T. Ishizuka

Clinicopathological and therapeutic significance of CXCL12 expression in lung cancer.

Interactions between CXCL12 and its receptors CXCR4 or CXCR7 are involved in tumor growth and metastasis in various types of human cancer. However, CXCL12 expression and its role in lung cancer are not fully elucidated. Here we examined the expression of CXCL12 in 54 lung cancer cell lines consisting of 23 small cell lung cancers (SCLCs) and 31 non-small cell lung cancers (NSCLCs). CXCL12 was overexpressed in lung cancer cell lines compared to non-malignant human bronchial epithelial cell lines (N = 6). CXCL12 expression was positively but weakly correlated with the expression of CXCR4 or CXCR7. We also examined CXCL12 expression in 89 NSCLC specimens and found that CXCL12 expression was significantly higher in tumor specimens from female patients, non-smokers and adenocarcinoma patients. Small interfering RNAs targeting CXCL12 inhibited cellular proliferation, colony formation and migration of CXCL12-overexpressing lung cancer cells; however, this inhibition did not occur in lung cancer cells that lacked CXCL12. Furthermore, the anti-CXCL12 neutralizing antibody mediated inhibitory effects in three lung cancer cell lines that overexpressed CXCL12, but not in two CXCL12 non-expressing lung cancer cell lines nor two non-malignant bronchial epithelial cell lines. The present study demonstrates that: CXCL12 is concomitantly overexpressed with CXCR4 or CXCR7 in lung cancers; CXCL12 is highly expressed in NSCLCs from females, non-smokers and adenocarcinoma patients; and disruption of CXCL12 inhibits the growth and migration of lung cancer cells. Our findings indicate that CXCL12 is required for tumor growth and provide a rationale for the anti-CXCL12 treatment strategy in lung cancer.

CXCR4+FOXP3+CD25+ Lymphocytes Accumulate in CXCL12-Expressing Malignant Pleural Mesothelioma

CXCL12 is a chemokine that binds to a G-protein-coupled receptor (CXCR4). CXCL12 is expressed in various tumors and is considered as playing an important role in tumor growth and invasion. The aim of this study is to investigate the expression of CXCL12 in human malignant mesothelioma (MM), the chemotactic effect of CXCL12 derived from MM, and the expression of CXCR4 in MM tissues in relation to regulatory T cells. CXCL12 expression was examined by immunostaining of tissue specimens from malignant pleural mesothelioma (MPM) and malignant peritoneal mesothelioma (MPEM). The MM group comprised 6 patients (4 men/2 women, MPM=4, MPEM=2, aged 56.0 ± 12.4 years) and the control (non-mesothelioma) group also had 6 patients (4 men/2 women aged 65.0 ± 6.7 years). CXCL12 mRNA expression was also examined by RT-PCR in MPM cell lines (H28, H2052, and H2058), while CXCR4 mRNA expression was examined by in situ hybridization in MPM tissue. CXCL12 was expressed in the cytoplasm of MM cells from all patients, but was not expressed in the control group. H2052 and H2058 cells expressed CXCL12 mRNA, but H28 cells did not. CXCL12 in MM tissue homogenate supernatant had a chemotactic effect on CXCR4-expressing THP-1 cells. CXCR4 mRNA was expressed by a part of LCA+CD3+ Foxp3+CD25+ T cells that were located adjacent to the border of CXCL12-expressing epithelioid MPM. These findings suggest that CXCL12 contributed to tumor-related inflammation by inducing the accumulation of CXCR4-expressing cells with regulatory T cell markers around MM.

Decreased interstitial FOXP3(+) lymphocytes in usual interstitial pneumonia with discrepancy of CXCL12/CXCR4 axis.

Regulatory T cells (Treg) play a critical role in immune homeostasis and expansion of Treg is controlled by chemokine receptors. The chemokine CXCL12 and its G-protein-coupled receptor (CXCR4) are involved in the development of idiopathic pulmonary fibrosis (IPF), but the association of Treg with the CXCL12/CXCR4 axis has not been documented. The aim of this study is to determine the distribution and extent of CXCL12/CXCR4 expression in idiopathic type of pulmonary fibrosis, and the relation of Treg expansion in the interstitium of pulmonary fibrosis patients to CXCL12/CXCR4 expression. CXCL12 expression was examined by immunostaining and ELISA in tissue specimens from patients with usual interstitial pneumonia (UIP, n=15), patients with fibrotic non-specific interstitial pneumonia (f-NSIP, n=4), and controls (n=6). CXCR4 expression was examined by in situ hybridization and immunoblotting. Expression of CD45, CD3, CD20, transcription factor forkhead box P3 (FOXP3), and CD25 was assessed by immunostaining. Fibrosis was evaluated by determining the established fibrosis (EF) score. The CXCL12/CXCR4 axis was upregulated in UIP and f-NSIP, and CXCL12 derived from lung tissue attracted CXCR4+ cells. CXCR4+ cells showed a CD3+ cell distribution pattern. The interstitial FOXP3+/CD3+ and CD25+/CD3+ cell ratios were lower in UIP than f-NSIP, but the CXCR4+/ CD3+ cell ratio was not different. The FOXP3+/CD3+ cell ratio and EF score were inversely correlated. These findings suggest that the CXCL12/CXCR4 axis contributes to inflammation in UIP and f-NSIP by promoting the accumulation CXCR4+ lymphocytes, and a decrease of Treg is correlated with the severity of fibrosis in UIP.

Acute impact of volcanic ash on asthma symptoms and treatment.

Information about the impacts of disasters on health is useful for establishing hazard prediction maps and action plans of disaster management. This study aims at learning effective asthma management from the volcano disaster of Mount Asama eruption in Japan on September 1, 2004. We conducted a cross-sectional study to assess the acute impact of volcanic ash on asthma symptoms and their treatment changes by using a questionnaire completed by 236 adult asthmatic patients and their physicians. In the ashfall over 100g/m2 area, 42.9% of asthma patients suffered exacerbations, PEF decreased, asthma treatments increased, and inhalation of β2 stimulants was used most for exacerbated asthma. Compared to severe asthma patients, mild and moderate asthma patients were most at risk. Severe asthma patients were not affected since most of them knew their asthma status was severe, and did not go outside and kept windows closed. Deteriorated asthma symptoms of wheezing, chest tightness and cough appeared in the ashfall over 100g/m2 area. Ash contained inhalable 10μm diameter particles, and included high concentrations of airway toxic substrates of silica. These data suggest that ashfall over 100 g/m2 is harmful, access to these areas by asthma patients needs to be restricted, and these areas need to improve asthma treatment. In addition, the increase in the proportion of asthma patients with wheeze and cough are diagnostic clues for ash-induced asthma in affected areas, and can be used by doctors to tell whether patients are receiving sufficient asthma treatment.

Analysis on the Co-Localization of Asbestos Bodies and Fas or CD163 Expression in Asbestos Lung Tissue by in-Air Micro-Pixe

To prevent and control diseases caused by exposure to various agents, it is necessary to determine the harmful level for intervention and to establish a method for measuring that level. In-air microparticle-induced X-ray emission (in-air micro-PIXE) analysis is based on irradiation of specimens with a proton ion microbeam, and has been modified for biological application. Two-dimensional analysis and quantitative analysis using the system confirmed that asbestos induced apoptosis by upregulating Fas expression and also revealed the accumulation of CD163-expressing macrophages in the lungs of patients with asbestosis. By quantitative comparison of the area of Fas or CD163 expression and the Fas- or CD163-negative area in asbestos lung tissue, the harmful levels which caused the expression of Fas or CD163 could be estimated on Silica, Ferrous iron, and Magnesium (the components of asbestos) deposition. These results indicate that the system could be useful for investigating the pathogenesis of inhaled particle-induced immune reactions and for determining harmful levels of exogenous agents.

Expectoration of bronchogenic tumour tissue

A 77-year-old man who smoked heavily was admitted to our hospital, complaining of haemoptysis. Transbronchial lung biopsy showed small-cell lung cancer (SCLC), stage T4N3M0.He achieved a partial response after four cycles of first-line chemotherapy, buthada recurrence and received second-linechemotherapy.After fourcyclesofchemotherapy,heagainhadrecurrenceof thetumourandacomputed tomography (CT) scan of the chest showed right hilar lymphadenopathy and a large subcarinalmediastinalmass (Fig. 1). Hewas treatedwith third-line chemotherapy, but developed stridor 4 days later. Chest radiograph was consistent with collapse of the right lower lobe (Fig. 2a). He had a paroxysm of coughing and expectorated a greyish red fragment of tissue measuring 3.0 cm 2.5 cm 1.0 cm (Fig. 3a). Histological examination of the expectorated tissue showed small-cell carcinoma (Fig. 3b). After expectoration of tumour tissue, the patient felt better and repeat chest X-ray indicated re-expansion of the right lung (Fig. 2b). A CT scan of the chest (not shown) showed a marked reduction in tumour bulk. He was generally well without any signs of recurrence after 1 year after the initial diagnosis of SCLC. The expectoration of lung tumours is extremely rare, with only 19 cases reported in the published work, comprising 5 cases of primary bronchogenic carcinoma and 14 cases of metastatic tumours from renal cell Images in Medicine

Hypoxemia with High Alveolar-Arterial Oxygen Gradient but no Lung Involvement in a Patient with Churg-Strauss Syndrome: Case Report:

Churg-Strauss syndrome (CSS) is characterized by asthma and/or a history of allergy, eosinophilia and an often life-threatening systemic necrotizing vasculitis. We describe a patient with CSS and hypoxemia with a high alveolar-arterial oxygen gradient (AaDO2), but no pulmonary parenchymal involvement. The patient also had a low diffusion capacity with normal lung volume and a high level of serum thrombomodulin, a marker of endothelial cell injury. Treatment for CSS, such as corticosteroid, improved both hypoxemia and AaDO2 consistent with amelioration of diffusion capacity and serum thrombomodulin level, suggesting that this pathosis involves microangiopathy with endothelial cell damage induced by vasculitis in pulmonary blood vessels.