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Biomedical subjects

N Shijubo

Publications and source records attributed to N Shijubo.

At least 19 recordsLinked to original sources
PubMed2003

Increased circulating interleukin-12 (IL-12) p40 in pulmonary sarcoidosis.

In sarcoidosis, a T helper 1 (Th1) response is an essential event and the up-regulation of interleukin-12 (IL-12) has been detected in affected disease sites. In order to investigate the clinical usefulness of circulating IL-12, we measured the serum concentrations of IL-12 by ELISA and performed immunohistochemistry using specific MoAbs for IL-12 in the lungs and scalene lymph nodes of patients with sarcoidosis. The serum concentration of IL-12 p40 was detectable in all 45 patients with pulmonary sarcoidosis and 18 normal controls, whereas that of IL-12 p70 was undetectable. The serum concentrations of IL-12 p40 in pulmonary sarcoidosis were significantly higher than those of the normal controls, especially in cases with abnormal intrathoracic findings detected by chest roentogenogram. The serum concentrations of interferon-gamma (IFN-gamma) also increased compared with those of normal controls and there was a significant positive correlation between the serum concentrations of IL-12 p40 and IFN-gamma. Furthermore, serum angiotensin-converting enzyme (ACE) and lysozyme, which are known to be useful markers for disease activity in sarcoidosis, correlated well with the serum concentrations of IL-12 p40. The positive 67Ga scan group (for lung field) had significantly elevated serum IL-12 p40 levels compared with those of the negative group. No bioactivity of IL-12 p70 was detected in three sarcoid cases sera by using the IL-12 responsive cell line. Finally, the immunohistochemical approach revealed that IL-12 p40 was expressed in the epithelioid cells and macrophages of sarcoid lungs and lymph nodes. We concluded that the production of IL-12 p40 was far greater in the sera and we have demonstrated this to be a useful clinical marker for disease activity and the Th1 response in pulmonary sarcoidosis.

Analysis of Variance↗
PubMed2001

IL-12 and IL-18 are increased and stimulate IFN-gamma production in sarcoid lungs.

Sarcoidosis is a systemic chronic granulomatous disease of unknown cause. Recent investigations revealed that the cytokine profile in inflamed lesions of sarcoidosis is Th1 dominant. To obtain better immunopathologic understanding of sarcoidosis, we examined the expression of IL-12 and IL-18 and their roles in IFN-gamma production in pulmonary sarcoidosis. Sarcoid cases had significantly elevated levels of IL-12 (p40 and p70) and IL-18 in bronchoalveolar lavage (BAL) fluids compared with healthy subjects. IL-12 p70 and IL-18 were immunohistochemically expressed in the epithelioid cells and giant cells of sarcoid granulomas. Significant induction of IFN-gamma, IL-12 p70, and IL-18 was observed from sarcoid BAL fluid cells with LPS stimulation, whereas LPS tended to induce only IL-12 p70 in BAL fluid cells from healthy subjects. Sarcoid cases had significantly greater IFN-gamma induction with LPS stimulation than healthy subjects did. IL-18 mRNA expression was observed in freshly isolated sarcoid BAL fluid cells as well as in LPS-stimulated sarcoid BAL fluid cells, but IFN-gamma and IL-12 mRNA expression was observed only in LPS-stimulated BAL fluid cells. Treatment with anti-IL-12- and anti-IL-18-neutralizing Abs significantly inhibited IFN-gamma production from LPS-stimulated BAL fluid cells of sarcoid cases. Coadministration of rIL-12 or rIL-18 induced greater IFN-gamma production in sarcoid BAL fluid cells than in normal BAL fluid cells. We concluded that bioactive IL-12 and IL-18 were produced in sarcoid BAL fluid cells and synergistically induced IFN-gamma production, indicating important cytokines in the Th1 response of sarcoidosis.

Adjuvants, Immunologic↗
PubMed2001

Mammary involvement in a patient with sarcoidosis.

Sarcoidosis is a systemic granulomatous disease of unknown etiology. Sarcoidosis affects multiple organs; the lungs, lymphoid system, eyes and skin are usually involved. Commonly, any organ system may be affected. Sarcoid involvement in the nervous system, locomotor system, lacrimal and salivary glands, heart, kidney and liver has been recognized in patients with sarcoidosis. However, sarcoid involvement of the breast parenchyma has been extremely rare in patients with sarcoidosis. Herein, we report a patient with a sarcoid breast mass who had bilateral hilar lymphadenopathy and lymphocytosis in bronchoalveolar lavage analysis.

Breast Diseases↗
PubMed2000

Mast cells correlate with angiogenesis and poor outcome in stage I lung adenocarcinoma.

Angiogenesis is in part related to mast cells. However, the biological significance of mast cells within lung carcinoma remains unclear. Immunohistochemistry was used to stain for tryptase, CD34 and vascular endothelial growth factor (VEGF) in 85 cases of stage I nonsmall cell lung carcinoma. VEGF was found in 33 of 53 adenocarcinomas and 14 of 32 squamous cell carcinomas. Cases of adenocarcinoma had significantly higher mast cell counts than those of squamous cell carcinoma. In adenocarcinoma, mast cell counts in VEGF-positive tumours were significantly higher than in VEGF-negative tumours, whereas in squamous cell carcinoma they were not. Good correlation was observed between intratumoural mast cell counts and microvessel counts. Double staining showed most intratumoural mast cells expressed VEGF. Importantly, only in lung adenocarcinoma, members in the high mast cell count group had significantly worse prognosis than those in the low mast cell count group. It is concluded that tumour-released vascular endothelial growth factors may be related to mast cell accumulation, intratumoural mast cells may produce vascular endothelial growth factor, and stromal mast cells correlate with angiogenesis and poor outcome in stage I lung adenocarcinoma.

Adenocarcinoma↗
PubMed2000

Association of Clara cell 10-kDa protein, spontaneous regression and sarcoidosis.

Sarcoidosis is a systemic granulomatous disorder with a high rate of spontaneous regression. Clara cell 10-kDa protein (CC10), the predominant product of nonciliated bronchiolar epithelial cells, is a potent immunoregulatory and anti-inflammatory agent. CC10 levels were measured in sera and bronchoalveolar lavage (BAL) fluids from 31 sarcoidosis patients (nine progressive disease and 22 regressive disease) and their relevance to spontaneous regression investigated. The inhibitory effects of recombinant CC10 on interferon gamma (IFN-gamma) production were examined using lipopolysaccharide (LPS)-stimulated sarcoid BAL fluid cells, and the blocking effects of monoclonal antibody TY-5, directed against CC10, on CC10 function were also tested. Serum and BAL fluid CC10 levels in the regressive disease group were significantly higher than those in the progressive disease group (serum, p<0.05; BAL fluid, p<0.005) and healthy subjects (serum, p<0.0001; BAL fluid, p<0.005). CC10 inhibited, in part, IFN-gamma production from LPS-stimulated sarcoid BAL fluid cells (CC10 inhibition: 1,000 ng x mL(-1), 30%; 100 ng x mL(-1), 14%). TY-5 restored IFN-gamma production by blocking CC10 function. Sarcoidosis patients with regressive disease showed increased Clara cell 10-kDa protein levels in their sera and bronchoalveolar lavage fluids. Clara cell 10-kDa protein may be a regulator of the inflammatory process in sarcoidosis.

Adult↗
PubMed2000

Lobar distribution of emphysema in computed tomographic densitometric analysis.

RATIONALE AND OBJECTIVES: The aims of this study were to determine the extent of emphysema in individual lobes and to investigate whether the lobar distribution of emphysema influences pulmonary function. METHODS: Helical CT and pulmonary function tests were performed in 50 emphysema patients. Percentages of low attenuation volume (extent of emphysema) were calculated for each lobe by using CT densitometric analysis. RESULTS: The extent of emphysema of the whole lung in these patients was 44%. Airflow limitation (r = -0.82, P<0.0001) and residual volume (r = -0.52, P<0.01) were closely correlated with the extent of emphysema in both lower lobes. Diffusing capacity (r = -0.61, P<0.0001) was closely correlated with the extent of emphysema in both upper lobes. On the basis of the lobar distribution of emphysema as determined by CT densitometry, we divided these emphysema patients into predominantly upper-lobe disease and predominantly lower-lobe disease groups. The predominantly lower-lobe disease group had significantly greater severe airflow limitation (P<0.0001), greater residual volume (P<0.01), and greater total lung capacity (P<0.05) than did the predominantly upper-lobe disease group. CONCLUSIONS: CT densitometry showed a distinct lobar distribution of emphysema. Pulmonary function is significantly different between predominantly upper- and lower-lobe emphysema groups.

Absorptiometry, Photon↗
PubMed2000

Development of an enzyme-linked immunosorbent assay for Clara cell 10-kDa protein: in pursuit of clinical significance of sera in patients with asthma and sarcoidosis.

We have produced nine monoclonal antibodies to human CC10/protein-1 and analyzed their characterization. TY-5, TY-7, and TY-8 recognized restricted possible hydrophobic epitopes and their binding to CC10 prevented the other clones from CC10 binding, suggesting that these antibodies induce strong conformational change. TY-1, TY-2, TY-3, TY-6, and 6D4 recognize amino acid residues 61-68 and the presence of disulfide bonds might be essential for epitope expression of these five clones. The best combination was TY-1 and TY-2 in developing an enzyme-linked immunosorbent assay (ELISA), whereas TY-5 was most suitable for immunohistochemistry and immunoblotting. We found significantly lower serum CC10 levels in asthmatic subjects and higher serum CC10 levels in sarcoidosis subjects than in controls. Data of CC10 levels in BAL fluids of sarcoidosis subjects were similar to those in the circulation. CC10-positive epithelial cells were significantly lower in small airways of asthmatic subjects than in controls, and CC10-positive epithelial cells were inversely correlated with T cell and mast cell accumulation in the airways of asthmatic subjects. CC10 may be a downregulator in both Th1- and Th2-mediated chronic inflammatory diseases. The use of these MoAbs and recombinant CC10 is a powerful tool to investigate the clinical roles of CC10/P1 and the structure and function of CC10/P1.

Antibodies, Monoclonal↗
PubMed2000

Increased levels of circulating interleukin-18 in patients with advanced tuberculosis.

Interleukin-18 (IL-18) has recently been identified as an interferon- gamma-inducing factor and it plays an important role in the Th1 response. We measured serum levels of IL-18 and interferon-gamma (IFN-gamma) in 43 patients with pulmonary tuberculosis and 25 healthy control subjects. Significantly increased levels of circulating IL-18 and IFN-gamma were found in pulmonary tuberculosis as compared with those in healthy control subjects. Circulating IL-18 and IFN-gamma correlated with the extent of disease in pulmonary tuberculosis. We found significantly increased levels of circulating IL-18 and IFN-gamma in the patients with high-grade fever. Circulating IL-18 significantly correlated with circulating IFN-gamma. IL-18 may play an important role in immune response to human infection with Mycobacterium tuberculosis.

Adolescent↗
PubMed2000

Increased levels of interleukin-18 in patients with pulmonary sarcoidosis.

Interleukin-18 (IL-18) has recently been identified as an interferon-gamma (IFN-gamma)-inducing factor, and it plays an important role in T helper 1 (Th1) response. We measured the serum levels of IL-18 and IFN- gamma in 37 patients with pulmonary sarcoidosis and 25 healthy control subjects. We also measured the levels of IL-18 and IFN-gamma in 10-fold concentrated bronchoalveolar lavage (BAL) fluids of 19 patients with pulmonary sarcoidosis and 9 healthy control subjects (all lifelong nonsmokers). The levels of serum IL-18 and IFN-gamma were significantly increased in patients with sarcoidosis. The levels of BAL fluid IL-18 were significantly elevated in patients with sarcoidosis, however, the IFN-gamma levels of the patients and control subjects were all below sensitivity. Serum IL-18 levels significantly correlated with serum IFN-gamma levels and lysozyme activity. The patients positive for gallium-67 ((67)Ga) scan had significantly elevated serum IL-18 levels as compared with those of the negative patients. BAL fluid IL-18 levels significantly correlated with serum IL-18 levels in patients with sarcoidosis, and there was a significant correlation between IL-18 levels and lymphocyte proportions in sarcoid BAL fluids. In patients with sarcoidosis, IL-18 seems to induce IFN-gamma production and IL-18 levels in sera may reflect disease activity of sarcoidosis.

Adult↗
PubMed2000

Enhanced mRNA expression of Th1 cytokines and IL-12 in active pulmonary sarcoidosis.

BACKGROUND AND AIM OF THE WORK: Active sarcoidosis is considered to be a Th1 dominant condition. We examined whether Th1 cytokines are highly expressed at inflammed lesions of Japanese patients with sarcoidosis. METHODS: To investigate the mRNA expression of Th1 cytokines and IL-12 in sarcoid BAL cells, we used semiquantitative reverse transcription--polymerase chain reaction method. RESULTS: The mRNA expressions of Th1 cytokines (IFN-gamma and IL-2) in active sarcoid BAL cells were significantly elevated as compared with those in healthy volunteers. The proportion of positive IL-4 mRNA expression in sarcoid BAL cells was not significantly higher than that in healthy volunteers. Further, there was no significant difference in IFN-gamma mRNA levels between the groups positive and negative for IL-4 mRNA expression. Although the proportion of positive expression of IL-12 mRNA in active sarcoid BAL cells was not significantly higher than that in healthy volunteers, the group positive for IL-12 mRNA expression had significantly elevated levels of IFN-gamma mRNA than did the negative group. CONCLUSIONS: These results may indicate that IL-12 induces IFN-gamma expression and subsequent Th1 dominant condition in Japanese patients with sarcoidosis.

Adult↗
PubMed2000

Vascular endothelial growth factor and osteopontin in tumor biology.

Tumor growth and metastasis are angiogenesis-dependent and tumor angiogenesis is a result of complex interplay of positive and negative regulators. Vascular endothelial growth factor (VEGF) occupies a particular place among the positive regulators of angiogenesis due to its potency and specificity for endothelial cells. VEGF upregulates several molecules such as growth factors, adhesion molecules, proteases, and protease receptors and it actually induces microvascular hyperpermeability, resulting in activation of thrombin from prothrombin. Osteopontin (OPN) is a secreted arginine-glycine-asparic acid (RGD)-containing phosphoprotein and it contains a predicted thrombin cleavage site. OPN binds to several integrins and CD44 variants. OPN has diverse functions such as cell adhesion, chemoattraction, and immunomodulation, and it induces endothelial cell migration and upregulates endothelial cell migration induced by VEGF. OPN expression is upregulated in human carcinomas. This review documents the functional roles of VEGF and OPN in angiogenesis and their clinical significance in tumor biology.

Animals↗
PubMed1999

Serum levels of Clara cell 10-kDa protein are decreased in patients with asthma.

Clara cell 10-kDa protein (CC10), the predominant product from nonciliated cells in the epithelial lining of bronchioles (Clara cells), has been shown to have immunomodulatory and antiinflammatory activity and may play a role in controlling airway inflammation. This study was designed to measure serum CC10 concentrations in healthy and asthmatic nonsmokers. Serum CC10 concentrations in asthmatic nonsmokers were significantly lower than in healthy nonsmokers. Asthmatic patients with a long duration of the disease (>/=10 years) had significantly lower serum CC10 levels than those with a short duration of the disease (<10 years). There was no significant difference in serum CC10 levels in asthmatic patients between the time of the asthmatic attack and the stable condition. Serum CC10 levels may reflect decreased production of CC10 caused by remodeling of the small airways in asthma.

Asthma↗
PubMed1999

Clara cell protein-positive epithelial cells are reduced in small airways of asthmatics.

Clara cell 10 kilodalton protein (CC10), the predominant product from nonciliated cells in the epithelial lining of bronchioles (Clara cells), has been shown to have immunomodulatory and anti-inflammatory activity, and may play roles in controlling inflammation in the airway. This study was designed to examine immunohistochemical expression of CC10 in epithelial cells in small airways (perimeter < 6 mm) of asthmatic and control nonsmokers who underwent lung resection because of peripheral lung carcinoma and to compare CC10-positive epithelial cell proportions with numbers of inflammatory cells in small airways of asthmatics. Significantly decreased proportions of CC10-positive epithelial cells and significantly increased numbers of T cells, activated eosinophils, and mast cells in small airways of asthmatics were found compared with those of control subjects. CC10-positive epithelial cell proportions inversely correlated with numbers of T cells and mast cells in small airways of asthmatics. Decreases of CC10-producing cells may give an accelerating cause for further aggravation of inflammatory responses in chronic asthma.

Asthma↗
PubMed1999

Vascular endothelial growth factor and osteopontin in stage I lung adenocarcinoma.

Tumor growth and metastasis are angiogenesis-dependent processes initiated and regulated by a number of cytokines. Vascular endothelial growth factor (VEGF) is a potent angiogenic protein with a selective mitogenic effect on vascular endothelial cells. Osteopontin (OPN) induces endothelial cell migration and upregulates endothelial cell migration induced by VEGF. To clarify the cooperative role of VEGF and OPN in tumor angiogenesis, we stained VEGF, OPN, and CD34 immunohistochemically in 87 cases of stage I non-small cell lung cancer (adenocarcinoma, 55, and squamous cell carcinoma, 32). Of the 87 patients studied, 27 patients had postoperative relapse and 60 patients did not. VEGF was found in 34 of 55 cases of adenocarcinomas and 14 of 32 squamous cell carcinomas, and OPN was found in 30 of 55 adenocarcinomas and 10 of 32 squamous cell carcinomas. In adenocarcinoma, microvessel counts of VEGF-positive and OPN-positive tumors were significantly higher than VEGF-negative and OPN-negative tumors, respectively, whereas in squamous cell carcinoma they were not. More importantly, patients with VEGF- and OPN-positive stage I lung adenocarcinoma had significantly worse prognosis as compared with other groups. Cooperation of OPN is important in VEGF-mediated tumor angiogenesis in stage I lung adenocarcinoma.

Adenocarcinoma↗
PubMed1999

Characterization of monoclonal antibodies to human protein 1/Clara cell 10 kilodalton protein.

Human protein 1/Clara cell Mr 10,000 protein consists of two identical subunits of seventy amino acid residues each. In the present study, eight clones of monoclonal antibodies against native protein 1 were prepared and their respective epitopes were immunochemically and immunohistochemically characterized using native protein 1, truncated recombinant protein 1 and synthesized peptides. Among the clones, three designated as TY-5, TY-7 and TY-8 recognized amino acid residues 7-16, residues 19-28, and residues 39-46, respectively, all of which comprise the hydrophobic cavity of protein 1, possibly associated with chemical binding function. With the exception of TY-4, the remaining clones recognized residues 61-68 which are exposed to solvent. The epitope of TY-4 remains undetermined. Proper selection and combination of clones and recombinant protein 1 may be useful for fundamental and clinical studies of protein 1.

Amino Acid Sequence↗
PubMed1998

BAL surfactant protein A and Clara cell 10-kDa protein levels in healthy subjects.

Lung surfactant protein A (SP-A) and Clara cell 10-kDa protein (CC10) are the most abundant proteins produced locally in the lower respiratory tract, as assessed in bronchoalveolar lavage (BAL) analysis. However, it is not known what factors influence SP-A and CC10 levels in BAL fluids, and the relationship between SP-A and CC10 levels in BAL fluids has been unclear. We measured SP-A and CC10 concentrations in BAL fluids from 11 healthy nonsmokers and 12 healthy smokers by enzyme-linked immunosorbent assays using specific antibodies. Mean SP-A and CC10 levels in BAL fluids of healthy smokers were significantly lower than those of healthy nonsmokers. SP-A values correlated significantly with CC10 and phospholipid values in BAL fluids. On BAL examinations using three 50-ml aliquots, the mean SP-A level in the second lavage was 2.0-fold and 2.4-fold, respectively, of that in the first and third lavages, and the mean CC10 level in the first lavage was 5.0-fold and 5.6-fold, respectively, of that in the second and third lavages. We conclude that BAL fluid SP-A and CC10 levels are influenced by the BAL methods and by cigarette smoking. There is a significant positive correlation between SP-A and CC10 values in BAL fluids of healthy subjects.

Adult↗
PubMed1998

Immunolocalization of extracellular matrix proteins and integrins in sarcoid lymph nodes.

To improve our understanding of the role of extracellular matrix (ECM) proteins and integrins during the processes of granuloma formation in sarcoidosis, we examined the distribution of ECM proteins and the expression of integrins in sarcoid lymph nodes by immunohistochemical methods. We also examined the expression of transforming growth factor-beta1 (TGF-beta1), which is one of major regulators for synthesis of ECM proteins. Most ECM proteins were detected in the periphery of the granulomas in a concentric pattern, and fibronectin was diffusely detected from an early to a regressive stage. Compared with normal lymph nodes, most beta1-integrin subfamilies (alpha1, alpha4, alpha5 and alpha6) were more strongly expressed on lymphocytes around the granulomas. Epithelioid cells exhibited strong expression of the alpha5 molecule. Fibroblasts exhibited the expression of the alpha2 and alpha5 molecules surrounding ECM proteins. The alpha5beta1 molecule had a distribution similar to that of fibronectin. TGF-beta1 was detected in epithelioid cells throughout the various evolutional stages and its expression was especially marked in mature granulomas. Interaction of fibronectin and the alpha5beta1 molecule may have an important role in the process of formation of sarcoid granuloma. The expression of TGF-beta1 may be involved in the regression of sarcoid granuloma by initiating fibrosis and atrophy of epithelioid cells.

Extracellular Matrix Proteins↗