The Role of Inflammation and Infection in Preterm Birth
Department of Obstetrics and Gynecology, Wayne State University, Detroit, Michigan, United States Seminars in Reproductive Medicine
(Impact Factor: 2.35).
02/2007; 25(1):21-39. DOI: 10.1055/s-2006-956773
Inflammation has been implicated in the mechanisms responsible for preterm and term parturition, as well as fetal injury. Out of all of the suspected causes of preterm labor and delivery, infection and/or inflammation is the only pathological process for which both a firm causal link with preterm birth has been established and a molecular pathophysiology defined. Inflammation has also been implicated in the mechanism of spontaneous parturition at term. Most cases of histopathological inflammation and histological chorioamnionitis, both in preterm and term labor, are sub-clinical in nature. The isolation of bacteria in the amniotic fluid, known as microbial invasion of the amniotic cavity, is a pathological finding; the frequency of which is dependent upon the clinical presentation and gestational age. This article reviews the role of inflammation in preterm and term parturition.
- "This is characterized by elevated concentrations of proinflammatory cytokines (e.g., IL-1b, IL-6) in amniotic fluid (Cox et al. 1997) and infiltration of the myometrium, cervix, and fetal membranes by neutrophils and macrophages (Thomson et al. 1999; Osman et al. 2003; Condon et al. 2004). The invading immune cells secrete proinflammatory cytokines and chemokines (Romero et al. 2007), resulting in activation of NF-kB and other proinflammatory transcription factors in the myometrium (Condon et al. 2004, 2006). Activated NF-kB, in turn, increases expression of genes promoting myometrial contractility, including the prostaglandin F 2 a receptor (Olson 2003), the gap junction protein, connexin 43 (CX43/Gja1) (Chow and Lye 1994), the oxytocin receptor (OXTR) (Fuchs et al. 1984), and cyclooxygenase-2 (COX-2) (Soloff et al. 2004; Hardy et al. 2006). "
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ABSTRACT: The molecular mechanisms that maintain quiescence of the myometrium throughout most of pregnancy and promote its transformation to a highly coordinated contractile unit culminating in labor are complex and intertwined. During pregnancy, progesterone (P4) produced by the placenta and/or ovary serves a dominant role in maintaining myometrial quiescence by blocking proinflammatory response pathways and expression of so-called "contractile" genes. In the majority of placental mammals, increased uterine contractility near term is heralded by an increase in circulating estradiol-17β (E2) and/or increased estrogen receptor α (ERα) activity and a sharp decline in circulating P4 levels. However, in women, circulating levels of P4 and progesterone receptors (PR) in myometrium remain elevated throughout pregnancy and into labor. This has led to the concept that increased uterine contractility leading to term and preterm labor is mediated, in part, by a decline in PR function. The biochemical mechanisms for this decrease in PR function are also multifaceted and interwoven. In this paper, we focus on the molecular mechanisms that mediate myometrial quiescence and contractility and their regulation by the two central hormones of pregnancy, P4 and estradiol-17β. The integrative roles of microRNAs also are considered.
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- "Although most normal term deliveries have evidence of bacteria in the chorioamnion , it is the association with inflammation that correlates with pathology and prematurity (Romero et al., 2007). An intrauterine infection gaining access to the FMs is thought to trigger prematurity by activating innate immune responses (Romero et al., 2007). Indeed, clinical and experimental studies have correlated bacteria/bacterial components and inflammation at the maternal–fetal interface with preterm birth (Elovitz and Mrinalini, 2004; Elovitz et al., 2006; Romero et al., 2006; Pettker et al., 2007; Koga et al., 2009; Pirianov et al., 2009; Burd et al., 2010; Cardenas et al., 2011). "
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ABSTRACT: There has been growing interest in the role of viral infections and their association with adverse pregnancy outcomes. However, little is known about the impact viral infections have on the fetal membranes (FM). Toll-like receptors (TLR) are thought to play a role in infection-associated inflammation at the maternal-fetal interface. Therefore, the objective of this study was to characterize the cytokine profile and antiviral response in human FMs exposed to viral dsRNA, which activates TLR3, and viral ssRNA, which activates TLR8; and to determine the mechanisms involved. The viral dsRNA analog, Poly(I:C), induced upregulated secretion of MIP-1α, MIP-1β, RANTES and TNF-α, and downregulated IL-2 and VEGF secretion. In contrast, viral ssRNA induced a broader panel of cytokines in the FMs by upregulating the secretion of IL-1β, IL-2, IL-6, G-CSF, MCP-1, MIP-1α, MIP-1β, RANTES, TNF-α and GRO-α. Using inhibitory peptides against TLR adapter proteins, FM secretion of MIP-1β and RANTES in response to Poly(I:C) was MyD88-dependent; MIP-1α secretion was dependent on MyD88 and TRIF; and TNF-α production was independent of MyD88 and TRIF. Viral ssRNA-induced FM secretion of IL-1β, IL-2, IL-6, G-CSF, MIP-1α, RANTES and GRO-α was dependent on MyD88 and TRIF; MIP-1β was dependent upon TRIF, but not MyD88; and TNF-α and MCP-1 secretion was dependent on neither. Poly(I:C), but not ssRNA, induced a FM antiviral response by upregulating the expression of inflammasome components, IFNβ, MxA, OAS and APOBEC3G. These findings demonstrate that human FMs respond to two viral signatures by generating distinct inflammatory cytokine/chemokine profiles and antiviral responses through different mechanisms.
Available from: Sofia Makieva
- "Preterm birth (PTB), the outcome of preterm labour (PTL), is a major cause of maternal and perinatal morbidity and mortality, occurring in 11% of recorded live births worldwide ranging from 5% in developed countries to 18% in developing countries (Blencowe et al., 2012). The exact cause of PTL is unknown, although the concomitant activation of endocrine and immune pathways are believe to drive events, resulting in spontaneous initiation of uterine contractions and cervical ripening (CR) (Norman et al., 2007; Romero et al., 2007; Smith et al., 2012). There is no fully effective agent for prevention of PTL. "
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Understanding the physiology of pregnancy enables effective management of pregnancy complications that could otherwise be life threatening for both mother and fetus. A functional uterus (i) retains the fetus in utero during pregnancy without initiating stretch-induced contractions and (ii) is able to dilate the cervix and contract the myometrium at term to deliver the fetus. The onset of labour is associated with successful cervical remodelling and contraction of myometrium, arising from concomitant activation of uterine immune and endocrine systems. A large body of evidence suggests that actions of local steroid hormones may drive changes occurring in the uterine microenvironment at term. Although there have been a number of studies considering the potential role(s) played by progesterone and estrogen at the time of parturition, the bio-availability and effects of androgens during pregnancy have received less scrutiny. The aim of this review is to highlight potential roles of androgens in the biology of pregnancy and parturition.METHODSA review of published literature was performed to address (i) androgen concentrations, including biosynthesis and clearance, in maternal and fetal compartments throughout gestation, (ii) associations of androgen concentrations with adverse pregnancy outcomes, (iii) the role of androgens in the physiology of cervical remodelling and finally (iv) the role of androgens in the physiology of myometrial function including any impact on contractility.RESULTSSome, but not all, androgens increase throughout gestation in maternal circulation. The effects of this increase are not fully understood; however, evidence suggests that increased androgens might regulate key processes during pregnancy and parturition. For example, androgens are believed to be critical for cervical remodelling at term, in particular cervical ripening, via regulation of cervical collagen fibril organization. Additionally, a number of studies highlight potential roles for androgens in myometrial relaxation via non-genomic, AR-independent pathways critical for the pregnancy reaching term. Understanding of the molecular events leading to myometrial relaxation is an important step towards development of novel targeted tocolytic drugs.CONCLUSIONS
The increase in androgen levels throughout gestation is likely to be important for establishment and maintenance of pregnancy and initiation of parturition. Further investigation of the underlying mechanisms of androgen action on cervical remodelling and myometrial contractility is needed. The insights gained may facilitate the development of new therapeutic approaches to manage pregnancy complications such as preterm birth.
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