Interstitial lung diseases (ILDs) are a diverse group of pulmonary disorders characterized by various patterns of inflammation and fibrosis in the interstitium of the lung. Because injury and/or regeneration of type II pneumocytes are prominent histological features of ILDs, substances derived from type II pneumocytes have been the focus of research investigating potential biomarkers for ILD. One important biomarker for ILD is the high-molecular-weight glycoprotein, Krebs von den Lungen-6 (KL-6). KL-6 is now classified as a human MUC1 mucin protein, and regenerating type II pneumocytes are the primary cellular source of KL-6/MUC1 in the affected lungs of patients with ILD. KL-6/MUC1 is detectable in the serum of patients with ILD, and extensive investigations performed primarily in Japan have revealed that serum KL-6/MUC1 is elevated in 70-100% of patients with various ILDs, including idiopathic interstitial pneumonias, collagen vascular disease-associated interstitial pneumonia, hypersensitivity pneumonia, radiation pneumonitis, drug-induced ILDs, acute respiratory distress syndrome, pulmonary sarcoidosis, and pulmonary alveolar proteinosis. The results from these various studies have supported the utility of KL-6/MUC1 as a serum biomarker for detecting these various ILDs. Moreover, KL-6/MUC1 serum levels have been demonstrated to be useful for evaluating disease activity and predicting the clinical outcomes of various ILD types. Based on these observations, we believe that KL-6/MUC1 is currently one of the best and most reliable serum biomarkers available for ILD management.

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Purpose: The aim of our study is to investigate the mechanism of metastasis, to detect novel metastasis-associated molecules, and to evaluate the molecules from the point of view of clinical application. A monoclonal antibody MH8-11, which we established, recognizes a glycoprotein that is identical to aminopeptidase N (APN/CD13). APN/CD13 degrades the extracellular matrix, while it is also involved in cell motility and improves angiogenesis. Experimental Design: We investigated the expression of APN/CD13 in 194 cases of non^small cell lung cancer (NSCLC) by immunohistochemical analyses and reverse transcription-PCR assay to determine the significance of this prognostic factor; 95 tumors were stage I, 36 were stage II, 39 were stage IIIA, and 24 were stage IIIB. Moreover, we investigated that the relationship between the expression of APN/CD13 and angiogenesis and prognosis for patients with NSCLC. Results: We found a correlation between the expression of APN/CD13 and angiogenesis (r = 0.659; P < 0.0001). In the 194 patients with NSCLC, we found 68 patients to be APN/ CD13+ and 126 patients to be APN/CD13À . The 5-year survival rate in patients with APN/CD13 + tumors was significantly lower than in those whose tumors had negative APN/CD13 (48.3% versus 67.1%; P = 0.0001). Conclusion: Our data suggest the expression of APN/CD13 for patients with NSCLC to be associated with a poor prognosis and angiogenesis.This is the first study to show the relationship between the expression of APN/CD13 and the prognosis of patients with NSCLC. The inhibition of APN/CD13 may be an effective new molecular target therapy for patients with NSCLC.

Smokers with airflow limitation had exaggerated subclinical atherosclerosis. This study suggests that middle-aged men who are susceptible to COPD may also be susceptible to vascular atherosclerosis by smoking, and atherosclerotic change starts early in the disease process of COPD.

Baseline serum KL-6 level is a sensitive predictor for the onset of AE in IPF.

SummaryFlow cytometric and immunocytochemical analyses of murine fetal thymus (FT) cells with antibodies to various surface markers and transcription factors reveal that the synthesis of TCF-1 and GATA-3 proteins begins simultaneously in a fraction of the most immature population of FT cells, which have the phenotype of CD4-CD8-CD44+CD25 -. No TCF-l-producing cell is found in the fetal liver (FL). In CD44+CD25 -FT cells, the production of TCF-1 is immediately followed by intracellular expression of CD3e. It is also found that the T cell development from FL, but not FT, progenitors in the FT organ culture system is severely inhibited by the addition ofantisense oligonucleotides for either TCF-1 or GATA-3. These results strongly suggest that TCF-1 and GATA-3 play essential roles in the initiation of the earliest steps of T cell development in the thymus.T cells are produced mainly in the thymus from progenitors emigrated from extrathymic hematopoietic organs (1-3), although it is still controversial whether these progenitors are prethymically committed to give rise to lymphocytes or T cells (2-4). In the murine fetuses, it is known that progenitors derived from fetal liver (FL) / or other fetal hematopoietic organs colonize the thymus around day 11 of gestation (5, 6), and that the differentiation and growth of T cells from these progenitors are induced or supported by the thymic microenvironment (7). The mechanisms of TCR gene rearrangement and the interaction of maturing T cells with the thymic microenvironment through TCR., so-called positive and negative selection, are becoming clearer (8, 9). On the other hand, our knowledge about the earlier stages, during which the TCR and coreceptors CD4 and/or CD8 have not yet been expressed on the cell surface, is still fragmental.T lineage cells in the fetal thymus (FT) that are negative for CD4 and CD8 can be divided into four subpopulations on the basis of CD44 and CD25. These are CD44 + CD25-, CD44+CD25 +, CD44-CD25 +, and CD44-CD25-, and it is well known that the differentiation proceeds in this order (10, 11). It has been shown that progenitors capable of generating B and myeloid cells are present IAbbreviations used in this paper: AGPC, acid guanidinium thiocyanatephenol-chloroform; AS, antisense; dGuo, deoxyguanosine; FL, fetal liver; FT, fetal thymus; HOS, high oxygen submersion; IC, intracellular; Lin, lineage markers; KT, reverse transcription; S, sense. in fetal as well as adult thymuses (12-15). These B and myeloid progenitors have not been well characterized, and it is unclear whether thymic B and myeloid cells are derived from a common progenitor or stem cell that is also able to generate T cells. In the murine fetus, the presence of B and myeloid progenitors has been shown in the FT at day 12 of gestation (15), and the phenotype of day 12 FT is exclusively CD44+CD25 -(16). On the other hand, progenitors in the CD44+CD25 + population of FT, which is equivalent to the c-kit+CD25 + population, are committed to T lineage (17). With adult thymocytes, it has be...

Background and aim There is a growing body of evidence demonstrating that plasminogen activator inhibitor-1 (PAI-1) is involved in the progression of pulmonary fibrosis. In fact, PAI-1 knockout mice are protected from bleomycin-induced pulmonary fibrosis. This study was conducted to determine whether the intrapulmonary administration of small interfering RNA (siRNA) targeting PAI-1 (PAI-1-siRNA) limits the development of bleomycin-induced pulmonary fibrosis. Methods Lung biopsies from patients with idiopathic pulmonary fibrosis (IPF) were stained for PAI-1. The distribution of siRNA in the lung, the PAI-1 level in bronchoalveolar (BAL) fluid and the extent of fibrotic changes in the lung were evaluated following the intranasal administration of PAI-1-siRNA in a mouse model of bleomycin-induced pulmonary fibrosis. The effect of PAI-1-siRNA on the epithelial to mesenchymal transition (EMT) was also evaluated using a mouse lung epithelial cell line, LA-4. Results PAI-1 was overexpressed in the hyperplastic type 2 pneumocytes lining the honeycomb lesions of patients with IPF. The single intranasal instillation of PAI-1-siRNA resulted in the diffuse uptake of siRNA into the epithelial cells lining the dense fibrotic lesions. The repeated administration of PAI-1-siRNA initiated during either the inflammatory or the fibrotic phase into bleomycin-injured mice reduced the PAI-1 level in BAL fluid and limited the accumulation of collagen in the lungs. EMT induced by transforming growth factor b (TGFb) in LA-4 cells was inhibited by transfection with PAI-1-siRNA. Conclusions The direct suppression of PAI-1 in the lung by the intrapulmonary administration of PAI-1-siRNA attenuated the development and progression of pulmonary fibrosis. The inhibition of EMT may be, at least in part, involved in this effect.