Inflammation-induced Preterm Labor Research Articles

Vascular endothelial growth factor induces mRNA expression of pro-inflammatory factors in the uterine cervix of mice

Inflammation is believed to play a role in uterine cervical remodeling and infection-induced preterm labor. One of the distinct features of remodeling uterine cervix is presence of prominent vascular events, such as angiogenesis, vasodilation, and vascular permeability. Although the functional significance of these features is not yet clear, we know that in most tissue types, vascular remodeling is intricately intertwined with inflammation. Since vascular endothelial growth factor (VEGF) is the major architect of vascular remodeling, we sought to examine and elucidate the potential relationship between VEGF and inflammation in the uterine cervix of non-pregnant mice. The animals used were divided into 4 treatment groups: A) negative control (vehicle only), B) positive control (lipopolysaccharide, LPS), C) recombinant VEGF-164 protein, and D) LPS + VEGF blocker (n = 3). After the appropriate treatments, the uterine cervices were harvested and analyzed using real-time PCR and confocal fluorescence microscopy. Results showed that exogenous VEGF upregulates expression of interleukin (IL)-6 and tumor necrosis factor (TNF)-α mRNAs, whereas VEGF blocker partially diminishes the LPS-induced expression of pro-inflammatory factors compared to the positive control group. We conclude that a positive feed-forward relationship likely exists between VEGF and inflammation in the uterine cervix, thus implicating VEGF in inflammation-induced preterm labor.

Anti-inflammatory mediators as physiological and pharmacological regulators of parturition

Increasing evidence highlights parturition as an inflammatory event characterized by leukocyte influx and proinflammatory mediator production in the intrauterine environment. While the mechanisms responsible for the initiation of this inflammatory cascade are not well understood, it is clear that these inflammatory events must be tightly regulated as the premature activation of these inflammatory signals is associated with adverse pregnancy outcomes, such as preterm labor, which is the leading cause of neonatal mortality and morbidity. In this article we highlight the importance of anti-inflammatory factors in regulating the inflammatory events surrounding parturition and discuss the use of anti-inflammatory mediators as potential novel therapeutic agents in the treatment of inflammation-induced preterm labor.

109: Increased MDR1 Expression in human placenta associated with inflammation-induced preterm labor

109: Increased MDR1 Expression in human placenta associated with inflammation-induced preterm labor

The Molecular Pathophysiology of Bacterially Induced Preterm Labor: Insights From the Murine Model

Premature delivery, the most important problem in obstetrics in developed countries, continues to vex clinicians and researchers. Despite decades of investigation, the pathophysiology of premature labor is incompletely understood, and therapies or preventive strategies tailored to each of the many potential causes do not exist. The present review addresses one cause of prematurity, namely, intrauterine bacterial infection. Given the vastness of the literature for even this single etiology, we focus on the mouse as a model organism from which much can be learned about mammalian parturition. The underpinnings of bacterially induced labor are believed to involve a signaling cascade that begins with recognition of offending pathogens by cell-surface receptors (toll-like receptors). This cascade then operates through multiple branching and redundant pathways to bring about the changes within the gestational compartment that produce cervical ripening, labor, and ultimately delivery. The major challenge facing researchers is to understand the levels of complexity in the host response, so that prevention and treatment strategies may be sufficiently focused to minimize unwanted side effects, yet sufficiently broad to be effective. Given the complexity of the problem, this understanding can be aided by efficient model systems, of which one in vivo example is the mouse, an organism that shares with humans many similarities in the biochemical and molecular aspects of inflammation-induced preterm labor. We propose that tools with the power to assess simultaneously the myriad elements of the hypothesized signaling cascade (ie, genomic and proteomic technologies) are important components of the solution to the puzzle of parturition.

267. Interleukin-10 inhibits TNFα synthesis and protects against LPS-induced miscarriage and preterm labour

The immune-deviating and anti-inflammatory cytokine interleukin-10 (IL-10) is expressed throughout pregnancy in the decidual and placental tissues. Mice with a null mutation in the IL-10 gene mice are fertile with no reduction in litter size, although fetal growth trajectories and placental structure are altered. IL-10 is known to terminate inflammatory responses and to limit inflammation-induced tissue pathology by inhibiting macrophage synthesis of tumor necrosis factor-α (TNFα). To investigate the anti-inflammatory role of IL-10 in pregnancy, the susceptibility of null mutant mice to low dose LPS-induced miscarriage and preterm labour has been evaluated. When IL-10 null mutant C57Bl/6 (IL-10–/–) and control (IL-10+/+) mice were given low dose E.coli LPS on d10 of pregnancy, IL-10 deficiency was associated with greater fetal loss with fewer mated IL-10–/– mice carrying viable fetuses at day 18 and increased rate of fetal resorption. In mice treated with LPS on day 17, preterm delivery within 24 h occurred in a higher proportion of IL-10–/– mice than IL-10+/+ mice. LPS induced very high and sustained TNFα and IL-6 content in serum, uterine and placental tissue in IL-10–/– mice, associated with upregulated mRNA expression of both cytokines in gestational tissues. These data show that IL-10 modulates placental resistance to inflammatory stimuli by down-regulating expression of the pro-inflammatory cytokines TNFα and IL-6. We conclude that IL-10 has a dual role in pregnancy, acting to regulate placental morphogenesis and fetal growth trajectory, and to protect against inflammation-induced miscarriage and preterm labour.

008.Placental inflammation and preterm labour: studies of pathophysiology and intervention using human ex-vivo models

Inflammatory processes and mediators are an integral aspect of the mechanics of parturition. Leukocyte infiltration/activation of the extraplacental membranes, cervix and uterus occurs prior to term labour and is accompanied by increased cytokine expression, eicosanoid production, and extracellular matrix degradation. These processes are propagated during labour to ensure progression through to delivery, and in normal parturition they occur in concert in a timely fashion. In contrast, pathological intrauterine inflammation appears to be a causative factor in a significant proportion of preterm births. While the presence of an infective organism in the amniotic cavity is confirmed in about half of pregnancies delivered with chorioamnionitis, in the remainder the cause of the excessive inflammatory response remains undetermined. We have established and applied various models employing human placental tissues to study the processes involved in triggering intrauterine inflammatory activation and potential pharmacological approaches for intervention. Of these, an ex-vivo fetal membrane perfusion model has been the most powerful, allowing multi-aspect analysis of membrane gene expression, inflammatory mediator production, histological and structural integrity in response to maternal challenge with endotoxin (lipopolysaccharide). Using a variety of techniques including oligonucleotide and protein arrays we have determined that a robust and rapid inflammatory response is manifested in both the maternal and fetal compartments after maternal (decidual) exposure to lipopolysaccharide; this is accompanied by a marked increase in apoptosis in the chorionic membrane, but no detectable changes in membrane integrity. We have evaluated in this model several anti-inflammatory drugs that inhibit the NF-κB pathway as potential pharmacologics for treating inflammation-induced preterm labour. Surprisingly, most were completely ineffective in suppressing lipopolysaccharide-induced cytokine production. Sulfasalazine, however, administered to the maternal face, effectively and rapidly abrogated the lipopolysaccharide response in both maternal and fetal compartments, with modest membrane transfer of drug. However, chorionic apoptosis was doubled in sulfasalazine-treated membranes, raising concerns over possible toxicity. Studies using these models are continuing to further evaluate the potential of novel and existing pharmacotherapies for the prevention of inflammation-associated preterm birth.