The immunology of pregnancy is complex and poorly defined. During the complex process of pregnancy, macrophages secrete many cytokines/chemokines and play pivotal roles in the maintenance of maternal-fetal tolerance. Here, we summarized the current knowledge of macrophage polarization and the mechanisms involved in physiological or pathological pregnancy processes, including miscarriage, preeclampsia, and preterm birth. Although current evidence provides a compelling argument that macrophages are important in pregnancy, our understanding of the roles and mechanisms of macrophages in pregnancy is still rudimentary. Since macrophages exhibit functional plasticity, they may be ideal targets for therapeutic manipulation during pathological pregnancy. Additional studies are needed to better define the functions and mechanisms of various macrophage subsets in both normal and pathological pregnancy.

/pdf/macrophage-polarization-in-physiological-and-pathological-1dye7urftw.pdf

Macrophage Polarization in Physiological and Pathological Pregnancy.

The signals and mechanisms that synchronize the timing of human parturition remain a mystery and a better understanding of these processes is essential to avert adverse pregnancy outcomes. Although our insights into human labor initiation have been informed by studies in animal models, the timing of parturition relative to fetal maturation varies among viviparous species, indicative of phylogenetically different clocks and alarms; but what is clear is that important common pathways must converge to control the birth process. For example, in all species, parturition involves the transition of the myometrium from a relaxed to a highly excitable state, where the muscle rhythmically and forcefully contracts, softening the cervical extracellular matrix to allow distensibility and dilatation and thus a shearing of the fetal membranes to facilitate their rupture. We review a number of theories promulgated to explain how a variety of different timing mechanisms, including fetal membrane cell senescence, circadian endocrine clocks, and inflammatory and mechanical factors, are coordinated as initiators and effectors of parturition. Many of these factors have been independently described with a focus on specific tissue compartments.In this review, we put forth the core hypothesis that fetal membrane (amnion and chorion) senescence is the initiator of a coordinated, redundant signal cascade leading to parturition. Whether modified by oxidative stress or other factors, this process constitutes a counting device, i.e. a clock, that measures maturation of the fetal organ systems and the production of hormones and other soluble mediators (including alarmins) and that promotes inflammation and orchestrates an immune cascade to propagate signals across different uterine compartments. This mechanism in turn sensitizes decidual responsiveness and eventually promotes functional progesterone withdrawal in the myometrium, leading to increased myometrial cell contraction and the triggering of parturition. Linkage of these processes allows convergence and integration of the gestational clocks and alarms, prompting a timely and safe birth. In summary, we provide a comprehensive synthesis of the mediators that contribute to the timing of human labor. Integrating these concepts will provide a better understanding of human parturition and ultimately improve pregnancy outcomes.

/pdf/novel-concepts-on-pregnancy-clocks-and-alarms-redundancy-and-1j6ij60k3z.pdf

Novel concepts on pregnancy clocks and alarms: redundancy and synergy in human parturition

Major clinical challenges for obstetricians and neonatologists result from early cervix remodeling and preterm birth. Complications related to cervix remodeling or delivery account for significant morbidity in newborns and peripartum mothers. Understanding morphology and structure of the cervix in pregnant women is limited mostly to the period soon before and after birth. However, evidence in rodent models supports a working hypothesis that a convergence of factors promotes a physiological inflammatory process that degrades the extracellular collagen matrix and enhances biomechanical distensibility of the cervix well before the uterus develops the contractile capabilities for labor. Contributing factors to this remodeling process include innervation, mechanical stretch, hypoxia, and proinflammatory mediators. Importantly, the softening and shift to ripening occurs while progesterone is near peak concentrations in circulation across species. Since progesterone is required to maintain pregnancy, the premise of this review is that loss of responsiveness to progesterone constitutes a common final mechanism for remodeling the mammalian cervix in preparation for birth at term. Various inputs are suggested to promote signaling between stromal cells and resident macrophages to drive proinflammatory processes that advance the soft cervix into ripening. With infection, pathophysiological processes may prematurely drive components of this remodeling mechanism and lead to preterm birth. Identification of critical molecules and pathways from studies in various rodent models hold promise for novel endpoints to assess risk and provide innovative approaches to treat preterm birth or promote the progress of ripening at term.

/pdf/contributions-to-the-dynamics-of-cervix-remodeling-prior-to-pzgdco4vut.pdf

Contributions to the dynamics of cervix remodeling prior to term and preterm birth.

This review focuses on the contribution of immune cell trafficking and activities during the initial phase of activation in the process of parturition. Although uterine contractile activity has been the predominant focus for the mechanism that initiates labor, significant cellular and biochemical chanes cause remodeling of the cervix well before term. A convergence of evidence suggests that inflammatory processes that involve prostaglandins, nitric oxide, cytokines, as well as systemic and paracrine endocrine mediators may enhance uterine contractility, promote ripening of the cervx, and thus constitute an integrative hypothesis for the initiation of labor. Techniques to study the uterus and cervix of pregnant and virgin C3H/HeN mice included light and fluorescence microscopy. Tissues were processed by histochemistry and immunofluorescence. Analytic approaches to enumerae macrophages and assess activation included quantitative stereologic morphometry and laser scanning cytometry. The transition between relative quiescene of the uterus and enhanced contractility involed migration of macrophages from the uterine endometrium and activation of macrophages in the cervix. Before birth, macrophages migrae into the cervix and are activated in the myometrium. Immune cell trafficking and activation are part of the initial mechanism that promotes ripening of the cervix, enhances uterine contractility, and initiates parturition. Markers for the conclusion of pregnancy may have diagnostic or therapeutic value to assess the normal progress of labor or identify women at risk of preterm labor.

The Role of Leukocyte Traffic and Activation in Parturition

The cervix is the essential gatekeeper for birth. Incomplete cervix remodeling contributes to problems with delivery at or post-term while preterm birth is a major factor in perinatal morbidity and mortality in newborns. Lack of cervix biopsies from women during the period preceding term or preterm birth have led to use of rodent models to advanced understanding of the mechanism for prepartum cervix remodeling. The critical transition from a soft cervix to a compliant prepartum lower uterine segment has only recently been recognized to occur in various mammalian species when progesterone in circulation is at or near the peak of pregnancy in preparation for birth. In rodents, characterization of ripening resembles an inflammatory process with a temporal coincidence of decreased density of cell nuclei, decline in cross-linked extracellular collagen, and increased presence of macrophages in the cervix. Although a role for inflammation in parturition and cervix remodeling is not a new concept, a comprehensive examination of literature in this review reveals that many conclusions are drawn from comparisons before and after ripening has occurred, not during the process. The present review focuses on essential phenotypes and functions of resident myeloid and possibly other immune cells to bridge the gap with evidence that specific biomarkers may assess the progress of ripening both at term and with preterm birth. Moreover, use of endpoints to determine the effectiveness of various therapeutic approaches to forestall remodeling and reduce risks for preterm birth, or facilitate ripening to promote parturition will improve the postpartum well-being of mothers and newborns.

/pdf/immunobiology-of-cervix-ripening-3npapjvvg8.pdf

Immunobiology of Cervix Ripening

Remodeling of the cervix occurs in advance of labor both at term and at preterm birth. Morphological characteristics associated with remodeling in rodents were assessed in cervix biopsies from women at term (39 weeks' gestation) and preterm (<33 weeks' gestation). Collagen I and III messenger RNA and hydroxyproline concentrations declined in cervix biopsies from women in labor at term and preterm compared to that in the cervix from nonlaboring women. Extracellular collagen was more degraded in sections of cervix from women at term, based on optical density of picrosirius red stain, versus that in biopsies from nonpregnant women. However, collagen structure was unchanged in the cervix from women at preterm labor versus the nonpregnant group. As an indication of inflammation, cell nuclei density was decreased in cervix biopsies from pregnant women irrespective of labor compared to the nonpregnant group. Moreover, CD68-stained macrophages increased to an equivalent extent in cervix subepithelium and stroma from groups in labor, both at term and preterm, as well as in women not in labor at term. Evidence for a similar inflammatory process in the remodeled cervix of women at term and preterm birth parallels results in rodent models. Thus, a conserved final common mechanism involving macrophages and inflammation may characterize the transition to a ripe cervix before birth at term and in advance of premature birth.

/pdf/density-of-stromal-cells-and-macrophages-associated-with-l4dwe7o076.pdf

Aurelija Dubicke

Papers

Density of Stromal Cells and Macrophages Associated With Collagen Remodeling in the Human Cervix in Preterm and Term Birth