Impact of oxidative stress on lung diseases

Reactive oxygen species (ROS) are products of normal cellular metabolism and are known to act as second messengers. Under physiological conditions, ROS participate in maintenance of cellular 'redox homeostasis' in order to protect cells against oxidative stress through various redox-regulatory mechanisms. Overproduction of ROS, most frequently due to excessive stimulation of either reduced nicotinamide adenine dinucleotide phosphate by cytokines or the mitochondrial electron transport chain and xanthine oxidase, results in oxidative stress. Oxidative stress is a deleterious process that leads to lung damage and consequently to various disease states. Knowledge of the mechanisms of ROS regulation could lead to the pharmacological manipulation of antioxidants in lung inflammation and injury.     

Brief Report: Mitochondrial fatty acid utilization increases chromatin oxidative stress in cardiomyocytes

The inability of adult mammalian cardiomyocytes to proliferate underpins the development of heart failure following myocardial injury. Although the newborn mammalian heart can spontaneously regenerate for a short period of time after birth, this ability is lost within the first week after birth in mice, partly due to increased mitochondrial reactive oxygen species (ROS) production which results in oxidative DNA damage and activation of DNA damage response. This increase in ROS levels coincides with a postnatal switch from anaerobic glycolysis to fatty acid (FA) oxidation by cardiac mitochondria. However, to date, a direct link between mitochondrial substrate utilization and oxidative DNA damage is lacking. Here, we generated ROS-sensitive fluorescent sensors targeted to different subnuclear compartments (chromatin, heterochromatin, telomeres, and nuclear lamin) in neonatal rat ventricular cardiomyocytes, which allowed us to determine the spatial localization of ROS in cardiomyocyte nuclei upon manipulation of mitochondrial respiration. Our results demonstrate that FA utilization by the mitochondria induces a significant increase in ROS detection at the chromatin level compared to other nuclear compartments. These results indicate that mitochondrial metabolic perturbations directly alter the nuclear redox status and that the chromatin appears to be particularly sensitive to the prooxidant effect of FA utilization by the mitochondria.     

Vascular cell-adhesion molecule-1 plays a central role in the proangiogenic effects of oxidative stress

Oxidative stress exacerbates neovascularization (NV) in many disease processes. In this study we investigated the mechanism of that effect. Mice deficient in superoxide dismutase 1 (Sod1(-/-) mice) have increased oxidative stress and show severe ocular NV that is reduced to baseline by antioxidants. Compared with wild-type mice with ischemic retinopathy, Sod1(-/-) mice with ischemic retinopathy had increased expression of several NF-κB-responsive genes, but expression of vascular cell-adhesion molecule-1 (Vcam1) was particularly high. Intraocular injection of anti-VCAM-1 antibody eliminated the excessive ischemia-induced retinal NV. Elements that contributed to oxidative stress-induced worsening of retinal NV that were abrogated by blockade of VCAM-1 included increases in leukostasis, influx of bone marrow-derived cells, and capillary closure. Compared with ischemia alone, ischemia plus oxidative stress resulted in increased expression of several HIF-1-responsive genes caused in part by VCAM-1-induced worsening of nonperfusion and, hence, ischemia, because anti-VCAM-1 significantly reduced the increased expression of all but one of the genes. These data explain why oxidative stress worsens ischemia-induced retinal NV and may be relevant to other neovascular diseases in which oxidative stress has been implicated. The data also suggest that antagonism of VCAM-1 provides a potential therapy to combat worsening of neovascular diseases by oxidative stress.     

Radicals and oxidative stress in diabetes.

Recent evidence is reviewed indicating increased oxidative damage in Type 1 and Type 2 diabetes mellitus as well as deficits in antioxidant defence enzymes and vitamins. Mechanisms are considered whereby hyperglycaemia can increase oxidative stress, and change the redox potential of glutathione and whereby reactive oxygen species can cause hyperglycaemia. It is argued that oxygen, antioxidant defences, and cellular redox status should now be regarded as central players in diabetes and the metabolic syndrome.     

氧化应激与动脉粥样硬化

动脉粥样硬化是一种以脂质沉积推动、以粥样斑块在动脉壁堆积进而造成动脉狭窄为主要病理过程的一种慢性心血管疾病,是导致患者高死亡率和高致残率的重要因素。粥样斑块的形成发展涉及多种细胞和分子,是机制复杂的慢性退化过程。氧化应激是机体活性氧成分与抗氧化系统之间失衡时引起的一系列的适应性反应,被认为是动脉粥样硬化形成和发展的关键机制之一。本综述将从机体内活性氧的不同来源出发,总结氧化应激与动脉粥样硬化之间的关系,归纳动脉粥样硬化中氧化应激对不同生物分子及生物过程的影响,并简要介绍抗氧化药物在动脉粥样硬化治疗中的研究和应用。     

Diabetic neuropathy and oxidative stress

This review will focus on the impact of hyperglycemia-induced oxidative stress in the development of diabetes-related neural dysfunction. Oxidative stress occurs when the balance between the production of reactive oxygen species (ROS) and the ability of cells or tissues to detoxify the free radicals produced during metabolic activity is tilted in the favor of the former. Although hyperglycemia plays a key role in inducing oxidative stress in the diabetic nerve, the contribution of other factors, such as endoneurial hypoxia, transition metal imbalances, and hyperlipidemia have been also suggested. The possible sources for the overproduction of ROS in diabetes are widespread and include enzymatic pathways, auto-oxidation of glucose, and mitochondrial superoxide production. Increase in oxidative stress has clearly been shown to contribute to the pathology of neural and vascular dysfunction in diabetes. Potential therapies for preventing increased oxidative stress in diabetic nerve dysfunction will be discussed.     

Oxidative stress in inflammation-based gastrointestinal tract diseases: challenges and opportunities

Oxygen free radicals in excessively high amounts are all very reactive chemically and can impose a detrimental influence on living organisms by provoking "oxidative stress" that can damage major cellular constituents. The latter includes the cell membrane, cytoplasmic proteins, and nuclear DNA. Conversely, nitric oxide (NO), superoxide anion, and related reactive oxygen species (ROS) when present in low amounts play an important role as regulatory mediators in signaling processes, through which, paradoxically, many ROS-mediated responses can protect the cells against oxidative stress by induction of "redox homeostasis." Therefore, diseases associated with free radical overproduction are provoked by "blazed ROS productions" far beyond the host's capacity to quench. Free radicals have been implicated in the pathogenesis of diverse gastrointestinal (GI) diseases including gastroesophageal reflux disease (GERD), gastritis, enteritis, colitis and associated cancers as well as pancreatitis and liver cirrhosis. This article provides an overview of the role of oxidative stress in inflammation-based GI tract diseases, including reflux esophagitis, Helicobacter pylori-associated gastritis, non-steroidal anti-inflammatory drug-induced enteritis, ulcerative colitis, and associated colorectal cancer. The challenging issue that ROS can contribute to diverse gastrointestinal dysfunction, or manifest dual roles in cancer promotion or cancer suppression will also be discussed for the opportunity to enhance understanding of inflammation-based GI diseases.     

High morning blood pressure surge is associated with oxidative stress and paraoxonase 1 activity in newly diagnosed hypertensive patients

Background: Both oxidative stress and morning surge (MS) of blood pressure (BP) were found to be closely related with cardiovascular and cerebrovascular diseases. We investigated the association between MS of BP and oxidative stress in newly diagnosed hypertensive patients. Methods: We prospectively included 237 newly diagnosed hypertensive patients in the present study (mean age: 51.6 ± 11.7 years). The patients were classified according to the extent of the sleep-through surge as follows: the top decile of sleep-through surge (>47.2 mmHg, n = 27; EMShigh group), versus all others (n = 210, EMSlow group). Total antioxidant capacity (TAC) and total oxidant status (TOS) levels were determined by using an automated measurement method. The oxidative stress index (OSI) was calculated as the ratio of TOS to TAC. Serum paraoxonase 1 (PON-1) activity was measured spectrophotometrically. Results: Patients in EMShigh group were found to have higher hs-CRP, TOS, and OSI values and lower TAC and PON-1 values (p < 0.01, for all). MS of BP was associated with hs-CRP, PON-1, TOS, TAC, and OSI levels in bivariate analysis. Multivariate linear regression analysis showed that MS of BP was significantly associated with PON-1(β = ?0.206, p < 0.001), OSI (β = 0.602, p < 0.001) and hs-CRP (β = 0.210, p < 0.001). Conclusion: Present study shows that OSI is increased and antioxidant PON-1 activity is decreased in patients with enhanced MS of BP. There is a close association between high MS of BP and oxidative stress markers in newly diagnosed hypertensive patients.     

赤芍总苷对高血压大鼠血管重构基质金属蛋白酶9、金属蛋白酶组织抑制因子1和血管壁氧化应激的干预作用

目的探讨赤芍总苷(TPG)对自发性高血压大鼠(SHR)血管重构基质金属蛋白酶9(MMP-9)、金属蛋白酶组织抑制因子1(TIMP-1)和血管壁氧化应激的干预作用。方法 30只8周龄雄性SHR大鼠随机分为3组:低剂量TPG组(低剂量组,n=10)、高剂量TPG组(高剂量组,n=10)、对照组(n=10);另外以Wistar大鼠作为空白组(n=8)。低剂量组、高剂量组分别以100、200 mg/(kg·d)的TPG灌胃,对照组、空白组以2 mL生理盐水灌胃。8周后,酶联免疫吸附测定法测定血清MMP-9、TIMP-1水平;活性氧(ROS)荧光探针检测胸主动脉壁细胞氧化应激水平;免疫组织化学染色检测主动脉MMP-9、TIMP-1蛋白表达。结果与空白组比较,对照组MMP-9、TIMP-1血清水平及血管壁MMP-9、TIMP-1蛋白表达均明显升高(P0.05)。TPG治疗后,MMP-9有所下降,高剂量组与对照组比较,差异有统计学意义(P0.05);但TIMP-1在低剂量组、高剂量组、对照组间差异无统计学意义(P0.05)。对照组胸主动脉ROS水平明显高于空白组,而低剂量组、高剂量组ROS水平较对照组下降。结论高血压血管重构存在血管氧化应激和MMP-9水平升高;TPG能够抑制动脉氧化应激和MMP-9水平,改善高血压血管重构,可作为高血压治疗的辅助药物。     

Oxidative stress in blood platelets from schizophrenic patients

Oxidative stress in blood platelets is observed in various diseases, including neuropsychiatric disorders. The aim of our study was to evaluate oxidative stress in blood platelets from patients with schizophrenic disorders by measuring the activity of the platelet antioxidative enzyme, superoxide dismutase (SOD), concomitant with the level of thiobarbituric acid reactive species (TBARS). In blood platelets obtained from schizophrenic patients (with paranoid schizophrenia according to DSM-IV criteria) and from healthy volunteers the level of reactive oxygen species was also measured via chemiluminescence. In resting blood platelets from schizophrenic patients the chemiluminescence was higher than in platelets from control subjects (P?<?0.05), but in thrombin-activated platelets an increase (about 53%) of chemiluminescence was observed, however this increase was lower than in thrombin-stimulated platelets from healthy subjects (101.5%). The results indicate that in platelets from schizophrenic patients generation of reactive oxygen species is enhanced. Moreover, we observed that SOD activity in blood platelets from schizophrenic patients was significantly lower than in control platelets and that a correlation exists between increased lipid peroxidation and inhibition of the activity of this antioxidative enzyme in schizophrenic platelets.     

Association between reactive oxygen metabolites and paraoxonase 1 activity during a physical activity increase intervention with older Japanese people

Aim: Considering the beneficial effects of physical activity on health and disease in older people, the aim of the present study was to investigate the changes in reactive oxygen metabolites and paraoxonase 1 (PON1) activity during an intervention period on increased physical activity among older people. Methods: Serum diacron reactive oxygen metabolites (d‐ROMs), PON1 activity and cardiometabolic variables were measured in 43 asymptomatic Japanese volunteers (18 men/25 women, mean age 68.9 years) in the pre‐ and post‐phase of a 6‐month intervention program aiming at a mild but sustained increase in physical activity. Results: While the d‐ROMs and PON1 activity levels were not significantly altered after the intervention, there was an inverse correlation between percentage changes of d‐ROMs and PON1 activity during this intervention period. Multiple regression analysis revealed their significant and inverse correlation as independent of percentage changes of the other cardiometabolic variables (β=?0.3, P < 0.05). Conclusions: The inverse d‐ROMs‐PON1 relationship may indicate the value of concurrent measurement of these two components of oxidation–antioxidation balance when studying the effects of physical activity in an older population. Further studies are necessary to confirm the observed relationship.     

Comprehensive geriatric assessment of elderly highlanders in Qinghai,China, III: Oxidative stress and aging in Tibetan and Han elderly highlanders

Background: Although there are several factors which may contribute to oxidative stress at high altitude, little is known about the association between oxidative stress and aging in the community‐dwelling elderly in the Tibetan Plateau. Methods: Reactive oxygen species (ROS) and comprehensive geriatric functions were examined among 235 community‐dwelling elderly subjects aged 60 years or more (146 Hans and 89 Tibetans). As a marker of ROS, the levels of reactive oxygen metabolites (ROM) were measured using the d‐ROM test. Results: The rate of dependence of basic activities of daily living (basic ADL) among Tibetan elderly highlanders was significantly higher than that among Han elderly highlanders. The d‐ROM level was higher among the Tibetan elderly than those among the Han elderly (Tibetan 465.6 ± 97.9 Carr U, Han 415.3 ± 72.0 Carr U, P = 0.003). The ROM level was higher among women than those among men. Stepwise multiple regression analysis showed that being Tibetan, female, and oxygen saturation were independent predictors of increasing d‐ROM level (Tibetan β, 0.241; female β, 0.206; oxygen saturation β, 0.218). The high levels of ROM (d‐ROM >500 Carr U) were significantly associated with dependence of basic ADL after adjustment for age, sex and ethnicity (odds ratio = 2.51, P = 0.028). Conclusion: The findings of this study imply the possibility that ROS is higher among Tibetan elderly highlanders than that of Han, which related to the geriatric items. Further studies are needed to show the impact of oxidative stress on the aging of highlanders.     

Critical role for oxidative stress, platelets, and coagulation in capillary blood flow impairment in sepsis

Sepsis is a complex multifaceted response to a local infectious insult. One important facet is the circulatory system dysfunction, which includes capillary bed plugging. This review addresses the mechanisms of capillary plugging and highlights our recent discoveries on the roles of NO, ROS, and activated coagulation in platelet adhesion and blood flow stoppage in septic mouse capillaries. We show that sepsis increases platelet adhesion, fibrin deposition and flow stoppage in capillaries, and that NADPH oxidase-derived ROS, rather than NO, play a detrimental role in this adhesion/stoppage. P-selectin and activated coagulation are required for adhesion/stoppage. Further, platelet adhesion in capillaries (i) strongly predicts capillary flow stoppage, and (ii) may explain why severe sepsis is associated with a drop in platelet count in systemic blood. Significantly, we also show that a single bolus of the antioxidant ascorbate (injected intravenously at clinically relevant dose of 10 mg/kg) inhibits adhesion/stoppage. Our data suggest that eNOS-derived NO at the platelet-endothelial interface is anti-adhesive and required for the inhibitory effect of ascorbate. Because of the critical role of ROS in capillary plugging, ascorbate bolus administration may be beneficial to septic patients whose survival depends on restoring microvascular perfusion.     

The effect of endurance exercise on both skeletal muscle and systemic oxidative stress in previously sedentary obese men

Background:

Obesity is associated with low-grade systemic inflammation, in part because of secretion of proinflammatory cytokines, resulting into peripheral insulin resistance (IR). Increased oxidative stress is proposed to link adiposity and chronic inflammation. The effects of endurance exercise in modulating these outcomes in insulin-resistant obese adults remain unclear. We investigated the effect of endurance exercise on markers of oxidative damage (4-hydroxy-2-nonenal (4-HNE), protein carbonyls (PCs)) and antioxidant enzymes (superoxide dismutase (SOD), catalase) in skeletal muscle; urinary markers of oxidative stress (8-hydroxy-2-deoxyguanosine (8-OHdG), 8-isoprostane); and plasma cytokines (C-reactive protein (CRP), interleukin-6 (IL-6), leptin, adiponectin).

Methods:

Age- and fitness-matched sedentary obese and lean men (n=9 per group) underwent 3 months of moderate-intensity endurance cycling training with a vastus lateralis biopsy, 24-h urine sample and venous blood samples taken before and after the intervention.

Results:

Obese subjects had increased levels of oxidative damage: 4-HNE (+37% P⩽0.03) and PC (+63% P⩽0.02); evidence of increased adaptive response to oxidative stress because of elevated levels of copper/zinc SOD (Cu/ZnSOD) protein content (+84% P⩽0.01); increased markers of inflammation: CRP (+737% P⩽0.0001) and IL-6 (+85% P⩽0.03), and these correlated with increased markers of obesity; and increased leptin (+262% P⩽0.0001) with lower adiponectin (−27% P⩽0.01) levels vs lean controls. Training reduced 4-HNE (−10% P⩽0.04), PC (−21% P⩽0.05), 8-isoprostane (−26% P⩽0.02) and leptin levels (−33% P⩽0.01); had a tendency to decrease IL-6 levels (−21% P=0.07) and IR (−17% P=0.10); and increased manganese SOD (MnSOD) levels (+47% P⩽0.01).

Conclusion:

Endurance exercise reduced skeletal muscle-specific and systemic oxidative damage while improving IR and cytokine profile associated with obesity, independent of weight loss. Hence, exercise is a useful therapeutic modality to reduce risk factors associated with the pathogenesis of IR in obesity.     

Melatonin long-lasting beneficial effects on pulmonary vascular reactivity and redox balance in chronic hypoxic ovine neonates

Pulmonary arterial hypertension of the neonate (PAHN) is a pathophysiological condition characterized by maladaptive pulmonary vascular remodeling and abnormal contractile reactivity. This is a multifactorial syndrome with chronic hypoxia and oxidative stress as main etiological drivers, and with limited effectiveness in therapeutic approaches. Melatonin is a neurohormone with antioxidant and vasodilator properties at the pulmonary level. Therefore, this study aims to test whether a postnatal treatment with melatonin during the neonatal period improves in a long-lasting manner the clinical condition of PAHN. Ten newborn lambs gestated and born at 3600 m were used in this study, five received vehicle and five received melatonin in daily doses of 1 mg kg⁻¹ for the first 3 weeks of life. After 1 week of treatment completion, lung tissue and small pulmonary arteries (SPA) were collected for wire myography, molecular biology, and morphostructural analyses. Melatonin decreased pulmonary arterial pressure the first 4 days of treatment. At 1 month old, melatonin decreased the contractile response to the vasoconstrictors K⁺, TX₂, and ET-1. Further, melatonin increased the endothelium-dependent and muscle-dependent vasodilation of SPA. Finally, the treatment decreased pulmonary oxidative stress by inducing antioxidant enzymes and diminishing pro-oxidant sources. In conclusion, melatonin improved vascular reactivity and oxidative stress at the pulmonary level in PAHN lambs gestated and born in chronic hypoxia.