Vaginal Progesterone, but not 17-alpha-hydroxyprogesterone caproate has anti-inflammatory effects: The rate of preterm birth in the United States is 11.39%, which is considered high for a developed nation. Two strategies for the prevention of preterm birth include the administration of vaginal progesterone to women with a short cervix (reduces the rate of preterm birth by 45%) or 17-alpha-hydroxyprogesterone caproate (17OHP-C) to women with a history of preterm birth. Yet, the mechanisms whereby progestogens prevent preterm birth are unclear. We have explored whether the beneficial effect of progestogens can be attributed to immunomodulation. We found that vaginal progesterone, but not 17-OHPC, has anti-inflammatory effects at the maternal-fetal interface. We observed that vaginal progesterone increased the number of regulatory T cells and reduced effector T cells, as well as pro-inflammatory macrophages and neutrophils at the maternal-fetal interface. In addition, the administration of vaginal progesterone prevented endotoxin-induced preterm birth, which is not observed with 17OHP-C. This study provides insight into the mechanisms whereby vaginal progesterone prevents preterm birth in women with a sonographic short cervix. Intra-amniotic administration of the alarmin HMGB1 induces spontaneous preterm labor and delivery: Sterile intra-amniotic inflammation is frequently present in patients with preterm labor and intact membranes, prelabor rupture of membranes, a sonographic short cervix and cervical insufficiency. The mechanisms responsible for sterile intra-amniotic inflammation induced preterm delivery have not been elucidated. We have proposed that alarmins released during the process of cellular stress or cell death can induce spontaneous preterm parturition. In support of this, we have found that the prototypic alarmin high-mobility group box-1 HMGB1 is present in high concentrations in women with preterm labor and sterile intra-amniotic inflammation. To determine whether an elevated amniotic fluid concentration of HMGB1 can induce preterm labor, we administered HMGB1 intraamniotically to pregnant mice under ultrasound guidance and found that this alarmin can induce preterm labor and delivery. This is the first evidence that an alarmin can induce preterm parturition. These observations are important because a substantial number of patients with intra-amniotic inflammation do not have microbial invasion of the amniotic cavity, which can be demonstrated using cultivation and molecular microbiologic techniques. These results identify novel mechanisms of disease for preterm labor, raise questions about the mechanisms whereby alarmins can induce preterm labor, and identify potential therapeutic targets. A decidual M1-like macrophage polarization in preterm labor: The M1/M2 macrophage paradigm has been implicated in the pathogenesis of immune-related diseases, as well as in the physiology of pregnancy. The uterine quiescence during most of pregnancy has been attributed to a switch to M2 macrophage phenotype, which in turn switches to M1 at the time of initiation of labor at term. There is little known about the phenotype in spontaneous preterm labor in humans. We reported a number of studies showing that in women with preterm labor/delivery, macrophages undergo an M1-like macrophage polarization (i.e. acquisition of a pro-inflammatory phenotype) in decidual tissues from women who underwent spontaneous preterm labor. Decidual M1-like macrophages showed a high expression of pro-inflammatory cytokines such as tumor necrosis alpha and interleukin 12; yet, this was blunted by targeting the PPAR-gamma pathway via treatment with rosiglitazone. In vivo experimentation also showed that treatment with rosiglitazone prevented preterm birth by attenuating the systemic inflammatory response and reducing the expression of macrophage-derived pro-inflammatory mediators induced by endotoxin. This study is the first demonstration that M1 macrophages are presented at the human maternal-fetal interface and that such a pro-inflammatory phenotype can be targeted by activating the PPAR-gamma pathway. The inflammasome in spontaneous labor at term: Transcriptomic studies have indicated that spontaneous parturition at term is characterized by an inflammatory signature. The first cytokine to be implicated in the mechanisms of normal parturition was Interleukin-1beta (IL-1beta) and is now well established that this cytokine plays a central role, both in term and preterm labor. However, spontaneous parturition at term represents an example of sterile inflammation, not microbial-induced inflammation. Therefore, a fundamental question is how IL-1beta is activated in spontaneous labor at term. We reported a number of studies showing that the inflammasome, a cytosolic signaling platform, participates in the activation of caspase-1 which, in turn, promotes the processing of mature IL-1beta in the chorioamniotic membranes from women who had undergone spontaneous labor at term. These observations are consistent with our previous reports that caspase-1 is overexpressed in women with spontaneous labor at term, as well as in those with preterm labor. This is the first demonstration that inflammasome complexes are involved in physiologic parturition.
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