interleukin-8 and Ovarian-Hyperstimulation-Syndrome

Ovarian hyperstimulation syndrome (OHSS) is a potentially life-threatening complication of assisted reproductive technologies. This complex syndrome is known to involve massive angiogenesis and inflammation. We have previously established the anti-angiogenic involvement of pigment epithelium-derived factor (PEDF) in the pathophysiology and treatment of OHSS.. Evaluate the anti-inflammatory role of PEDF in OHSS.. In vivo mouse OHSS model and in vitro cultures of granulosa cells.. Changes in the expression of PEDF, IL-6, IL-8, and vascular endothelial growth factor (VEGF) were measured by quantitative PCR and ELISA; OHSS symptoms were recorded (body and ovarian weight gain and peritoneal vascular leakage quantified by the modified Miles's assay).. Rat granulosa cell-line stimulated with lysophosphatidic acid (LPA), exhibited a significant increase in IL-6 expression, concomitantly with a decrease in PEDF level (P < .01). Co-stimulation with recombinant PEDF (rPEDF) decreased the expression of IL-6 significantly (P < .05). Furthermore, the expression of IL-6 and IL-8 increased in LPA-stimulated human primary granulosa cells (P < .01). Co-stimulation with rPEDF decreased the expression of LPA-induced IL-6 and IL-8 mRNA and protein by 4- and 2- to 5-fold, respectively. IL-8-stimulated human primary granulosa cells exhibited increased expression of VEGF mRNA; co-stimulation with hCG induced a significantly higher increase in the expression of VEGF mRNA (P < .001), which was counteracted by rPEDF. Subcutaneous injection of 0.5 mg/kg rPEDF to OHSS-induced mice reduced the increased expression of IL-6 in the ovary (P < .01) and alleviated the severity of all OHSS parameters.. Our findings provide a framework that correlates down-regulation of OHSS symptoms caused by PEDF with both angiogenic and inflammatory pathways.

Topics: Adult; Animals; Cell Culture Techniques; Disease Models, Animal; Eye Proteins; Female; Granulosa Cells; Humans; Inflammation; Interleukin-6; Interleukin-8; Mice; Neovascularization, Pathologic; Nerve Growth Factors; Ovarian Hyperstimulation Syndrome; Rats; Serpins; Vascular Endothelial Growth Factor A; Young Adult

Leukocyte infiltration and angiogenesis in the forming corpus luteum are prerequisites for normal ovarian function and may also underlie disorders like ovarian hyperstimulation syndrome. We examined whether ovarian angiogenesis could be affected by an interaction between granulosa-lutein (GL) cells and leukocytes.. We found that GL cells isolated from the follicular fluid synthesize and secrete the chemokine interleukin-8 (IL-8), which activates IL-8-receptor-specific Ca(2+) and p38 mitogen-activated protein kinase signalling in monocytes and induces a directed migration of these cells towards the chemical gradient. Monocytes were found to further enhance IL-8 release, which suggests that these cells promote a massive leukocyte infiltration of the forming corpus luteum. A possible utility of leukocyte infiltration is the modulation of angiogenesis. We found that GL cells induce migration and capillary tube formation by endothelial cells in vitro. Furthermore, monocytes altered the profile of angiogenic factors released by GL cells, which supports the theory that an interaction between GL cells and leukocytes regulates ovarian angiogenesis. In addition, we found a correlation between increased secretion of pro-angiogenic cytokines and number of oocytes collected during IVF, which suggests that ovarian angiogenesis is related to the clinical response during ovarian stimulation.. An intricate communication may exist between infiltrating leukocytes and ovarian GL cells during the formation of corpus luteum, affecting neo-vascularization of the luteal tissue.

Topics: Angiogenesis Inducing Agents; Calcium; Cell Movement; Female; Follicular Fluid; Granulosa Cells; Human Umbilical Vein Endothelial Cells; Humans; In Vitro Techniques; Interleukin-8; Leukocytes; Luteal Cells; Neovascularization, Pathologic; Oocytes; Ovarian Hyperstimulation Syndrome; p38 Mitogen-Activated Protein Kinases

Ovarian hyperstimulation syndrome (OHSS) is a serious complication of ovarian stimulation with massive ascites, pleural effusion and hemoconcentration. The pathophysiological signal mechanisms of OHSS are still unclear and merit further investigation.. Various angiogenic cytokines of follicular fluid and ascites of patients with risk of OHSS were measured, and examined for inducing endothelial permeability. These include vascular endothelial growth factor (VEGF), interleukin (IL)-6, IL-8, basic fibroblast growth factor, tumor necrosis factor-alpha, IL-1alpha, IL-1beta and platelet-derived growth factor. We explore the molecular signal pathways of major contributing cytokines in granulosa-lutein cells and endothelial cells possibly involved in OHSS.. Neutralizing antibodies of VEGF or IL-8 significantly decreased follicular fluid- and ascites-induced endothelial permeability. Human chorionic gonadotrophin induced VEGF secretion of granulosa-lutein cells through the Sp1 and CREB dependent pathways. IL-8 activated CXCR1/2 of endothelial cells leading to VEGF receptor (VEGFR)-2 transactivation. Both VEGF and IL-8 of follicular fluid enhanced endothelial permeability via VEGFR-2-mediated Rho/Rock activation, actin polymerization and phosphorylations of VE-cadherin and occludin, resulting in opening of adherens junctions and tight junctions. Dopamine (2 microM) inhibited follicular fluid-induced VEGFR-2 signals and endothelial permeability, without diminishing migration and tube formation.. Our results suggest that VEGF and IL-8 secreted from corpora luteae may play major roles in OHSS. Delineation of signal pathways would be helpful for treatment. Dopamine may block VEGF- and IL-8-induced endothelial permeability by inhibiting common VEGFR-2 dependent signals.

Topics: Actins; Ascites; Cells, Cultured; Chorionic Gonadotropin; Dopamine; Endothelium, Vascular; Female; Follicular Fluid; Humans; Interleukin-8; Luteal Cells; Ovarian Hyperstimulation Syndrome; Permeability; Signal Transduction; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2

Lysophosphatidic acid (LPA) was found at significant amounts in follicular fluid of preovulatory follicle. The lysophospholipase D activity of serum from women receiving ovarian stimulation was higher than women with natural cycles. Angiogenic cytokines, including IL-6, IL-8, and vascular endothelial growth factor, increased in plasma and ascites of patients with ovarian hyperstimulation syndrome. The role of LPA in ovarian follicles is unclear.. Our objective was to investigate the expression of LPA receptors and function of LPA in granulosa-lutein cells.. Granulosa-lutein cells were obtained from women undergoing in vitro fertilization. We examined the expression of LPA receptors using RT-PCR. The effects of LPA on the expression of IL-6, IL-8, and vascular endothelial growth factor were examined. Signal pathways of LPA were delineated. The functions of secretory angiogenic factors were tested using human umbilical vein endothelial cells.. The LPA1, LPA2, and LPA3 receptors' mRNA was identified in granulosa-lutein cells. LPA enhanced IL-8 and IL-6 expressions in a dose- and time-dependent manner. LPA functioned via LPA receptors, Gi protein, MAPK/ERK, p38, phosphatidylinositol 3-kinase/Akt, and nuclear factor-kappaB, and transactivation of epidermal growth factor receptor. LPA induced IL-8 and IL-6 through different pathways. LPA-induced IL-8 and IL-6 increased permeability of human umbilical vein endothelial cell monolayer.. LPA induces IL-8 and IL-6 expressions through LPA receptors and nuclear factor-kappaB dependent pathways in granulosa-lutein cells. The LPA in preovulatory follicles may play a role in the angiogenesis of corpus luteum. Large amounts of LPA-induced IL-8 and IL-6 from multiple corpora luteae of stimulated ovaries may be one of the pathophysiological causes of ovarian hyperstimulation syndrome.

Topics: Cells, Cultured; Corpus Luteum; Female; Gene Expression Regulation; Humans; Interleukin-6; Interleukin-8; Luteal Cells; Lysophospholipids; Neovascularization, Physiologic; NF-kappa B; Ovarian Hyperstimulation Syndrome; Receptors, Lysophosphatidic Acid; Signal Transduction; Up-Regulation

The aims of this study were to determine if differences in serum pro-inflammatory cytokines, vascular endothelial growth factor (VEGF) and clinical pregnancy rate, could be observed in women with severe ovarian hyperstimulation syndrome (OHSS) in those who did and did not have liver dysfunction. Twenty-nine in-vitro fertilization patients with severe OHSS were included. The patients were divided into the normal liver function tests (LFT) group (n = 14) and the abnormal LFT group (n = 15) according to the LFT on day of admission. Periodic measurements of serum interleukin (IL)-6, IL-8, tumour necrosis factor-alpha (TNF-alpha), VEGF, oestradiol, progesterone concentrations, and LFT were performed during hospitalization. Concentrations of IL-6 in the active phase of OHSS were significantly higher in the abnormal LFT group than in the normal LFT group (19.7 +/- 15.7 versus 8.1 +/- 7.0 pg/ml, respectively). The severity of liver dysfunction was not correlated with concentrations of oestradiol, progesterone, haematocrit, white blood cell counts, or any studied cytokine. The clinical pregnancy rate was significantly lower in the abnormal LFT group (46.7%) than in the normal LFT group (85.7%). These results suggest that IL-6 cytokine system may play a role in the pathogenesis of liver dysfunction in severe OHSS. Abnormal LFT were associated with lower clinical pregnancy rates.

Topics: Adult; Alanine Transaminase; Aspartate Aminotransferases; Cytokines; Embryo Implantation; Endothelial Growth Factors; Estradiol; Female; Fertilization in Vitro; Humans; Interleukin-6; Interleukin-8; Liver; Lymphokines; Ovarian Hyperstimulation Syndrome; Pregnancy; Progesterone; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

The aim of this study was to examine the role of serum and follicular fluid pro-inflammatory cytokines and vascular endothelial growth factor (VEGF) in the prediction of ovarian hyperstimulation syndrome (OHSS). A total of 156 consecutive women undergoing in-vitro fertilization were recruited. The study group comprised 12 women who subsequently developed moderate (n = 7) or severe (n = 5) OHSS. The two control groups were comprised of a randomized selection of 12 high-risk and 12 low-risk women in whom OHSS did not develop. Serum was collected on days of human chorionic gonadotrophin, oocyte retrieval, and embryo transfer. Serum and follicular fluid concentrations of interleukin (IL)-6, IL-8, tumour necrosis factor-alpha (TNF-alpha), and VEGF were measured. Follicular fluid IL-6 concentrations at the time of oocyte retrieval and serum IL-8 concentrations at the time of embryo transfer were significantly higher in the OHSS compared to the two control groups (P = 0.026 and P = 0.017 respectively). Serum concentrations of TNF-alpha and VEGF showed no statistically significant difference between the OHSS group and the controls at any studied time point. This study suggests that follicular fluid IL-6 concentrations at the time of oocyte retrieval and serum IL-8 concentrations on the day of embryo transfer may serve as early predictors for this syndrome.

Topics: Adult; Case-Control Studies; Chorionic Gonadotropin; Cytokines; Embryo Transfer; Endothelial Growth Factors; Estradiol; Female; Follicular Fluid; Humans; Interleukin-6; Interleukin-8; Lymphokines; Ovarian Hyperstimulation Syndrome; Predictive Value of Tests; Progesterone; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

To report serum concentrations of several cytokines (interleukin-6, interleukin-8, tumor necrosis factor-alpha, and vascular endothelial growth factor) before and after the reinfusion of ultrafiltrated ascitic fluid.. A case report of a woman hospitalized for the treatment of severe OHSS at the Department of Obstetrics and Gynecology, Tottori University Hospital. The serum concentrations of cytokines were analyzed by ELISA.. Cytokine concentrations declined in parallel with the improvement of clinical conditions and resolution of OHSS.. Measurement of serum cytokine concentrations may be useful in evaluating the severity of OHSS.

Topics: Adult; Ascitic Fluid; Cytokines; Endothelial Growth Factors; Female; Humans; Interleukin-6; Interleukin-8; Lymphokines; Ovarian Hyperstimulation Syndrome; Tumor Necrosis Factor-alpha; Ultrafiltration; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

To determine the prognostic value of various cytokine levels in ascites and pleural effusion during the evolution of severe ovarian hyperstimulation syndrome (OHSS).. A longitudinal study.. University teaching hospital.. Twenty patients with severe OHSS who required either paracentesis or thoracentesis or both from whom ascites (n = 56) or pleural effusion (n = 12) samples were obtained. Control peritoneal fluid was obtained from 20 patients undergoing ovarian stimulation for IVF.. Abdominal paracentesis for tense ascites and thoracentesis for massive pleural effusion. Control peritoneal fluid was obtained before oocyte retrieval.. Levels of interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6), interleukin-8 (IL-8), tumor necrosis factor-alpha (TNF-alpha), vascular endothelial growth factor (VEGF), E2, and progesterone concentrations in ascites and pleural effusion.. Levels of VEGF and IL-6 in ascites dropped significantly during the course of OHSS and were not correlated with E2 concentrations. Levels of VEGF were significantly correlated with levels of IL-1 beta, IL-8, and TNF-alpha, as well as progesterone concentrations, hematocrit, and white blood cell counts. None of the cytokine levels measured in pleural effusion were correlated with the course of OHSS.. These results suggest that local cytokines might be involved in the evolution of severe OHSS and possibly serve as prognostic markers for this syndrome.

Topics: Adult; Ascites; Cytokines; Drainage; Endothelial Growth Factors; Female; Fertilization in Vitro; Humans; Insemination, Artificial; Interleukin-1; Interleukin-6; Interleukin-8; Lymphokines; Ovarian Hyperstimulation Syndrome; Paracentesis; Pleural Effusion; Prognosis; Punctures; Time Factors; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

The objective of this study was to follow the kinetics of four inflammatory cytokines in the plasma and ascitic fluid of seven patients who developed severe ovarian hyperstimulation syndrome (OHSS) after induction of ovulation for in-vitro fertilization. Blood samples were obtained from these patients at three different times: upon hospitalization; when significant clinical improvement was evident; and after complete resolution. Samples were analysed for interleukin-1 (IL-1), interleukin-6 (IL-6), interleukin-8 (IL-8) and tumour necrosis factor alpha (TNF-alpha). Ascitic fluid was obtained by therapeutic paracentesis from all study patients during the active phase and analysed for these cytokines. Two control groups were available: the first included 15 women undergoing controlled ovarian stimulation for in-vitro fertilization without developing OHSS, while the second consisted of 25 healthy women not undergoing ovulation induction or any other medical treatment. High concentrations of IL-1, IL-6 and TNF-alpha were detected in all individuals upon admission for severe OHSS. Concentrations dropped significantly along with clinical improvement, reaching normal values after complete resolution. A statistically significant correlation was found between plasma cytokine concentrations and certain biological characteristics of the syndrome such as leukocytosis, increased haematocrit, and elevated plasma 17-beta-oestradiol concentrations. Ascitic fluid obtained from the study patients contained high IL-6 and IL-8 concentrations, while other cytokines were unaltered. These results suggest close association between inflammatory cytokines and the pathophysiology of the ovarian hyperstimulation syndrome.

Topics: Adult; Ascitic Fluid; Case-Control Studies; Cytokines; Female; Fertilization in Vitro; Humans; Inflammation Mediators; Interleukin-1; Interleukin-6; Interleukin-8; Kinetics; Ovarian Hyperstimulation Syndrome; Ovulation Induction; Pleural Effusion; Tumor Necrosis Factor-alpha