Endometriosis

Preterm birth is associated with 5 to 18% of pregnancies and is a leading cause of infant morbidity and mortality. Spontaneous preterm labor, a syndrome caused by multiple pathologic processes, leads to 70% of preterm births. The prevention and the treatment of preterm labor have been long-standing challenges. We summarize the current understanding of the mechanisms of disease implicated in this condition and review advances relevant to intra-amniotic infection, decidual senescence, and breakdown of maternal-fetal tolerance. The success of progestogen treatment to prevent preterm birth in a subset of patients at risk is a cause for optimism. Solving the mystery of preterm labor, which compromises the health of future generations, is a formidable scientific challenge worthy of investment.

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Preterm labor: One syndrome, many causes

The preterm parturition syndrome

Proteinase-activated receptors

Inflammation is a process by which tissues respond to various insults. It is characterized by upregulation of chemokines, cytokines, and pattern recognition receptors that sense microbes and tissue breakdown products. During pregnancy, the balance of Th1 (cell-mediated immunity) and Th2 (humoral immunity) cytokines is characterized by an initial prevalence of Th2 cytokines, followed by a progressive shift toward Th1 predominance late in gestation, that when is abnormal, may initiate and intensify the cascade of inflammatory cytokine production involved in adverse pregnancy outcomes. Maternal and placental hormones may affect the inflammatory pathway. Hypoxia and the innate immune response are 2 adaptive mechanisms by which organisms respond to perturbation in organ function, playing a major role in spontaneous abortion, intrauterine growth restriction, preeclampsia, and preterm delivery. The interaction between tissue remodeling factors, like matrix metalloproteinases, and vasoactive/hemostatic factors, like prostaglandin and coagulation factors, mediates this adaptive response.

http://journals.sagepub.com/doi/pdf/10.1177/1933719108329095

Inflammation and Pregnancy

Preterm birth is a leading cause of neonatal morbidity and mortality. Despite a growing body of evidence correlating inflammation with preterm birth, the signal transduction pathways responsible for the emptying of the uterus in the setting of intrauterine inflammation has not been elucidated. We now report a unique, reproducible mouse model of localized intrauterine inflammation. This model results in 100% preterm delivery with no maternal mortality. Using our model, we also show that platelet-activating factor is a crucial mediator of both inflammation-induced preterm birth and fetal demise. Using C3H/HeJ mice, we demonstrate that toll-like receptor-4 (TLR-4) plays a role in lipopolysaccharide-induced preterm birth but not in inflammation-induced fetal death. Immunohistochemistry studies demonstrate the presence of the platelet-activating factor receptor in both endometrial glands and smooth muscle in uterine tissues. Molecular studies demonstrate the differential expression of platelet-activating factor receptor and TLR-4 in uterine and cervical tissue throughout gestation. Quantitative polymerase chain reaction revealed an up-regulation of TLR-4 in the fundal region of the uterus in response to intrauterine inflammation. The use of this model will increase our understanding of the significant clinical problem of inflammation-induced preterm birth and will elucidate signal transduction pathways involved in an inflammatory state.

A New Model for Inflammation-Induced Preterm Birth: The Role of Platelet-Activating Factor and Toll-Like Receptor-4

OBJECTIVE: To sequence and characterize the expression of the prothrombinase Fgl-2 in the Sprague-Dawley rat. METHODS: Reverse-transcriptase polymerase chain reaction was performed on RNA from spontaneously cycling adult pregnant Sprague-Dawley rats by using specific Fgl-2 primers. The resulting amplicon was also used to screen a rat spleen bacteriophage library and to probe a Northern blot of various tissues. The rat Fgl-2 amino acid sequence was compared with the known sequences in mouse and human. RESULTS: Fgl-2-specific amplicon bands were observed in the rat brain, kidney, liver, ovary, spleen, and gestational day 22 and postpartum uterus. The rat Fgl-2 cDNA and amino acid sequence were found to be homologous with those of human (86% and 74%, respectively) and mouse (91% and 87%, respectively). Northern blotting demonstrated two different-sized transcripts (1.3 and 3.4 kb), and expression was observed in the cervix, heart, liver, ovary, and nongestational and gestational day 22 myometrium. CONCLUSION: Thrombin is classically generated from the cleavage of the proenzyme prothrombin by activated factors V and X. In tissues thrombin appears to be generated by a novel prothrombinase Fgl-2 (fibrinogen-like protein) whose activity is stimulated by proinflammatory mediators. Fgl-2 provides the mechanistic coupling between proinflammatory cytokines and the generation of active thrombin independent of the coagulation cascade. Our studies confirmed the expression of Fgl-2 mRNA in several rat tissues, including the pregnant uterus, where it could play a key role in the initiation of parturition especially in response to local or systemic infection.

Cloning and tissue expression of the tissue prothrombinase Fgl-2 in the Sprague-Dawley rat.

A 32-year-old infertility patient with a previous diagnosis of stage IV endometriosis experienced shortness of breath and chest pain. She was diagnosed with a pulmonary embolism by spiral volumetric computed tomography (SVCT) and anticoagulated during hospitalization, although no history of thrombosis was ever identified. She continued to have intermittent symptoms of chest pain, back pain, and shortness of breath for the next 1.5 months. Repeat SVCT revealed a large, right-sided pleural effusion with associated consolidation but no evidence of pulmonary embolism. To obtain a definitive diagnosis, a thoracoscopic pleural biopsy was performed and showed thoracic endometriosis involving the pleura. The patient desired to retain her fertility and opted for treatment with depot medroxyprogesterone. She has been asymptomatic for 2 years with this treatment. This case illustrates the importance of recognizing thoracic endometriosis syndrome and the difficulty diagnosing this condition considering its nonspecific features.

Thoracic endometriosis syndrome resembling pulmonary embolism.

Regarding recall bias in the association between idiopathic premature ovarian failure and fragile X premutation

To investigate expression of the constitutive androstane receptor (CAR) in the pregnant rat cervix. Rat uterine tissue was obtained on gestational days 12, 16, 20, 21, and 22 (the day of parturition), and postpartum day 1. In addition, liver, lung, kidney, heart, and skeletal muscle tissue were obtained. Expression of the two known CAR isoforms was evaluated using reverse transcriptase-polymerase chain reaction. These studies confirmed CAR expression in the liver; however, CAR was not demonstrated in the myometrium or cervical tissue. The currently described CAR1 and CAR2 isoforms are not expressed in rat uterine tissue; therefore, they do not appear to participate in parturition in the pregnant rat.

Daniel F. Rychlik

Papers

A New Model for Inflammation-Induced Preterm Birth: The Role of Platelet-Activating Factor and Toll-Like Receptor-4

Cloning and tissue expression of the tissue prothrombinase Fgl-2 in the Sprague-Dawley rat.

Thoracic endometriosis syndrome resembling pulmonary embolism.

Regarding recall bias in the association between idiopathic premature ovarian failure and fragile X premutation

Constitutive androstane receptor expression in the rat cervix during gestation.