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Biomedical subjects

Y Fukuchi

Publications and source records attributed to Y Fukuchi.

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

Infection of replication-deficient adenoviral vector enhances interleukin-8 production in small airway epithelial cells more than in large airway epithelial cells.

OBJECTIVE: In clinical trials or experiments of gene therapy, airway administration of an adenoviral-based vector (E1A-deleted) elicits a dose-dependent inflammatory response with limitation in the duration of transgene expression. The purpose of this study was to evaluate the possibility that the adenoviral-based vector directly enhances IL-8 production independent of adenoviral E1A in normal human airway epithelial cells and to examine the different responses between primary human bronchial epithelial cells (HBE) and primary human small airway epithelial cells (HSAE) in production of IL-8 following exposure to an adenovirus vector. METHODOLOGY: Interleukin (IL)-8 levels were evaluated in the culture medium from HBE and HSAE treated with increasing doses of E1A-deleted adenoviral vector contained the Escherichia coli LacZ reporter gene (AdCMVLacZ). To clarify the mechanism of enhancing IL-8 production in airway epithelial cells by infection with adenovirus vector, alphavbeta5 agonistic antibody as an analogue of adenoviral capsid and adenoviral capsid vector denatured by exposure to ultraviolet (UV) light were used in the present study. RESULTS: Inoculation of HBE with AdCMVLacZ at a multiplicity of infection (MOI) of between 1 and 200 resulted in a dose-dependent expression of LacZ, and maximal expression was observed at a MOI of 100. In contrast, inoculation of HSAE with AdCMVLacZ resulted in maximum expression of LacZ at a MOI of 10. Interleukin-8 levels in culture media from the same experiments revealed significantly greater production of IL-8 in HSAE inoculated with AdCMVLacZ at a MOI of 50, compared to HBE under the same conditions. The capsid-denatured adenoviral vector did not enhance IL-8 production, and alphavbeta5 agonistic antibody induced IL-8 enhancement. CONCLUSION: These results suggest that the adenoviral vector directly induces the expression of airway epithelial inflammatory cytokines in the pathogenesis of inflammation and that small airway cells have a greater affinity for adenovirus than other airway epithelial cells.

Adenoviruses, Human↗
PubMed2001

Protection against Fas-mediated and tumor necrosis factor receptor 1-mediated liver injury by blockade of FADD without loss of nuclear factor-kappaB activation.

OBJECTIVE: To investigate the role of FADD (Fas-associated protein with death domain) in Fas and tumor necrosis factor receptor 1 (TNFR1)-mediated hepatic injury and inflammatory response in vivo. SUMMARY BACKGROUND DATA: Fas and TNFR1 are cell surface molecules that trigger apoptosis or inflammation on engagement by a specific ligand or antibody. FADD is recruited to the cytoplasmic domain of these receptors on their activation and works as a common mediator to induce apoptosis. It is known that a blockade of FADD can inhibit apoptosis mediated by Fas or TNFR1 in vitro. However, it is not known whether the blockade can prevent organ injury and whether the inflammatory cascade is affected in vivo. METHODS: A FADD deletion mutant lacking the death effector domain was introduced into mice by transduction with an adenovirus vector, and the effect of this FADD dominant negative mutant was examined in several liver injury models. RESULTS: Hepatic injury induced by anti-Fas monoclonal antibody or tumor necrosis factor (TNF)-alpha plus D-galactosamine was markedly ameliorated by the FADD dominant negative transduction, which abrogated the death rate. Further, the FADD dominant negative transduction efficiently blocked T cell- mediated concanavalin A-induced hepatitis while not affecting TNF-alpha production or TNF-alpha-induced nuclear factor-kappaB activation in the liver. CONCLUSIONS: These results provide the basis for a novel therapeutic modality in which an unfavorable apoptotic process can be inhibited without affecting a favorable response for liver regeneration; this would be relevant to the clinical treatment of acute and chronic liver diseases as well as to some inflammatory disorders with hypercytokinemia, such as sepsis.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Upregulation of ET-1 and its receptors and remodeling in small pulmonary veins under hypoxic conditions.

Pulmonary veins show greater sensitivity to endothelin (ET)-1-induced vasoconstriction than pulmonary arteries, and remodeling was observed in pulmonary veins under hypoxic conditions. We examined, using an immunohistochemical method, the expression of Big ET-1, ET-converting enzyme (ECE), and ET(A) and ET(B) receptors in rat pulmonary veins under normoxic and hypoxic conditions. In control rats, Big ET-1 and ECE were coexpressed in the intima and media of the pulmonary veins, with an even distribution along the axial pathway. ET(A) and ET(B) receptors were expressed in the pulmonary veins, with a predominant distribution in the proximal segments. The expression of Big ET-1 was more abundant in the pulmonary veins than in the pulmonary arteries. After exposure to hypoxia for 7 or 14 days, the expression of Big ET-1, ECE, and ET receptors increased in small pulmonary veins. Increases in the medial thickness, wall thickness, and immunoreactivity for alpha-smooth muscle actin were also observed in the small pulmonary veins under hypoxic conditions. The upregulation of ET-1 and ET receptors in the small pulmonary veins is associated with vascular remodeling, which may lead to the development of hypoxic pulmonary hypertension.

Actins↗
PubMed2001

Distal airspace enlargement in the fawn-hooded rat: influences of aging and alveolar wall destruction.

BACKGROUND: A recent study has revealed that the peripheral airspace in the lungs of the fawn-hooded rat (FHR) is enlarged. However, morphological and functional factors of the FHR lung have not been fully investigated. OBJECTIVE: The purpose of our study was to examine the structural and functional changes in the FHR lung and to investigate the influence of aging on this process. Furthermore, morphological and functional measurements of the lungs of FHRs (4-48 weeks of age) were performed and the results compared with those of age-matched Wistar control rats (WCRs). METHODS: All animals were studied under controlled conditions, and morphological and functional changes of the lungs were examined. Measurements of body and lung weights were recorded, and the lungs were subjected to morphological evaluation. Morphological measurements: mean linear intercept (MLI) and destructive index were determined. Functional evaluation of the lungs: total lung capacity, pressure-volume curve, and exponential constant (K) which describes the shape of the curve were analyzed. In addition, right ventricular hypertrophy measurements were performed to assess the severity of pulmonary hypertension. Statistical analysis was performed using the unpaired t test, analysis of variance, and the Fisher post hoc test (p < 0.05). RESULTS: Morphological analysis revealed a significant increase in airspace size (MLI) in all FHRs as compared with the WCRs which was evident from an early age (4 weeks). The increase in MLI did not progress age dependently in the FHR, whereas a tendency for an age-dependent increase in MLI was observed in the WCR. The destructive index measurements revealed that the increase in MLI of FHR was not accompanied by alveolar wall destruction. Concerning the functional examination, a leftward and upward shift of the pressure-volume curve was observed in the FHRs as compared with the WCRs at all ages. As compared with the WCRs, a higher K value was observed in all FHRs which was evident from an early age (4 weeks). Age-dependent changes similar to those in MLI were observed in the K in both rat strains. CONCLUSIONS: The results of our study suggest that FHRs manifest characteristics of distal airspace enlargement accompanied by increased lung distensibility without alveolar wall destruction at an early age and that the changes do not progress age dependently. Neither an accelerated aging process nor destruction of the alveolar walls appears to be the mechanism responsible for the enlarged airspace in this rat strain.

Aging↗
PubMed2001

Role of osteopontin in the pathogenesis of bleomycin-induced pulmonary fibrosis.

Pulmonary fibrosis is initiated by migration, adhesion, and proliferation of fibroblasts. Osteopontin (OPN) is one of the cytokines produced by activated macrophages and mediates various functions, including cell attachment and migration, by interacting with alphav integrin. In this study, we have investigated the role of OPN in the pathogenesis of pulmonary fibrosis. We developed a mouse model for pulmonary fibrosis by intratracheal instillation of bleomycin (BLM). OPN was strongly expressed in alveolar macrophages accumulating in the fibrotic area of the lung. OPN messenger RNA (mRNA) in the lung was notably induced by BLM instillation, and the development of the fibrotic process was associated with an increase in the expression of OPN mRNA and protein. In vitro, recombinant OPN enhanced migration, adhesion, and platelet-derived growth factor (PDGF)-mediated DNA synthesis of murine fibroblast cell line NIH3T3. These effects of OPN on fibroblasts were significantly suppressed by addition of antimouse alphav integrin monoclonal antibody (RMV-7). Furthermore, treatment of mice with RMV-7 repressed the extent of pulmonary fibrosis in this model. Conclusively, these data suggest that OPN produced by alveolar macrophages functions as a fibrogenic cytokine that promotes migration, adhesion, and proliferation of fibroblasts in the development of BLM-induced pulmonary fibrosis.

Animals↗
PubMed2001

Discrepant distribution of big endothelin (ET)-1 and ET receptors in the pulmonary artery.

Since pulmonary vasculature is complex in terms of regional difference in structure and function, it is important to understand the site of endothelin (ET) synthesis and the distribution of the ET system along the axial pathways of pulmonary artery. The expression of big ET-1, ET converting enzyme (ECE) and ET(A) receptors were examined in rat pulmonary arteries under normal and hypoxic conditions using an immunohistochemical method and Northern blot analysis. In normal conditions, big ET-1 was expressed in the intima and media of pulmonary arteries with a predominant distribution in the distal segments and a preferential localization in the media, while ETA receptors were dominantly expressed in the proximal segments. ECE was constitutively expressed in the intima and media. Following exposure to hypoxia, messenger ribonucleic acid (mRNA) expression of ET-1 and ET(A) receptors were up-regulated by two-fold and immunoreactivities for big ET-1, ECE, and ET(A) receptors significantly increased by two to five-fold in the distal segments. Smooth muscle cells are an important source of endothelin-1 in the pulmonary artery. The distribution of big endothelin-1 and endothelin A receptors in pulmonary arteries was discrepant in normal conditions while their expression concomitantly increased in the distal segments in hypoxic conditions. This heterogeneity may play an important role in the regulation of pulmonary vascular tone.

Animals↗
PubMed2001

Association of Gc-globulin variation with susceptibility to COPD and diffuse panbronchiolitis.

Chronic obstructive pulmonary disease (COPD) and diffuse panbronchiolitis (DPB) are both characterized by chronic airflow limitation. Although the aetiology of these diseases is under investigation, it is commonly hypothesized that neutrophils have a major role in the disease pathogenesis. The variation of the genes related to chemotaxis of neutrophils may confer a risk for the development of both COPD and DPB. In the present report, the authors investigated the association between genetic variation that codes for the 416th and 420th amino acid of Gc-globulin, reported to be associated with chemotaxis of neutrophils, and susceptibility to COPD and DPB. Blood samples obtained from patients with COPD (n=63), DPB (n=82), and-control subjects (n=82) were used for the genotyping assay. The proportion of GC*1F homozygotes was significantly higher in the COPD patients than the control subjects (COPD 36.5% versus control 20.7%), and the odds ratio for GC*IF homozygotes was 2.2 (95%, confidence interval 1.1-4.6) for the COPD group. There was no difference on the distribution of the other genotypes (GC*1F-1S heterozygotes, GC*1S homozvgotes, GC*2-1F heterozygotes, GC*2-1S heterozygotes and GC*2 homozygotes) or the allele frequencies among these groups. These findings suggest that the GC*IF gene polymorphism of Gc-globulin may be one of the risk factors for chronic obstructive pulmonary disease. However, no association between this polymorphism of Gc-globulin and susceptibility to diffuse panbronchiolitis was found.

Aged↗
PubMed2001

[Cytotoxic activity and cytokine gene induction of Asp-hemolysin to vascular endothelial cells].

We examined the effects of Asp-hemolysin from Aspergillus fumigatus Fresenius-Muramatsu strain on the viability and cytokine gene expression of human umbilical vein endothelial cells (HUVEC). The cell viability of HUVEC was reduced to 50% by 100 micrograms/ml of Asp-hemolysin. However, lower concentration of Asp-hemolysin (< 30 micrograms/ml) had no effect on the cell viability. The mRNA expression of such cytokines as tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1 beta, IL-6, IL-8 and granulocyte-macrophage colony stimulating factor (GM-CSF) were also observed in HUVEC cultured with 30 micrograms/ml of Asp-hemolysin.

Cells, Cultured↗
PubMed2001

[Effects of low density lipoprotein and oxidized low density lipoprotein on the cytotoxic activity of Asp-hemolysin to murine macrophages].

We examined the effects of human low density lipoprotein (LDL) and oxidized LDL (Ox-LDL) on the cytotoxic activity of Asp-hemolysin from Aspergillus fumigatus Fresenius-Muramatsu strain to mouse peritoneal macrophages (M phi). The inhibitory effects of LDL and Ox-LDL on the cytotoxic activity of Asp-hemolysin to M phi increased in a dose-dependent manner, and the effect of Ox-LDL was greater than the inhibitory effect of LDL. Furthermore, the binding of Asp-hemolysin to LDL or Ox-LDL was observed by western blot analysis of the culture medium. These results suggest that the inhibition by LDL or Ox-LDL on the cytotoxic activity of Asp-hemolysin to M phi was due to the binding of LDL or Ox-LDL to Asp-hemolysin in the culture medium.

Animals↗
PubMed2001

[Interactions between Asp-hemolysin from Aspergillus fumigatus and blood plasma components].

Asp-hemolysin is a cytolytic toxin that is produced by Aspergillus fumigatus. This toxin is lytic for erythrocytes of humans, rabbits and sheep. However, Asp-hemolysin is inactivated by the addition of serum or blood plasma. This study was undertaken to identify plasma components inhibitory to the hemolytic activity of Asp-hemolysin. alpha 2-Macroglobulin (alpha 2M) was isolated from the human blood plasma by affinity chromatography on a column containing Asp-hemolysin coupled to Sepharose. However, the hemolytic activity was only partially inhibited by alpha 2M. Apolipoprotein B (apoB)-containing lipoproteins, such as low density lipoprotein (LDL), inhibit the activity of this hemolytic toxin. When 20 micrograms apoB was added, the hemolytic activity was almost completely inhibited. Furthermore, similar inhibition was observed in the filtrates separated from the incubation mixture of Asp-hemolysin with LDL or apoB following ultrafiltration through a membrane with a molecular mass cutoff of 100,000. These results suggest that the inhibition by LDL is due to apoB binding to Asp-hemolysin. The binding activity of LDL to Asp-hemolysin was measured. LDL binds to Asp-hemolysin with an affinity as high as the LDL receptor. The apparent Kd, determined by Scatchard plot analysis, was 8.9 x 10(-9) M 125I-LDL. Oxidized LDL (Ox-LDL), but not acetylated LDL, inhibited the hemolytic activity of this toxin. The inhibitory effects of Ox-LDL increased with the time of Cu(2+)-induced LDL oxidation. Similar inhibition was observed in the filtrate separated from the incubation mixture of Asp-hemolysin with Ox-LDL (for 2 h of oxidation) following ultrafiltration through a membrane with a molecular mass cutoff of 100,000. However, at longer LDL oxidation times, the inhibition by the filtrates was less than the control mixture without ultrafiltration. These results suggest that the inhibition of the hemolytic activity by Ox-LDL was due to the binding of Ox-LDL to Asp-hemolysin at short LDL oxidation times.

Animals↗
PubMed2001

Compound heterozygosity for alpha-1-antitrypsin (S(iiyama) and QO(clayton)) in an Oriental patient.

Alpha-1-antitrypsin (alpha1AT) deficiency is extremely rare among Orientals. We treated a 37-year-old man with severe pulmonary emphysema associated with a low serum concentration of alpha1AT. Mutation analysis of the alpha1AT gene was performed using a reverse transcription-polymerase chain reaction followed by sequencing. The patient proved to be a compound heterozygote carrying a S(iiyama) deficient allele and a QO(clayton) null allele. This is the first Japanese case of alpha1AT deficiency to arise from such compound heterozygosity in a family with no apparent consanguineous marriage, suggesting that the gene frequency for deficient alleles might be somewhat higher than previously estimated.

Adult↗
PubMed2001

[Gene therapy for pulmonary hypertension].

Pulmonary hypertension is a life-threatening disease characterized by progressive vascular remodeling, ultimately producing right ventricular failure. Recently, continuous intravenous infusion of prostacyclin has become recognized as a therapeutic breakthrough that can improve hemodynamics and surgical in patients with pulmonary hypertension. Nevertheless, gene therapy is also expected as a valuable therapeutic approach in pulmonary hypertension for the reason that transgene expression is located mainly in the lung. Previous study demonstrated that intratracheal gene transfer of endothelial derived nitric oxide synthase, prostacyclin I synthase, vascular endothelial growth factor etc. resulted in a reduction of pulmonary arterial pressure in experimental animals with pulmonary hypertension. Major hurdle in current gene therapy for pulmonary hypertension may be the limited duration of transgene expression in lung tissue. However, rather than a limitation, this feature may be a advantage in some situations where expression during only a few weeks may provide both adequate therapeutic efficacy and limited side effects. Development of second-generation gene delivery system will provide new tools to prolong the duration of transgene expression.

Animals↗
PubMed2001

[Genetic variation of NADPH/NADH oxidase and susceptibility to diffuse panbronchiolitis (DPB) and chronic obstructive pulmonary disease (COPD)].

Diffuse panbronchiolitis (DPB) and chronic obstructive pulmonary disease (COPD) are both characterized by chronic airflow obstruction of unknown etiology. It is hypothesized that neutrophils play the major role in the pathogenesis of these diseases. Recent studies have suggested that genetic factors may be related to individual susceptibility to these diseases. We have investigated the association between the C 242 T polymorphism of p 22 phox, a critical subunit of superoxide-generating NADH/NADPH oxidase, and susceptibility to DPB and COPD. Blood samples obtained from both patients with DPB (n = 82), COPD (n = 53), and control subjects (n = 82) were used for this genotyping assay; and the polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) were performed to genotype the gene. The frequency of the C allele was 0.91, 0.92, 0.92 in the DPB, COPD, and control groups, respectively. There were no differences in the distribution of the genotype of p 22 phox among these groups, either. We concluded that there is no association between the C 242 T polymorphism of p 22 phox, and susceptibility to DPB and COPD.

Bronchiolitis↗
PubMed2001

[Health status and lifestyle issues of homeless people in Sapporo city, 2000].

OBJECTIVE: To clarify the health status and lifestyle issues of homeless people in Sapporo city, voluntary "health consultations and medical examinations" were carried out near an emergency kitchen. METHODS: The voluntary activities were held in a park near the shelter tents of homeless people seven times from December 1999 to December 2000. The homeless people who consulted us, medical doctors, were asked detailed questions about past history, present illness, subjective symptoms, lifestyles and so on, and were examined for their blood pressure and urinary parameter. RESULTS: A total of 60 homeless people, including 59 men and 1 woman, were consulted and examined, Fifty-seven percent of them were 50 years old of older, and 30% had been homeless for less than half a year. Forty percent had some dental problems, 28% suffered neck stiffness, and 27% back pain. The medical examination found 53% of them to be hypertensive and 26% to be diabetic. Twenty-five percent had meals only once a day, 55% had meat or fish in their diet not more than twice a week and 57% had vegetables in their diet not more than twice a week. Forty-two percent slept not more than 5 hours a day, 13% often drank alcohol in the daytime, and 83% were smokers. CONCLUSION: The present results suggest that lifestyle-related chronic diseases are more significant problems among homeless people in Sapporo city than common infectious diseases such as tuberculosis or dysentery, probably because it is colder and therefore there are fewer homeless people in Sapporo city than in other major cities in Japan such as Tokyo and Osaka. Further studies of the homeless people living in such a cold environment are warranted to develop better health policies for them in the context of their social and economical determinants. In addition, it is important to establish a more reliable registration system for these people in order to plan and provide a comprehensive social and health support network as needed.

Adult↗
PubMed2001

[A case of chondrosarcoma originating from the rib and presenting as a posterior mediastinal tumor-like shadow].

A 66-year-old man was admitted to our hospital because of induction therapy of interferon for chronic hepatitis due to hepatitis C virus. On routine investigation, a mass-like lesion was detected at the level of the hilum of the left lung on the chest plain radiograph. On the thoracic CT, the heterogeneous tumor, including calcification, was 6 cm in diameter in the posterior mediastinal area, and the rib and vertebra had been damaged by it. The tumor extended to the descending aorta and the left main bronchus. A small nodule in the left S1 + 2 was noted on another slice section of this thoracic CT. The possible diagnoses, based on these radiological findings, for this tumor were primary lung cancer, posterior mediastinal tumor and malignant tumor originating from the chest wall. The diagnosis of chondrosarcoma was made based on the histological findings of the specimen obtained from the tumor. This tumor could not be resected in this case, because it had extensively damaged the rib and vertebra, and the nodular lesion in the left S1 + 2 was regarded as a metastasis from it. Although reports of chondrosarcoma originating from a rib and presenting as a posterior mediastinal tumor-like shadow are rare, chondrosarcoma should be considered as a possible diagnosis for such tumors-posterior mediastinal masses with characteristic findings such as a large tumor in contact with the chest wall, and containing calcification, with destruction of bone and dissection of the rib as shown in our CT findings.

Aged↗