N epsilon-(hexanoyl) lysine, a new oxidative stress marker, is increased in metabolic syndrome, but not in obstructive sleep apnea.

BACKGROUND: It is well known that oxidative stress is induced by metabolic syndrome (MetS), leading to cardiovascular diseases. On the other hand, obstructive sleep apnea syndrome (OSAS) is frequently complicated with MetS, and OSAS is also considered to induce oxidative stress. Thus, we examined the plasma and urine markers of oxidative stress and antioxidant status in patients with OSAS with or without MetS. METHODS: Sixty-nine Japanese men suspected of having OSAS were recruited. We divided all patients into 3 groups: nonobese patients, obese patients without MetS, and patients with MetS. Oxidative stress markers, plasma and urine 8-hydroxydeoxyguanosine (8-OHdG) and plasma N epsilon-(hexanoyl) lysine (HEL), and an antioxidant status marker, plasma total antioxidant status, were measured by enzyme-linked immunosorbent assay. RESULTS: The plasma HEL level was significantly increased in patients with MetS, whereas neither plasma and urine 8-OHdG levels nor plasma total antioxidant status level was different in patients with MetS. Furthermore, the plasma HEL level was significantly and positively correlated with fasting plasma glucose, serum insulin, and homeostasis model assessment-insulin resistance index in all subjects. CONCLUSIONS: The oxidative stress is strongly associated with the presence of MetS but not related to the presence or severity of OSAS. Furthermore, we demonstrated that the plasma concentration of HEL is a more sensitive biomarker of oxidative stress in patients with MetS than the plasma and urine levels of 8-OHdG.

Pioglitazone, a peroxisome proliferator-activated receptor gamma ligand, suppresses bleomycin-induced acute lung injury and fibrosis.

BACKGROUND: Peroxisome proliferator-activated receptor-gamma (PPARgamma) 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 PPARgamma 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- beta (TGF-beta) 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-alpha (TNF-alpha) in bronchoalveolar lavage fluid on day 3. PGZ also inhibited BLM-induced TNF-alpha 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-beta-induced procollagen I and connective tissue growth factor (CTGF) expression in MRC-5 cells. CONCLUSION: These results suggest that activation of PPARgamma ameliorates BLM-induced acute inflammatory responses and fibrotic changes at least partly through suppression of TNF-alpha, procollagen I and CTGF expression. Beneficial effects of this PPARgamma ligand on inflammatory and fibrotic processes open new perspectives for a potential role of PPARgamma as a molecular target in fibroproliferative lung diseases.

Serum levels of adipocytokines, adiponectin and leptin, in patients with obstructive sleep apnea syndrome.

OBJECTIVE: Obstructive sleep apnea syndrome (OSAS) is frequently complicated by metabolic syndrome, including diabetes and hypertension. Both OSAS and metabolic syndrome are strongly associated with obesity. Recently, adiponectin and leptin, which are secreted by adipose tissue, have been considered to play important roles in the progression of these diseases. Thus, to examine the association between leptin, adiponectin and OSAS, we measured the serum level of these adipocytokines in the same OSAS patients. METHODS AND PATIENTS: Sixty-eight consecutive Japanese men, who recorded all-night polysomnography, were enrolled in this study, and were divided into three groups, control (n=15), moderate OSAS (n=21) and severe OSAS (n=32). We measured serum levels of adiponectin and leptin by ELISA. RESULTS: Serum leptin levels were positively correlated with apnea hypopnea index (AHI) (r=0.552, p<0.001), the percentage of time with less than 90% hemoglobin saturation level in total sleep time (%T<90) (r=0.399, p<0.001) and body mass index (BMI) (r=0.807, p<0.0001). These parameters were suggested as the determinant factor for the serum leptin level by stepwise multiple regression analysis. On the other hand, serum adiponectin levels showed a positive correlation with age (r=0.361, p=0.005) and HDL-cholesterol level (r=0.274, 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. CONCLUSION: These 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.

[A case of racemose hemangioma of a bronchial artery complicated with atrial septal defect and localized peripheral ground-glass opacity].

We report a case of racemose hemangioma of the right bronchial artery complicated with an atrial septal defect (ASD) and ground-glass opacity localized in the right upper lung lobe. A 42-year-old woman was admitted for the pre-operative assessment of ASD. Aortography and selective angiography revealed that the right bronchial artery was markedly dilated and convoluted, draining into the right intercostal arteries and the right upper pulmonary vein. The patient was suffering from exertional dyspnea, but produced no bloody sputum. Since videobronchoscopy showed normal mucosal findings without bronchiectasis, primary racemose hemangioma of the right bronchial artery was diagnosed, and was treated by ligation of the bronchial artery and patch-closure of the ASD. The ground-glass opacity observed preoperatively in the periphery of the right upper lung lobe vanished after surgery. This opacity was considered to have been localized pulmonary congestion due to augmented hydrostatic pressure in the right upper pulmonary vein, induced by increased pulmonary blood flow through the ASD and the drainage route of the racemose bronchial artery into right upper pulmonary vein.

Increased serum thymidine kinase activity in acute sarcoidosis.

This is the first case report of acute sarcoidosis with increased serum thymidine kinase (TK) activity. A 43-year-old male presented fever, swelling of parotid glands, lymphadenopathy, and peripheral neuropathy. Sarcoidosis was pathologically diagnosed by lung and parotid gland biopsy. His serum TK, which was increased to 11.2 U/l at diagnosis (normal <5 U/l), normalized after glucocorticoid therapy. Serum TK has been considered as a good marker of the proliferative activity of various types of neoplasms. Its rise in sarcoidosis has, however, not been described. Because acute sarcoidosis sometimes resembles malignant lymphoma, the possible rise of serum TK in sarcoidosis may be worthy of note.

Stimulation of vascular endothelial growth factor gene transcription by all trans retinoic acid through Sp1 and Sp3 sites in human bronchioloalveolar carcinoma cells.

In this study, we examined the effects of all trans-retinoic acid (at-RA) on the vascular endothelial growth factor (VEGF) expression in human bronchioloalveolar carcinoma NCI-H322 cells to evaluate the potential of at-RA to affect tumor progression. Northern blot and enzyme-linked immunosorbent assay analyses indicate that VEGF production is significantly increased by 1 microM of at-RA. A series of 5'-deletion and site-directed mutation analyses indicated that G+C-rich sequence located at -81 and -52 was required for at-RA- and retinoic acid receptor alpha-mediated induction of VEGF promoter. Electrophoretic mobility shift and supershift assays showed that major constituents of nuclear factors binding to G+C-rich sequences are Sp1 and Sp3. Pretreatment with cycloheximide, a protein synthesis inhibitor, prevented the at-RA-mediated induction of VEGF mRNA expression. Likewise, at-RA-mediated VEGF expression was completely blocked in the presence of genistein, an inhibitor for tyrosine kinases. These results suggest that an increase in transcription of the VEGF promoter by at-RA is mediated through Sp1 site, and both new protein synthesis and tyrosine kinase activation are necessary for this induction. Because VEGF can promote neovascularization in cancer cells, an induction of VEGF by at-RA may preclude the therapeutic application of at-RA to cancer patients.

Inducible expression of endothelial PAS domain protein-1 by hypoxia in human lung adenocarcinoma A549 cells. Role of Src family kinases-dependent pathway.

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.