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Biomedical subjects

N Kawada

Publications and source records attributed to N Kawada.

At least 37 records · Page 2Linked to original sources
PubMed2001

Prevention of rat hepatic fibrosis by the protease inhibitor, camostat mesilate, via reduced generation of active TGF-beta.

BACKGROUND & AIMS: Proteolytic release and activation of latent transforming growth factor beta (TGF-beta) by the hepatic stellate cells (HSCs) are key events for pathogenesis of hepatic fibrosis, and protease inhibitors suppress TGF-beta generation by cultured HSCs, suggesting their potential use as antifibrogenic agents. We explored this idea using camostat mesilate, a serine protease inhibitor, to determine its effects and mechanisms of action in vivo. METHODS: Camostat mesilate was either added to cultured rat HSCs or administered orally to rats during porcine serum treatment, followed by overexpression of urokinase. We measured cellular and hepatic levels of plasmin, TGF-beta, TGF-beta activity, activated HSC markers (increased cell number, morphologic change, and expression of both alpha-smooth muscle actin and collagen(alpha2)[I]), and fibrosis (Azan-staining and quantification of hydroxyproline content). RESULTS: Camostat mesilate (500 micromol/L) inhibited generation of TGF-beta by suppressing plasmin activity and reduced the activity of TGF-beta, which blocked in vitro activation of HSCs. In the in vivo model, camostat mesilate (1-2 mg/g of diet) markedly attenuated an increase in hepatic plasmin and TGF-beta levels, HSC activation, and hepatic fibrosis without apparent systemic or local side effects, all of which were reverted by restoration of hepatic plasmin activity. CONCLUSIONS: Camostat mesilate prevents porcine serum-induced rat hepatic fibrosis via a profound reduction in TGF-beta generation.

Animals↗
PubMed2001

Kupffer cell-mediated recruitment of rat dendritic cells to the liver: roles of N-acetylgalactosamine-specific sugar receptors.

BACKGROUND & AIMS: Tissue recruitment of dendritic cells (DCs) is essential for antigen presentation. This study aimed to examine cellular and molecular mechanisms for DC recruitment to the liver. METHODS: Purified rat DCs were injected into circulation and their traffics were analyzed in normal and Kupffer cell-depleted rats by intravital confocal microscopy and immunohistology. Affinities of DCs to sinusoidal cells were examined by a cell-binding assay. DC precursor recruitment was induced by particulate injection. RESULTS: Both DC precursors and DCs at the antigen-transporting stage could be recruited to the liver, and their majority initially showed a selective binding to Kupffer cells. In the Kupffer cell-depleted rats, DCs could neither be recruited to the liver nor adhere to sinusoidal walls. Pretreatment with varied monosaccharides showed that sugar residues consisting of N-acetylgalactosamine were necessary for this binding. The binding was calcium-dependent, implying the C-type lectin involvement. Furthermore, DCs could endocytose N-acetylgalactosamine polymers in a receptor-specific manner. CONCLUSIONS: The DC-Kupffer cell binding through N-acetylgalactosamine-specific C-type lectin-like receptors is crucial for DC recruitment to the liver. Rat DCs at least partly possess receptors for endocytosis of galactosylated antigens. These DC receptors as well as Kupffer cell lectins are presumably responsible for this binding.

Acetylgalactosamine↗
PubMed2001

The effect of leukotriene D(4) inhalation on the antigen-induced airway hyperresponsiveness and inflammation in 5-lipoxygenase gene-deficient mice.

BACKGROUND: The role of 5-lipoxygenase (5-LO) products in the asthmatic bronchoconstriction is evident. However, the role of 5-LO products in airway hyperresponsiveness (AHR) and airway inflammation is still under discussion. The aim of the present study is to investigate the role of leukotriene D(4) (LTD(4)) in AHR and allergic airway eosinophilia in mice. METHODS: The effect of LTD(4) inhalation on antigen-induced AHR and airway eosinophilia was investigated in 5-LO gene-deficient mice. RESULTS: After three inhalations of LTD(4), airway responsiveness to acetylcholine was not altered in normal or allergic wild-type and 5-LO knockout (KO) mice. In contrast, the number of eosinophils in 5-LO KO allergic mice increased to the level of wild-type allergic mice after the inhalation of LTD(4). These observations were confirmed by a histopathological study of the lungs. No change in the cytokine levels in bronchoalveolar lavage fluid and serum immunoglobulin levels was shown after LTD(4) inhalation. CONCLUSION: These findings suggest that LTD(4) plays a role in eosinophilic airway inflammation but not in AHR in mice.

Administration, Inhalation↗
PubMed2001

Role of mast cells in antigen-induced airway inflammation and bronchial hyperresponsiveness in rats.

The participation of mast cells in the induction of antigen-induced airway inflammation and bronchial hyperresponsiveness (BHR) to acetylcholine (ACh) was investigated using pharmacological agents and mast cell-deficient rats (Ws/Ws). A significant increase in the number of leukocytes in bronchoalveolar lavage fluid (BALF) and bronchial responsiveness to ACh were observed 24 h after antigen (ovalbumin) challenge in sensitized Brown-Norway (BN) rats. Disodium cromoglycate and terfenadine did not inhibit antigen-induced airway inflammation and BHR in sensitized BN rats. In contrast, cyclosporin A (CyA), FK-506 and prednisolone significantly inhibited antigen-induced airway inflammation and BHR in sensitized BN rats. In addition, disodium cromoglycate, terfenadine and prednisolone, but not CyA and FK-506, inhibited homologous passive cutaneous anaphylaxis in rats. Furthermore, a significant increase in the number of leukocytes in BALF and BHR was also observed in Ws/Ws rats 24 h after inhalation of antigen; however, the magnitude of BHR in Ws/Ws rats was lower than that in the congenic rats. These findings suggest that mast cells play a partial role in the development of antigen-induced BHR in rats and that the induction of BHR is barely suppressed by mast cell stabilizing agents.

Acetylcholine↗
PubMed2001

[Right ventricular outflow tract reconstruction with PTFE mono-cusped transannular patch for tetralogy of Fallot].

Conotruncal repair for tetralogy of Fallot consists of (1) precise closure of the VSD with the membranous flap and (2) reconstruction of the right ventricular outflow tract (RVOT) by a short transannular patch (< 30% of the RV length) with a wide PTFE monocusp. This report describes the mid-term results in 46 patients with tetralogy of Fallot who underwent conotruncal repair with PTFE monocusped transannular patch and have been followed up for 4 years or more. There was no early and late death and no patient required reoperation. No patient has had a significant residual defect or tricuspid regurgitation (> II). The right and left ventricular pressure ratio was 0.41 +/- 0.12 and the pressure gradient across RVOT was 10.5 +/- 5.9 mmHg, signifying sufficient relief of RVOT obstruction. The mobility of the PTFE monocusp was echocardiographically detected in 86% over a mean follow-up period of 84 +/- 34 months and % freedom from pulmonary regurgitation (> II) was 85.9% at 10 years postoperatively. Excellent long-term durability of the PTFE monocusp provided the normal right vent performance with RVEDV of 91.8 +/- 29.5% of normal and a central venous pressure of 5 +/- 1 mmHg. In conclusion, conotruncal repair with a wide and short transannular patch has provided good mid-term results with the excellent long-term durability of PTFE monocusp.

Adolescent↗
PubMed2001

[Exchange transfusions in sepsis after the pediatric open heart surgery].

We experienced 2 cases of septic children after open heart surgery. Both of them recovered by using exchange blood transfusion technique. We use irradiated and dialysed fresh blood for exchange blood transfusion. After this procedure, they recovered from sepsis, as the datas improving, white blood cell reduced from 19,700 +/- 3,710 to 8,200 +/- 2,360, CRP reduced from 5.46 +/- 1.65 to 1.89 +/- 0.70, T-Bil reduced from 7.61 +/- 2.66 to 3.02 +/- 0.89, and BUN reduced from 525.92 +/- 6.64 to 19.76 +/- 5.34. Furthermore, blood pressure and urine volume were stable between exchange blood transfusion, although after open heart surgery. Therefore this procedure has benefits for the compromised, septic patients, performed open heart surgery, because of its stability of the circulating circumstances. And using the irradiated and dialysed fresh blood provides stable condition eventhough under high dose catecholamine use.

Anti-Bacterial Agents↗
PubMed2000

Clinicopathological characterization of prion: a novel marker of activated human hepatic stellate cells.

BACKGROUND/AIMS: We recently demonstrated prion as a new marker for hepatic stellate cell activation in rats. Here, we have examined prion expression in normal and diseased human livers. METHODS: Prion expression was examined at protein level by immunohistochemistry and at mRNA level by in situ hybridization. RESULTS: While normal livers were negative for prion, all liver specimens but one from patients with chronic liver disease were positively stained. In chronic hepatitis, prion protein expression was found not only in the sinusoidal lining cells within the lobules but also in mesenchymal cells in expanded portal tracts. In alcoholic liver disease, prion-positive cells were found mainly in the areas of alcoholic hepatitis. Immunoelectronmicroscopy revealed that prion-positive cells were activated stellate cells. In situ hybridization demonstrated that the distribution of prion mRNA is similar to that of prion protein. In chronic hepatitis, the number of prion-positive cells correlated with the grade of activity but not with the stage of fibrosis. In alcoholic liver disease, levels of prion protein expression were significantly increased in the presence of alcoholic hepatitis. CONCLUSION: Prion as a novel marker of activated stellate cells correlates well with disease activity in human chronic liver diseases.

Biomarkers↗
PubMed2000

Allergen-induced airway inflammation and bronchial responsiveness in interleukin-5 receptor alpha chain-deficient mice.

OBJECTIVE: The role of IL-5 receptor alpha chain (IL-5Ralpha) in the onset of bronchial hyperresponsiveness (BHR) to acetylcholine was investigated by testing IL-5Ralpha knockout (IL-5Ralpha KO) mice. METHODS: Mice were immunized with antigen at intervals of 12 days. Starting 10 days after the secondary immunization, mice were exposed to antigen three times every fourth day. Twenty-four hours after the last antigen challenge, bronchial responsiveness to acetylcholine was measured and bronchoalveolar lavage was carried out. RESULTS: Twenty-four hours after the last antigen inhalation, total and differential cells counts of bronchoalveolar lavage revealed a significant increase in eosinophils and lymphocytes in ovalbumin-exposed wild-type mice. In IL-5Ralpha KO mice, there was little increase of eosinophils in bronchoalveolar lavage fluid (BALF). The production of IL-5 in BALF increased in both mice after repeated antigen challenge, and there was no significant difference between wild-type and IL-5Ralpha KO mice. Similar to the BAL study, histological sections of lung tissue from ovalbumin-exposed wild-type mice exhibited airway eosinophilic inflammation, which was attenuated by the deficiency of IL-5Ralpha chain. There was no significant difference in serum antigen-specific IgE levels between wild-type and IL-5Ralpha KO mice after immunization nor antigen inhalation. Repeated antigen provocation caused BHR to acetylcholine in wild-type mice. In contrast, no BHR was observed in IL-5Ralpha KO mice after repeated inhalation of antigen. CONCLUSION: These findings indicate that IL-5Ralpha plays an important role in the development of antigen-induced airway eosinophilia and BHR in mice.

Acetylcholine↗
PubMed2000

Inhibition of hepatic stellate cell proliferation and activation by the semisynthetic analogue of fumagillin TNP-470 in rats.

Proliferation and activation of hepatic stellate cells (HSCs) are critical steps for the development of postnecrotic fibrosis in the liver. The present study aimed to reveal the inhibitory effect of the semisynthetic analogue of fumagillin TNP-470 on these events for its possible use as an antifibrogenic agent. Rat models of carbon tetrachloride (CCl(4))- and dimethylnitrosamine-induced hepatic fibrosis were used for an in vivo study. In both models, the fibrotic area was considerably decreased by concurrent repetitive subcutaneous injections of 30 mg/kg body weight of TNP-470. In CCl(4)-induced fibrosis, factor VIII-related antigen-positive blood vessels, desmin-, or alpha-smooth muscle actin (alphaSMA)-positive mesenchymal cells, bromodeoxyuridine (BrdU)-positive mesenchymal cells also decreased in number by treatment with TNP-470. In in vitro experiments, a supplement of 1,000 ng/mL TNP-470 suppressed BrdU incorporation and cyclins D1, D2, and E expression by cultured HSCs in the absence and/or presence of platelet-derived growth factor (PDGF). Expression of HSC activation markers, i.e., alphaSMA and PDGF receptor beta, was also suppressed. The present results indicate that TNP-470 inhibits HSC proliferation by blocking the cell-cycle transition from G1 to S and HSC activation, and, as the consequence, prevents the progression of hepatic fibrosis, probably being coupled with its antiangiogenic effect.

Actins↗
PubMed2000

Proteome analysis of rat hepatic stellate cells.

Proteome analysis was performed on cellular and secreted proteins of normal (quiescent) and activated rat hepatic stellate cells. The stellate cells were activated either in vitro by cultivating quiescent stellate cells for 9 days or in vivo by injecting rats with carbon tetrachloride for 8 weeks. A total of 43 proteins/polypeptides were identified, which altered their expression levels when the cells were activated in vivo and/or in vitro. Twenty-seven of them showed similar changes in vivo and in vitro, including up-regulated proteins such as calcyclin, calgizzarin, and galectin-1 as well as down-regulated proteins such as liver carboxylesterase 10 and serine protease inhibitor 3. Sixteen of them showed different expression levels between in vivo and in vitro activated stellate cells. These results were reproducibly obtained in 3 independent experiments. The up-regulation of calcyclin, calgizzarin, and galectin-1, as well as the down-regulation of liver carboxylesterase 10 were directly confirmed in fibrotic liver tissues. Northern blots confirmed up-regulation of the messenger RNAs (mRNAs) of calcyclin, calgizzarin, and galectin-1 in activated stellate cells, indicating that these changes were controlled at the mRNA level. In addition a list compiling over 150 stellate cell proteins is presented. The data presented here thus provide a significant new protein-level insight into the activation of hepatic stellate cells, a key event in liver fibrogenesis.

Animals↗
PubMed2000

In vivo and in vitro interactions between human colon carcinoma cells and hepatic stellate cells.

Stromal reaction is important for the growth of cancer both in primary and metastatic sites. To demonstrate this reaction during the hepatic metastasis of human colon carcinoma, we histologically investigated alterations to the distribution and phenotype of hepatic stellate cells (HSCs), the only mesenchymal cells in the liver parenchyma, using a nude mouse model. Intrasplenically injected colon carcinoma LM-H3 cells migrated into the space of Disse and underwent proliferation, in close association with hepatocytes and HSCs, at 2 days. At 14 days, HSCs were accumulated around the tumor mass and expressed alpha-smooth muscle actin, a marker for HSC activation. We next investigated in vitro the growth factors involved in the interactions between LM-H3 cells and HSCs. Conditioned medium of rat HSCs which underwent culture-induced activation contained platelet-derived growth factor (PDGF)-AB, hepatocyte growth factor (HGF) and transforming growth factor (TGF)-beta, and could augment LM-H3-cell proliferation and migration. Neutralizing antibodies against PDGF-AA and PDGF-BB and those against PDGF-BB and HGF inhibited proliferation and migration, respectively, of LM-H3 cells, whereas antibody against TGF-beta had no effect. LM-H3 cells expressed PDGF receptors-alpha and -beta and c-met. Conditioned medium of LM-H3 cells contained PDGF-AB, and could enhance HSC proliferation and migration. This augmenting effect was suppressed by treatment with anti-PDGF-AB antibody. The present study has demonstrated that bidirectional interactions involving PDGF and HGF take place in vitro between colon carcinoma cells and HSCs, raising the possibility that similar interactions might be involved in the stromal reaction during hepatic metastasis.

Adenocarcinoma↗
PubMed2000

Assessment of coronary flow reserve using fast velocity-encoded cine MR imaging: validation study using positron emission tomography.

OBJECTIVE: Previous studies using intravascular Doppler sonography and positron emission tomography (PET) have shown that the hemodynamic significance of coronary artery stenosis can be evaluated by measuring coronary flow reserve. The purpose of this study was to assess whether MR imaging measurements of coronary flow reserve in the left anterior descending artery are comparable with those obtained with PET in the corresponding territory. SUBJECTS AND METHODS: MR imaging and PET flow measurements were obtained in 10 healthy volunteers. Blood flow velocity in the left anterior descending artery was measured with breath-hold velocity-encoded cine MR imaging before and after IV administration of dipyridamole. The coronary flow velocity reserve measured by MR imaging was compared with the myocardial perfusion reserve in the anterior myocardium quantified on using PET and (15)O-labeled water. RESULTS: The average flow velocity reserve in the left anterior descending artery measured on MR imaging was 2.44+/-1.14 in healthy volunteers, which was comparable with the myocardial perfusion reserve measured by PET (2.52+/-0.84). MR imaging and PET measurements of the coronary flow reserve showed a significant correlation (r = 0.79, p<0.01). CONCLUSION: MR imaging measurement of the flow velocity reserve in the proximal left anterior descending artery correlates well with the myocardial perfusion reserve obtained with PET and (15)O-labeled water.

Adult↗
PubMed2000

Early form of ovarian cancer originating in inclusion cysts. A case report.

BACKGROUND: Most surface epithelial-stromal tumors of the ovary are thought to arise from epithelial inclusion cysts; thus, those cysts and the original surface epithelium are precursor lesions of ovarian carcinoma. CASE: A 46-year-old woman underwent a hysterectomy, right salpingo-oophorectomy and wedge biopsy of the left ovary because of a uterine myoma and right dermoid cyst. Histologic examination incidentally showed a tiny focus of well-differentiated serous carcinoma originating in inclusion cysts in the biopsied left ovary. Relaparotomy was performed, and only metaplastic epithelium in the inclusion cysts was found in the remnant of the left ovary. This finding was thought to be the origin of an ovarian cancer. CONCLUSION: Carcinoma precursors should occur in epithelial inclusion cysts of the ovary, as in the cervix and endometrium, but have been reported only rarely. Their incidental finding may help identify patients at risk of developing ovarian carcinoma.

Diagnosis, Differential↗
PubMed2000

Outcomes of dysplastic nodules in human cirrhotic liver: a clinicopathological study.

The number of dysplastic nodules detected clinically has increased since patients with hepatitis virus-associated cirrhosis, who are at increased risk for hepatocellular carcinoma (HCC), began to undergo regular cancer surveillance. Although it is potentially important to determine which type(s) of nodule may be prone to progress to HCC, outcomes of dysplastic nodules have not been fully investigated. This prompted us to examine the outcomes of dysplastic nodules in cirrhotic patients clinicopathologically. We studied 33 dysplastic nodules of <20 mm in maximum diameter, diagnosed by fine needle aspiration biopsy under ultrasonography (US). These nodules were clinically followed, mainly by US examination, for up to 70 months. When the nodules enlarged or exhibited changes on US, they were histologically reexamined by second biopsy. Surprisingly, 15 of the 33 nodules (45.5%) disappeared, 14 nodules (42.4%) remained unchanged, and only 4 nodules (12.1%) progressed to HCC. The latter 4 nodules were all hyperechoic on US and were composed of clear cells with fatty change or small cells with increased nuclear density, and in all 4 patients serum was positive for hepatitis C virus antibody. Univariate analyses revealed that, although not significant, the hyperechoic nodules or nodules with small cell change showed a higher HCC progression rate in comparison with the hypoechoic nodules or the nodules without small cell change. In summary, most of the dysplastic nodules we followed disappeared or remained unchanged, but some progressed to HCC. Hyperechoic nodules in patients with hepatitis C virus-associated cirrhosis, which show small cell change with increased nuclear density, may be prone to progress to HCC.

Adult↗
PubMed1999

ROCK inhibitor Y-27632 attenuates stellate cell contraction and portal pressure increase induced by endothelin-1.

By using a selective ROCK inhibitor Y-27632, the role of Rho-ROCK signaling in the function of hepatic stellate cells in culture was studied. Stellate cells maintained the "star-like" configuration of the quiescent stage in the presence of Y-27632, while the expression of smooth muscle alpha-actin and PDGF receptor beta was not affected by the agent. Serum-stimulated migration of the cells was significantly suppressed by Y-27632. The contraction of stellate cells induced by 5 nM endothelin-1 was attenuated by the agent in a dose-dependent manner. Formation of F-actin stress fibers and phosphorylation of myosin light chain was apparently reduced by Y-27632 even under the stimulation with endothelin-1. On the other hand, ex vivo liver perfusion experiment revealed that endothelin-1 (2 nM)-induced increase of portal vein constriction was almost completely inhibited by 20 microM Y-27632 with a concomitant improvement of hepatocyte degeneration. These results suggest that ROCK is one of the key regulators of stellate cell motility and that the clinical application of ROCK inhibitors such as Y-27632 should be considered in the reduction of portal hypertension in liver fibrosis and cirrhosis.

Actins↗