Biomedical subjects

Yasushi Hirota

Publications and source records attributed to Yasushi Hirota.

At least 19 recordsLinked to original sources

PubMed2005

Mechanical stretch upregulates IGFBP-1 secretion from decidualized endometrial stromal cells.

Decidualization is an essential process of endometrial differentiation for embryo implantation and maintenance of pregnancy. Recently, uterine movement-induced mechanical stress was noticed to have possible effects on endometrial functions. In this study, we addressed the possible effect of mechanical stress on the process of decidualization of endometrial stromal cells (ESC). ESC were cultured on flexible-bottomed culture plates. After decidualization was achieved with estradiol and progesterone for 12 days, cultures were continued for 24 h with or without cyclic stretch (25% elongation) in serum-free conditions at a rate of 2 cycles/min using a computer-operated cell tension system. Concentrations of insulin-like growth factor-binding protein-1 (IGFBP-1), a marker of decidualization, in the conditioned medium were measured by specific ELISA, and IGFBP-1 mRNA expression in the ESC was measured by RT-PCR. Cyclic stretch remarkably increased IGFBP-1 secretion from decidualized ESC. It also increased IGFBP-1 mRNA in decidualized ESC. The increase in IGFBP-1 secretion was inhibited by actinomycin D but not by indomethacin, PD-98059, or H-89. Conditioned medium of decidualized ESC cultured with cyclic stretch increased IGFBP-1 secretion from decidualized ESC cultured under stationary conditions. These findings imply that uterine movement modulates decidualization of the endometrium and has a regulatory effect on reproduction.

Cells, Cultured↗

PubMed2005

Activation of protease-activated receptor 2 stimulates proliferation and interleukin (IL)-6 and IL-8 secretion of endometriotic stromal cells.

BACKGROUND: Inflammation has been proposed to play essential roles in the pathophysiology of endometriosis, in which neutrophils and mast cells have been suggested to be involved. We studied whether the protease-activated receptor 2 (PAR2), which is activated by enzymes from neutrophils and mast cells, in endometriotic stromal cells (ESC) has any implication in the development of the disease. METHODS: Cultured ESC were stimulated with various concentrations of a specific PAR2 agonist peptide. Proliferating activity of the cells was determined using immunostaining of proliferating cell nuclear antigen (a cell proliferation marker), 5-bromo-2'-deoxyuridine incorporation into DNA and cell count. The concentrations of interleukin (IL)-6 and IL-8 were measured using specific enzyme-linked immunosorbent assay kits. The phosphorylation of three mitogen-activated protein kinases (MAPK), i.e. p38 MAPK, p42/44 MAPK and stress-activated protein Kinase/c-jun N terminal Kinase, in ESC was examined with Western blot analysis. RESULTS: Activation of PAR2 stimulated the proliferation of ESC and the secretion of IL-6 and IL-8 from ESC in a dose-dependent manner. Activation of PAR2 stimulated the phosphorylation of all three MAPK, and inhibitors of each MAPK suppressed the PAR2 activation-induced proliferation of ESC. CONCLUSIONS: The activation of PAR2 in ESC may be involved in the pathophysiology of endometriosis by inducing the growth and inflammation of endometriotic lesions.

Blotting, Western↗

PubMed2005

Thromboxane A2 up-regulates neutrophil elastase release in Syrian hamsters with trinitrobenzene sulfonic acid-induced colitis.

Neutrophil elastase (NE) is a factor that aggravates colitis. We investigated the influence of thromboxane A2 (TXA2) and leukotriene B4 (LTB4) on NE release in Syrian hamsters with trinitrobenzene sulfonic acid-induced colitis. Colonic specimens with colitis were incubated with U-46619 (a TXA2 analogue) or LTB4 in vitro and NE release was examined. As a result, U-46619 increased NE release, while LTB4 had no effect. The NE release induced by U-46619 was inhibited by a TP-receptor antagonist. To demonstrate that TXA2 caused NE release in vivo as well, while LTB4 did not, colitis animals were treated with nordihydroguaiaretic acid (NDGA), a dual inhibitor of cyclooxygenase/lipoxygenase; and colonic luminal TXB(A)2 and LTB4 levels and NE activity were determined. The TXB(A)2 level was significantly correlated with NE activity, while no correlation was found between LTB4 and NE activity. An inhibitory effect of NDGA on the ulcer area was also observed, and NE activity was significantly correlated with the ulcer area. The suppression of TXA2 production by NDGA may result in the inhibition of NE release so that colonic tissue damage becomes less severe. Regulation of NE release is a new biological action of TXA2 that has not been reported before.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed2005

Serum adiponectin concentrations are decreased in women with endometriosis.

BACKGROUND: Adiponectin is a pleiotropic cytokine originally discovered as an adipocyte-specific gene product. Serum adiponectin concentrations have been reported to be low in women with endometrial cancer, breast cancer and uterine leiomyoma, suggesting possible involvement of adiponectin in these estrogen-related diseases. We thus addressed the relevance of adiponectin to endometriosis, an estrogen-dependent disease, in the present study. METHODS: Women with (n = 48) and without (n = 30) endometriosis undergoing laparoscopy were recruited in this study. Blood samples were collected, and serum adiponectin concentrations were measured using a specific enzyme-linked immunosorbent assay. The relationship between laparoscopic findings and serum adiponectin concentrations was analysed. RESULTS: The adiponectin concentrations in the serum of the women with endometriosis (median, 13.1 microg/ml; interquartile range, 10.2 - 16.7) were significantly lower than those of the women without endometriosis (15.9 microg/ml, 13.5 - 19.5; P = 0.008). A significant negative correlation was found between serum adiponectin concentrations and both endometriosis scores (R = - 0.307, P = 0.006) and adhesion scores (R = - 0.254, P = 0.026) of the revised American Society for Reproductive Medicine classification of endometriosis. CONCLUSIONS: The present findings suggest that adiponectin is implicated in the pathophysiology of endometriosis.

Adiponectin↗

PubMed2005

GnRH II as a possible cytostatic regulator in the development of endometriosis.

BACKGROUND: GnRH II is the second form of GnRH and is widely distributed in peripheral tissues of the female reproductive tract as well as in the central nervous system. In the present study, we studied the possible implication of GnRH II in endometriosis. METHODS: Effects of GnRH II on 5-bromo-2'-deoxyuridine (BrdU) uptake by cultured endometriotic stromal cells were examined. Effects of GnRH II on interleukin (IL)-1beta-induced expression of cyclooxygenase (COX)-2 and IL-8 were also studied. mRNA levels of GnRH I, GnRH II, type I GnRH receptor and type II GnRH receptor were determined by real-time quantitative RT-PCR in endometrial tissues of women with or without endometriosis and in endometriotic tissues. RESULTS: GnRH II dose-dependently suppressed BrdU uptake by endometrial stromal cells. Treatment with IL-1beta markedly increased mRNA levels of COX-2 and IL-8 in endometrial stromal cells and IL-8 protein secretion by these cells, while these increments were significantly suppressed by supplementation with GnRH II. The mRNA levels of GnRH II were lower in endometrial and endometriotic tissues of women with endometriosis than in endometrial tissues of women without endometriosis, both in the proliferative phase and the secretory phase. In addition, as for GnRH I, type I GnRH receptor and type II GnRH receptor, the mRNA levels were lower in endometrial tissues of women with endometriosis than in those without endometriosis in the secretory phase. CONCLUSIONS: In the light of the demonstrated antiproliferative and anti-inflammatory effects of GnRH II on endometrial stromal cells, the lower expression of GnRH II in eutopic and ectopic endometrium of women with endometriosis suggests that endogenous GnRH II-mediated cytostatic regulation may be impaired in the development of endometriosis.

Adult↗

PubMed2005

Development of an experimental model of endometriosis using mice that ubiquitously express green fluorescent protein.

BACKGROUND: Aiming at improving an animal model of endometriosis, we developed a homologous mouse model using 'green mice' that ubiquitously express green fluorescent protein. METHODS: Endometrial fragment obtained from estradiol (E2)-supplemented ovariectomized 'green mice' was minced and injected into the peritoneal cavity of ovariectomized wild-type mice. The recipient wild mice were raised with or without E2 supplementation for 2 weeks, and then were euthanized. Endometriotic lesions that developed in the abdomen were examined both macroscopically and microscopically under fluorescence, and weight of the lesions was measured. RESULTS: The endometriotic lesions were more clearly detected under fluorescence imaging than by conventional macroscopic examination. Histologically, endometriotic lesions deriving from 'green mice' were sharply distinguished from surrounding host tissues under fluorescence microscopy. More lesions developed in E2-supplemented than control recipient mice. The measured fluorescence intensity of endometriotic lesions showed significant positive correlation with their weight (R=0.844, P<0.0001), and was significantly higher in E2-supplemented mice than in vehicle-supplemented mice (P=0.0062). CONCLUSION: The present endometriosis model using 'green mice' would be useful for expeditious identification and quantitative evaluation of endometriotic lesions.

Animals↗

PubMed2005

Possible involvement of thrombin/protease-activated receptor 1 system in the pathogenesis of endometriosis.

Endometriosis is known to be associated with local inflammatory reactions. Given the emerging concept of thrombin and its specific receptor, protease-activated receptor 1 (PAR1), as important players in inflammation and cell proliferation, we investigated whether thrombin and PAR1 might be involved in the pathophysiology of the disease, using a primary cell culture system of endometriotic tissues. PAR1 mRNA was expressed in primary endometriotic stromal cells (ESCs). Thrombin and SFLLRN (Ser-Phe-Leu-Leu-Arg-Asp), a PAR1 agonist peptide, increased the mRNA expression of IL-8, monocyte chemoattractant protein-1 (MCP-1), and cyclooxygenase-2 (COX-2) and the protein secretion of IL-8 nd MCP-1 in ESCs. The addition of thrombin inhibitor d-phenylalanyl-l-prolyl-l arginine chloromethyl ketone (PPACK) together with thrombin inhibited the thrombin-induced secretion of IL-8 and MCP-1. Thrombin, but not SFLLRN, activated matrix metalloproteinase-2 in ESCs, and the effect was inhibited by PPACK. Thrombin and SFLLRN increased proliferating cell nuclear antigen-positive ratio of ESCs, indicating their cell proliferation-stimulating effects. The thrombin-induced increase in proliferating cell nuclear antigen-positive ratio was diminished by PPACK. These findings imply that the thrombin system might be involved in the pathophysiology of endometriosis, stimulating inflammatory responses of endometriotic cells and their mitogenic activity.

Chemokine CCL2↗

PubMed2005

Possible implication of midkine in the development of endometriosis.

BACKGROUND: The present study was conducted to assess whether midkine (MK), a multifunctional molecule known to stimulate tumor growth, may be involved in the development of endometriosis. METHODS: The mitogenic activity of MK on cultured endometriotic stromal cells was examined by measuring 5-bromo-2'-deoxyuridine (BrdU) incorporation. Concentrations of MK in the peritoneal fluid (PF) of women without or with endometriosis and those under GnRH agonist treatment were measured using a specific enzyme immunoassay. The expression of MK mRNA in peritoneal bone marrow-derived cells, peritoneum and endometriotic tissues was evaluated by RT-PCR. RESULTS: MK significantly increased BrdU incorporation into the DNA of cultured endometriotic stromal cells. The MK concentrations in the PF of the women with advanced endometriosis (stages II, III and IV) Median: 1.21 ng/ml; interquartile range 0.80-2.27 were significantly higher than those of the women without endometriosis and with stage I endometriosis (0.06 ng/ml, 0.67-1.26, P < 0.05). As for the menstrual phase, the MK concentration in PF in the inteal phase (1.32 ng/ml. 0.72-2.21) were significantly higher than those in the follicular phase (0.95 ng/ml, 0.68-1.24, P < 0.05). In addition, women with adnexal adhesions had higher concentrations of MK in PF than those without adhesions (P < 0.05). The MK concentrations of the women under GnRH agonist treatment were significantly lower than those of the other groups (P < 0.001). The expression of MK mRNA was detected in peritoneal bone marrow-derived cells, peritoneum and endometriotic tissues. CONCLUSIONS: The present findings suggest that MK may play roles, such as stimulation of endometriotic cell proliferation, in the development of endometriosis.

Adult↗

PubMed2005

Elevated interleukin-16 levels in the peritoneal fluid of women with endometriosis may be a mechanism for inflammatory reactions associated with endometriosis.

OBJECTIVE: To investigate the role of interleukin (IL)-16 in peritoneal fluid in the pathogenesis of endometriosis. DESIGN: Comparative and laboratory study. SETTING: University of Tokyo Hospital. PATIENT(S): Peritoneal fluids (PFs) were collected from women without endometriosis (n = 34) and with endometriosis (stages I/II, n = 30; stages III/IV, n = 58). Peritoneal fluid mononuclear cells (PFMCs) were collected from six women. INTERVENTION(S): The PFs were collected; PFMCs were isolated and cultured with or without recombinant human (rh) IL-16. MAIN OUTCOME MEASURE(S): Concentrations of IL-16 in PFs were measured by enzyme-linked immunosorbent assay (ELISA). Concentrations of IL-6, tumor necrosis factor-alpha (TNF-alpha), and IL-1beta in culture media of PFMCs were determined by ELISA. RESULT(S): The IL-16 concentrations in the PF of women with advanced endometriosis (stages III/IV) (330 pg/mL, 231-501; median, interquartile range) were significantly higher (P=.0016) than those without endometriosis (229 pg/mL, 174-311). The PFMCs cultured with rhIL-16 released an increased amount of IL-6, TNF-alpha and IL-1beta, which was a 1.17-, 1.33-, and 1.54-fold increase, respectively, over that in the control culture. CONCLUSION(S): The present study indicates that IL-16 in PF may play a role in the pathogenesis of endometriosis by initiating or sustaining inflammatory responses in the peritoneal cavity.

Adult↗

PubMed2005

Sciatic endometriosis diagnosed by computerized tomography-guided biopsy and CD10 immunohistochemical staining.

OBJECTIVE: To report a case of sciatic endometriosis diagnosed by computerized tomography (CT)-guided biopsy in combination with CD10 immunohistochemical staining. DESIGN: Case report. SETTING: University hospital. PATIENT(S): A 33-year-old Japanese woman complaining of right-sided sciatica. INTERVENTION(S): Transgluteal computerized tomography (CT)-guided needle biopsy of a mass in the course of the right sciatic nerve was conducted for a histologic diagnosis. MAIN OUTCOME MEASURE(S): Histologic study with hematoxylin and eosin staining and CD10 immunohistochemical staining was performed. RESULT(S): Computerized tomography-guided biopsy was performed without any complication. CD10 staining distinguished endometrial stromal cells. CONCLUSION(S): Computerized tomography-guided biopsy followed by CD10 immunohistochemical staining is a minimally invasive procedure for accurate diagnosis of sciatic endometriosis.

Adult↗

PubMed2005

Changes in plasma coagulation markers with prophylactic treatment of low molecular weight heparin after cesarean section.

Cesarean section has been identified as a major risk factor for thromboembolism, and additional risk factors place some women at a much higher risk during puerperium. Recently, low molecular weight heparins (LMWHs) have been used for thromboembolism prophylaxis after cesarean section. We investigated the effect of risk factors of thromboembolism on plasma coagulation markers when the LMWH dalteparin was used following cesarean section. Twenty-four women with risk factors other than cesarean section (high-risk group) and 13 without any other risk factors (low-risk group) received dalteparin starting immediately after cesarean section until the patients were mobilized. Sixteen women without any other risk factors served as controls (control group). Activated partial thromboplastin times, thrombin-antithrombin complex, alpha (2)-plasmin inhibitor-plasmin complex, and activated factor X levels were not different between the high-risk and the low-risk groups. However, fibrinogen/fibrin degradation products D-dimer levels were higher in the high-risk group than in the low-risk and control groups on days 3 and 7 after cesarean section. These findings suggest that the D-dimer levels may be elevated by some risk factors and that postoperative D-dimer determinations may be useful in assessing the risk of thromboembolism during LMWH treatment after cesarean section.

Adult↗

PubMed2005

Concentration of adiponectin in peritoneal fluid is decreased in women with endometriosis.

PROBLEM: Adiponectin is a novel adipocytokine of extreme importance for the metabolism. Recent studies have indicated that adiponectin suppresses inflammation, angiogenesis, and fibrosis, which are central pathogenic factors for endometriosis. We addressed the possibility that adiponectin is implicated in endometriosis. METHOD OF STUDY: We measured concentrations of adiponectin in peritoneal fluid (PF) of women with (n = 54) or without (n = 26) endometriosis using specific enzyme-linked immunosorbent assay. RESULTS: Adiponectin concentrations in PF of women with endometriosis were significantly lower than those of women without endometriosis. With respect to the stages of the disease, the concentrations of adiponectin in women with stage III/IV endometriosis were significantly lower compared to those in women without endometriosis and with stage I/II endometriosis. Body mass index were comparable among the groups. CONCLUSIONS: These findings imply that adiponectin may be an anti-endometriotic factor, possibly due to its anti-inflammatory, anti-angiogenic, and anti-fibrotic properties.

Adiponectin↗

PubMed2005

Pathophysiological studies of trinitrobenzene sulfonic acid-induced colitis in Syrian hamsters (Mesocricetus auratus).

We developed a colitis model in Syrian hamsters (Mesocricetus auratus) to investigate the relationship between colitis and neutrophil elastase (NE). Colitis was induced by a single intracolonic dose of trinitrobenzene sulfonic acid (TNBS; 90 mg/ml) dissolved in 15% (vol/vol) ethanol. The ulcer area, tissue myeloperoxidase (MPO) activity, and luminal NE activity all were increased on Days 1 and 5, corresponding with the acute inflammatory histopathological changes. These acute inflammatory parameters subsequently decreased by Day 14, and chronic inflammatory histopathological changes became evident. Recurrence of inflammation was not observed during the period up to Day 28. To evaluate our colitis model, the effects of prednisolone were examined. Prednisolone was administered orally once on the day before induction of colitis, and animals were treated twice daily thereafter. Although prednisolone had little effect on the tissue MPO activity, prednisolone inhibited the ulcer area and NE activity. In addition, the effects of an NE-specific inhibitor (ONO-6818) on our TNBS-induced colitis model were examined. In the subcutaneous treatment study, ONO-6818 was administered once before the induction of colitis. Although ONO-6818 had little effect on the tissue MPO activity, the ulcer area and NE activity were decreased in the ONO-6818-treated group. The inhibitory effects on the ulcer area and NE activity were confirmed after oral treatment with ONO-6818 after induction of colitis. We conclude that our colitis model is useful for investigating the relationship between colitis and NE, and inhibition of NE activity can prevent the progression of ulceration.

Animals↗

PubMed2004

Evidence for the presence of protease-activated receptor 2 and its possible implication in remodeling of human endometrium.

Protease-activated receptor 2 (PAR2) is activated by various proteases released from the leukocytes, such as neutrophils and mast cells. Because these leukocytes reside in the endometrium, we speculated that PAR2 might be activated there. In this study, we investigated the presence and possible roles of PAR2 in the endometrium. During the menstrual cycle, the expression of PAR2 mRNA in human endometrial tissues is increased from the late secretory phase to the menstrual phase and in early pregnancy. In vitro, PAR2 agonist peptide (PAR2AP) stimulated IL-8 production in both endometrial epithelial cells (EECs) and stromal cells (ESCs). PAR2AP also stimulated the mRNA expression of stem cell factor, a known activator for mast cells, in ESCs, and activated matrix metalloproteinase-7, an epithelial cell-specific matrix metalloproteinase, in EECs. In addition, PAR2AP significantly increased the 5-bromo-2'-deoxyuridine incorporation in ESCs. PAR2AP induced the phosphorylation of three MAPKs, i.e. p38 MAPK, p42/44 MAPK, and stress-activated protein kinase/c-Jun N-terminal kinase, in ESCs. Inhibitors of all three MAPKs inhibited PAR2AP-induced secretion of IL-8 in both EECs and ESCs. This is the first report demonstrating the presence of PAR2 in the human endometrium. The increased expression of PAR2 around the menstrual period, its up-regulation of molecules important for endometrial remodeling, and its mitogenic effect on endometrial cells raise the expectation of the possible involvement of PAR2 in menstruation and other architectural changes of the endometrium occurring during the menstrual cycle. MAPKs may mediate PAR2 functions in these processes.

Adult↗

PubMed2004

Mechanical stretch stimulates interleukin-8 production in endometrial stromal cells: possible implications in endometrium-related events.

Uterine movement is suggested to play roles in various events related to the uterus. In view of the current concept underscoring the biological implications of mechanical stretch, we speculated that the mechanical stretch exerted by uterine movement might stimulate the production of biochemical mediators in endometrial cells and contribute to inflammation-associating processes, such as menstruation and endometriosis. To address the possible effects of mechanical stretch in the endometrium, endometrial stromal cells (ESC) were cultured on flexible-bottomed culture plates, and cyclic stretch (25% elongation) was applied in serum-free conditions at a rate of two cycles per minute using a computer-operated cell tension system. IL-8 concentrations in the conditioned medium were measured using ELISA, and IL-8 mRNA expression in ESC was measured by RT-PCR. Cyclic stretch increased the secretion of IL-8 from ESC. The increase in IL-8 secretion was inhibited by PD98059, an inhibitor of extracellular signal-regulated kinase 1/2. The increase was also inhibited by progesterone. In addition, the conditioned medium of ESC cultured with cyclic stretch stimulated the mRNA expression of IL-8 in ESC cultured under stationary conditions. These findings imply that uterine movement has an impact on endometrium-related physiology and pathology by stimulating the production of a biochemical mediator(s) in the endometrium.

Adult↗

PubMed2004

Evidence for the presence of toll-like receptor 4 system in the human endometrium.

We investigated whether Toll-like receptor (TLR) 4 is at work in the human endometrium. The expression of TLR4 mRNA in endometrial epithelial cells (EECs) and stromal cells (ESCs) was detected by RT-PCR and in situ hybridization. Western blotting analysis revealed the TLR4 protein expression in both cell populations. Treatment of lipopolysaccharide (LPS), the actions of which are mediated through TLR4, significantly increased IL-8 secretion from cultured ESCs in a dose-dependent fashion. The stimulatory effect of LPS was inhibited by the addition of neutralizing antibodies for TLR4 and CD14. LPS also stimulated nuclear translocation of nuclear factor-kappaB in ESCs, which was also inhibited by these antibodies. On the other hand, LPS did not stimulate IL-8 secretion in cultured EECs. However, LPS stimulated IL-8 secretion from EECs in the presence of soluble CD14. Flow cytometric analysis revealed that CD14 was expressed on the cell surface of ESCs but not EECs. In addition, immunohistochemical analysis showed that CD14 was stained in ESCs but not EECs. Pretreatment of interferon-gamma (IFN-gamma) enhanced LPS-induced IL-8 secretion from ESCs. IFN-gamma increased the expression of TLR4 mRNA. It also increased the amounts of mRNA for CD14, MD2, and MyD88, which are needed for LPS recognition in concert with TLR4. In summary, we demonstrated that both ESCs and EECs express TLR4 and respond to LPS through TLR4. We further showed that EECs, not ESCs, required soluble CD14 for TLR4 activation. Interestingly, IFN-gamma, an antiinfectious cytokine, was found to activate the TLR4 system in ESCs. Altogether, the results imply that the TLR4 system might represent local immunity in the human endometrium with differential modes of TLR4 actions between ESCs and EECs.

Adaptor Proteins, Signal Transducing↗

PubMed2004

Concentration of osteoprotegerin (OPG) in peritoneal fluid is increased in women with endometriosis.

BACKGROUND: Failure of apoptosis of refluxed endometrial cells within the peritoneal cavity is a possible etiologic factor for development of endometriosis. Osteoprotegerin (OPG) is a survival factor that exerts its effect by binding to tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), thus preventing TRAIL from binding to the apoptosis receptors DR4 and DR5. In the present study, we addressed the possibility that the TRAIL/OPG system is involved in the pathogenesis of endometriosis. METHODS: Concentrations of OPG and TRAIL in the peritoneal fluid (PF) of women with or without endometriosis were measured using specific enzyme-linked immunoabsorbent assay. The expression of DR4 and DR5 in the endometriotic tissue was examined by reverse transcription-polymerase chain reaction. RESULTS: OPG concentrations in PF of women with endometriosis were significantly higher than those of women without endometriosis (P=0.006). With respect to the stages of the disease, the concentrations of OPG in women with stage III/IV endometriosis were significantly higher than in those without endometriosis and those with stage I/II endometriosis. On the other hand, the ratios of TRAIL/OPG concentrations were significantly lower in stage III/IV endometriosis compared to those in non-endometriosis and stage I/II endometriosis. DR5 mRNA expression was clearly detected in all the endometriotic tissues studied. CONCLUSIONS: These findings suggest that the TRAIL/OPG system is involved in the pathophysiology of endometriosis, possibly affecting the apoptosis of endometriotic cells.

Adult↗

PubMed2004

Possible pathophysiological roles of mitogen-activated protein kinases (MAPKs) in endometriosis.

PROBLEM: Endometriosis accompanies local inflammatory reactions in the peritoneal cavity. We examined the phosphorylation of mitogen-activated protein kinases (MAPKs), i.e. extracellular signal-regulated kinase (ERK), p38 MAPK (p38) and c-Jun N-terminal kinase (JNK) in endometriotic stromal cells, and their possible pathophysiological roles in endometriosis in relation to proinflammatory substances. METHOD OF STUDY: Endometriotic stromal cells were isolated from endometriomas and were cultured for the experiments. Phosphorylation of MAPKs in endometriotic stromal cells treated with interleukin (IL)-1beta, tumor necrosis factor (TNF)alpha and H(2)O(2) were examined by Western blot analysis. Effects of PD98059, SB202190 and SP600125 (inhibitors of ERK, p38 and JNK, respectively) on IL-1beta-induced secretion of IL-6 and IL-8, and on IL-1beta-induced expression of cyclo-oxygenase-2 (COX-2) in endometriotic cells were studied. In addition, eutopic endometrial tissues were collected, and the phosphorylation rate of p38 in eutopic endometrial tissues and endometriotic tissues were determined. RESULTS: IL-1beta, TNFalpha and H(2)O(2) stimulated the phosphorylation of ERK, p38 and JNK, while the total amounts of proteins of the respective MAPKs were virtually the same compared with those in the unstimulated controls. Both SB202190 and SP600125 suppressed IL-1beta-induced secretion of IL-6 and IL-8, and PD98059 suppressed IL-1beta-induced secretion of IL-8. Both SB202190 and PD98059 suppressed IL-1beta-induced expression of COX-2 in endometriotic cells. The p38 phosphorylation rates in the endometriotic tissues were significantly higher than those in the eutopic endometrial tissues of the same patients. CONCLUSIONS: Given the current theory that inflammatory changes are involved in the progression of endometriosis, MAPKs could play as pivotal intracellular signal transducers in endometriotic cells, and thus have a pathophysiological role in the disease.

Anthracenes↗