First trimester HtrA1 maternal plasma level and spontaneous preterm birth.

OBJECTIVES: High temperature requirement A1 (HtrA1) is a serine protease detected in maternal plasma and in placental tissues during normal gestation and in various pathological conditions. The purpose of this study was to determine whether the maternal plasma concentration of HtrA1 in first trimester, alone or combined with other maternal factors, can be used to identify women at risk for spontaneous preterm birth (SPTB). STUDY DESIGN: This is a cohort study on pregnant women at 12 weeks of gestation recruited between 2014 and 2016 and prospectively followed until delivery. One hundred and fifty-nine women were included in the study: 140 women delivered at term and 19 (11.9%) delivered spontaneously preterm. Plasma samples were assessed for HtrA1 by ELISA and data were compared between women which delivered at term with women which delivered preterm. A multiple logistic regression analysis was used to estimate the independent effect of women's characteristics on the probability of a SPTB. RESULTS: SPTB was significantly associated with log HtrA1 values at 12 weeks of gestation, BMI before pregnancy and physical activity. In particular, the probability of a SPTB increases of 79% for every added unit of log HtrA1, while decreases of 18% for every added unit of BMI. In addition, physical activity was found as an important protective factor. The ROC curve showed that the model had a good accuracy in predicting SPTB, with an AUC equal to 0.83 (95%CI: 0.73-0.91). CONCLUSIONS: Maternal plasma HtrA1 may be considered a marker of SPTB. In addition, our model indicates two factors that could be modified to reduce the risk of SPTB, i.e. BMI before pregnancy and maternal physical activity.

Association between first trimester plasma htra1 level and subsequent preeclampsia: A possible early marker?

INTRODUCTION: Preeclampsia (PE) is associated with risk of maternal and fetal mortality and morbidity. Several promising predictors of PE have been identified, but early pregnancy screening for PE remains insufficient, and randomized controlled trials that used biomarkers to identify high-risk women have been disappointed. Our aim is to identify a possible early marker of PE. METHODS: 158 women attending a routine antenatal care visit were recruited from 2014 to 2016 and prospectively followed until delivery (14 of whom had a diagnosis of PE). We have tested the plasma concentration of High temperature requirement factor A1 (HtrA1) at 12 weeks of gestation by ELISA technique in order to identify women at risk for developing PE. A multiple logistic regression analysis was used to estimate the independent effect of women' characteristics on the probability of developing PE. Likelihood ratio test and Hosmer-Lemeshow test were used to select the most parsimonious model and to evaluate the model's goodness of fit. Predictiveness of preeclampsia was estimated by ROC curve. RESULTS: PE cases had significantly higher BMI, before and after pregnancy, shorter gestational age at delivery and higher HtrA1values than healthy women. In addition, higher HtrA1 values in the first trimester maternal plasma, BMI before pregnancy and gestational age at delivery are significantly associated with subsequent development of PE. ROC curve showed a good accuracy in predicting preeclampsia, with an AUC of 0.83. CONCLUSIONS: These results suggest the HtrA1 as early predictive marker of PE having a strong clinical relevance for disease prevention.

Romina: A powerful strawberry with in vitro efficacy against uterine leiomyoma cells.

Uterine leiom yomas are benign tumors highly prevalent in reproductive women. In thecurrent study, initially, we aimed to screen five different strawberry cultivars (Alba, Clery, Portola, Tecla, and Romina) to identify efficient cultivars in terms of phytochemical characterization and biological properties by measuring phenolic and anthocyanin content as well as antioxidant capacity, and by measuring apoptotic rate and reactive oxygen species (ROS) production in uterine leiomyoma cells. Next, we focused on the most efficient ones, cultivar Alba (A) and Romina (R) as well as Romina anthocyanin (RA) fraction for their ability to regulate oxidative phosphorylation (oxygen consumption rate [OCR]) glycolysis (extracellular acidification rate [ECAR]), and also fibrosis. Leiomyoma and myometrial cells were treated with a methanolic extract of A and R (250 µg/ml) or with RA (50 µg/ml) for 48 hr to measure OCR and ECAR, as well as gene expression associated with fibrosis. In the leiomyoma cells, RA was more effective in inducing apoptosis and increasing intracellular ROS levels, followed by R and A. In myometrial cells, all strawberry treatments increased the cellular viability and decreased ROS concentrations. Leiomyoma cells showed also a significant decrease in ECAR, especially after RA treatment, while OCR was slightly increased in both myometrial and leiomyoma cells. R and RA treatment significantly decreased collagen 1A1, fibronectin, versican, and activin A messenger RNA expression in leiomyoma cells. In conclusion, this study suggests that Romina, or its anthocyanin fraction, can be developed as a therapeutic and/or preventive agent for uterine leiomyomas, confirming the healthy effects exerted by these fruits and their bioactive compounds.

Pre-eclampsia onset and SPARC: A possible involvement in placenta development.

Pre-eclampsia (PE) is a multisystem disorder commonly diagnosed in the latter half of pregnancy and it is a leading cause of intrauterine fetal growth retardation (IUGR). The aim of this study was to investigate the localization and the role of SPARC, secreted protein acidic, and rich in cysteine, in PE and PE-IUGR placentas in comparison with normal placentas. SPARC was mainly expressed in the villous and extravillous cytotrophoblastic cells in first trimester, whereas in PE, PE-IUGR and at term placentas, SPARC immunostaining was visible in both cytotrophoblastic cells and syncytiotrophoblast. SPARC expression significantly decreased in normal placenta from first to third trimester and a further significant reduction was demonstrated in PE and PE-IUGR. The latter downregulation of SPARC depends on hypoxic condition as shown by in vitro models. In conclusion, SPARC can play a pivotal role in PE and PE-IUGR onset and it should be considered as a key molecule for future investigations in such pathologies.

Extracellular matrix in uterine leiomyoma pathogenesis: a potential target for future therapeutics.

BACKGROUND: Uterine leiomyoma (also known as fibroid or myoma) is the most common benign tumor of the uterus found in women of reproductive age. It is not usually fatal but can produce serious clinical symptoms, including excessive uterine bleeding, pelvic pain or pressure, infertility and pregnancy complications. Due to lack of effective medical treatments surgery has been a definitive choice for the management of this tumor. OBJECTIVE AND RATIONALE: Extracellular matrix (ECM) accumulation and remodeling are thought to be crucial for fibrotic diseases such as uterine leiomyoma. Indeed, ECM plays important role in forming the bulk structure of leiomyoma, and the ECM-rich rigid structure within these tumors is thought to be a cause of abnormal bleeding and pelvic pain. Therefore, a better understanding of ECM accumulation and remodeling is critical for developing new therapeutics for uterine leiomyoma. SEARCH METHODS: PubMed and Google Scholar were searched for all original and review articles/book chapters related to ECM and medical treatments of uterine leiomyoma published in English until May 2017. OUTCOMES: This review discusses the involvement of ECM in leiomyoma pathogenesis as well as current and future medical treatments that target ECM directly or indirectly. Uterine leiomyoma is characterized by elevated levels of collagens, fibronectin, laminins and proteoglycans. They can induce the mechanotransduction process, such as activation of the integrin-Rho/p38 MAPK/ERK pathway, resulting in cellular responses that are involved in pathogenesis and altered bidirectional signaling between leiomyoma cells and the ECM. ECM accumulation is affected by growth factors (TGF-ß, activin-A and PDGF), cytokines (TNF-α), steroid hormones (estrogen and progesterone) and microRNAs (miR-29 family, miR-200c and miR-93/106b). Among these, TGF-ßs (1 and 3) and activin-A have been suggested as key players in the accumulation of excessive ECM (fibrosis) in leiomyoma. The presence of elevated levels of ECM and myofibroblasts in leiomyoma supports the fibrotic character of these tumors. Interestingly, ECM may serve as a reservoir of profibrotic growth factors and enhance their activity by increasing their stability and extending their duration of signaling. At present, several classes of compounds, including gonadotropin-releasing hormone (GnRH) agonist (leuprolide acetate), GnRH antagonist (cetrorelix acetate), selective progesterone receptor modulators (ulipristate acetate and asoprisnil), antiprogestin (mifepristone) and natural compounds like vitamin D and resveratrol have been studied as medical treatments that target ECM in uterine leiomyoma. WIDER IMPLICATIONS: Although several types of drugs (mostly antiproliferative agents) are available for leiomyoma treatment, none of them were introduced specifically as antifibrotic agents. In light of its critical role in the process of fibrosis in leiomyoma, we propose that ECM should be considered as a crucial target for future therapeutics. Thus, the introduction of drugs that are specifically antifibrotic could be a good solution to control abnormal leiomyoma growth and associated clinical symptoms. The antifibrotic compounds can be introduced based on their ability to regulate ECM components and their receptors, as well as growth factors, cytokines, steroid hormones and their corresponding receptors and intracellular signaling pathways, as well as microRNAs, involved in ECM production in leiomyoma.

Effect of omiganan on colonic anastomosis healing in a rat model of peritonitis.

BACKGROUND: This study investigates the effects of the antimicrobial cationic peptide omiganan-alone and combined with the antibiotic imipenem-on colonic anastomosis healing in presence of intraperitoneal sepsis induced in a rodent model of cecal ligation and puncture (CLP). METHODS: Forty male Wistar rats were divided into 5 groups of 8 animals. Group 1 (control group) underwent laparotomy and cecal mobilization and the next day received left colon anastomosis. In group 2 (CLP without treatment), group 3 (CLP + imipenem), group 4 (CLP + omiganan), and group 5 (CLP + omiganan + imipenem), the left colon anastomosis was performed the day after CLP. Imipenem and omiganan were administered by intraperitoneal injection immediately before anastomosis construction and subsequently at 24 h intervals until the 7th postoperative day, when rats were sacrificed. Anastomotic bursting pressure was measured in situ. Tissue samples were collected for determination of hydroxyproline content and histological characteristics. RESULTS: Only rats receiving omiganan + imipenem displayed re-epithelialization, reduced neovascularization of granulation tissue, and a bursting pressure that was similar to that of controls. Omiganan-alone and combined with imipenem-was associated with a better control of inflammatory parameters than imipenem alone. In addition omiganan, like imipenem, counteracted the collagen depletion typical of sepsis. CONCLUSIONS: This experimental study demonstrates the efficacy of the new antimicrobial agent omiganan, alone and in combination with imipenem, in delaying the effects of intraperitoneal sepsis on colonic anastomosis healing and provides evidence of the value of omiganan as a therapeutic agent.

Molecular targets of dietary phytochemicals for possible prevention and therapy of uterine fibroids: Focus on fibrosis.

Uterine fibroids (myomas or leiomyomas) are common benign tumors of reproductive aged women. Fibroids are clinically apparent in 20-50% of women, and cause abnormal uterine bleeding, abdominal pain and discomfort, pregnancy complications and infertility. Unfortunately, limited numbers of medical treatment are available but no effective preventive strategies exist. Moreover, the benefits of medical treatments are tempered by lack of efficacy or serious adverse side effects. Fibrosis has recently been recognized as a key pathological event in leiomyoma development and growth. It is defined by the excessive deposition of extracellular matrix (ECM). ECM plays important role in making bulk structure of leiomyoma, and ECM-rich rigid structure is believed to be a cause of abnormal bleeding and pelvic pain/pressure. Dietary phytochemicals are known to regulate fibrotic process in different biological systems, and being considered as potential tool to manage human health. At present, very few dietary phytochemicals have been studied in uterine leiomyoma, and they are mostly known for their antiproliferative effects. Therefore, in this review, our aim was to introduce some dietary phytochemicals that could target fibrotic processes in leiomyoma. Thus, this review could serve as useful resource to develop antifibrotic drugs for possible prevention and treatment of uterine fibroids.

Low HtrA1 expression in patients with long­standing ulcerative colitis and colorectal cancer.

The association between inflammatory bowel disease (IBD) and colorectal cancer (CRC) is being increasingly investigated. HtrA1 overexpression inhibits cell growth and proliferation by influencing apoptosis, invasiveness and migration of tumour cells. In the present study, HtrA1 expression was analysed in 228 colon tissue samples from patients with CRC, adenoma with high-grade dysplasia (AHD), adenoma with low-grade dysplasia (ALD), ulcerative colitis of >10 year duration (UCL), ulcerative colitis of <5 year duration (UCS) and colonic diverticulitis (D), and was compared with its expression in normal colon tissues (NCTs) collected 5 cm from the CRC lesion and in healthy colon mucosa (HC), to establish whether HtrA1 can serve as a biomarker for these conditions. All tissue specimens came from Italian Caucasian subjects. The main finding of the present study was that HtrA1 expression was significantly reduced in CRC and UCL tissues compared with that observed in both NCT and HC samples and with tissues from the other patients. In particular, a similar HtrA1 expression was detected in the stromal compartment of UCL and CRC samples. In contrast, the HtrA1 level was significantly lower (p=0.0008) in UCL compared with UCS tissues, suggesting an inverse relationship between HtrA1 expression and ulcerative colitis duration. HtrA1 immunostaining in the stromal compartment of AHD and ALD tissues showed no differences compared with the HC tissues. No data are available on the immunohistochemical localization of HtrA1 in CRC or IBD. The present findings suggest that HtrA1 could serve as a marker to identify UCL patients at high risk of developing CRC.

An anthocyanin rich strawberry extract induces apoptosis and ROS while decreases glycolysis and fibrosis in human uterine leiomyoma cells.

Uterine leiomyomas are highly prevalent benign tumors in reproductive aged women. Unfortunately, medical treatments are still limited and no preventive therapies have been developed. In the present study, we investigated the therapeutic effects of strawberry extract on uterine leiomyoma cells. Leiomyoma and myometrial cells were treated with strawberry (cultivar Alba) extract (250 µg/ml) for 48 h to measure apoptosis, reactive oxygen species (ROS), oxidative phosphorylation (OCR, oxygen consumption rate) and glycolysis (ECAR, extracellular acidification rate) as well as fibrosis associated gene and/or protein expression. In leiomyoma cells, strawberry increased the percentage of apoptotic and dead cells. Strawberry significantly increased ROS concentration in leiomyoma cells, while decreased it in myometrial cells. After strawberry treatment, leiomyoma cells showed a significant decreased rate of ECAR, while OCR was unchanged in both myometrial and leiomyoma cells. Strawberry significantly decreased collagen1A1, fibronectin and versican mRNA expression in leiomyoma cells. The reduced protein expression of fibronectin was observed by strawberry extract in leiomyoma cells as well. Furthermore, strawberry was able to reduce activin A induced fibronectin, collagen1A1, and versican as well as activin A and PAI-1 mRNA expression in leiomyoma cells. This study suggests that strawberry can be developed as therapeutic and/or preventive agent for uterine leiomyomas.

Dietary phytochemicals for possible preventive and therapeutic option of uterine fibroids: Signaling pathways as target.

A growing interest has emerged on dietary phytochemicals to control diverse pathological conditions. Unfortunately, dietary phytochemical research in uterine fibroids is still under construction. Uterine fibroids/leiomyomas are benign tumors developing from the myometrium of the uterus in premenopausal women. They may occur in more than 70% of women, and approximately 25% of women show clinically significant symptoms. These include heavy and prolonged menstrual bleeding, pelvic pressure (urinary frequency, incontinence, and difficulty with urination), pelvic pain, pelvic mass, infertility, and reproductive dysfunction. Due to lack of medical treatments surgery has been definitive choice for fibroid management. Moreover, surgery negatively affects women's quality of life, and its associated cost appears to be expensive. The molecular mechanism of fibroids development and growth is not fully elucidated. However, accumulated evidence shows that several signaling pathways, including Smad 2/3, PI3K/AKT/mTOR, ERK 1/2 and ß-catenin are involved in the leiomyoma pathogenesis, indicating that they could serve as targets for prevention and/or treatment of this tumor. Therefore, in this review, we discuss the involvement of signaling pathways in leiomyoma development and growth, and introduce some potential dietary phytochemicals that could modulate those signaling pathways.

Analysis of cell-cell junctions in human amnion and chorionic plate affected by chorioamnionitis.

Chorioamnionitis is an acute inflammatory reaction associated with the premature rupture of the fetal membranes. It is caused mainly by invasion of bacteria from the vaginal tract that can penetrate the intact membranes and invade the amnion cavity and the decidua. Tight junctions (TJs) and adherent junctions (AJs) are intercellular junctions crucial for epithelia adhesion and permeability regulation in a wide variety of tissues and organs. Our aim is to investigate if TJ and AJ molecules are involved in human chorioamnionitis. We studied the protein expression (by immunohistochemistry and western blotting) and the mRNA levels (by RT-PCR) of some junction proteins such as Zonula Occludens-1 (ZO-1), occludin, VE-cadherin and ß-catenin in fetal membranes from women with chorioamnionitis compared to those membranes derived from idiopathic pregnancies. Western blotting and immunohistochemical data established that occludin expression was decreased in amnion with chorioamnionitis compared to amnion from idiopathic pregnancies. Samples tested for ZO-1, VE-cadherin and ß-catenin (proteins and mRNAs) showed no differences between idiopathic and pathological membranes. One of the most relevant results is the decrease of occludin in membranes with chorioamnionitis. Since we have previously demonstrated that some cytokines, particularly elevated in the chorioamnionitis, cause the disruption of TJs in placental villi, we suggest that the decrease of occludin in amnion may be the first change that leads to the rupture of the amniotic membrane in this pathology.

Possible involvement of inflammatory/reparative processes in the development of uterine fibroids.

Uterine leiomyomas are benign tumors in the smooth muscle layer of the uterus. The most common histological type is the "usual leiomyoma", characterized by overexpression of ECM proteins, whereas the "cellular type" has higher cellular content. Our objective is to investigate the involvement of inflammatory and reparative processes in leiomyoma pathobiology. Using a morphological approach, we investigate the presence of inflammatory cells. Next, we determine the localization of the ECM, the presence/absence of fibrotic cells via α-sma and desmin and the immunohistochemical profile of the mesenchymal cells with respect to CD34. Finally, we explore the effect of inflammatory mediators (TNF-α, IL-1ß, IL-6, IL-15, GM-CSF and IFN-γ) on pro-fibrotic factor activin A mRNA expression in vitro. Higher numbers of macrophages were found inside and close to leiomyomas as compared to the more distant myometrium. Cellular leiomyomas showed more macrophages and mast cells than the "usual type". Inside the fibroid tissue, we found cells positive for α-sma, but negative for desmin and a large amount of collagen surrounding the nodule, suggestive of myofibroblasts producing ECM. In the myometrium and leiomyomas of the "usual type", we identified numerous CD34+ fibroblasts, which are known to give rise to myofibroblasts upon loss of CD34 expression. In leiomyomas of the "cellular type", stromal fibroblasts were CD34-negative. Finally, we found that TNF-α increased activin A mRNA in myometrial and leiomyoma cells. In conclusion, this study demonstrates the presence of inflammatory cells in uterine leiomyomas, which may contribute to excessive ECM production, tissue remodeling and leiomyoma growth.

Growth factors and pathogenesis.

Growth factors are relatively small and stable, secreted or membrane-bound polypeptide ligands, which play an important role in proliferation, differentiation, angiogenesis, survival, inflammation, and tissue repair, or fibrosis. They exert multiple effects through the activation of signal transduction pathways by binding to their receptors on the surface of target cells. A number of studies have demonstrated the central role of growth factors and their signaling pathways in the pathogenesis of uterine leiomyomas. Numerous differentially expressed growth factors have been identified in leiomyoma and myometrial cells. These growth factors can activate multiple signaling pathways (Smad 2/3, ERK 1/2, PI3K, and ß-catenin) and regulate major cellular processes, including inflammation, proliferation, angiogenesis, and fibrosis which are linked to uterine leiomyoma development and growth. In this chapter, we discuss the role of growth factors and their signaling pathways in the pathogenesis of uterine leiomyomas.

Management of fibroids in perimenopausal women.

PURPOSE OF REVIEW: This article reviews fibroids management in the perimenopausal period, and addresses future directions in care. RECENT FINDINGS: Aromatase inhibitors, selective estrogen receptor modulators and antiprogestogens for medical management and minimally surgical techniques are promising treatments. SUMMARY: The disease and the symptoms may persist in the peri and postmenopausal periods. The assumption that they will resolve with the onset of the menopause is too simplistic and not always valid. The number of perimenopausal women who wish to retain their uterus for reasons other than childbearing is increasing. The accurate diagnosis of these conditions may result in minor surgical or medical treatments being directed at the specific pathology and may avoid the need for major surgery.

The novel role of HtrA1 in gingivitis, chronic and aggressive periodontitis.

Proteolytic tissue degradation is a typical phenomenon in inflammatory periodontal diseases. HtrA1 (High temperature requirement A 1) has a serine protease activity and is able to degrade fibronectin whose fragments induce the expression and secretion of several matrix metalloproteinases (MMPs). The aim of this study was to investigate for the first time if HtrA1 has a role in gingivitis and in generalized forms of chronic and aggressive periodontitis. Expression of HtrA1 was investigated in 16 clinically healthy gingiva, 16 gingivitis, 14 generalized chronic periodontitis and 10 generalized aggressive periodontitis by immunohistochemistry and real-time PCR. Statistical comparisons were performed by the Kruskall-Wallis test. Significantly higher levels of HtrA1 mRNA and protein expression were observed in pathological respect to healthy tissues. In particular, we detected an increase of plasma cell HtrA1 immunostaining from gingivitis to chronic and aggressive periodontitis, with the higher intensity in aggressive disease. In addition, we observed the presence of HtrA1 in normal and pathological epithelium, with an increased expression, particularly in its superficial layer, associated with increasingly severe forms of periodontal disease. We can affirm that HtrA1 expression in plasma cells could be correlated with the destruction of pathological periodontal tissue, probably due to its ability to trigger the overproduction of MMPs and to increase the inflammatory mediators TNF-α and IL-1ß by inhibition of TGF-ß. Moreover, epithelial HtrA1 immunostaining suggests a participation of the molecule in the host inflammatory immune responses necessary for the control of periodontal infection.

Use of dietary phytochemicals to target inflammation, fibrosis, proliferation, and angiogenesis in uterine tissues: promising options for prevention and treatment of uterine fibroids?

Uterine leiomyomas (fibroids, myomas) are the most common benign tumors of female reproductive tract. They are highly prevalent, with 70-80% of women burdened by the end of their reproductive years. Fibroids are a leading cause of pelvic pain, abnormal vaginal bleeding, pressure on the bladder, miscarriage, and infertility. They are the leading indication for hysterectomy, and costs exceed 6 billion dollars annually in the United States. Unfortunately, no long-term medical treatments are available. Dysregulation of inflammatory processes are thought to be involved in the initiation of leiomyoma and extracellular matrix deposition, cell proliferation, and angiogenesis are the key cellular events implicated in leiomyoma growth. In modern pharmaceutical industries, dietary phytochemicals are used as source of new potential drugs for many kinds of tumors. Dietary phytochemicals may exert therapeutic effects by interfering with key cellular events of the tumorigenesis process. At present, a negligible number of phytochemicals have been tested as therapeutic agents against fibroids. In this context, our aim was to introduce some of the potential dietary phytochemicals that have shown anti-inflammatory, antiproliferative, antifibrotic, and antiangiogenic activities in different biological systems. This review could be useful to stimulate the evaluation of these phytochemicals as possible therapies for uterine fibroids.

Ulipristal acetate modulates the expression and functions of activin a in leiomyoma cells.

Uterine leiomyoma is the most common benign gynecological tumor in women of reproductive age and represents the single most common indication for hysterectomy. A development of new treatments is necessary for a medical management, and in this direction, several hormonal drugs are under investigation. Ulipristal acetate (UPA; a selective progesterone receptor modulator) is considered as one of the most promising because progesterone has a critical role in development and growth of uterine leiomyoma. The effect of steroids is partly mediated by growth factors like activin A which increases extracellular matrix expression contributing to the growth of leiomyoma. The present study aimed to test whether UPA acts on leiomyoma cells affecting expression and functions of activin A system. Cultured myometrial and leiomyoma cells were treated with UPA, and messenger RNA (mRNA) expression levels of activin A (inhibin ßA [INHBA] subunits), its binding proteins (follistatin [FST] and FST-related gene), and its receptors (activin receptor-like kinase 4 [ALK4], activin receptor type [ActR] II, and ActRIIB) were evaluated. The effect of UPA on activin A modulation of fibronectin and vascular endothelial growth factor A (VEGF-A) mRNA expression in cultured myometrial and leiomyoma cells was also studied. Ulipristal acetate decreased INHBA, FST, ActRIIB, and Alk4 mRNA expressions in leiomyoma cultured cells. In addition, UPA was able to block the activin A-induced increase in fibronectin or VEGF-A mRNA expression in myometrial and in leiomyoma cultured cells. The present data show that UPA inhibits activin A expression and functions in leiomyoma cells, and this may represent a possible mechanism of action of the drug on uterine leiomyoma.

Tranilast, an orally active antiallergic compound, inhibits extracellular matrix production in human uterine leiomyoma and myometrial cells.

OBJECTIVE: To determine the effect of tranilast (an antiallergic drug known to suppress fibrosis or to stabilize mast cells) on extracellular matrix production in human leiomyoma and myometrial cells. DESIGN: Laboratory study. SETTING: University-affiliated laboratory. PATIENT(S): Seven premenopausal women who were admitted to the hospital for myomectomy or hysterectomy. INTERVENTION(S): Cells were treated with tranilast (300 µM) for 48 hours to measure extracellular matrix and activin-A expression by real-time reverse-transcription polymerase chain reaction and/or immunocytochemistry. MAIN OUTCOME MEASURE(S): The expression of fibronectin, collagen1A1, versican, and activin-A in myometrial and leiomyoma cells. RESULT(S): Tranilast decreased fibronectin, collagen 1A1, and versican messenger RNA (mRNA) expression in human primary leiomyoma cell culture. Similar results were found in an immortalized human leiomyoma cell line. Tranilast also decreased the mRNA expression of fibronectin, collagen 1A1, and versican in human primary myometrial cells. The reduced expression of fibronectin and collagen 1 were observed by immunocytochemistry as well. Tranilast also reduced profibrotic growth factor, activin-A mRNA expression in primary myometrial and leiomyoma cells. CONCLUSION(S): Our results indicate that tranilast reduced fibronectin, collagen 1A1, versican, and activin-A expression in leiomyoma and myometrial cells, demonstrating its potential as an antifibrotic therapy for human leiomyomas.