Biomedical subjects

K Okabe

Publications and source records attributed to K Okabe.

At least 55 records · Page 3Linked to original sources

PubMed1999

Physiological significance of hyperpolarization-activated inward currents (Ih) in smooth muscle cells from the circular layers of pregnant rat myometrium.

The properties of hyperpolarization-activated current in pregnant rat uterus (17-19 days gestation) were investigated using microelectrode and patch-clamp techniques, and isometric tension recording. The resting membrane potentials were -58.4 mV and -48.5 mV in longitudinal and circular muscle cells, respectively. Application of hyperpolarizing current pulses produced a time-dependent anomalous inward rectification of membrane potential only in circular muscle cells. Under voltage-clamp conditions, inward currents (Ih) were activated by long hyperpolarizing pulses below -60 mV in circular but not in longitudinal muscle cells. Application of extracellular but not intracellular Cs+ reduced the amplitude of I(h) in a concentration-dependent manner (an IC50( of 0.15 mM). The reversal potential for Ih was -26.2 mV and the slope conductance was 5 nS/pF. Changes in [K+]o and [Na+]o shifted the reversal potential, and Ih amplitude increased with excess [K+]o and decreased with low [Na+]o. The steady-state activation of Ih was well fitted by a Boltzmann equation with a half-activation potential of -84.3 mV and a slope factor of 9.6 mV. Time courses of activation and deactivation of the current strongly depended on membrane potential, and were well fitted by a single exponential function. The activation time constant of Ih was dependent on temperature. In isometric tension recording, application of extracellular Cs+ to the circular muscles reduced the frequency, but not the amplitude, of spontaneous contractions in a concentration-dependent manner. It is concluded that in pregnant rat uterus Ih channels are predominantly distributed in smooth muscle cells from the circular layer. Since Ih is activated at the resting membrane potential, it is likely that this current contributes to the maintenance of resting membrane potential and spontaneous activity in circular smooth muscle cells of late pregnant rats.

Algorithms↗

PubMed1999

Novel carboxamide derivative (IS-741) attenuates lung injury in rats with cerulein-induced pancreatitis complicated by endotoxemia.

The therapeutic effects of an intravenously injected carboxamide derivative (IS-741) on lung injury were studied in rats with cerulein-induced pancreatitis complicated by endotoxemia. Pancreatitis was induced by four intramuscular injections of cerulein (50 microg/kg at 1-hr intervals). Pancreatitis rats were injected intraperitoneally with 10 mg/kg of lipopolysaccharide (LPS) 6 hr following the first cerulein injection as a challenge of endotoxemia. Rats were divided into four groups: group I, pancreatitis with LPS; group II, pancreatitis with LPS treated with a continuous intravenous injection of IS-741 at 0.03 mg/kg/hr); group III, pancreatitis with LPS treated with a continuous intravenous injection of IS-741 at 0.3 mg/kg/hr); and group IV, pancreatitis with LPS treated with a continuous intravenous injection of IS-741 at 3 mg/kg/hr). IS-741 was administered 30 min before the endotoxemia challenge. Intense mononuclear cell infiltration and lung hemorrhage occurred in untreated pancreatitis rats with LPS (group I), but hemorrhage was not seen in group IV rats receiving a continuous injection of IS-741 shortly before the induction of endotoxemia. The IS-741-treated rats (groups II, III, and IV) had lower serum concentrations of cytokine-induced neutrophil chemoattractant (CINC), as well as fewer pulmonary infiltrates immunoreactive for CINC or Mac-1 (CD11b/CD18). The number of neutrophils infiltrating the lung in groups II, III, and IV was significantly lower than that of group I. Conversely, CINC production by bronchoalveolar macrophages in vitro were stimulated by LPS but were reduced by the presence of IS-741. The carboxamide derivative IS-741 effectively prevented pancreatitis-associated lung injury following the challenge of endotoxemia.

Acute Disease↗

PubMed1999

A synthetic selective inhibitor of factor Xa, DX-9065a, reduces monocyte chemoattractant protein-1 expression after ischemia-reperfusion injury in rat liver.

Activated factor X (FXa) is a trypsinlike serine protease involved in the cascade of blood coagulation. The monocyte chemoattractant protein-1 (MCP-1) may be important in the pathophysiology of liver ischemia-reperfusion injury. We investigated the effects of a selective FXa inhibitor, DX-9065a, on MCP-1 expression after ischemia-reperfusion in the rat liver. Liver ischemia was induced in rats by occluding the portal vein for 30 min. DX-9065a was injected intravenously 5 min before vascular clamping. Serum concentrations of MCP-1 were measured by enzyme-linked immunosorbent assay. The levels of MCP-1 mRNA in the liver after reperfusion were determined by northern blot analysis. In vitro MCP-1 production by peritoneal macrophages in response to alpha-thrombin was examined. Serum concentrations of MCP-1 increased and peaked at 6 hr after reperfusion. However, pretreatment of animals with DX-9065a resulted in significantly smaller increases in the serum concentration of MCP-1 after reperfusion in a dose-dependent manner. Pretreatment with DX-9065a significantly reduced MCP-1 mRNA levels in the liver after ischemia-reperfusion. In vitro MCP-1 production by peritoneal macrophages was enhanced by alpha-thrombin. In addition, DX-9065a significantly reduced tissue factor mRNA levels in peripheral monocytes after ischemia-reperfusion, compared to untreated animals. In conclusion, a selective inhibitor of FXa, DX-9065a, limited MCP-1 production after ischemia-reperfusion of the rat liver.

Animals↗

PubMed1999

A phase II study employing combination regimens containing KRN8602 in drug-resistant acute myeloid leukemia and acute lymphoblastic leukemia. KRN8602 Leukemia Study Group.

We conducted a phase II multicenter study in order to evaluate the efficacy and toxicity of two combination regimens containing KRN8602 (MX2) for drug-resistant acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). AML was treated with KRN8602, 15 mg/m2 i.v. push for 5 days, and cytarabine (AraC), 100 mg/m2 by 24 h coutinuous infusion for 7 days. ALL was treated with KRN8602, 15 mg/m2 i.v. push for 5 days, vincristine (VCR), 1.4 mg/m2 i.v. push, once weekly, and prednisolone (PSL), 40 mg/m2, 3 h infusion for 5 days. In AML and ALL, the complete remission (CR) rate was 36.4% (16 of 44) and 24.1% (seven of 29), and the overall response rate (CR+PR) was 52.3% (23 of 44) and 51.7% (15 of 29), respectively. Among the 29 relapsed cases of AML, a higher CR rate, 51.7% (15 of 29), was obtained. A high incidence of nausea/vomiting and anorexia was observed, and some patients experienced central nervous system disorders and peripheral neuropathy. There was a low incidence of severe neurotoxicities; all other toxicities were manageable. KRN8602 was found to overcome drug resistance clinically, confirming results based on the preclinical studies. We conclude that KRN8602 is an effective novel anthracycline for drug-resistant acute leukemias.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1999

Platelet-activating factor antagonist (TCV-309) attenuates the priming effects of bronchoalveolar macrophages in cerulein-induced pancreatitis rats.

We investigated the role of platelet-activating factor (PAF) as a priming signal for cytokine-induced neutrophil chemoattractant (CINC) expression by bronchoalveolar macrophages in acute pancreatitis. Pancreatitis was induced by four intramuscular injections of cerulein (50 micrograms/kg at 1-h intervals) in Wistar rats. The animals were injected intraperitoneally with 10 micrograms/kg of lipopolysaccharide (LPS) as a septic challenge. Pancreatitis rats were treated with a bolus intravenous injection of TCV-309 (3 or 30 micrograms/kg) 30 min before the septic challenge. Intense mononuclear cell infiltration and lung hemorrhage occurred in pancreatitis rats complicated with sepsis but were not seen in pancreatitis rats receiving a bolus TCV-309. Pancreatitis rats treated with TCV-309 had lower serum concentrations of CINC after septic challenge and lower levels of CINC messenger RNA (mRNA) in the lung, as well as fewer pulmonary infiltrates immunoreactive for CINC or Mac-1 (CD11b/CD18). In vitro CINC production in response to LPS by bronchoalveolar macrophages obtained from pancreatitis rats 6 h after the first cerulein injection, immediately before septic challenge, was enhanced but was significantly reduced in a TCV-309-sensitive manner. LPS-stimulated in vitro CINC production by naive bronchoalveolar macrophages was significantly enhanced by pretreatment with PAF. TMB-8 (an inhibitor of calcium release from endoplasmic reticulum) or W7 (calmodulin antagonist) completely abrogated the chemoattractant production by bronchoalveolar macrophages pretreated with PAF after LPS stimulation. Altered intracellular calcium, due to Ca2+ efflux from intracellular stores, may be involved in the "priming" of bronchoalveolar macrophages to release CINC after triggering with LPS during acute cerulein-induced pancreatitis. The PAF antagonist TCV-309 effectively prevented hyperactivity of bronchoalveolar macrophages and pancreatitis-associated lung injury after the septic challenge.

Animals↗

PubMed1999

The novel carboxamide derivative IS-741 reduces neutrophil chemoattractant production by bronchoalveolar macrophages in rats with cerulein-induced pancreatitis complicated by sepsis.

BACKGROUND/AIMS: The priming mechanism of macrophages to secrete cytokines in acute pancreatitis is important for remote organ failure following septic complication. The effects of novel carboxamide derivative, IS-741, on neutrophil chemoattractant production by bronchoalveolar macrophages were studied in rats with cerulein-induced pancreatitis complicated by sepsis. METHODS: Pancreatitis was induced by four intramuscular injections of cerulein (50 microg/kg at 1-hour intervals). Pancreatitis rats were injected intraperitoneally with 10 mg/kg of lipopolysaccharide (LPS) 6 h following the first cerulein injection as a septic challenge. Pancreatitis rats received a continuous intravenous injection of IS-741 (3 mg/kg/h) 30 min before the septic challenge. RESULTS: Intense mononuclear cell infiltration and lung hemorrhage occurred in untreated pancreatitis rats complicated with sepsis, but hemorrhage was not seen in septic pancreatitis rats receiving a continuous intravenous injection of IS-741 shortly before sepsis induction. The IS-741-treated rats had lower serum concentrations of cytokine-induced neutrophil chemoattractant (CINC), as well as fewer the pulmonary neutrophils and infiltrates immunoreactive for CINC or Mac-1 (CD11b/CD18). CONCLUSION: The novel carboxamide derivative IS-741 reduced CINC production by bronchoalveolar macrophages and effectively prevented pancreatitis-associated lung injury following the septic challenge.

Animals↗

PubMed1999

A prospective randomized trial of KRN8602 and cytosine arabinoside vs. daunorubicin and cytosine arabinoside in adult patients with newly diagnosed acute myelogenous leukemia. The KRN8602 Leukemia Study Group.

A prospective randomized study was conducted to compare the efficacy and toxicity of two anthracyclines for the treatment of patients with acute myelogenous leukemia (AML). Fifty-eight patients were randomized and received induction therapy consisting of cytosine arabinoside (AraC) 100 mg/m2/day for 7 days combined with either KRN8602 (3'-deamino-3'-morpholino-13-deoxo-10-hydroxycarminomycin hydrochloride [KRN]) 15 mg/m2/day for 5 days (KRN/AraC group) or daunorubicin (DNR) 40 mg/m2/day for 3 days (DNR/AraC group). Complete remission rate was 78.6% (22/28) in the KRN/AraC group and 73.1% (19/26) in the DNR/AraC group. There was a higher incidence of nausea/vomiting and anorexia observed in the KRN/AraC group compared to the DNR/AraC group, while the incidence of other adverse effects (stomatitis, diarrhea, and infectious complications) were similar between both groups. No electrocardiogram (ECG) abnormalities were observed after treatment in the KRN/AraC group, while in the DNR/AraC group, one patient showed ECG abnormality and three patients exhibited either arrhythmia, heart failure, or tachycardia. Mental disorder was reported in two cases in the KRN/AraC group. These findings suggest that KRN/AraC is similar in effectiveness to DNA/AraC but more toxic in central nervous system and gastrointestinal symptoms and less toxic regarding cardiac function in patients with previously untreated AML.

Adolescent↗

PubMed1999

Neutrophil elastase enhances macrophage production of chemokines in receptor-mediated reaction.

Proteases influence various leukocyte effector functions. We investigated the specific binding activity of neutrophil elastase (NE) on rat peritoneal macrophages to stimulate chemokine production in vitro. NE enhanced macrophage production of monocyte chemo-attractant protein-1 (MCP-1) (CC-chemokine) and cytokine-induced neutrophil chemo-attractant (CINC) (CXC-chemokine). However, the serine protease inhibitor, phenylmethylsulfonyl fluoride (PMSF), significantly reduced these chemokine productions by macrophages stimulated with NE. 125I-NE was significantly bound to macrophages, but 125I-NE binding was inhibited by addition of unlabeled NE. In addition, NE significantly stimulated [3H]thymidine incorporation into DNA on 3T3 fibroblasts in a dose-dependent manner. These results suggest that NE stimulates chemokine production by macrophages. This may be a receptor-mediated reaction. Thus, NE not only degrades extra-cellular matrix but also stimulates chemokine production by macrophages.

3T3 Cells↗

PubMed1999

Augmentation and suppression of action potentials by estradiol in the myometrium of pregnant rat.

The purpose of this study was to investigate the actions of estradiol on spontaneous and evoked action potentials in the isolated longitudinal smooth muscle cells of the pregnant rat. Single cells were obtained by enzymatic digestion from pregnant rat longitudinal myometrium. Action potentials and currents were recorded by whole-cell current-clamp and voltage-clamp methods, respectively. The acute effects of 17beta-estradiol on action potentials and inward and outward currents were investigated. The following results were obtained. The average resting membrane potential of single myometrial cells was -54 mV (n = 40). In many cells, an electrical stimulation evoked a membrane depolarization, and action potentials were superimposed on the depolarization. In some cells, spontaneous action potentials were observed. Estradiol (30 microM) slightly depolarized the membrane (ca. 5 mV) and attenuated the generation of action potentials by reducing the frequency and amplitude of the spikes. Afterhyperpolarization was also attenuated by estradiol (30 microM). On the other hand, in 5 of 35 cells, estradiol increased the first spike amplitude and action potential duration, while frequency of the spike generation and afterhyperpolarization were inhibited. In voltage-clamped muscle cells, estradiol inhibited both inward and outward currents. Acute inhibition or augmentation of spike generation by estradiol is due to the balance of inhibition of inward and outward currents. Inhibition of both currents also prevented afterhyperpolarization, causing potential-dependent block of Ca spikes.

Action Potentials↗

PubMed1999

[Thymic enlargement exhibiting remarkable respiration-induced changes in form].

The patient was a 30-year-old woman. During an examination for a painful bruise on her back, an anterior mediastinal mass lesion was detected by computed tomographic (CT) scan. A second CT scan 6 days later showed pronounced expansion of the anterior mediastinal mass shadow. A third CT scan performed 18 days later, however, disclosed that the mass had contracted back to the size observed with the initial CT scan. Respiration-induced changes in size were suspected, and breathing dynamic cine magnetic resonance imaging (MRI) was performed. The MRI findings clearly demonstrated that the anterior mediastinal mass shadow contracted on inspiration and expanded on expiration. The patient was admitted for suspected thymoma, and hyperthyroidism was diagnosed. After her thyroid function normalized, a subtotal thyroidectomy and thymectomy were simultaneously performed. The pathologic diagnosis was thymus enlargement and hyperthyroidism, respectively. Breathing dynamic cine MRI provided extremely valuable films that demonstrated remarkable respiration-induced changes in the shape of the enlarged thymus.

Adult↗

PubMed1999

[Five cases of pulmonary thromboembolism after chest surgery].

The incidence of pulmonary thromboembolism after chest surgery is increasing. Five cases of it in recent two years were described. Four cases were lung cancer, and the other was myasthenia gravis. All lung cancer cases were after left lobectomy, and the findings of thromboembolism were mainly detected in right lung. Though hypocapnia is characteristic of pulmonary thromboembolism, arterial blood gas tests did not show it in all cases. Slight hypoxemia and arrhythmia are noteworthy signs of pulmonary thromboembolism after chest surgery. As thrombolytic and anticoagulation therapy, urokinase and heparin were very useful in four of five cases. Four patients made a rapid recovery from pulmonary thromboembolism, but one died of cerebral hemorrhagic infarction. The other patient did not recover in spite of intense medication, extracorporeal membrane oxygenation, and pulmonary embolectomy. To prevent pulmonary thromboembolism after chest surgery, appropriate countermeasures should be considered.

Aged↗

PubMed1999

[Pilot late phase II study of KRN8602 (MX2), a novel anthracycline derivative, for acute leukemia--a dose finding study in combination].

In order to determine the clinically optimal dose of KRN8602, a new anthracycline derivative, in combination therapy for acute leukemia, we performed a pilot late phase II study in combination with cytarabine (Ara-C) for acute myelogenous leukemia (AML), and with vincristine (VCR) and prednisolone (PSL) for acute lymphocytic leukemia (ALL). KRN8602 was given at a dose of 12 or 15 mg/m2 for 5 consecutive days, Ara-C at a dose of 100 mg/m2 for 7 consecutive days, VCR 1.4 mg/m2 (max. 2.0 mg/body) weekly for 4 weeks, and PSL 40 mg/m2 for principally 28 consecutive days. Of 14 patients with relapsed or refractory leukemia entered in the study, thirteen patients were evaluable for safety and 12 were evaluable for response. In AML, there was 1 partial response (PR) in 4 patients at a dose of 12 mg/m2. Against 1 complete response (CR) and 3 PRs in 4 patients at a dose of 15 mg/m2. In ALL, there was 1 PR in 1 case at a dose of 12 mg/m2, and 1 CR and 2 PR in 3 at a dose of 15 mg/m2. Major toxicities were nausea/vomiting and anorexia, but incidences and grades of toxicities were not dose-dependent, and all toxicities were tolerable and manageable. From these results it is concluded that the optimal dose of KRN8602 is 15 mg/m2 for 5 consecutive days in combination with Ara-C for AML, and with VCR and PSL for ALL.

Adult↗

PubMed1998

High levels of hepatocyte growth factor/scatter factor in diffuse-type bronchioloalveolar cell carcinoma.

BACKGROUND: Hepatocyte growth factor/scatter factor (HGF/SF) is a potent mitogen for various neoplastic cells, including neoplastic bronchial epithelia. METHODS: Immunoreactive hepatocyte growth factor/scatter factor (HGF/SF) was measured in extracts prepared from 129 nonsmall cell lung carcinoma (NSCLC) specimens, using an enzyme-linked immunosorbent assay. These specimens represented 5 cases of solitary/localized bronchioloalveolar cell carcinoma (BAC), 4 cases of diffuse/infiltrative BAC, 90 cases of non-BAC adenocarcinoma, 25 cases of squamous cell carcinoma, and 5 cases of large cell carcinoma. RESULTS: The mean concentration of immunoreactive HGF/SF was more than 19-fold higher in tissue extracts from diffuse-type BAG (265.0 +/- 110.2 ng/100 mg protein) than in those from solitary-type BAC (13.9 +/- 15.9, P < 0.005), non-BAC adenocarcinoma (13.8 +/- 14.9, P < 0.001), squamous cell carcinoma (13.2 +/- 14.4, P < 0.001), or large cell carcinoma (11.2 +/- 6.5, P < 0.005). When immunohistochemical staining for HGF/SF was performed, intense HGF/SF staining was uniformly observed in diffuse-type BAC tumor cells, but not in solitary-type BAC. CONCLUSIONS: Although BAC is included as a subtype of adenocarcinoma in the World Health Organization classification, diffuse-type BAC should be considered a distinct biologic entity, at least in terms of HGF/SF expression, from solitary-type BAC or non-BAC adenocarcinoma. In addition, the solitary and diffuse forms of BAC are known to be associated with different prognoses; for the latter, the prognosis is much poorer than for the former. The results of this study may at least partly explain this difference in prognosis.

Adenocarcinoma↗

PubMed1998

Tumor necrosis factor-beta is associated with thymic apoptosis during acute rejection.

BACKGROUND: Intrathymic events undergoing allograft rejection remain undefined. The present study investigated the role of tumor necrosis factor-beta on acute thymic involution in rat hepatic allograft recipients during rejection. METHODS: Apoptosis and cellular phenotypic changes in the thymus were studied after hepatic transplantation. RESULTS: Thymocytes in both the medulla and cortex were sparse during acute rejection. Phenotypically, CD4+CD8+ T cells decreased significantly, whereas there were relative increases in CD4-CD8-, CD4+CD8-, and CD4-CD8+ T cells in untreated allograft recipients. Additionally, thymic apoptosis was found by in situ DNA end labeling and electron microscopy. Apoptotic cells were predominantly distributed in the cortex. Biologic lymphotoxin (tumor necrosis factor-beta)/tumor necrosis factor-alpha cytotoxic activity in the serum was significantly increased in untreated hepatic allograft recipients. Tumor necrosis factor-beta mRNA was detected in untreated allograft livers, and intraperitoneal administration of recombinant human tumor necrosis factor-beta induced extensive apoptosis of thymocytes in vivo. In contrast, no significant thymic involution was observed in donor-specific blood transfusion-treated allograft and isograft recipients. Intraperitoneal administration of rabbit anti-human tumor necrosis factor-beta polyclonal antibody or recombinant human interleukin-10 inhibited thymic apoptosis in untreated hepatic allograft recipients. CONCLUSIONS: Allograft rejection, but not donor-specific transfusion-induced immunologic unresponsiveness, is associated with thymic involution, a process that may be mediated by tumor necrosis factor-beta.

Acute Disease↗

PubMed1998

Neutrophil elastase enhances intercellular adhesion molecule-1 expression.

BACKGROUND: Elastase released from activated neutrophils is an important mediator of inflammatory tissue damage. We investigated the effect of human neutrophil elastase (NE) inhibitor (ONO-5046) on reperfusion injury after pancreaticoduodenal transplantation in rats by measuring the expression of intercellular adhesion molecule-1 (ICAM-1). Additional in vitro experiments were conducted to investigate the effect of NE on ICAM-1 mRNA transcription in a rat endothelial cell line (WK-5) and human umbilical vein endothelial cells (HUVEC). METHODS: In an in vivo experiment, male Wistar rats were transplanted with syngeneic pancreaticoduodenal grafts. An NE inhibitor, ONO-5046, was injected intravenously 5 min before vascular clamping and immediately after reperfusion at a dose of 10 mg/kg. ICAM-1 expression was determined by immunostaining and Northern analysis. In in vitro experiments, the effects of NE and chemical agents on ICAM-1 mRNA transcripts were determined in WK-5 cells and HUVEC. RESULTS: Pretreatment with ONO-5046 decreased ICAM-1 immunostaining in the pancreatic graft and inhibited the increase in ICAM-1 mRNA levels in grafts after reperfusion. ICAM-1 mRNA levels in WK-5 cells and HUVEC showed stimulation by NE, while ONO-5046 inhibited this increase. Calcium ionophore (A23187) augmented NE stimulation of ICAM-1 mRNA levels in these cells. In contrast, a phospholipase C inhibitor (U73122) blunted NE induction of ICAM-1 mRNA, and either calcium chelator (TMB-8) or a nuclear factor-kappa B inhibitor (pyrrolidine dithiocarbamate) completely inhibited induction. CONCLUSION: These results indicate that NE stimulates ICAM-1 expression in pancreatic grafts via intracellular Ca2+ influx and a phospholipase C signal transduction.

Animals↗

PubMed1998

A significant reduction of macrophages expressing inducible nitric oxide synthase in rat hepatic allografts pretreated with donor-specific blood.

BACKGROUND: A single intravenous injection of donor-specific blood (DST) 7 days before transplantation significantly prolongs survival of hepatic allografts from fully allogeneic ACI(RT1a)-->LEW(RT1(1)) rats. The aim of this study was to investigate the kinetics of nitric oxide synthesis by macrophages in rat hepatic allografts treated with DST. METHODS: We investigated macrophages expressing inducible nitric oxide synthase in animal group I (receiving isografts), group II (hepatic allografts), and group III (hepatic allografts after donor-specific blood). RESULTS: Serum nitrite/nitrate, interferon-gamma, and tumor necrosis factor-alpha concentrations increased significantly in group II for 7 days after transplantation but were significantly much lower in groups I and III. Numbers of macrophages immunostained with an anti-macrophage nitric oxide synthase monoclonal antibody and inducible nitric oxide synthase mRNA levels in liver specimens also were much lower in groups I and III than in group II. In addition, Northern blot analysis demonstrated abundant interleukin-10 mRNA transcripts in the DST-treated hepatic allografts compared to untreated allografts. Double immunostaining revealed anti-macrophage synthase-containing cells, including both ED1+ and ED2+ cells, in liver and spleen as more numerous in group II. CONCLUSIONS: Inducible nitric oxide synthase is suppressed in immunologic unresponsiveness to grafts after donor-specific blood transfusion.

Animals↗

PubMed1998

Monocyte chemoattractant protein-1 enhances expression of intercellular adhesion molecule-1 following ischemia-reperfusion of the liver in rats.

Intercellular adhesion molecule-1 (ICAM-1) is important in neutrophil-dependent injury. We investigated the effects of monocyte chemoattractant protein-1 (MCP-1) produced by Kupffer cells on ICAM-1 expression after ischemia-reperfusion in rat liver by occluding the portal vein for 30 minutes. Serum concentrations of MCP-1 increased persistently. By Northern analysis, MCP-1 mRNA increased early and persisted. Kupffer cells harvested 6 hours after reperfusion also expressed this transcript. The transcript and protein also were produced by Kupffer cells from naive controls in response to reactive oxygen species. ICAM-1 mRNA transcripts increased, peaked 3 hours after reperfusion, and decreased gradually thereafter. The level of ICAM-1 mRNA transcripts in the WK-5 rat endothelial cell line were markedly enhanced by MCP-1. These results suggest that MCP-1 released by Kupffer cells early after ischemia-reperfusion modulates neutrophil-dependent tissue injury via ICAM-1.

Animals↗

PubMed1998

Infiltrating CD45RC- T cells are associated with immunologic unresponsiveness induced by donor class I major histocompatibility complex antigens in rats.

It has previously been shown that a single intravenous injection of freshly heparinized donor-specific blood transfusion (DST) before transplantation significantly prolongs the survival of fully allogeneic ACI (RT1a)-to-LEW(RT1(1)) rat hepatic allografts. Additionally, we have shown that pretreatment of LEW rats with PVG.r1 blood, which shares only the RT1.A major histocompatibility complex (MHC) region with ACI, significantly prolongs the survival of ACI hepatic allografts. In this study, we report the cellular identity of hepatic allograft leukocyte infiltrates following transplantation. Fluorescence-activated cell sorting (FACS) analysis revealed that CD4+ T cells infiltrating liver allografts could be divided into two subsets, CD45RC- CD4+ and CD45RC+ CD4+ T cells, and that the ratio of CD45RC- CD4+/CD45RC+ CD4+ T cells was significantly higher in hepatic allografts of recipients pretreated with DST or PVG.r1 blood as compared to untreated allografts. Further, CD8+ T cells that accumulated in the liver grafts could be similarly divided into two subsets, and the ratio of CD45RC- CD8+/CD45RC+ CD8+ T cells was also significantly higher in hepatic allografts of recipients pretreated with DST or PVG.r1 blood. Reverse transcriptase polymerase chain reaction (RT-PCR) analysis revealed that CD45RC- CD4+ T cells harvested from hepatic allografts pretreated with PVG.r1 blood expressed interleukin-4 (IL-4) and interleukin-10 (IL-10), but not interleukin-2 (IL-2) or interferon-gamma (IFN-gamma). In contrast, CD45RC- CD8+ T cells from hepatic allografts pretreated with PVG.r1 blood expressed IL-4, IL-10, and IFN-lambda, but not IL-2. These results indicate that the CD45RC leukocyte common antigen could be used to differentiate CD4+ and CD8+ T cells following pretreatment with DST or PVG.r1 blood. Persistent infiltration of CD45RC- CD4+ and CD45RC- CD8+ T cells, capable of secreting Th2-type cytokines may prevent allograft rejection by causing immunologic unresponsiveness.

Animals↗