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Biomedical subjects

M Torisu

Publications and source records attributed to M Torisu.

At least 37 records · Page 2Linked to original sources

Immunologic assessment of host defense impairment in patients with septic multiple organ failure: relationship between complement activation and changes in neutrophil function.

BACKGROUND: The pathogenesis of gram-negative sepsis-induced multiple organ failure (MOF) remains to be elucidated. METHODS: Blood samples were obtained from eleven patients with septic MOF, three patients with sepsis, three patients who underwent operation, and three healthy volunteers. In these patients the relationship between changes in polymorphonuclear neutrophil (PMN) function and complement activation was investigated. RESULTS: PMNs from patients with sepsis exhibited enhanced endothelial cell adhesion, enhanced chemotaxis, increased oxygen radical generation, and increased lysosomal enzyme release. Although PMNs from patients with septic MOF also exhibited enhanced adhesion and chemical mediator production, chemotaxis was markedly depressed. Complement activation in septic MOF was indicated by decreases in total complement activity and complement component 4 (C4) and increases in C3a and C4a des-Arginine. Increases in plasma concentrations of circulating immunoglobulin G immune complexes and decreases in PMN Fc gamma R expression suggest that the classic pathway is the main pathway of complement activation. On the other hand, we could not detect decreases in C4 or increases in C4a des-Arginine in patients with sepsis, suggesting that the alternate pathway is the main pathway of complement activation. Increases in serum concentrations of the membrane attack (SC5b-9) complex also suggested that activated complement itself may participate in organ injury in patients with septic MOF. Moreover, PMN up-regulation of surface inhibitory factors of complement activation likely allows these neutrophils to survive and function. CONCLUSIONS: The combination of changes in PMN function and complement activation appears to be intimately associated with the pathogenesis of septic MOF.

Adult

Characterization of neutrophil activation by repeated injection of endotoxin in rabbits. Role of neutrophils in the generalized Shwartzman reaction.

The relationship between activated neutrophils and end-organ injury in endotoxemia was studied. The function of peripheral blood neutrophils (PMNs) in rabbits with the generalized Shwartzman reaction (GSR) was compared to that of PMNs rabbits receiving a single injection of endotoxin. The following results were obtained: (1) PMNs from rabbits with the GSR demonstrated enhanced adherence to endothelial cells and increased mitochondrial ATP production; (2) the GSR did not enhance chemotaxis and oxygen radical production of PMNs; (3) a single injection of endotoxin did not cause necrosis of visceral organs; (4) in vitro detachment of endothelial cells by PMNs was increased in rabbits with the GSR; (5) in vivo administration of monoclonal antibody (mAb) against CD11b/CD18 (Mac-1) suppressed the increase in PMN adherence; and (6) hemorrhagic necrosis did not occur when mAb to Mac-1 was injected. Thus, enhanced adherence of PMNs to endothelial cells appears to play a key role in endotoxin-induced end-organ injuries in this animal model.

Animals

Effects of granulocyte colony stimulating factor and monobactam antibiotics (Aztreonam) on neutrophil functions in sepsis.

Possible clinical use of a recombinant human granulocyte colony stimulating factor (rG-CSF) and a newly developed monobactam antibiotics (Aztreonam) for the treatment of gram-negative sepsis was investigated. Gram-negative sepsis was induced in male WKA rats by cecal ligation and puncture (CLP). Untreated CLP rats all died by septicemia with severe peripheral blood leukocytopenia within 5 days after the operation. When we administered 2.0 micrograms/kg of rG-CSF and/or 20 mg/kg of Aztreonam intravenously just after the operation, the rats survived longer than the untreated CLP rats. These drugs were found to be more effective when used in combination. Since these rats showed an increase in leukocyte counts, we next examined the changes in the functions of polymorphonuclear leukocytes (PMNs, mainly neutrophils) after the treatment. PMNs from untreated CLP rats at 24 hr after the operation exhibited enhanced plastic-dish adherence, suppressed chemotaxis, and depressed O2 production when compared with PMNs from control animals. A single injection of rG-CSF restored both the depressed chemotaxis and the O2 production to levels greater than those of controls. Although a single injection of Aztreonam could not improve the suppressed O2 production, it could restore the depressed chemotaxis. Interestingly, simultaneous injection of Aztreonam with rG-CSF significantly enhanced the effect of rG-CSF on the PMN functions. These data suggest that the Aztreonam and rG-CSF may be useful for the treatment of gram-negative sepsis, especially when used in combination.

Animals

An eosinophil chemotactic lymphokine in the supernatant of lymphokine-activated killer (LAK) cell culture: relationship to interleukin-5.

The administration of interleukin-2 (IL-2) systemically or locally to cancer patients, either alone or in combination with lymphokine-activated killer (LAK) cells, frequently results in eosinophilia. To investigate the mechanism of such eosinophil accumulation, we measured in vitro eosinophil chemotactic activity (ECA) in the supernatant of LAK cell cultures by a modified Boyden's chamber method. Consequently, a potent and specific ECA was found in the cell-free supernatant of LAK cell cultures. On the other hand, no ECA was found in the supernatant of normal lymphocyte cultures, nor in IL-2 itself. This activity plateaued when 3 x 10(6) lymphocytes were incubated with 1000 U/ml IL-2 for more than 3 days. Sephadex G-100 gel chromatography indicated that the molecular weight of this eosinophil chemotactic factor (ECF) was approximately 45,000 Da. The ECF was stable when heated to 56 degrees C for 30 min but was inactivated by trypsin, indicating that the ECF is a lymphokine which has very similar characteristics to those of IL-5. Using ELISA for hIL-5, the IL-5 level in the supernatant of LAK cell cultures increased dose dependently with increasing IL-2 concentrations. These results suggest that IL-5 may be responsible for the local recruitment of eosinophils in IL-2/LAK therapy.

Animals

Spontaneous rupture of splenic angiosarcoma: a case report of chemotherapeutic approach and review of the literature.

Angiosarcoma of the spleen is a rare disease, and the prognosis of this disease is extremely unfavorable. We herein review the case of a 45-year-old Japanese woman, who received a combined chemotherapy with cyclophosphamide, Adriamycin, vincristine, and prednisone after splenectomy and experienced a good response. The various types of chemotherapy for this disease are also discussed with references to the above case because no effective chemotherapeutic protocol for angiosarcomas has yet to be established.

Antineoplastic Combined Chemotherapy Protocols

An adult case of bleeding Meckel's diverticulum diagnosed by preoperative angiography.

A 19-year-old woman in her 6th month of pregnancy was admitted to our hospital after passing a massive bloody stool. Romanoscopy and upper gastrointestinal panendoscopy revealed no abnormality, but a superior mesenteric arteriography demonstrated an embryonic artery with the extravasation of contrast medium in the distal end of the ileal artery. After the diagnosis of a bleeding Meckel's diverticulum had been established, an emergency operation was successfully performed. At laparotomy, a Meckel's diverticulum was found, about 70 cm toward the oral side from the ileocecal valve, and part of the ileum, including the diverticulum, was resected. Histological examination indicated that the diverticulum had a normal ileal layer with ectopic gastric mucosa and pancreatic tissue. Furthermore, multiple ulcers were observed in the adjacent ileum. Blood coagulation was observed at the site of one of these ulcers, and this was presumed to be the source of the hemorrhage.

Adult

Primary carcinoma of the cystic duct.

After we encountered one case of cystic duct carcinoma out of 110 cases of gallbladder carcinoma treated from 1976 to 1991, we reviewed the 14 treated Japanese cases, including our own, as well as the 18 Western cases hitherto reported in order to examine the clinical features of carcinoma of the cystic duct and to evaluate the various options for treatment. The patients' ages were similarly distributed between the Japanese and Western patients with a mean age of 62 years. Males were predominantly affected in the western countries with a ratio of male to female of 3.5:1; the ratio was similar in Japan. Gallstones were present in six of 18 Western cases and in two of 14 Japanese cases; both groups had a much lower rate of accompanying gallstones than did gallbladder carcinoma patients. Despite the depth of invasion, the prognosis of carcinoma of the cystic duct was relatively good, mainly owing to the absence of either lymph node metastases or distant metastasis. Although the lymph nodes and bile duct are not usually involved in carcinoma of the cystic duct, cholecystectomy, either with or without lymph node dissection, usually produced an unsatisfactory outcome, possibly due to bile duct invasion and perineural invasion. Thus, combined resection of the gallbladder and bile duct with lymph node dissection is the choice of treatment for carcinoma of the cystic duct.

Adult

Potential role of hepatic macrophages in neutrophil-mediated liver injury in rats with sepsis.

We investigated the pathogenesis of septic liver injury in rats caused by cecal ligation and puncture. In this model, numerous neutrophils accumulated in the liver in parallel with the development of liver dysfunction. The supernatants of hepatic macrophages isolated from these septic rats 24 hr after cecal ligation and puncture had enhanced chemotactic activities for human neutrophils. These results suggest that in sepsis, hepatic macrophages attract neutrophils to the liver. Human neutrophils preincubated in this macrophage supernatant had the following biological activities not seen in the sham-operated controls. (a) They became more adherent to cultured endothelial cells through up-regulation of adhesion molecules such as CD11b/CD18, (b) their chemiluminescence was markedly elevated. These functional changes of cecal ligation and puncture hepatic macrophages were the same as those in endotoxin-pretreated hepatic macrophages after isolation from normal rats. Therefore we suspect that hepatic macrophages are activated by portal vein endotoxin in sepsis. These activated hepatic macrophages secreted chemical mediators of inflammation, including leukotriene B4 and tumor necrosis factor. In conclusion, hepatic macrophages seem to interact closely with neutrophils and play an important role in the pathogenesis of septic liver injury.

Animals

The role of eosinophils in interleukin-2/lymphokine-activated killer cell therapy.

When interleukin-2 alone or in combination with lymphokine-activated killer (LAK) cells is administered to patients with cancer, peripheral or local eosinophilia is frequently seen. To evaluate the role of eosinophils in this setting, we studied the functional changes of human eosinophils induced by the supernatant of LAK cell cultures. The chemotactic activity, change in chemiluminescence, superoxide production, expression of leukocyte integrins (CD11/CD18 family), and adherent activity to plastic dishes were investigated after stimulation of eosinophils with LAK cell culture supernatant. The chemotactic activity of eosinophils in the supernatant of LAK cell cultures was increased significantly, and this activity was chemotactic rather than chemokinetic by checkerboard analysis. Both chemiluminescence and superoxide production of stimulated eosinophils increased significantly compared with resting. In addition, eosinophil-adherent activity to plastic dishes was also increased. Among leukocyte integrins, CD11b expression on stimulated eosinophils increased. Moreover, eosinophil antibody-dependent cellular cytotoxicity against Raji cells was enhanced after stimulation with the supernatant of LAK cell cultures. These results suggest that the eosinophils activated by LAK cells may play an important role in the antitumor effect of interleukin-2/LAK cell therapy.

Antibody-Dependent Cell Cytotoxicity

Prolonged lung edema formation during the generalized Shwartzman reaction in rabbits--can it be a model for septic lung disease?

Pulmonary edema formation and the role of polymorphonuclear leukocytes (PMN) was evaluated during the generalized Shwartzman reaction (GSR) model in rabbits. Chemiluminescence (CL) and superoxide (O2-) production activity stimulated by FMLP were measured in circulating PMN after a single intravenous injection of endotoxin (E. coli 026:B6, 40 micrograms/kg) (E1). CL peaked at 36 hr after E1 injection and then decreased gradually to a normal range within 7 days. O2- production changed in a similar fashion. On the other hand, the PMN count peaked at 72 hr and remained at a high value until day 7. To induce GSR, a second venous injection of endotoxin (40 micrograms/kg) (E2) was administered 36 hr after the first one (E1). Four times as many PMN were observed in the lung capillaries 4 hr after the second endotoxin injection than after the first endotoxin injection (4 hr). The degree of lung edema formed increased after E2, but did not increase after E1. An alveolar hyaline-like exudate was observed 24 hr after E2. A continuous intravenous injection of superoxide dismutase (SOD) plus catalase or PMN depletion, prevented the development of post-E2 lung edema. If E2 was given 7 days after E1, no lung edema formed at all. These data indicate that oxygen free radicals from activated PMN by endotoxin play an important role in prolonged lung edema formation in the GSR model.

Animals

[The role of eosinophil chemotactic factor in localized tissue eosinophilia by parasitic infection].

Eosinophil chemotactic factors (ECFs) are thought to play an important role in the recruitment of eosinophils to parasitic inflammatory regions. ECF-A derived from mast cells, lymphokines from lymphocytes and ECFs from complements are well known as host-derived ECFs. On the other hand, ECF from parasites (ECF-P) and cytokines such as ESP (eosinophil stimulation promoter) and interleukin-5 are reported to be responsible for the eosinophil accumulation in parasitic inflammatory regions. In a series of our experiments using Anisakis larvae, we discovered a mechanism of eosinophil recruitment which could be accelerated by priming with ECF-P in parasite infected eosinophil phlegmon.

Animals

Characteristics of alveolar macrophages in experimental septic lung.

We investigated the pathogenesis of lung injury in sepsis (septic adult respiratory distress syndrome) by focusing on the functional changes of alveolar macrophages (AMs). Sepsis was induced in male WK rats by cecal ligation and puncture. Histological examination of the lungs from this experimental model revealed edematous change at 24 h after the surgery. The protein and endotoxin concentrations in the bronchoalveolar lavage fluid (BALF) increased with time after the surgery. The time course studies of AM function after surgery indicated that AMs from septic rats were activated by endotoxins. Specifically, this was suggested by the finding that AM adherence to and spreading on a plastic dish had increased. On stimulation, these AMs enhanced generation of superoxide anions and increased release of lysosomal enzymes, such as beta-glucuronidase. On the other hand, AMs in sepsis generated much smaller amounts of arachidonate lipoxygenase metabolites, such as leukotriene B4 (LTB4) and 12- and 5-hydroxyeicosatetraenoic acids (HETEs), on stimulation than did AMs from sham rats or untreated rats. However, the concentrations of immunoreactive LTC4 in the BALF of septic rats seemed to be higher than in untreated rats. It is suggested that the AMs of septic rats released lipoxygenase metabolites in alveoli and that these AMs could not be stimulated in vitro. These functional changes in the AMs of septic rats progressed along with the sepsis. These results implicate AMs in the development and progression of septic lung injury by releasing superoxide anions, beta-glucuronidase, and arachidonate metabolites. Furthermore, we speculate that reduced production of LTB4 by septic AMs may increase host susceptibility to severe pulmonary infection during septic ARDS.

Animals

Suppression by interferon-gamma of tumor cell-induced increase in mesothelial permeability.

The effect of interferon-gamma (IFN-gamma) on the interaction between tumor cells and mesothelial cell layers was studied from the aspect of changes in mesothelial permeability. Mesothelial permeability was assessed as the percentage diffusion of radiolabeled albumin across the mesothelial cell sheets on Matrigel-coated filter cup assemblies. When lined gastric carcinoma cells (KATO-III) were seeded on the confluent mesothelial cell layers, the fine cobblestone appearance of the cell sheet was disrupted and mesothelial permeability significantly increased. The increase in permeability was suppressed by the addition of as little as 1 U/ml of IFN-gamma. The effect of IFN-gamma was observed when either the conditioned medium of tumor cells alone or the IFN-gamma-resistant tumor cells, K-562, was placed onto the mesothelium. The cobblestone appearance of the cell sheet was relatively well preserved in the presence of IFN-gamma. In contrast, IFN-alpha did not suppress tumor-induced mesothelial permeability. These results suggest that IFN-gamma has the potential to protect the human mesothelial cell layers against tumor cells.

Cell Communication

The increase of low density subpopulations and CD10 (CALLA) negative neutrophils in severely infected patients.

We investigated the changes in polymorphonuclear leukocyte (PMN) subpopulations that accompany severe bacterial infection and examined their usefulness as a parameter for assessing the severity of infection. The Percoll density gradient was used to fractionate neutrophils into subpopulations of high density (1.09-1.10), intermediate density (1.08-1.09), and low density (1.07-1.08) with the majority of neutrophils from normal volunteers being of high density. By contrast, neutrophils from infected patients were of intermediate or low density, while those from severely infected patients showed a high percentage of the low density fraction with functional changes in lower chemotactic and beta-gulcuronidase activity. When each density subpopulation in the normal blood neutrophils was tested, low density PMNs had the lowest chemotaxis and minimal beta-glucuronidase activity. These results indicate that the increase in low density PMNs in patients with severe infection clearly reflects the functional impairment of PMNs. Flow cytometric analysis demonstrated that the neutrophils from severely infected patients had an decrease in CD10 expression. The percentage of CD10 positive PMNs correlated well with the severity of infection and with the clinical course of the patients. Thus, we conclude that PMN-density and CD10 expression change during severe bacterial infection, and that the measurement of PMN-subpopulations may be used to complement the clinical assessment of the severity of infections.

Bacterial Infections

Pilonidal sinus on the neck.

A recurrent nuchal abscess was treated in a 21-year-old obese young man with a total excision of the lesion. In the histopathological findings, many similarities were found between this lesion and pilonidal sinus. We discuss the pathogenesis of this lesion, as well as our belief that this case was a rare example of pilonidal sinus on the neck.

Adult

A case of linitis plastica of the rectum treated by pelvic exenteration after aggressive immunochemotherapy.

Multidisciplinary treatment was administered to a 32 year-old man with primary linitis plastica of the rectum, which was considered inoperable due to an extensive local spread at the first operation. Thirty KE of OK-432 was injected into the tumor per week (total 90-KE) and 5 KE of OK-432 was inoculated into the intracutaneous space per week (total 125 KE). Also methotrexete (MTX 50 mg) and 5-FU (500 mg) combined were given each week by intra-arterial infusion (total 20 courses). After this immuno-chemotherapy the CEA decreased from the pretreatment value of 12.7 ng/ml to 3.6 ng/ml and the tumor size was reduced. A total pelvic exenteration could then be performed almost curatively. As a result, this patient was able to return to the society with a better quality of life and has survived for 20 months since presentation.

Adult