infection and inflammation in a mouse model of preterm labour
Author: Rinaldi, Sara Francesca
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2013
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Increasing evidence highlights that term labour is an inflammatory event associated with increased production of pro-­‐inflammatory mediators and leukocyte influx into the intrauterine tissues. Preterm labour (PTL), defined as labour before 37 weeks gestation, is a major clinical problem, and preterm birth is the leading cause of neonatal mortality and morbidity worldwide. The causes of PTL are poorly understood, but intrauterine infection and inflammation have been shown to be important factors. Therefore, there is growing interest in the hypothesis that preterm labour may occur as a result of the premature activation of the inflammatory pathways normally initiated with labour at term, either idiopathically, or in response to a pathological intrauterine infection. The aim of this thesis was to use a mouse model of infection-­induced PTL to: characterise the local inflammatory and immune response to an intrauterine infection; investigate the potential of anti‐inflammatory agents to delay delivery of pups and to improve their survival; and to investigate the role of specific immune cell populations in infection-­induced preterm labour. To characterise the inflammatory and immune response to intrauterine infection, CD1 mice received an intrauterine injection of PBS vehicle or increasing doses of bacterial-­derived lipopolysaccharide (LPS) on day 17 of gestation. Time to delivery, and the number of live born pups were determined. Intrauterine administration of increasing doses of LPS dose-­dependently induced preterm labour and reduced the proportion of live born pups. Analysis of tissues harvested six hours post-­surgery demonstrated that in response to intrauterine LPS administration, there was increased expression of inflammatory cytokines and chemokines within the utero-­placental tissues, amniotic fluid and maternal serum; and an influx of neutrophils into the decidua, compared to mice receiving PBS. Given these results, the potential of anti‐inflammatory agents to delay LPS-­induced preterm delivery and improve pup survival was then investigated using the same mouse model. Prior to intrauterine LPS administration, mice were pre-­‐treated with epi-­lipoxin, BML-­111 (a stable lipoxin analogue), or IL-­10. Time to delivery was unaffected by pre-­treatment with the anti-­inflammatory agents, however epi-­lipoxin significantly increased the proportion of live born pups in mice delivering preterm, compared to mice receiving only LPS. To further investigate the role of immune cells in infection-­induced PTL, antibody-­based depletion strategies were used to selectively deplete specific immune cell populations to determine whether they played a causative role in LPS­‐induced preterm delivery. Despite successful depletion of macrophages or neutrophils, it was not found to significantly affect LPS-­induced preterm delivery, suggesting these immune cells are not required for the induction of preterm labour in response to intrauterine infection. However, it is likely that they contribute to the intrauterine inflammatory response as depletion resulted in altered inflammatory signalling within the intrauterine tissues. Collectively, this work has demonstrated that the presence of intrauterine bacterial LPS, as a surrogate model of infection, induces a robust inflammatory and immune response within the utero‐placental tissues that involves the increased production of inflammatory mediators and the influx of immune cells into the decidua, which ultimately leads to PTL. Whilst the anti-­inflammatory treatments tested here did not delay LPS-­induced PTL, epi-­lipoxin attenuated LPS-­induced mortality in pups born preterm, suggesting this anti‐inflammatory agent may be useful in protecting the fetus from the adverse effects of infection-­induced preterm birth. Using models such as the one described here, are vital to improving our understanding of the events regulating the induction of PTL and will ultimately aid the search for novel therapeutic options for the treatment of PTL.
Supervisor: Norman, Jane ; Jabbour, Henry ; Rossi, Adriano Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: preterm labour ; inflammatory pathways ; LPS administration