脯氨酰羟化酶与低氧诱导因子在慢性阻塞性肺疾病患者中的表达及临床意义

COPD是一种以进行性发展的气流受限为特征、可预防的肺部疾病.由于呼吸功能的损伤,COPD患者通常合并缺氧.低氧诱导因子(hypoxia-inducible factor,HIF)是一种缺氧状态下的关键转录因子.但在其进行代偿调节的同时,也会给机体带来病理性损害,如低氧性肺动脉高压、促进肿瘤生长等.脯氨酰羟化酶可直接调控HIF,是缺氧反应的真正触发器,一定程度上预防了COPD合并肺动脉高压、肺癌的发生.     

Reversible hypertension following coeliac disease treatment: the role of moderate hyperhomocysteinaemia and vascular endothelial dysfunction

The vascular endothelium maintains a relatively vasodilated state via the release of nitric oxide (NO), a process that could be disrupted by hyperhomocysteinaemia. Since endothelial dysfunction is associated with increased systemic vascular resistance that is the hallmark of sustained arterial hypertension, we hypothesised that in patients with both hypertension and coeliac disease with hyperhomocysteinaemia (via malabsorption of essential cofactors), treatment of the latter disease could improve blood pressure (BP) control. A single patient with proven sustained hypertension and newly-diagnosed coeliac disease had baseline and post-treatment BP and endothelial function assessed by ambulatory BP monitoring (ABPM) and brachial artery forearm occlusion plethysmography respectively. This 49 year-old woman had uncomplicated sustained hypertension proven on repeated ABPM carried out 6 weeks apart (daytime mean 151/92 mm Hg and 155/95 mm Hg), and sub-clinical coeliac disease (gluten-sensitive enteropathy). Initial assessments revealed raised homocysteine levels with low normal vitamin B(12) level. It was likely that she had impaired absorption of essential cofactors for normal homocysteine metabolism. She adhered to a gluten-free diet and was give oral iron, folate and B(6) supplementations as well as B(12) injections for 3 months. Her BP had improved by 6 months and normalised by 15 months (daytime ABPM mean 128/80 mm Hg). There was parallel restoration of normal endothelial function with normalisation of her homocysteine levels. These observations suggest that sub-clinical coeliac disease related hyperhomocysteinaemia might cause endothelial dysfunction, potentially giving rise to a reversible form of hypertension. In addition, this case study supports the notion that irrespective of aetiology, endothelial dysfunction may be the precursor of hypertension. This highlights the need to resolve co-existing vascular risk factors in patients with hypertension.     

维生素C在小鼠小肠高铁吸收中的作用

目的 探索维生素C在小肠高铁吸收中的作用.方法 用正常铁、高铁和高铁加维生素C的不同饲料喂养成年小鼠,1 w后处死取材.血清铁和总铁结合力使用试剂盒检测,十二指肠的二价金属转运蛋白1(DMT1)和铁转运蛋白(FPN)的mRNA表达使用半定量RT-PCR测定.结果 维生素C可减少高铁饮食引起的血清铁和转铁蛋白结合力升高(P＜0.05),同时维生素C抑制了高铁诱导的十二指肠DMT1和FPN表达增加(P＜0.05).结论 维生素C在机体高铁状态下具有抑制肠铁吸收的作用.     

Hepatitis C virus-induced oxidative stress suppresses hepcidin expression through increased histone deacetylase activity

Chronic hepatitis C is characterized by iron accumulation in the liver, and excessive iron is hepatotoxic. However, the mechanism by which hepatitis C virus (HCV) regulates iron metabolism is poorly understood. Hepcidin plays a pivotal role as a negative regulator of iron absorption. The aim of the current study was to elucidate the mechanisms that govern hepcidin expression by HCV. Huh 7 cells, Huh7.5 cells, full-length HCV replicon cells established from Huh7.5 cells, and adenoviruses expressing HCV-core or HCV nonstructural proteins 3 through 5 (NS3-5) were used. Hepcidin expression was significantly lower in HCV replicon cells and in HCV core-expressing Huh7 cells. The expression was inversely correlated with the amount of reactive oxygen species (ROS) production. Anti-oxidants restored hepcidin expression in HCV replicon cells and Huh7 cells expressing HCV core. In HCV replicon cells, histone deacetylase (HDAC) activity was elevated at baseline and after exposure to hydrogen peroxide. Anti-oxidants reduced HDAC activity in a dose-dependent manner. HDAC inhibition increased hepcidin expression without affecting ROS production in HCV replicon cells. HCV-induced ROS stabilized the expression of two negative hepcidin regulators, HIF1alpha and HIF2alpha, and its expression was decreased by a HDAC inhibitor or an anti-oxidant. HCV-induced ROS also caused hypoacetylation of histones and inhibited binding of two positive regulators, C/EBPalpha and STAT3, to the hepcidin promoter, whereas anti-oxidant treatment of cells recovered C/EBPalpha and STAT3 binding to the hepcidin promoter. In addition, an HDAC inhibitor restored their binding to the hepcidin promoter via acetylation of histones. CONCLUSION: HCV-induced oxidative stress suppresses hepcidin expression through increased HDAC activity.     

Von Hippel-Lindau protein and respiratory diseases

Von Hippel-Lindau protein (pVHL) was first identified as a tumor suppressor gene as mutations in the VHL gene predispose individuals to systemic benign or malignant tumors and cysts in many organs, including renal cell carcinoma of the clear-cell type and hemangioblastoma. Although pVHL is best known to act as a component of ubiquitin protein ligase for the proteasomal degradation of hypoxia inducible factor (HIF)-α, pVHL also interacts with extracellular matrix proteins and cytoskeleton, regulating extracellular matrix assembly, cell signaling, and many other cellular functions. Recent studies suggest that pVHL contributes to many lung diseases, including pulmonary arterial hypertension, lung cancer, pulmonary fibrosis, and acute respiratory distress syndrome. Mutation or loss of function of pVHL activates HIF and induced expression of vascular endothelial growth factor, endothelin-1, and FoxM1, leading to pulmonary arterial hypertension. Loss of pVHL in lung cancer cells promotes epithelial-mesenchymal transition and cancer migration and invasion while decreasing lung cancer cell proliferation and colonization. In patients of idiopathic pulmonary fibrosis, elevated expression of pVHL induces expression of fibronectin/integrin α5β1/focal adhesion kinase signaling, resulting in fibroproliferation and fibrosis. In alveolar epithelial cells, pVHL mediates Na-K-ATPase degradation in an HIF independent pathway, causing decreased edema clearance during hypoxia. These studies suggest that pVHL plays key roles in the pathogenesis of many lung diseases, and further investigations are warranted to elucidate the underlying molecular mechanisms.     

Effects of angiotensin converting enzyme inhibitor and calcium antagonist on endothelial function in patients with essential hypertension.

The endothelium plays an important role in maintaining vascular tone and function. Essential hypertension is associated with alterations in endothelial function. The effects of antihypertensive agents on endothelial function have not been fully evaluated in human hypertension and data on the forearm circulation of humans are controversial. The aim of this study was to determine whether treatment with an angiotensin converting enzyme (ACE) inhibitor or a calcium antagonist improves endothelial dysfunction in hypertensive patients and whether the mechanism involved could be related to antioxidant activity. Endothelial function was estimated using venous occlusion plethysmography in 18 hypertensive patients and 11 healthy volunteers. The patients in the hypertension group were treated with enalapril or amlodipine. The change of forearm blood flow (FBF) was measured during acetylcholine infusion through the brachial artery and also during intra-arterial vitamin C infusion to explore the effects of vitamin C on responses to acetylcholine. FBF response to acetylcholine was significantly enhanced by intra-arterial infusion of vitamin C in the hypertensive group before antihypertensive treatment. Co-infusion of L-NMMA(N(G)-monomethyl-L-arginine), an inhibitor of nitric oxide synthase, blunted forearm blood flow response to acetylcholine. After antihypertensive treatment with enalapril or amlodipine for 2 months in the hypertensive group, endothelium-dependent vasorelaxation (vasodilatory response to acetylcholine) was significantly improved. Even though the mechanisms leading to depressed endothelial function in essential hypertension remain to be elucidated, our study shows that treatment with an ACE inhibitor or a calcium antagonist resulted in demonstrable improvement by a mechanism that is probably related to antioxidant activity.     

Preventive nutrition: disease-specific dietary interventions for older adults.

Disease prevention through dietary management is a cost-effective approach to promoting healthy aging. Fats, cholesterol, soluble fiber, and the trace elements copper and chromium affect the morbidity and mortality of CHD. Decreasing sodium and increasing potassium intake improves control of hypertension. Calcium and magnesium may also have a role in controlling hypertension. The antioxidant vitamins A and beta-carotene, vitamin C, vitamin E, and the trace mineral selenium may protect against types of cancer. A decrease in simple carbohydrates and an increase in soluble dietary fiber may normalize moderately elevated blood glucose levels. Deficiencies of zinc or iron diminish immune function. Adequate levels of calcium and vitamin D can help prevent senile osteoporosis in both older men and women.     

Pulmonary hypertension in non-transfusion-dependent thalassemia: Correlation with clinical parameters,liver iron concentration,and non-transferrin-bound iron

Abstract

Background

Pulmonary hypertension is a major cardiac complication in non-transfusion-dependent thalassemia (NTDT). Several clinical and laboratory parameters, including iron overload, have been shown to have a positive correlation with the incidence of pulmonary hypertension. Non-transferrin-bound iron (NTBI) is a form of free-plasma iron that is a good indicator of iron overload.

Objectives

The aim of this study was to determine the prevalence of pulmonary hypertension in patients with NTDT and to investigate its correlation with the clinical parameters, liver iron concentration (LIC) and NTBI.

Methods

Patients with NTDT were evaluated using echocardiography, and magnetic resonance imaging for cardiac T2* and LIC. Pulmonary hypertension was de?ned as peak tricuspid regurgitation velocity ≥2.9 m/s measured using trans-thoracic echocardiography. Clinical parameters and the status of iron overload as determined by LIC, serum ferritin, and NTBI level were evaluated for their association with pulmonary hypertension.

Results

Of 76 NTDT patients, mean age 23.7 ± 8.5 years, seven patients (9.2%) had pulmonary hypertension. Previous splenectomy (71.4 vs. 24.6%, P-value 0.019), higher cumulative red blood cell (RBC) transfusions (received ≥10 RBC transfusions 85.7 vs. 33.3%, P-value 0.011), higher nucleated RBCs (353 ± 287 vs. 63 ± 160/100 white blood cells, P-value <0.001), and a high NTBI level (5.7 ± 3.0 vs. 3.3 ± 2.8 µmol/l, P-value 0.034) were associated with pulmonary hypertension. There was no significant correlation between LIC or serum ferritin and pulmonary hypertension.

Conclusion

Pulmonary hypertension in NTDT is common, and is associated with splenectomy and its related factors. NTBI level shows a significant correlation with pulmonary hypertension.     

Pulmonary thromboembolism associated with familial protein C deficiency type I]

A 66-year-old man was admitted to our hospital because of progressive dyspnea on effort. Arterial blood gas analysis showed severe hypoxemia, and a chest radiograph revealed reticular shadows in both lower lungs and an increase of the cardiothoracic ratio. Echocardiography demonstrated mild indentation of the interventricular septum toward the left ventricle, moderate pericardial effusion and pulmonary hypertension. From these data, we diagnosed pulmonary thromboembolism and started anticoagulation therapy. After the addition of the administration of warfarin and oxygen therapy, his symptoms disappeared. However, we could not obtain more supporting evidence of thromboembolization by methods of ventilation-perfusion scanning, digital subtraction angiography of the pulmonary artery, or venography. Blood coagulation analysis demonstrated that the patient's plasma protein C antigen levels and its activity were depleted. The patient's son had a history of thrombophlebitis and pulmonary embolization, and his data of protein C antigen levels was also decreased. Therefore, this patient was found to have a character of familial protein C deficiency type I. We could not get the conclusive proof of pulmonary thromboembolism, but we considered that the presence of familial protein C deficiency may cause exacerbation of pulmonary hypertension.     

铁代谢与心血管疾病

铁代谢异常与多种心血管疾病密切相关。慢性心力衰竭、肺动脉高压常与铁缺乏并存,铁超负荷可促进冠心病的发生发展。现简要综述常见心血管疾病中铁代谢异常的表现特征及可能的机制。     

Ascorbate modulates antibacterial mechanisms in experimental pneumococcal pneumonia

To evaluate the influence of vitamin C on pulmonary antibacterial mechanisms, normal CD-1 mice were administered sodium ascorbate (200 mg/kg/24 h) and challenged intratracheally with type 3 Streptococcus pneumoniae. Survival rates were similar in ascorbate-treated and control animals. When infected with a high inoculum (1 X 10(6) cfu), animals given vitamin C demonstrated a significant enhancement in their capacity to clear viable pneumococci from the lungs at 24 h after challenge; the augmented pulmonary clearance was associated with an increased influx of granulocytes at 6 and 24 h. After infection with a lower inoculum (1 X 10(5) cfu), animals treated with the vitamin exhibited a significant advantage in pulmonary clearance and granulocyte recruitment but at 6 h only. After a very low inoculum challenge (1 X 10(4) cfu), the clearance of viable pneumococci was retarded in ascorbate-treated mice. In vitro, the pneumococcidal capacity of resident alveolar macrophages from animals given vitamin C was significantly reduced, but the ability of these cells to generate leukocyte chemoattractant activity after stimulation with the calcium ionophore A23187 remained unaltered. We conclude that in the mouse, large doses of vitamin C alter pulmonary defense mechanisms against S. pneumoniae; however, these changes do not appear to convey a substantial advantage to the host.     

Effect of venous air embolization on pulmonary microvascular protein permeability

OBJECTIVE: An increase in pulmonary lymph flow and lymph protein clearance following pulmonary air embolization has been interpreted as evidence of increased pulmonary microvascular permeability. The authors hypothesized that air embolization does not alter the pulmonary microvascular permeability to protein and that this could be demonstrated by determining the effect of air embolization on the pulmonary solvent drag reflection coefficient (sigma(f)). METHODS: Anesthetized dogs were instrumented with left atrial balloon-tipped catheters, pulmonary lymphatic cannulae, and inferior vena caval catheters. Values were determined for pulmonary lymph flow (Q(L)) and the lymph-to-plasma protein concentration ratio (C(L)/C(P)) at baseline, after C(L)/C(P) was decreased to a filtration independent value by raising left atrial pressure via progressive balloon inflation and after 2 h of air embolization into the inferior vena cava with continued left atrial hypertension. RESULTS: Q(L) increased and C(L)/C(P) decreased to a filtration-independent value following induction of left atrial hypertension. Air embolization induced during left atrial hypertension resulted in no significant change in C(L)/C(P). The authors were unable to demonstrate that sigma(f) changed following pulmonary air embolization. CONCLUSIONS: Utilizing the washdown technique, the authors could not find any evidence that pulmonary microvascular protein permeability is altered by air embolization.     

Vitamin C improves endothelial function of epicardial coronary arteries in patients with hypercholesterolaemia or essential hypertension--assessed by cold pressor testing.

AIMS: There is evidence that formation of free radicals increases in patients with hypertension or hypercholesterolaemia, which may contribute to endothelial dysfunction of epicardial coronary arteries due to inactivation of the vasodilator NO. The present study was designed to test whether the abnormal constriction of epicardial coronary arteries due to sympathetic stimulation by the cold pressor test in patients with essential hypertension or hypercholesterolaemia could be reversed by administration of the antioxidant vitamin C. METHODS and RESULTS: In 28 patients without relevant coronary artery stenosis the cold pressor test was performed before and after a 3 g infusion of vitamin C. In five normal controls the cold pressor test led to a similar increase in luminal area before and after vitamin C (3.7+/-1.3% and 1.9+/-0.8%, ns vs before vitamin C). In nine hypercholesterolaemic patients the cold pressor test led to a -14.1+/-2.8% reduction in cross-sectional area before vitamin C. This constriction was significantly improved after vitamin C to -7.6%+/-2.0, P=0.027 vs before vitamin C. In nine hypertensive patients, the cold pressor test led to a -17.1+/-3.2% decrease in cross-sectional area before vitamin C, which was improved to -7.1+/-3.1 after vitamin C, P=0.004 vs before vitamin C. This increase in luminal area was significant in each group in comparison with normal controls (each P<0.05). Administration of saline (placebo group, five patients) had no significant effect on cold pressor test-induced constriction (-6.9+/-3.9% before and -6. 8+/-3.7% after saline). CONCLUSION: The antioxidant vitamin C reverses cold pressor test-induced vasoconstriction of epicardial coronary arteries in patients with hypertension or hypercholesterolaemia. Our data suggest that enhanced oxidative stress contributes to impaired endothelial function in this patient population.     

Disorders of thrombocyte function and/or endothelial cell damage as a cause of primary pulmonary hypertension?

The pathophysiology of pulmonary hypertension is, in many cases, unclear and this is true especially for patients with dietary pulmonary hypertension. This paper discusses the hypothesis that platelets, directly or through their interaction with the pulmonary endothelial cell, are involved in the development of pulmonary hypertension. Platelets release vasoactive substances during aggregation or activation and these substances lead to pulmonary vasoconstriction and pulmonary hypertension. The primary target of the activated platelets could be the endothelial cell which has also been demonstrated in animal experiments with crotalaria-induced pulmonary hypertension. Changes in thromboxane--platelets and prostacyclin--endothelial cell interactions could be the basic mechanism responsible for endothelial proliferation and pulmonary vasoconstriction. It has not been ascertained, however, whether the activation of platelets or endothelial dysfunction is the primary lesion. In various animal experiments, changes in platelet function and endothelial damage, as well, have been shown to be initiated by exogenous influences. The investigation of platelets or endothelial cell function in patients with pulmonary hypertension showed evidence of platelet activation but not platelet hyperreactivity. An impaired fibrinolytic activity, which was found in the majority of these patients, was regarded as indicative of endothelial dysfunction. An interference in the physiological interaction of circulating platelets and endothelial cells in the lung with resulting endothelial proliferation and vessel occlusion could well be the initial factor. This process would be self-perpetuating in the development of pulmonary hypertension. An additional example of dietary-induced pulmonary hypertension was observed in patients in Spain after the ingestion of toxic oil.(ABSTRACT TRUNCATED AT 250 WORDS)     

Restoration of nitric oxide availability after calcium antagonist treatment in essential hypertension

Essential hypertension is associated with impaired endothelium-dependent vasodilation caused by oxygen free radical-induced nitric oxide (NO) breakdown. Because calcium antagonists can improve endothelial function in patients with essential hypertension, in this study we tested the hypothesis that this beneficial effect could be related to restoration of NO availability by antioxidant properties. In 15 healthy subjects and 15 hypertensive patients, we studied forearm blood flow (strain-gauge plethysmography) modifications induced by intrabrachial acetylcholine (ACh; 0.15, 0.45, 1.5, 4.5, and 15 microg/100 mL per minute), an endothelium-dependent vasodilator in basal conditions, during infusion of N:(G)-monomethyl-L-arginine (L-NMMA, 100 microg/100 mL forearm tissue per minute), an NO-synthase inhibitor, vitamin C (8 mg/100 mL forearm tissue per minute), and finally, simultaneous infusion of L-NMMA and vitamin C. The response to sodium nitroprusside (SNP; 1, 2, and 4 microg/100 mL forearm tissue per minute) was also evaluated. In control subjects, vasodilation to ACh was inhibited by L-NMMA and not changed by vitamin C. In hypertensive patients, vasodilation to ACh was blunted as compared with control subjects and resistant to L-NMMA. Vitamin C, which decreased plasma isoprostanes and increased plasma antioxidant capacity, increased the response to ACh and restored the inhibiting effect of L-NMMA. In hypertensive patients, the study was repeated after 3-month treatment with nifedipine gastrointestinal therapeutic system (30 to 60 mg/daily). Nifedipine treatment decreased circulating plasma lipoperoxides and isoprostanes and increased plasma antioxidant capacity. Moreover, nifedipine increased the vasodilation to ACh but not to SNP and restored the inhibiting effect of L-NMMA on ACh-induced vasodilation, whereas vitamin C no longer exerted its facilitating activity. These results indicate that nifedipine increases endothelium-dependent vasodilation by restoring NO availability, an effect probably determined by antioxidant activity.     

大剂量维生素C对体外循环导致的红细胞变形性改变的作用

本文报告51例经体外循环(CPB)手术的先天性心脏病患者红细胞变形性(RCD)的改变,大剂量维生素C(260 mg/kg)的作用和中度以上肺动脉高压(PH)对RCD的影响。结果表明,大剂量维生素C能减少RCD下降,促使RCD的恢复,PH对RCD的恢复有延缓作用。     

Metabolic factors involved in the therapeutic response of patients with hepatitis C virus-related chronic hepatitis

BACKGROUND: The purpose of the present paper was to investigate the factors possibly involved in the failure of pegylated interferon (Peg IFN) plus ribavirin treatment at standard dosage in hepatitis C virus (HCV) 1b patients, with chronic hepatitis. METHODS: A fully screened population of 40 virological non-responders (NR) to combined antiviral therapy was selected and matched, 1:1, with a similar cohort of end-therapy virological responders (R). RESULTS: Waist circumference, glucose metabolic impairment, body mass index, non-genetic iron overload, steatosis and fibrosis severity and, finally, arterial hypertension were statistically more frequent in the NR group on Peg IFN plus ribavirin. Increased waist circumference was the strong independent predictor of therapeutical failure. Interestingly, the concomitant presence of cofactors was more significantly represented in NR, whereas in the R cohort this association was found in a few cases only. CONCLUSION: Insulin-resistance syndrome could contribute to non-response in treated chronic HCV patients, suggesting the presence of dysmetabolic factors that frequently cluster in a critical combination.     

Two antioxidants are better than one

New evidence suggests that the cellular oxygen-sensing hypoxia-inducible factor(HIF) pathway may be protected by a double buffer of cellular antioxidant defense. Key players in the oxygen-dependent regulation of this pathway are the prolyl hydroxylase domain-containing enzymes (PHDs) that catalyze the prolyl-4-hydroxylation of HIFα, dependent on the presence of oxygen, 2-oxoglutarate, and iron in the ferrous (Fe(2+)) form. Vitamin C is also required as a cofactor, possibly to maintain the catalytic iron center in its functional Fe(2+)) state, although both the mechanism and the in vivo requirement are not absolutely clear.