Hideki Fujimori

The Receptor for Advanced Glycation End Products Is Induced by the Glycation Products Themselves and Tumor Necrosis Factor-α through Nuclear Factor-κB, and by 17β-Estradiol through Sp-1 in Human Vascular Endothelial Cells

The binding of advanced glycation end products (AGE) to the receptor for AGE (RAGE) is known to deteriorate various cell functions and is implicated in the pathogenesis of diabetic vascular complications. Here we show that AGE, tumor necrosis factor-α (TNF-α), and 17β-estradiol (E2) up-regulated RAGE mRNA and protein levels in human microvascular endothelial cells and ECV304 cells, with the mRNA stability being essentially invariant. Transient transfection experiments with human RAGE promoter-luciferase chimeras revealed that the region from nucleotide number −751 to −629 and the region from −239 to −89 in the RAGE 5′-flanking sequence exhibited the AGE/TNF-α and E2 responsiveness, respectively. Site-directed mutation of an nuclear factor-κB (NF-κB) site at −671 or of Sp-1 sites at −189 and −172 residing in those regions resulted in an abrogation of the AGE/TNF-α- or E2-mediated transcriptional activation. Electrophoretic mobility shift assays revealed that ECV304 cell nuclear extracts contained factors which retarded the NF-κB and Sp-1 elements, and that the DNA-protein complexes were supershifted by anti-p65/p50 NF-κB and anti-Sp-1/estrogen receptor α antibodies, respectively. These results suggest that AGE, TNF-α, and E2 can activate the RAGE gene through NF-κB and Sp-1, causing enhanced AGE-RAGE interactions, which would lead to an exacerbation of diabetic microvasculopathy.

The Receptor for Advanced Glycation Endproducts Is Induced by the Glycation Products Themselves and TNF-α through NF-κB, and by 17β-estradiol through Sp-1 in Human Vascular Endothelial Cells

The binding of advanced glycation end products (AGE) to the receptor for AGE (RAGE) is known to deteriorate various cell functions and is implicated in the pathogenesis of diabetic vascular complications. Here we show that AGE, tumor necrosis factor-α (TNF-α), and 17β-estradiol (E2) up-regulated RAGE mRNA and protein levels in human microvascular endothelial cells and ECV304 cells, with the mRNA stability being essentially invariant. Transient transfection experiments with human RAGE promoter-luciferase chimeras revealed that the region from nucleotide number −751 to −629 and the region from −239 to −89 in the RAGE 5′-flanking sequence exhibited the AGE/TNF-α and E2 responsiveness, respectively. Site-directed mutation of an nuclear factor-κB (NF-κB) site at −671 or of Sp-1 sites at −189 and −172 residing in those regions resulted in an abrogation of the AGE/TNF-α- or E2-mediated transcriptional activation. Electrophoretic mobility shift assays revealed that ECV304 cell nuclear extracts contained factors which retarded the NF-κB and Sp-1 elements, and that the DNA-protein complexes were supershifted by anti-p65/p50 NF-κB and anti-Sp-1/estrogen receptor α antibodies, respectively. These results suggest that AGE, TNF-α, and E2 can activate the RAGE gene through NF-κB and Sp-1, causing enhanced AGE-RAGE interactions, which would lead to an exacerbation of diabetic microvasculopathy.

Advanced glycation endproducts inhibit prostacyclin production and induce plasminogen activator inhibitor-1 in human microvascular endothelial cells

Summary Several thrombogenic abnormalities are associated with diabetes. To investigate the underlying molecular mechanisms, we examined the effects of advanced glycation endproducts (AGE), non-enzymatically glycated protein derivatives, on the production of prostacyclin (PGI2), an anti-thrombogenic prostanoid, and of plasminogen activator inhibitor-1 (PAI-1), a fast-acting serine protease inhibitor of fibrinolysis, in human microvascular endothelial cells (EC). Firstly, AGE-bovine serum albumin (BSA) but not non-glycated BSA, was found to considerably decrease the production of PGI2 to about two-thirds of the control value. Secondly, quantitative reverse transcription-polymerase chain reaction showed that AGE-BSA increased the EC levels of mRNA coding for PAI-1, this being associated with a concomitant increase in the immunoreactive PAI-1 contents and the anti-fibrinolytic activity. Thirdly, the effects of AGE on PGI2 and PAI-1 syntheses in EC were found to be mediated by a receptor for AGE (RAGE) because antisense DNA against RAGE mRNA could reverse the AGE effects. Further, it was found that AGE decreased the intracellular cyclic AMP concentrations in EC and that cyclic AMP agonists such as dibutyryl cyclic AMP, forskolin and PGI2 analogue reduced the AGE-stimulated PAI-1 production, suggesting the involvement of cyclic AMP in the AGE-signalling pathway. The results thus suggest that AGE have the ability to cause platelet aggregation and fibrin stabilization, resulting in a predisposition to thrombogenesis and thereby contributing to the development and progression of diabetic vascular complications. [Diabetologia (1998) 41: 1435–1441]

Long-term Results of Endarterectomy, Anatomic Bypass and Extraanatomic Bypass for Aortoiliac Occlusive Disease

Over the past 20 years, 214 patients in our hospital were operated on for aortoiliac occlusion, including an endarterectomy for 88 legs in 64 patients, an anatomic bypass for 178 legs in 105 patients, and an extraanatomic bypass for 51 legs in 45 patients. The extraanatomic group was older than the other two groups (70 years versus 64 years), and also showed a higher instance of critical ischemic symptoms than the other groups (49% versus 16%). The 10-year primary patency rate was 88% for an endarterectomy, 91% for an anatomic bypass, and 73% for an extraanatomic bypass. The 10-year survival rate was 71% for an endarterectomy, 49% for an anatomic bypass, and 24% for an extraanatomic bypass. The possible complications related to each surgical method included sexual dysfunction resulting from endarterectomy, and graft infection and anastomotic aneurysm in the prosthetic bypass. No ischemic symptoms in the donor limb were noted following an extraanatomic bypass. The selection of the appropriate surgical method for aortoiliac occlusion should thus be made after a careful review of the patients general condition, the morphology of arterial occlusion, and the risk of possible complications for each type of surgery.

New indication for preoperative marking of small peripheral pulmonary nodules in thoracoscopic surgery

The aim of this work was to analyze parameters to determine the possibility for detection of tumor location, and clarify the indication for preoperative marking of small peripheral pulmonary nodules in thoracoscopic resection. In a series of 97 patients who underwent video-assisted thoracoscopic surgery, information on standard uptake values (SUVs) and the detectability of tumor location was assessed. In patients whose lesions were <15 mm in diameter and where the distance to the pleura was >10 mm, lesions were not detected. Multivariate analysis to determine the factors related to the possibility of detecting tumor localization revealed that the distance to the pleural surface (P=0.0001), and the ratio of solid portion (P=0.0104) were statistically significant. In the non-solid tumor group, we should perform preoperative marking for tumors located more than 3 mm in depth from the visceral pleura. In the solid tumor group, the linear function (depth=0.4×size-0.9) may be used to separate detectable and undetectable groups. However, the sensitivity was 90.3% even if this formula was applied. Here we advocate the algorithm for detection of indication for preoperative marking using the ratio of solid portion, tumor size and SUV of fluorodeoxyglucose positron emission tomography.

Double-Barrel Reconstruction for Complex Bronchial Disruption Due to Blunt Thoracic Trauma

We herein present a case of a 20-year-old man who presented with complex rupture of bronchus after blunt chest trauma. The involvement of both the main bronchus and right upper bronchus separately is unusual. Emergency double-barrel bronchial reconstruction was performed with complete preservation of the right lung. Such a serious bronchial injury with a positive outcome has not been reported so far. The features of this uncommon entity are discussed.

Management of tracheobronchial ulceration induced by high-dose brachytherapy.

The most severe complication of high-dose endobronchial brachytherapy is fatal hemoptysis. Intractable tracheobronchial ulceration due to high-dose endobronchial brachytherapy often develops into tracheobronchial necrosis and fatal hemoptysis. Our experience demonstrated that when bleeding from tracheobronchial ulcer, after high-dose endobronchial brachytherapy occurs, blocking the blood supply to the tracheobronchial ulcer alone is ineffective. Prophylactic tracheobronchial wrapping using the omentum should be added before the occurrence of fatal hemoptysis. This is the first report that describes an effective management for preventing fatal hemoptysis.

What factors determine the survival of patients with an acute exacerbation of interstitial lung disease after lung cancer resection

PurposesAcute exacerbation of interstitial pneumonia (AEIP) is a leading cause of death after lung cancer resection in patients with interstitial lung disease.MethodsWe retrospectively analyzed 1763 patients with non-small cell lung cancer with a clinical diagnosis of interstitial lung disease (ILD) who underwent lung cancer resection between 2000 and 2009 at 61 hospitals in Japan. AEIP occurred in 164 of 1763 (9.3%) patients with a mortality rate of 43.9% (72/164). Univariate and multivariate analyses were carried out to identify possible risk factors of fatal AEIP. We then analyzed the 164 patients who developed postoperative AEIP and identified the preoperative and postoperative risk factors.ResultsA multivariate regression analysis identified that the sex, percent vital capacity, neoadjuvant radiation, preoperative history of AEIP, preoperative use of steroids, usual interstitial pneumonia pattern on CT, and surgical procedures were independent preoperative risk factors for death due to AEIP. ILD patients with emphysema somehow showed a lower risk of fatal AEIP than those without emphysema in this study.ConclusionsThis study revealed eight risk factors for fatal AEIP.