Masaki Tominaga

Serum level of periostin can predict long-term outcome of idiopathic pulmonary fibrosis

BACKGROUND KL-6 and surfactant proteins A and D are the only established serum biomarkers of idiopathic pulmonary fibrosis (IPF). We have previously shown that serum levels of periostin, a unique matricellular protein, are elevated and correlated with pulmonary function in patients with IPF. We sought to determine whether the serum periostin levels correlate with overall survival (OS) and time-to-event (TTE), as a parameter reflecting long-term outcome, and with the extent of abnormality on chest high-resolution computed tomography (HRCT) scores in patients with IPF. METHODS Twenty-nine patients with IPF were analyzed retrospectively. The mean observation period was 1035.2 ± 663.1 days (range, 112-1800 days). High-resolution computed tomography (HRCT) scores were calculated based on the extent of abnormality evidenced by HRCT. We evaluated if there were any correlations between the serum periostin levels and clinical parameters, including HRCT score, using Spearmans rank correlation coefficients and analyzed predictors of OS and TTE using the log-rank tests. RESULTS We showed that the serum periostin levels significantly correlated with the increase of honeycombing score on HRCT during a 6-month period. Log-rank tests showed that a higher serum periostin level was a predictor of a shortened OS and TTE. Greater extents of fibrotic lesions on HRCT scan were predictors of shortened OS and TTE. CONCLUSIONS In IPF patients, the serum periostin level may be a good predictive biomarker for an increase in the radiological fibrotic area and long-term outcome.

IL-38: A new factor in rheumatoid arthritis

The newly characterized cytokine IL-38 (IL-1F10) belongs to the IL-1 family of cytokines. Previous work has demonstrated that IL-38 inhibited Candida albicans-induced IL-17 production from peripheral blood mononuclear cells. However, it is still unclear whether IL-38 is an inflammatory or an anti-inflammatory cytokine. We generated anti-human IL-38 monoclonal antibodies in order to perform immunohistochemical staining and an enzyme-linked immunosorbent assay. While human recombinant IL-38 protein was not cleaved by recombinant caspase-1, chymase, or PR3 in vitro, overexpression of IL-38 cDNA produced a soluble form of IL-38 protein. Furthermore, immunohistochemical analysis showed that synovial tissues obtained from RA patients strongly expressed IL-38 protein. To investigate the biological role of IL-38, C57BL/6 IL-38 gene-deficient (−/−) mice were used in an autoantibody-induced rheumatoid arthritis (RA) mouse model. As compared with control mice, IL-38 (−/−) mice showed greater disease severity, accompanied by higher IL-1β and IL-6 gene expression in the joints. Therefore, IL-38 acts as an inhibitor of the pathogenesis of autoantibody-induced arthritis in mice and may have a role in the development or progression of RA in humans.

Association of anti-aminoacyl-transfer RNA synthetase antibody and anti-melanoma differentiation-associated gene 5 antibody with the therapeutic response of polymyositis/dermatomyositis-associated interstitial lung disease

BACKGROUND We attempted to clarify whether the presence of anti-aminoacyl-transfer RNA synthetase antibody (anti-ARS Ab) or anti-melanoma differentiation-associated gene 5 antibody (anti-MDA5 Ab) is associated with the therapeutic response of polymyositis/dermatomyositis-associated interstitial lung disease (PM/DM-ILD). METHODS We retrospectively investigated 22 patients with PM/DM-ILD (10 positive for anti-ARS Ab and nine positive for anti-MDA5 Ab) for whom antibody analysis of conserved serum was possible. We assessed mortality in the first three months as the therapeutic response in the acute phase and compared changes in clinical data for up to one year considered as the chronic phase. We classified the clinical changes over the year into three groups: Improvement (increased % vital capacity [%VC] or diffusing capacity of the lung for carbon monoxide [%DLCO]≥10 or 15%), deterioration (decreased %VC or %DLCO≥10 or 15%), and no change (remainder of the changes). The extent of abnormality demonstrated by high-resolution computed tomography (HRCT) was scored. RESULTS Positivity for anti-MDA5 Ab, but not for anti-ARS Ab, was associated with mortality in the first 3 months. Evaluation of the therapeutic response in the first year showed that positivity for the anti-ARS Ab, but not for the anti-MDA5 Ab, was associated with an improvement in %DLCO and a decline in the serum KL-6 levels. Positivity for the anti-ARS Ab or negativity for anti-MDA5 Ab was associated with a greater decrease in bronchial dilatation as seen by HRCT. CONCLUSIONS Anti-ARS and anti-MDA5 Abs are associated with the therapeutic response of PM/DM-ILD.

Overexpression of IL-38 protein in anticancer drug-induced lung injury and acute exacerbation of idiopathic pulmonary fibrosis

BACKGROUND Interleukin (IL)-38, a member of the IL-1 family, shows high homology to IL-1 receptor antagonist (IL-1Ra) and IL-36 receptor antagonist (IL-36Ra). Its function in interstitial lung disease (ILD) is still unknown. METHODS To determine the expression pattern of IL-38 mRNA, a panel of cDNAs derived from various tissues was analyzed by quantitative real-time PCR. Immunohistochemical reactivity with anti-human IL-38 monoclonal antibody (clone H127C) was evaluated semi-quantitatively in lung tissue samples from 12 patients with idiopathic pulmonary fibrosis/usual interstitial pneumonia (IPF/UIP), 5 with acute exacerbation of IPF, and 10 with anticancer drug-induced ILD (bleomycin in 5 and epidermal growth factor receptor-tyrosine kinase inhibitor in 5). Control lung tissues were obtained from areas of normal lung in 22 lung cancer patients who underwent extirpation surgery. RESULTS IL-38 transcripts were strongly expressed in the lung, spleen, synoviocytes, and peripheral blood mononuclear cells, and at a lower level in pancreas and muscle. IL-38 protein was not strongly expressed in normal pulmonary alveolar tissues in all 22 control lungs. In contrast, IL-38 was overexpressed in the lungs of 4 of 5 (80%) patients with acute IPF exacerbation and 100% (10/10) of the patients with drug-induced ILD. IL-38 overexpression was limited to hyperplastic type II pneumocytes, which are considered to reflect regenerative change following diffuse alveolar damage in ILD. CONCLUSIONS IL-38 may play an important role in acute and/or chronic inflammation in anticancer drug-induced lung injury and acute exacerbation of IPF.

A case of multiple pulmonary cavernous hemangioma.

A 61‐year‐old male who originally visited a different hospital, underwent a health checkup in which multiple lung nodules were detected. Multiple well‐defined small nodules were observed in both lungs, with lesions reaching the arteries. Metastatic lung cancer, with unknown origin, was suspected. A computed tomography‐guided percutaneous lung biopsy was performed; however, a pathological diagnosis could not be established. Then the patient was referred to our hospital for surgical lung biopsy. Macroscopically, the nodule was dark‐red in color and solid without a capsule. Microscopically, the nodule was composed of dilated vascular spaces lined by flattened bland cells. They were positive for CD34, but were negative for TTF‐1, consistent with lesions of endothelial origin. Microscopic and immunohistochemical findings supported the diagnosis of multiple pulmonary cavernous hemangiomas. After diagnosis, the lesions were left untreated and thereafter showed no signs of deterioration.

Clinical implications of the novel cytokine IL-38 expressed in lung adenocarcinoma: Possible association with PD-L1 expression

Interleukin (IL)-38, a novel member of the IL-1 cytokine family, is homologous to IL-1 receptor antagonist (IL-1Ra) and IL-36Ra, and has been reported to act as an antagonist. IL-38 expression is found in tonsil, placenta, and spleen, and recent studies suggest an association between IL-38 and autoimmune diseases. However, whether IL-38 plays a role in carcinogenesis or cancer growth is unclear. In the present study, we identified increases in IL-38 expression by immunohistochemistry in multiple types of cancer cells. In the examination of 417 surgically resected primary lung adenocarcinomas, Fisher’s exact tests showed significant associations between high IL-38 expression and high tumor grades, an advanced T status, advanced N status, advanced stage, and the presence of pleural and vessel invasions. Survival analyses by the Kaplan-Meier method showed that patients with high expression of IL-38 had significantly shorter disease-free survival and shorter overall survival after surgery than patients with low expression of IL-38 (log-rank test: P = 0.0021 and P = 0.0035, respectively). Moreover, programmed cell death-ligand 1 (PD-L1)-positive cases showed higher expression of IL-38 than PD-L1-negative cases (Wilcoxon rank-sum test: P < 0.0001). In conclusion, IL-38 was expressed in tumor cells of various cancers, and IL-38 expression was associated with poor survival of lung adenocarcinoma patients. IL-38 may affect host immunity or the tumor microenvironment, and contribute to the progression of lung adenocarcinoma.

A Case of Dental Technicians' Pneumoconiosis

A 40-year-old female dental technician visited our hospital for the investigation of a chest X-ray abnormality. Chest computed tomography demonstrated centrilobular nodules and lung volume reduction, and her serum KL-6 level was elevated. A histological analysis of the specimens obtained on a surgical lung biopsy showed peribronchiolar fibrosis with pigmented macrophages and cholesterol clefts. An energy-dispersive X-ray analysis showed that these lung tissues contained some metals, including indium. The serum indium level was also elevated. We diagnosed this patient with pneumoconiosis caused by exposure to sandblasting certain dental metals. This is the first reported case of pneumoconiosis in a dental technician associated with exposure to indium.

A case of lipoid pneumonia caused by inhalation of vaporized paraffin from burning candles

A 66-year-old woman was referred to our hospital for investigation of interstitial lung disease. She had spent most of her time in a shrine, and had always been exposed to vaporized paraffin from burning candles. Chest High-resolution computed tomography (HRCT)showed ground-glass attenuation with thickening of septal lines, wh create the so-called “crazy-paving appearance”. Although bronchoalveolar lavage(BAL) and transbronchial biopsy were performed to aid in diagnosis, the findings did not reveal any conclusive information. Improvements on chest radiographs and in the patients symptoms were observed without any therapeutic intervention; however, one year later, her chest X-ray showed deteriorative changes. Surgical lung biopsy was performed, and the pathological findings were consistent with those of lipoid pneumonia. The patient showed spontaneous remission of the disease. The cause of exogenous lipoid pneumonia was attributed to inhalation of vaporized paraffin from burning candles in the shrine. This is the first case of lipoid pneumonia that was found to develop from exposure to vaporized paraffin.

An Autopsy Case of Anti-melanoma Differentiation-associated Gene-5 Antibody-positive Clinical Amyopathic Dermatomyositis Complicated by Rapidly Progressive Interstitial Lung Disease

A 62-year-old man presented with heliotrope rash, Gottrons sign, and mild muscle weakness. Both of his lung fields showed interstitial changes that worsened rapidly. He was diagnosed with clinical amyopathic dermatomyositis with rapidly progressive interstitial lung disease. The patient died of respiratory failure, despite the administration of immunosuppressive therapy. Autopsy revealed diffuse alveolar damage. An antibody analysis, which was performed postmortem, detected the presence of anti-melanoma differentiation-associated gene (MDA)-5 antibodies. Clinicians should note the clinical, radiologic, and serologic findings to predict anti-MDA-5 antibody-associated rapidly progressive interstitial lung disease.

Successful treatment of a patient with chyluria due to lymphangioleiomyomatosis using sirolimus

Lymphangioleiomyomatosis (LAM) is a rare and progressive neoplastic disease of young woman, characterized by the proliferation of abnormal smooth muscle-like cells (LAM cells) in the lungs and axial lymphatics. A 44-year-old woman was referred to our hospital because pleural effusion was detected during a health checkup. She had chylothorax, chylous ascites, and chyluria, and her computed tomography scan showed a solid tumor in the pelvis. Surgical biopsy was performed; she was diagnosed as having LAM. We could not control the fluid collection and chyluria using standard medical treatments. Therefore, we chose to administer sirolimus, and her symptoms dramatically improved. The mechanism of chyluria presumably involved LAM cell infiltrates in the ureter via the lymphatic vessel flow, which causes LAM to develop because of ureter wall exposure.