Hiroyuki Itaya

Expression of Tumor Necrosis Factor-α in Cultured Human Endothelial Cells Stimulated With Lipopolysaccharide or Interleukin-1α

Abstract —Tumor-necrosis factor-α (TNF-α) is a proinflammatory cytokine with a wide variety of biological effects. The most important source of this cytokine is monocytes/macrophages. It is a potent agonist in the activation of endothelial cells; however, the precise role of endothelial cells as a source of TNF-α is not known. In the present study, we addressed the possibility that TNF-α is produced by cultured human umbilical vein endothelial cells (HUVEC) stimulated with factors such as lipopolysaccharide (LPS) or interleukin-1α (IL-1α). LPS and IL-1α induced expression of TNF-α mRNA in HUVEC. IL-1α induced expression and secretion of TNF-α protein, but LPS did not induce production of TNF-α protein. Most of the TNF-α protein in cell lysate was found in the membrane fraction. The mRNA for TNF-α–converting enzyme (TACE) was expressed in unstimulated HUVEC, and its level was not altered by treatment with LPS or IL-1α. Transfection of HUVEC with full-length cDNA encoding the precursor TNF-α enhanced secretion of TNF-α protein by these cells, and treatment of the cells with a TACE inhibitor reduced the secretion. These results suggest that HUVEC produce TNF-α and have TACE activity. Secreted TNF-α may be involved in autocrine activation of endothelial cells, and TNF-α retained in cell membrane may serve as a juxtacrine system to activate target cells on the endothelial surface.

Desferrioxamine, an iron chelator, upregulates cyclooxygenase-2 expression and prostaglandin production in a human macrophage cell line

Prostaglandins (PGs) play regulatory roles in a variety of physiological and pathological processes, including the immune response, cytoprotection and inflammation. Desferrioxamine (DFX), an iron chelator, is known to reduce free radical-mediated cell injury and to upregulate certain inflammatory mediators. We investigated the effects of DFX on the production of PGs and the expression of cyclooxygenase-2 (COX-2), the rate-limiting enzyme in the synthesis of PGs, using a human macrophage cell line, U937. Our results showed that COX-2 expression and PGE(2) production are upregulated by DFX treatment and that this upregulation is dependent on both COX-2 promoter activity and alteration of mRNA stability. COX-2 promoter activity may be, at least in part, mediated by activation of the extracellular signal-regulated kinase pathway. These findings suggest that iron metabolism may regulate inflammatory processes by modulating PGs as well as other inflammatory mediators.

Production of growth related oncogene protein-α in human umbilical vein endothelial cells stimulated with soluble interleukin-6 receptor-α: role of signal transducers, janus kinase 2 and mitogen-activated kinase kinase

Growth-related oncogene protein-alpha (GRO-alpha) is a member of the C-X-C chemokine family with a wide variety of biological activities. We studied the production of GRO-alpha by human umbilical vein endothelial cells (HUVEC) in response to the stimulation with soluble form of interleukin-6 receptor alpha (sIL-6R). sIL-6R stimulated HUVEC to express GRO-alpha mRNA and secrete GRO-alpha protein in concentration-and time-dependent manners. The sIL-6R-induced GRO-alpha expression was inhibited by the pretreatment of the cells with AG490, a janus kinase 2 (JAK2) inhibitor, or with U0126, a MAP kinase-ERK kinase (MEK) inhibitor. sIL-6R also induced the phosphorylation of both Src homology 2-protein tyrosine phosphatase-2 (SHP-2), signal transducer and activator of transcription 3 (STAT3) and MEK. AG490 pretreatment inhibited the MEK phosphorylation but did not affect the STAT3 phosphorylation. We conclude that sIL-6R induces GRO-alpha expression in HUVEC through the activation of JAK2 and MEK.

Reoperative coronary artery bypass grafting without cardiopulmonary bypass

Between October 1995 and February 1997, 2 men and 4 women aged 53 to 75 years (mean, 66.3) underwent reoperative coronary artery bypass grafting without cardiopulmonary bypass. Isolated reoperative circumflex or intermediate artery bypass was performed through a left thoracotomy (n = 2), reoperative bypass to the left anterior descending coronary artery was performed through a median sternotomy (n = 3), and bypass to the right coronary artery was performed through an upper median laparotomy (n = 1). Single coronary bypass grafting utilizing arterial grafts (left internal thoracic artery: 3, right gastroepiploic artery: 3) was performed in all cases. There were no operative deaths. All cases required neither cathecolamine nor intraaortic balloon pumping). Peri/post operative blood transfusion was necessary in only one case. Postoperative coronary angiography revealed that the 6 arterial grafts were patent. Reoperative coronary artery bypass grafting without cardiopulmonary bypass can be performed with low perioperative morbidity and mortality, easy postoperative management, satisfactory graft patency, and good symptomatic improvement.

Rate of Stenotic Bicuspid Aortic Valve Aortic Dilatation After Aortic Valve Replacement, Calculated Using a 3-Dimensional Reconstruction Tool

BACKGROUND Progression of asymmetric dilated aorta associated with bicuspid aortic valve (BAV) is difficult to evaluate conventionally. The aim of the study was to calculate the rate of progression of the dilated BAV aorta after aortic valve replacement (AVR) using a 3-dimensional (3-D) reconstruction tool.Methods and Results:Fourteen stenotic BAV and 14 stenotic tricuspid aortic valve (TAV) patients with mildly dilated ascending aorta were reviewed. A patient-specific 3-D aortic model was reconstructed from preoperative and postoperative computed tomography data (BAV, 2.5±1.9 years after AVR; TAV, 2.2±1.8 years after AVR). Aortic diameter, including the longest and shortest, was measured on the maximum perpendicular cross-section tangential to the 3-D centerline of the reconstructed model. The longest diameter was defined as that passing through the distal point of the greater curvature of the aorta. The shortest diameter was defined as perpendicular to the longest. The progression rates were compared between the BAV and TAV groups. The progression rate of ascending aortic diameter was greater for BAV (longest diameter, 1.02±1.03 vs. -0.075±0.78 mm/year, P<0.001; shortest diameter, 0.41±0.62 vs. -0.016±0.59 mm/year, P=0.003). The longest diameter of the proximal arch also grew more rapidly in the BAV group (P<0.001). CONCLUSIONS Ascending aortic dilatation with stenotic BAV progresses after AVR at a maximum rate of 1.02±1.03 mm/year. Expansion toward the greater curvature frequently progresses to the proximal arch.

Aortic valve perforation due to latent infective endocarditis

A 64-year-old man underwent aortic valve replacement for aortic regurgitation. The aortic valve was perforated in the noncoronary cusp. Pathological findings showed that the perforation probably occurred due to infective endocarditis. However, the patient had no obvious inflammatory signs preoperatively, to suggest latent infective endocarditis.

A Case Report of Double Aortic Arch, Vascular Ring Associated with Tracheal Stenosis.

重複大動脈弓,血管輪は先天性動脈奇形では比較的希な疾患であるが心内奇形を合併しない限り,循環動態に影響を及ぼすことはなくその予後は良好である.しかしながら初発症状が喘鳴,嚥下困難といった呼吸器や消化器症状であるため確定診断にいたるまで時間を要し予期せぬ合併症に見舞われることがある.われわれは喘鳴を初発症状としたEdwards IA型の血管輪を経験した.血管輪離断術を行ったが呼吸状態の改善を認めず,2回目の手術にて動脈管索離断術およびaortopexyを施行し,人工呼吸器より離脱できた.大動脈弓離断により,気管外からの圧迫は解除されたが気管チューブの刺激による気管内壁の肥厚が原因となって,気管内腔の狭小化をきたしたものと思われた.血管輪には気管軟化症に伴う気管狭窄が知られているが,その他の機序による気管狭窄も念頭に入れ早期診断と適切な治療法の選択が望まれる.