Takeo Yoshinouchi

Non-specific interstitial pneumonia as pulmonary involvement of systemic sclerosis

The pathological features of lung disease in nine patients with systemic sclerosis (SSc) were evaluated. The patients comprised one man and eight women, with a median age of 58 years. SSc was diagnosed according to the criteria of the American Rheumatism Association. In all patients, high resolution computed radiographic scanning of the lungs (HRCT) was performed, and apparent honeycomb formation was seen in four patients. Pathologically, four patients were diagnosed with usual interstitial pneumonia (UIP), three with non-specific interstitial pneumonia (NSIP) group II, one NSIP group II–III, and one NSIP group II with diffuse alveolar damage. HRCT showed no apparent honeycomb formations in patients diagnosed with NSIP. This is the first report describing NSIP as a pulmonary complication of SSc.

Sequential changes of KL-6 in sera of patients with interstitial pneumonia associated with polymyositis/dermatomyositis

OBJECTIVE KL-6 is a mucin-like high molecular weight glycoprotein, which is strongly expressed on type II alveolar pneumocytes and bronchiolar epithelial cells. It has been demonstrated that the KL-6 antigen is a useful marker for estimating the activity of interstitial pneumonia. In this study, it is hypothesised that serum KL-6 is a useful marker to evaluate the activity of interstitial pneumonia associated with polymyositis/dermatomyositis (PM/DM). METHODS KL-6 was measured in sera in 16 patients diagnosed with PM/DM. Five had non-specific interstitial pneumonia (NSIP), three had diffuse alveolar damage (DAD), and eight had no pulmonary involvement, and 10 were normal non-smokers as a control group. The correlation was also evaluated between the KL-6 level and each clinical course in patients with pulmonary involvement associated with PM/DM. Immunohistochemical analysis using monoclonal anti-KL-6 antibody was also performed. RESULTS KL-6 concentrations in sera of patients with interstitial pneumonia associated with PM/DM were significantly high compared with those of PM/DM without interstitial pneumonia, and normal non-smokers. KL-6 concentrations in sera in patients with DAD significantly increased compared with those of other groups. KL-6 values in sera changed according to the progression or improvement of interstitial pneumonia. Immunohistochemical study using pulmonary tissues obtained from patients with DAD demonstrated that the hyaline membrane, proliferating type II pneumocytes, bronchial epithelial cells and some endothelial cells in pulmonary veins were stained by antihuman KL-6 antibody. CONCLUSION These data demonstrate that measurement of serum KL-6 was a useful marker to evaluate the activity of acute interstitial pneumonia associated with PM/DM.

Transforming growth factor beta1 gene polymorphism in rheumatoid arthritis.

Objective: Rheumatoid arthritis (RA) is a chronic inflammatory disease and synovial cells, antigen presenting cells, lymphocytes, and their cytokines might be associated with the disease. Transforming growth factor β1 (TGFβ1) has been reported to have important roles in unresolved inflammation, immune suppression, fibrosing processes, and angiogenesis. TGFβ1 is highly expressed in joints in RA and is considered to be a regulator of anti-inflammation in RA. Polymorphisms of TGFβ1 have been reported to be associated with the production of TGFβ1 protein, and to increase the risk of acquiring several diseases. It was speculated that these polymorphisms might also be involved in RA, and therefore the TGFβ1 codon 10 T869C polymorphism in a series of patients and controls was investigated. Method: A total of 155 patients with RA and 110 healthy subjects were studied. DNA was extracted from peripheral leucocytes and TGFβ1 codon 10 T869C polymorphism was determined by polymerase chain reaction restriction fragment polymorphism. Results: A significantly higher proportion of patients with RA with the T allele (CT type or TT type) was found compared with the CC type (p=0.039). Conclusion: The T allele, previously reported to be linked with production of TGFβ1, may be associated with an increased risk of RA.

Nonspecific interstitial pneumonia as pulmonary involvement of primary Sjögren's syndrome.

Abstract. The pathologic patterns of lung involvement in nine patients with Sjögrens syndrome (SjS) are evaluated. The patients consisted of three males and six females, with a median age of 59 years. The SjS was diagnosed according to the criteria of the First International Seminar on SjS. In all patients, high-resolution computed radiographic scanning (HRCT) of the lungs was performed, and apparent honeycomb or microhoneycomb formation was observed in six patients. Pathologically, six patients were diagnosed with usual interstitial pneumonia (UIP), and three were diagnosed with nonspecific interstitial pneumonia/fibrosis (NSIP) (group II). There were no apparent honeycomb formations on HRCT in patients diagnosed with NSIP. In conclusion, NSIP is also a possible histologic classification of interstitial pneumonia associated with SjS.

Clinical features of non-specific interstitial pneumonia

The clinical features of 24 patients with non-specific interstitial pneumonia (NIP) were evaluated. The patients consisted of seven men and 17 women, with a median age of 60 years. In seven patients, the disease was idiopathic and eight had collagen vascular diseases. Cough, dyspnoea and fever were frequently observed. The time interval between the onset of symptoms and open lung biopsy was 3 months. Mild increases of IgG, CRP, and LDH were also frequently observed. The average per cent VC was 65.1 +/- 3.2% and the average PaO2 was 71.3 +/- 2.4 Torr. Bronchoalveolar lavage was done in 20 patients, and a moderate increase in lymphocytes (27.8 +/- 6.7%) with a low CD4/CD8 ratio (0.86 +/- 0.22) was observed. Multiple patchy infiltration or diffuse interstitial shadows, located predominantly in the lower fields of both lungs were the characteristic chest CT findings. Lung biopsies in this group were characterized by varying proportions of chronic interstitial inflammation and fibrosis which was temporarily uniform. Patients were given steroid pulse therapy or oral steroids. The results were mild to marked improvements in chest roentgenographic findings and lung functions. Four patients (16.7%) died because of respiratory failure caused by NIP. This is the first report to describe clinical features of NIP since the original report by Katzenstein and Fiorelli.

Hepatocyte growth factor(HGF): a new biochemical marker for acute myocardial infarction.

SummaryThe purpose of this study was to investigate the use of hepatocyte growth factor as a biochemical marker for acute myocardial infarction. Several biochemical markers are used for noninvasive detection of acute myocardial infarction. However, hepatocyte growth factor has not been used previously for this purpose. We measured hepatocyte growth factor, creatine phosphokinase, and MB isoenzyme (CK-MB) levels in 6 patients with stable effort angina after diagnostic catheterization (controls) and in 12 patients with acute myocardial infarction (AMI). The measurements in the AMI patients were recorded twice a day for the first 3 days after onset of chest pain and once a day for the next 4 days. Furthermore, in each patient we evaluated the time to reach the maximum level and the time for the level to decline to less than half the maximum. Hepatocyte growth factor levels (ng/ml) were 0.3±0.1 for angina pectoris patients, and 15.7±9.1 within 6h and 12.5±4.6 within 12h after the onset for AMI patients, respectively. The correlation coefficients between hepatocyte growth factor and creatine phosphokinase and between hepatocyte growth factor and CK-MB were 0.68 and 0.74, respectively. The time to reach the maximum (h) and the time to decline to less than half of the maximum level (days) were 6.6±2.6 and 1.2±0.2 for hepatocyte growth factor, 19.4±8.7 and 2.5±1.4 for creatine phosphokinase, and 16.6±7.7 and 1.5±0.4 for CK-MB, respectively. Hepatocyte growth factor is useful as a prognostic indicator and reflects the clinical course in patients with acute myocardial infarction.

Detection of antivimentin antibody in sera of patients with idiopathic pulmonary fibrosis and non-specific interstitial pneumonia

It has been suggested that the humoral immune system plays a role in the pathogenesis of non‐specific interstitial pneumonia (NSIP). Although some circulating autoantibodies to cytoskeletal protein(s) have been suggested, the antimyofibroblast antibody has not been investigated in patients with idiopathic pulmonary fibrosis (IPF) and NSIP. The purpose of this study is to evaluate the existence of antimyofibroblast antibody in the sera of patients with IPF and NSIP. The MRC5 cell line was used as a model of myofibroblast. The anti‐MRC5 cell antibody was characterized in a patient with NSIP using Western blotting. Since we found that one of the anti‐MRC5 antibodies was an antivimentin antibody, we established an enzyme‐linked immunosorbent assay (ELISA) to measure the levels of antivimentin antibody in the sera of patients with IPF (n = 12) and NSIP (n = 23). Initially, two anti‐MRC5 cell antibodies were detected in the sera of patients with NSIP, one of which was characterized as the antivimentin antibody by Western blotting. The other was characterized as an antivimentin fragment antibody. We established an ELISA to measure the antivimentin antibody and found significantly higher levels in patients with IPF and NSIP than in normal volunteers. One of the anti‐MRC5 cell antibodies in the serum of a patient with NSIP was against vimentin. The serum levels of antivimentin antibody were increased in patients with IPF and NSIP compared with that of normal volunteers. These results suggest that the antivimentin antibody may be involved in the process of lung injury in IPF and NSIP.

Lymphocyte subsets in lung tissues of interstitial pneumonia associated with untreated polymyositis/dermatomyositis

Abstract. This study was designed to evaluate the distribution of lymphocyte subsets in lung specimens obtained by surgical lung biopsy from 12 patients with interstitial pneumonia associated with untreated polymyositis/dermatomyositis (PM/DM). Differences of histological findings and distributions of lymphocyte subsets between PM and DM were also evaluated. Distributions of B lymphocytes, CD4-positive T lymphocytes, and CD8-positive T lymphocytes were evaluated immunohistochemically. Interstitial pneumonia was pathologically classified as basically nonspecific interstitial pneumonia (NSIP) in all patients. Immunohistochemically, the distribution of B lymphocytes was mostly restricted to inside and/or around lymphoid follicles. The CD4-positive T lymphocytes were distributed diffusely in fibrotic areas and unrelated to lymphoid follicles. Most CD8-positive T lymphocytes were diffusely distributed, especially in relatively normal alveoli. There were no significant differences in the distribution of lymphocyte subsets between PM and DM. Although the distribution of B lymphocytes and CD4- and CD8-positive T lymphocytes in the lung were different, there were no significant differences in distributions of lymphocyte subsets between PM and DM.

Measurement of hepatocyte growth factor in serum and bronchoalveolar lavage fluid in patients with pulmonary fibrosis

The present study evaluated the clinical significance of hepatocyte growth factor (HGF) in patients with pulmonary fibrosis. Twenty-one patients with a diagnosis of pulmonary fibrosis [14 with idiopathic pulmonary fibrosis (IPF) and seven with pulmonary fibrosis associated with a collagen vascular disorder (PF-CVD]) and 21 normal subjects as control were studied. HGF levels in sera of patients with pulmonary fibrosis (0.34 +/- 0.02 ng ml-1) were elevated significantly as compared with normal subjects (0.21 +/- 0.01 ng ml-1) (P < 0.0001). HGF/albumin levels in broncho-alveolar lavage fluid (BALF) of patients with pulmonary fibrosis (72 +/- 17 ng g-1 albumin) were also significantly elevated as compared with normal subjects (under the detection limit) (P < 0.01). HGF levels in sera correlated significantly with elastase levels in sera and C-reactive protein, and correlated negatively with PaO2. HGF levels in sera were significantly higher in smokers with pulmonary fibrosis (0.42 +/- 0.03 ng ml-1) as compared with non-smokers with pulmonary fibrosis (0.29 +/- 0.03 ng ml-1) (P < 0.005). HGF/albumin levels in BALF correlated significantly with elastase/albumin levels in BALF, lactate dehydrogenase/albumin in BALF, Immunoglobulin A/albumin in BALF, total cell count/albumin in BALF, total number of alveolar macrophage/albumin in BALF, total number of neutrophil/albumin in BALF, CEA/albumin in BALF, CA19-9/albumin in BALF, and SCC/albumin in BALF. These results suggest that following lung injury, HGF may be a mediator involved in the repair which leads to pulmonary fibrosis.

Immunohistochemical distribution of SP-D, compared with that of SP-A and KL-6, in interstitial pneumonias

The immunohistochemical distribution of SP-D was compared with that of SP-A and KL-6 using a monoclonal antibody in lung tissues of 15 cases of collagen vascular disease-associated interstitial pneumonia (CVD-IP), 4 cases of hypersensitivity pneumonitis (CHP), and 6 cases of other diseases to determine their differences in distribution. In this study, the main targets were alveolar epithelial cells, especially those in the regenerating stage, as well as lymph vessels and stroma. The cytoplasm of type II alveolar epithelial cells and Clara cells was positive for SP-D, with sharp margins; interestingly, however, during the process of regeneration large positive cells were intermingled with relatively small negative cells, even in the same row of cells. In sharp contrast, staining for SP-A and KL-6 was positive in the cytoplasm of all the regenerating alveolar epithelial cells, as well as Clara cells. Staining for KL-6 was usually positive in the surface of air spaces in linear fashion. Staining for SP-A was also positive in elastic fibers in vascular walls. In areas of destruction of pulmonary structures, loose stroma and the endothelial cells of lymph vessels as well as their contents were distinctly positive for SP-A and/or KL-6 but not SP-D. Judging from these results in pulmonary tissues of CVD-IP and HP, SP-D might be a marker for maturity of regenerating epithelial cells. Both SP-A and KL-6 were detected in intimate relationship to the stage of regeneration of alveolar epithelial cells and were expressed before SP-D. In addition, the lymph vessels play a very important role in transfer of KL-6 into the bloodstream.