Serum B cell-activating factor (BAFF) level in connective tissue disease associated interstitial lung disease.

BACKGROUND: Interstitial lung diseases (ILDs) are common in patients with connective tissue diseases (CTDs). Although the diagnosis of an underlying CTD in ILD (CTD-ILD) affects both prognosis and treatment, it is sometimes difficult to distinguish CTD-ILD from chronic fibrosing interstitial pneumonia (CFIP). B cell-activating factor belonging to the tumour necrosis factor family (BAFF) plays a crucial role in B cell development, survival, and antibody production. METHODS: We examined serum levels of BAFF, surfactant protein D (SP-D), and Krebs von den Lungen-6 (KL-6) in 33 patients with CTD-ILD, 16 patients with undifferentiated CTD-ILD, 19 patients with CFIP, and 26 healthy volunteers. And we analysed the relationship between serum BAFF levels and pulmonary function, as well as the expression of BAFF in the lung tissue of patients with CTD-ILD. RESULTS: Serum levels of BAFF were significantly higher in CTD-ILD patients compared to healthy subjects and CFIP patients. However, there were no significant differences in serum levels of SP-D and KL-6. Furthermore, serum BAFF levels in CTD-ILD patients were inversely correlated with pulmonary function. BAFF was strongly expressed in the lungs of CTD-ILD patients, but weakly in normal lungs. DISCUSSION: This is the first study to demonstrate that serum BAFF levels were significantly higher in CTD-ILD patients compared to healthy subjects and CFIP patients. Furthermore, serum BAFF levels were correlated with pulmonary function. We consider that serum BAFF levels in patients with CTD-ILD reflect the presence of ILDs disease activity and severity. CONCLUSION: These finding suggest that BAFF may be a useful marker for distinguishing CTD-ILD from CFIP.

Considerations on the mechanisms of alveolar remodeling in centriacinar emphysema.

Chronic obstructive pulmonary disease is mainly characterized by irreversible airflow limitation, and its major pathological change is alveolar destruction and enlargement, which induces emphysema. In this study, we used stereoscopic microscopy to observe the cut surfaces of 21 surgically resected or autopsied lungs showing centriacinar emphysema. We identified columnar structures of various sizes in the cystic spaces. These columnar structures constituted two types: one that was associated with pulmonary artery and another that was not. We examined these structures in detail by light microscopy and performed statistical analyses. Columnar structures without pulmonary artery showed destruction and accumulation of alveoli, including abnormally aggregated elastic fibers. In contrast, pulmonary architecture was preserved in columnar structures with pulmonary artery. In columnar structures without pulmonary artery, statistically significant correlations were observed between the thickness of columnar structures and size of centriacinar cystic spaces and between the thickness of columnar structures and aggregation of elastic fibers in columnar structures. Electron microscopy showed that the columns were composed of aggregated elastic fibers, collagen fibers, mesenchymal cells, pigmented macrophages, and the alveolar epithelial cells covering them. Immunohistochemistry showed that the aggregated elastic fibers were positive for alpha-1 antitrypsin. We concluded that columnar structures without pulmonary artery are a hallmark of alveolar wall destruction seen in pulmonary emphysema.

Clinical and pathological findings of interstitial lung disease patients with anti-aminoacyl-tRNA synthetase autoantibodies.

OBJECTIVE: The aim of this study was to investigate the clinicopathological characteristics of interstitial lung disease (ILD) patients with anti-aminoacyl-tRNA synthetase (anti-ARS) autoantibodies. Patients and Methods We examined 14 ILD patients with anti-ARS autoantibodies between 2004 and 2007 and retrospectively investigated their clinical, radiographic, and pathological findings. RESULTS: Anti-Jo-1 antibodies were the most common (10 of 14), followed by anti-OJ, anti-KS, and anti-EJ (1 each for 3 patients); 1 patient with polymyositis had both anti-Jo-1 and anti-PL-12 antibodies. Ten patients had a chronic clinical course, whereas 4 presented with subacute deterioration. Of 8 patients with myositis, 1 (12.5%) had myositis-preceding ILD, 3 (37.5%) had ILD-preceding myositis, and 4 (50%) had simultaneous onset. Chest high-resolution computed tomography frequently showed lung-base predominant ground glass opacities (GGO) with volume loss. The results of surgical lung biopsies indicated that 4 patients had nonspecific interstitial pneumonia (NSIP) and/or organizing pneumonia (OP) patterns. All but 1 received corticosteroid therapy, and 6 patients were also given cyclosporin. The mean duration of follow-up was 22 months (range, 5-47 months). ILD improved in 9 patients and stabilized in 3; however, in 1 patient, it initially improved during 6 months, then progressively worsened despite treatment, and finally resulted in death. CONCLUSION: These results indicate that ILD patients with anti-ARS antibodies usually have a chronic clinical course, lung-base predominant GGO with volume loss, NSIP and/or OP patterns, and a good response to corticosteroid treatment; however, some have a rapidly worsening course and recurrence, despite therapy.

Two forms of diffuse alveolar damage in the lungs of patients with acute respiratory distress syndrome.

Acute respiratory distress syndrome is a severe disease, the treatment and pathophysiology of which are not completely established. The pathology of acute respiratory distress syndrome involves diffuse alveolar damage, which comprises severe alveolar epithelial cell damage, hyaline membrane formation, and festinate myofibroblast proliferation and fibrosis in the intra-alveolar spaces. We performed a clinicopathologic investigation of 26 autopsy cases of diffuse alveolar damage. Three cases of them were diagnosed as acute interstitial pneumonia that is idiopathic illness and resembles pathologically organizing diffuse alveolar damage. Immunohistochemical staining for types I and IV collagen, alpha-smooth muscle actin, and Ki-67 was carried out, and the sites of myofibroblast proliferation and type I collagen production were examined. All diffuse alveolar damage cases in the proliferative phase showed intra-alveolar myofibroblast proliferation. When diffuse alveolar damage was diagnosed pathologically as being due to severe infection, all 7 patients showed multiple organ dysfunction syndrome, whereas only 2 of 7 patients showed interstitial myofibroblast proliferation. When diffuse alveolar damage was attributed to tumor treatment with chemotherapy or to drug toxicity, 3 of 16 patients showed multiple organ dysfunction syndrome; 15 of 16 showed interstitial myofibroblast proliferation, 3 of 3 acute interstitial pneumonia patients did not show multiple organ dysfunction syndrome; and 3 of 3 acute interstitial pneumonia showed marked interstitial myofibroblast proliferation. These results suggest that the pathophysiologic mechanism of diffuse alveolar damage caused by severe infection is one of systemic circulation disturbance, although the mechanism underlying diffuse alveolar damage due to tumor with chemotherapy or drug toxicity appears to involve interstitial pneumonia-like lesions that are similar to acute interstitial pneumonia.

[Two lung adenocarcinoma patients with multiple brain metastasis treated with Gefitinib and surviving more than 2 years].

Case 1 is a 78-year-old woman in whom lung adenocarcinoma with multiple brain metastasis (cT2N3M1, stage IV) was diagnosed. She was treated with Gefitinib alone. Her lung tumor and metastatic brain lesions decreased 6 months after the start of therapy. She has no recurrence and is still alive with a good performance status after 25 months. Case 2 is an 80-year-old woman in whom lung adenocarcinoma with multiple brain (cT2N3M1, stage IV) was diagnosed. She was also treated with Gefitinib alone and her lung tumor and metastatic brain becomes improved 6 months after the start of therapy. She maintained a good performance status for more than 2 years (29 months). However, 29 months after beginning treatment, she had recurrence in bone and died 2 months later, 31 months after the start of therapy. The prognosis of non-small cell lung cancer with multiple brain metastasis is very poor and the efficacy of chemotherapy for the treatment of multiple brain metastases is limited, and longterm survival remains disappointing. We report two lung adenocarcinoma patients with multiple brain metastasis who survived more than 2 years by treatment with Gefitinib alone.

[A case of bronchiolitis obliterans syndrome successfully treated by Tiotropium bromide].

A 48-year-old woman was admitted with dyspnea on effort. She suffered from adult T-cell leukemia and received peripheral blood stem cell transplantation (PBSCT). Eight months after the PBSCT, she developed dyspnea on effort and was treated with bronchodilator, inhaled corticosteroid, anti-leukotriene drug, theophylline and oxytropium bromide. However her symptoms progressed and she was admitted. We diagnosed bronchiolitis obliterans syndrome (BOS) because of obstructive pulmonary dysfunction, diffuse patchy high density of the lung field on chest computed tomography and decreased ventilation with peripheral patchy accumulation on ventilation scintigraphy. She was treated with corticosteroid and cyclosporine A and her symptoms and her pulmonary function were improved. However, in parallel with corticosteroid tapering, her symptoms and pulmonary functions worsened. Treatment with Tiotropium bromide was started and her pulmonary function improved significantly. Her pulmonary function did not worsen and tapering steroid dose was successfully achieved. PBSCT was reported to up-regulate the muscarinic receptor activity in lung. Tiotropium bromide might become one additional option for the treatment of BOS.

Hermansky-Pudlak syndrome with a novel mutation.

We report a case of Hermansky-Pudlak syndrome (HPS) with a novel mutation in the HPS1 gene. This case showed oculocutaneous albinism and lysosomal ceroid accumulation, however platelet dysfunction was not observed. Histopathological findings of the biopsied lung tissue were compatible with HPS. Sequencing analysis showed the insertion of C in the codon 178 (739 bp) of the HPS1 gene forming a stop codon at codon 181. To the best of our knowledge, this is a novel HPS1 gene mutation.

TNF-related apoptosis-inducing ligand is involved in neutropenia of systemic lupus erythematosus.

Neutropenia is a common laboratory finding in systemic lupus erythematosus (SLE). However, the molecular mechanism of SLE neutropenia has not been fully explained. In this study, we examined whether TNF-related apoptosis-inducing ligand (TRAIL) is involved in the pathogenesis of SLE neutropenia using samples from SLE patients. Serum TRAIL levels in SLE patients with neutropenia were significantly higher than those of SLE patients without neutropenia and healthy volunteers. Serum TRAIL levels showed a significant negative correlation with neutrophil counts in SLE patients. The expression of TRAIL receptor 3 was significantly lower in SLE patients with neutropenia than in patients without neutropenia or in healthy volunteers. Treatment with glucocorticoids negated the decrease of TRAIL receptor 3 expression on neutrophils of SLE patients. TRAIL may accelerate neutrophil apoptosis of neutrophils from SLE patients, and autologous T cells of SLE patients, which express TRAIL on surface, may kill autologous neutrophils. Interferon gamma and glucocorticoid modulated the expression of TRAIL on T cells of SLE patients and also modulated the expression of cellular Fas-associating protein with death domain-like interleukin-1 beta-converting enzyme (FLICE)-inhibitory protein (cFLIP), an inhibitor of death receptor signaling, in neutrophils. Thus, our results provide a novel insight into the molecular pathogenesis of SLE neutropenia.

[Intense 18F-fluorodeoxyglucose uptake caused by pulmonary Mycobacterium intracellulare infection].

A 70-year-old woman was admitted to our hospital for the evaluation of a pulmonary nodule in the left S5 segment. On 18F-fluorodeoxyglucose positron emission tomography (18FDG-PET), the nodule showed substantial uptake of 18F-fluorodeoxyglucose. Bronchoscopy was performed, but the cytology was negative. For a pathological diagnosis, a lung biopsy was carried out using video-associated thoracoscopy. The biopsy specimen showed granuloma formation with multinuclear giant cells. An acid-fast bacteria culture of the specimen was positive for Mycobacterium intracellulare. An atypical mycobacterium infection should be considered as a possibility when the 18FDG-PET of patients with pulmonary nodules is interpreted.