p=0.039). Although there was no significant correlation between serum adiponectin levels and AHI or %T<90, serum adiponectin levels were chosen at a determinant factor of %T<90. ConclusionThese results suggested that the increasing severity of OSAS induces an increase in setum leptin concentration, but the serum adiponectin levels may be regulated independently of the degree of OSAS, obesity and serum leptin levels in patients with OSAS.

Background: Peroxisome proliferator-activated receptor-γ (PPARγ) ligands have been shown to possess potent anti-inflammatory actions. Idiopathic interstitial pneumonia is defined as a specific form of chronic fibrosing lung disease characterized by progressive fibrosis which leads to deterioration and destruction of the lungs. Objective: To investigate whether the PPARγ ligand pioglitazone (PGZ) inhibited bleomycin (BLM)-induced acute lung injury and subsequent fibrosis. Methods: BLM was administered intratracheally to Wistar rats which were then treated with PGZ. Rat alveolar macrophages were stimulated with BLM for 6 h with or without PGZ pretreatment for 18 h. MRC-5 cells (human lung fibroblasts) were treated with PGZ for 18 h. After the treatment, the cells were stimulated with transforming growth factor- β (TGF-β) for 6 h. Results: PGZ inhibited BLM-induced acute lung injury and subsequent lung fibrosis when it was administered from day –7. PGZ treatment suppressed the accumulation of inflammatory cells in lungs and the concentration of tumor necrosis factor-α (TNF-α) in bronchoalveolar lavage fluid on day 3. PGZ also inhibited BLM-induced TNF-α production in alveolar macrophages. Furthermore, PGZ inhibited fibrotic changes and an increase in hydroxyproline content in lungs after instillation of BLM, even when PGZ was administered in the period from day 7 to day 28. Northern blot analyses revealed that PGZ inhibited TGF-β-induced procollagen I and connective tissue growth factor (CTGF) expression in MRC-5 cells. Conclusion: These results suggest that activation of PPARγ ameliorates BLM-induced acute inflammatory responses and fibrotic changes at least partly through suppression of TNF-α, procollagen I and CTGF expression. Beneficial effects of this PPARγ ligand on inflammatory and fibrotic processes open new perspectives for a potential role of PPARγ as a molecular target in fibroproliferative lung diseases.

Hypoxia is a potent inducer of tumor angiogenesis, the process of which is mostly mediated by induction of vascular endothelial growth factor (VEGF). In this study, we investigated the effect of hypoxia on the expression of hypoxia-inducible factor-1alpha (HIF-1alpha) and endothelial PAS domain protein-1 (EPAS1). These two similar but distinct basic helix-loop-helix-PAS proteins have been postulated to activate VEGF expression in response to hypoxia. We showed that EPAS1, but not HIF-1alpha, is abundantly expressed in human lung adenocarcinoma A549 cells. Exposure of cultured A549 cells to hypoxia increased EPAS1 mRNA and protein levels. A specific inhibitor for Src family kinases, PP1, abolished the hypoxia-induced expression of EPAS1. Transient transfection assays revealed that forced expression of EPAS1 increased the reporter gene activity driven by EPAS1 promoter as well as by VEGF promoter. Finally, overexpression of EPAS1 by infection of adenoviral vector expressing EPAS1 cDNA evidently induced the endogenous EPAS1 gene expression. Together, these data demonstrate Src family kinases mediate the hypoxia-mediated EPAS1 gene expression, which in turn positively autoregulates its own expression. Given an EPAS1 as a potent activator of the VEGF gene, these findings will provide a novel insight into the mechanisms underlying the enhancement of growth property of EPAS1-expressing tumor cells under the hypoxic environment.

Homozygous mutant klotho (KL(-/-)) mice exhibit multiple phenotypes resembling human aging. In the present study, we focused on examining the pathology of the lungs of klotho mice and found that it closely resembled pulmonary emphysema in humans both histologically and functionally. Histology of the lung of KL(-/-) mice was indistinguishable from those of wild-type littermates up to 2 wk of age. The first histologic changes appeared at 4 wk of age, showing enlargement of the air spaces accompanied by destruction of the alveolar walls, and progressed gradually with age. In addition to these changes, we observed calcium deposits in type I collagen fibers in alveolar septa and degeneration of type II pneumocytes in 8- to 10-wk-old KL(-/-) mice. Pulmonary function tests revealed prolonged expiration time in KL(-/-) mice, which is comparable with the pathophysiology of pulmonary emphysema. The expression level of messenger RNA for type IV collagen, surfactant protein-A and mitochondrial beta-adenosine triphosphatase was significantly increased in KL(-/-) mice, which may represent a compensatory response to alveolar destruction. Additionally, the heterozygous mutant klotho mice also developed pulmonary emphysema late in life, around 120 wk of age. These findings indicate that klotho gene expression is essential to maintaining pulmonary integrity during postnatal life. The klotho mutant mouse is a useful laboratory animal model for examining the relationship between aging and pulmonary emphysema.