Tomoe Nishimaki

Pulmonary Hypertension in Rats 1.

We administered human interleukin (IL)-6 to rats to examine whether it is implicated in the development of pulmonary hypertension (PH). The rats injected with IL-6 developed PH as determined by the weight ratio of the right ventricle to the left ventricle+septum. This ratio decreased with the appearance of IgG anti-human IL-6 antibody. Histologically we observed in the lungs, luminal occlusion of small muscular arteries, capillaries filled with fibrin thrombi, and localized hemorrhage. IL-6 increased the number of platelets, and the number of platelets correlated with the extent of PH. Thus, it seems likely that (IL-6) is involved in the formation of PH in this model.

Immunohistological Study of Endothelin-1 and Endothelin-A and B Receptors in Two Patients with Scleroderma Renal Crisis

Abstract: Scleroderma renal crisis (SRC) developed in two patients with systemic sclerosis (SSc) and they died from respiratory failure. Findings on autopsy revealed congestion and oedema in both lungs and intimal thickening of the small renal arteries in both patients. Immunohistological investigations showed positive staining of anti-human endothelin (ET)-1 in the media of the small renal arteries and ET-B receptor in the medial smooth muscle of the small renal arteries. This observation suggests an important pathophysiological role of ET-1 in the development of SRC in some patients with SSc.

Clinico-Laboratory Characteristics of Patients with Dermatomyositis Accompanied by Rapidly Progressive Interstitial Lung Disease

Abstract: The clinico-laboratory features of 16 patients with dermatomyositis (DM) were compared between patients with accompanying rapidly progressive interstitial lung disease (RP-ILD, n= 7) and those with chronic interstitial lung disease (C-ILD, n= 9), and also between deceased (seven RP-ILD and three C-ILD) and living patients (six C-ILD). The extent of muscle weakness of the extremities and frequency of autoantibody positivity were significantly lower in DM patients with RP-ILD than in DM patients with C-ILD. Furthermore, significantly lower serum ceatine kinase/lactate dehydrogenase levels (0.26 ± 0.27) were found in the 10 patients who died than in the six living patients (1.21 ± 1.09). A higher CD4+/CD8+ T-lymphocyte ratio in the peripheral blood (3.51 ± 2.65) was detected in the four DM patients with RP-ILD who died than in the six living DM patients with C-ILD (1.22 ± 0.49).

Pulmonary hypertension in connective tissue disease. Clinical analysis of sixty patients in multi-institutional study.

SummaryClinical features and prognosis of sixty patients with connective tissue disease accompanied by pulmonary hypertension (PH) (26 MCTD, 20 SLE, and 14 PSS) reported retrospectively by multiinstitutions were compared. Though the obtained data were incomplete and lacking in uniformity, no significant difference in the clinical features among the three diseases were observed except high incidence of pulmonary fibrosis and low% VC in PSS with PH patients. Statistically significant difference, however, was observed between live and dead patients of three diseases gathered in post sternal pain, pulmonary diastolic murmur, right ventricular hypertrophy on ECG and mean pressure of pulmonary artery. Higher incidence of anti-nRNP antibody was observed in SLE with PH and PSS with PH patients than with the general population. A quicker occurrence of PH and shorter survival time were observed in MCTD patients with PH than in SLE and PSS patients with PH.

Interleukin-6 induces proliferation of rat hepatocytes in vivo

Abstract Background/Aims: The aim of this study was to assess the effect of interleukin-6 (IL-6) on the proliferation of hepatocytes and to study the interaction between IL-6 and hepatocyte growth factor (HGF) in vivo . Methods: IL-6 was injected at a dose of 200 μg/mg subcutaneously into rats every day for 14 days. Liver and blood samples were obtained at 1, 3, 7 and 14 days during IL-6 administration. Hepatocyte proliferative activity of sera was measured using 3 H-thymidine incorporation into cultured rat hepatocytes. To evaluate the proliferative activity of the hepatocytes in tissue sections, hepatic DNA content and immunostaining of the liver tissue sections for proliferating cell nuclear antigen (PCNA) were performed. Plasma HGF levels were measured using specific EIA. In addition, total RNA was extracted from the liver and expression of HGF mRNA was detected by RT-PCR. Results: The DNA contents of liver taken from IL-6-treated rats were increased during IL-6 administration compared with untreated rats. Sera taken from IL-6-treated rats at various intervals during administration also significantly increased 3 H-thymidine incorporation by cultured rat hepatocytes compared with sera from untreated rats, suppressing 3 H-thymidine incorporation at day 1 and 3 by anti-HGF antibody. IL-6 itself did not increase 3 H-thymidine incorporation. Increased expression of PCNA in these hepatocytes was noted from 1 day after IL-6 administration, and at 14 days, the number of PCNA-positive cells was sevenfold greater than in the livers of untreated rats. However, plasma HGF levels showed a peak at day 1, decreased gradually from day 3, and became undetectable by day 14. HGF mRNA expression in livers of IL-6-treated rats was suppressed from day 3 to day 14 of IL-6 administration. Conclusions: These data show that IL-6 induces an early phase of liver cell growth in vivo and suggest that an increase level of HGF mediates this effect.

Anticardiolipin Antibodies Are Associated with Pulmonary Hypertension in Patients with Mixed Connective Tissue Disease or Systemic Lupus Erythematosus

Anticardiolipin antibodies (aCL) were studied in relation to pulmonary hypertension (PH) in 22 patients with mixed connective tissue disease (MCTD) or systemic lupus erythematosus (SLE). The mean pulmonary arterial pressure (mPAP) values were similar in the 12 MCTD and 10 SLE patients: 26 +/- 11 and 25 +/- 11 mm Hg, respectively. However, the frequency of PH was higher in SLE (60%) than in MCTD patients (33%). The titers of aCL were significantly higher in SLE (38 +/- 27 IU/ml) than in MCTD (17 +/- 7 IU/ml; p < 0.02). Two SLE patients with high titers of aCL had multiple cerebral infarction and transverse myelitis, and deep vein thrombosis, respectively. A significant correlation between the titers of aCL and mPAP was observed in patients with MCTD (p < 0.05), but not in patients with SLE.

Protective effect of beraprost sodium, a stable prostacyclin analogue, in development of monocrotaline-induced pulmonary hypertension.

Experimental pulmonary hypertension (PH) was induced by a single injection of monocrotaline (MCT), a pyrrolizidine alkaloid extracted from Crotalaria spectabilis. The effect of beraprost sodium, a stable prostacyclin analogue, on the development of MCT-induced PH in rats was studied. Chronic administration of beraprost sodium at a dose of 30 micrograms/kg/day initiated on the same day as MCT injection decreased the degree of PH determined by weight ratio of right ventricular free wall to that of left ventricle plus septum depending on the duration of administration. Although the injection of prostaglandin E1 (PGE1) at a dose of 200 micrograms/kg/day initiated 1 week after MCT injection did not decrease the degree of PH significantly, beraprost sodium administration at doses of 30 and 100 micrograms/kg/day decreased the degree of PH significantly. The cytoprotective effect of beraprost sodium against endothelial cell (EC) damage is believed to be involved in inhibiting development of PH in MCT-injected rats. The amounts of cytokines such as interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor (TNF) produced by alveolar macrophages decreased in accordance with the inhibiting effect of beraprost sodium on development of PH, indicating that beraprost sodium inhibited the development of PH in MCT-injected rats not only through its effect of vasodilation and anti-platelet aggregation in pulmonary circulation but also through its antiinflammatory effects.

Soluble P-selectin in the plasma of patients with connective tissue diseases

We measured the soluble P-selectin (sP-selectin) in plasma of 54 patients with connective tissue diseases and 12 normal controls by a 2-step sandwich enzyme immunoassay. Our purpose was 2-fold: to determine (1) whether the level of sP-selectin of such patients is higher than normal, and (2), if it is, whether it correlates with any of the laboratory data currently available. The mean levels in patients with systemic lupus erythematosus (SLE), mixed connective tissue disease (MCTD) and rheumatoid arthritis (RA) were 306, 1,048 and 844 ng/ml, respectively, compared with 220 ng/ml for controls. The mean levels in patients with SLE and nephropathy, MCTD and either nephropathy or thrombosis, and malignant RA were 351, 1,116 and 1,721 ng/ml, respectively. No correlation was found between the levels of sP-selectin and other laboratory data (WBC, CRP, ESR, antinuclear antibody, RF, aCL) except the number of platelets (y = 0.057, r = 0.37). In the clinical course of patients with lupus nephritis and MCTD with nephropathy, sP-selectin became a sensitive parameter. Thus, the level of sP-selectin is higher than normal in patients with connective tissue diseases, especially when complications exist, and it does not correlate with any of the laboratory data currently available except the number of platelets. Measurement of sP-selectin levels should be included in the laboratory tests of patients with connective tissue diseases, especially when complicated by nephropathy or thrombosis.

Clinicolaboratory characteristics of patients with primary biliary cirrhosis associated with CREST symptoms.

Aims: Patients with primary biliary cirrhosis (PBC) occasionally suffer complications from other autoimmune diseases. When PBC was associated with calcinosis, Raynauds phenomenon, esophageal dysmotility, sclerodactyly and telangiectasias (CREST) symptoms, it has been proposed that it is a distinct clinical entity. This study aimed to investigate whether PBC associated with CREST symptoms is a distinct disease complex. Method: Clinicolaboratory data, HLA type of leukocytes and disease prognosis were compared between 31 patients with PBC associated with CREST symptoms and 68 patients with PBC alone. Results: The characteristic findings and significant differences observed in patients with PBC associated with CREST symptoms compared with PBC alone are as follows: all women with older age with milder clinical features of both PBC (asymptomatic PBC in 84%) and CREST syndrome (incomplete CREST in 81%), more frequent occurrence of esophageal varices (28.6 vs. 9.3%), better prognosis (87.5 vs. 45.5% in 10 years survival), lower serum levels of AST (39.8 vs. 63.6 IU/l) and IgM (460 vs. 676 mg/dl), higher prevalence of discrete speckled pattern of antinuclear antibodies (93.5 vs. 12.3%), higher median titers of anti-CENP-B antibodies (1.22 vs. 0.31), lower median titers of antimitochondrial antibody (1:80 vs. 1:160), and a higher prevalence of HLA-DR9 (54.5 vs. 24.3%). Conclusion: These findings support the presence of a subgroup in PBC as PBC associated with CREST symptoms.

An autopsy case of ulcerative colitis associated with Takayasu’s disease with a review of 13 Japanese cases

SummaryAn autopsy was performed on a 42-year-old Japanese female who had been suffering from both ulcerative colitis (UC) and Takayasu’s disease. Her UC started at age 27 with bloody stool, and Takayasu’s disease was diagnosed at age 30 on the basis of absence of pulse in her left arm. After more than ten years she died of multiple cerebral infarction. An autopsy study revealed the scarring stage of UC in the entire colon and aortitis in the aortic arch and its major branches and pulmonary arteries. Her HLA type was positive for HLA-A2, 24, Bw52 and 61. Clinical features of a total of 13 Japanese cases that had both UC and Takayasu’s disease have been reviewed in the Japanese and Western literature.