Relationship between lung injury and lung lipid peroxidation caused by recurrent endotoxemia

We compared the relationship between lung lipid peroxidation and the histologic and physiologic changes seen after repeated doses of low dose endotoxin in unanesthetized sheep. Thirty-two sheep with lung lymph fistula were given from 1 to 10 doses of 1 micrograms/kg Escherichia coli endotoxin, 12 h apart. Animals were killed 5 h after 1, 3, 5, or 9 doses of endotoxin or 3 to 5 days after the tenth dose of endotoxin. The lipid peroxidation process was monitored by circulating conjugated dienes and lung tissue malondialdehyde (MDA) content. We found that conjugated dienes and MDA were increased after one dose of endotoxin corresponding in time with the increased prostanoid production and increased permeability. Acute lung inflammation was also evident histologically. Lipid peroxidation was not increased, however, when 3 to 7 doses were given. The permeability change was also markedly attenuated whereas severe lung inflammation was still present on histologic examination. After 9 doses, we noted a fourfold increase in lung tissue MDA that corresponded histologically with a marked mononuclear cell infiltration. Physiologic changes included a sustained 50% increase in oxygen consumption. However, lung lymph flow was not increased, again, reflecting lung inflammation with no change in lung vascular permeability. The MDA remained increased 5 days after the last dose of endotoxin along with a marked lung mononuclear cell infiltration. The lung MDA content corresponded with the level of increase in VO2, but not with changes in pulmonary vascular permeability. Conjugated dienes were increased only after the first injection of endotoxin. The lung lipid peroxidation process does not appear to correspond to physiologic or histologic lung changes after recurrent exposures to endotoxin.     

Phagocyte-induced lipid peroxidation of lung surfactant.

Surfactant therapy is given routinely to premature newborns with respiratory failure. However, alterations in surfactants have been shown to be a significant factor in some forms of respiratory failure in newborns in animal models of lung injury. To investigate whether antioxidant supplementation might help to protect exogenous surfactant from damage by oxygen free radicals, we examined the influence of vitamin E in combination with surfactant on superoxide production as estimated by the nitroblue tetrazolium reduction test, and measured surfactant peroxidation with a new colorimetric method with or without addition of superoxide dismutase (SOD) or vitamin E. Our results showed that surfactant interacts with free radicals; surfactant reduced superoxide production by neutrophils and was peroxidized when incubated with resting and with stimulated cells. Vitamin E supplementation decreased superoxide radical production and in a dose-dependent manner decreased surfactant peroxidation. The decrease in lipid peroxidation by SOD was not significant. These findings suggest that phagocytes induce lipid peroxidation of lung surfactant, a reaction that might be prevented by antioxidants.     

Role of subcutaneous tissue endotoxin in the production of prostanoid-induced lung injury: comparison with intravenous endotoxin response

Local injection of endotoxin into soft tissues of the flank results in hypoxia and pulmonary hypertension. Our purpose was to determine whether this was caused by tissue prostanoid production or production by the lung as is seen with endotoxemia. Twenty-six sheep were prepared with lung and flank tissue lymph fistulae. Thirteen sheep were given 2 micrograms/kg Escherichia coli endotoxin into the flank soft tissue, six of which were pretreated with ibuprofen, 12.5 mg/kg. Thirteen sheep were given intravenous endotoxin, 2 micrograms/kg, with six pretreated with ibuprofen. An early hypertensive phase was noted with both insults characterized by pulmonary hypertension, hypoxia, and increased lung lymph flow (QL). With subcutaneous tissue endotoxin, there was a significant increase in tissue lymph TxB2 and 6-keto-PGF1 alpha when compared to lung lymph and increased values in venous plasma compared to arterial plasma, indicating tissue to be the source. With intravenous endotoxin, lung lymph and aortic plasma levels were significantly higher than tissue lymph and venous plasma, respectively. The hypoxia, hypertension and increased prostanoids were prevented using ibuprofen. An increased lung permeability phase was noted with intravenous endotoxin but not with tissue endotoxin. As expected, this phase was not inhibited with ibuprofen and, therefore, not prostanoid-induced.     

砷中毒患者红细胞免疫功能与脂质过氧化的相关关系

目的 了解燃煤型砷中毒患者红细胞（RBC）免疫功能与脂质过氧化关系。方法 将燃煤型砷中毒患者分为轻、中、重3组，选择距病区12km外的非燃用砷煤居民作对照组，分别检测各组RBC免疫功能和血浆MDA、SOD、GSH-Px，并分别与对照组比较。结果 燃煤型砷中毒患者RBC免疫功能损伤RBC-ICR高于对照组，RBC-CbRR低于对照组，患者MDA高于对照组，而SOD、GSH-Px则低于对照组。结论 氧化自由基堆积造成脂质过氧化损伤，这可能是患者RBC免疫功能受损的重要原因。     

脂质和蛋白质过氧化与系统性红斑狼疮临床指标的相关性研究

目的 探讨脂质和蛋白质过氧化与系统性红斑狼疮(SLE)临床指标的相关性.方法 测定60例SLE患者与60名正常对照血浆中超氧化物歧化酶(SOD)的活动度、丙二醛(MDA)和蛋白质羰基的浓度.分析氧化航氧化指标与SLE病情活动及其他临床指标的相关性.结果 狼疮病例组和健康对照组相比,SOD活动度显著降低(P＜0.01),MDA和蛋白质羰基的浓度显著升高(P＜0.01).不同疾病活动度的SLE患者MDA、蛋白质羰基、SOD水平差异有统计学意义.机体的过氧化状态与SLE患者病程中出现的肾脏损伤和心血管病变存在一定联系.氧化/抗氧化指标与临床指标的相关性分析显示:氧化/氧化指标与抗核抗体、抗dsDNA抗体、C反应蛋白、低密度脂蛋白存在一定相关性.结论 SOD活动度的降低,MDA和蛋白质羰基浓度的升高提示SLE患者处于氧化应激状态,机体过氧化状态与SLE疾病活动和临床表现显著相关.     

Platelet heterogeneity. Relationship between buoyant density, size, lipid peroxidation and platelet age

Human platelets were separated into 2 density populations by repeated centrifugations of platelet-rich plasma at increasing gravitational force. The heaviest platelet fraction was rich in larger platelets. The lightest platelet fraction was rich in smaller platelets. In both fractions and in the platelet button, lipid peroxidation (malonaldehyde-MDA-production after addition of thrombin) was measured at basal condition, on the 1st, 3rd, 5th, 7th and 9th day after aspirin ingestion. At basal conditions and after ingestion of aspirin, MDA production was higher in the heavy-large platelets than in light-small ones, but a parallel increase of MDA production was observed in the light and in the heavy population and in the platelet button. The data are not compatible with the hypothesis that platelet density and size are age-related. Aspirin inhibits platelet lipid peroxidation by permanently acetylating their cyclooxygenase and if the heaviest platelets were the young ones, lipid peroxidation should reappear sooner in them.     

Relationship between insulin resistance and lipid peroxidation and antioxidant vitamins in hypercholesterolemic patients

BACKGROUND: Several studies have reported that insulin resistance and compensatory hyperinsulinemia increased lipid peroxidation, suggesting the linking to each other. We investigated the relationships between insulin resistance index HOMA-IR and lipid peroxidation, plasma antioxidant status in non-diabetic, hypercholesterolemic patients. METHODS: We measured the urinary excretion of 8-epi-prostaglandin F(2)(alpha)(PGF(2)(alpha)) levels as a measure of lipid peroxidation in vivo, total radical trapping antioxidant potential (TRAP) and fat-soluble antioxidant vitamins in 76 non-diabetic subjects with hypercholesterolemia (mean age 59 years, 25 males and 51 females). Insulin resistance was evaluated by homeostasis model assessment (HOMA-IR) derived from fasting glucose and insulin concentrations. RESULTS: HOMA-IR was positively correlated with the urinary excretion of PGF(2)(alpha) (r=0.222, p<0.05) and negatively correlated with the TRAP (r=-0.211, p<0.05) in total subjects. Furthermore, there were significant inverse relationships between HOMA-IR and lipid corrected fat-soluble vitamins such as beta-carotene (r=-0.297, p<0.01) and gamma-tocopherol (r=-0.243, p<0.05) and also significant inverse relation was found between lipid corrected beta-carotene and the urinary PGF(2)(alpha)excretion (r=-0.205, p<0.05). When total subjects were divided into three groups according to tertiles of HOMA-IR, significant differences in urinary PGF(2)(alpha)excretion (p<0.05) and lipid corrected beta-carotene (p<0.005) among the three groups were observed. The highest HOMA-IR group had the higher levels of urinary PGF(2)(alpha)excretion and lower levels of plasma beta-carotene compared with the lowest HOMA-IR group. CONCLUSION: Our data showed that the insulin resistance of hypercholesterolemic patients increased oxidative stress and negatively influenced plasma antioxidant system. These results provide evidence in understanding mechanism linking insulin resistance and oxidative stress accompanied by reduced antioxidant system.     

Enhanced pulmonary and systemic response to endotoxin in transgenic sickle mice

Some suggest that sickle cell disease (SCD) is associated with a "proinflammatory state" that predisposes patients to acute chest syndrome in the setting of triggering factors. Conflicting data emerged when inflammation markers in SCD were compared with healthy individuals. Therefore, we examined transgenic sickle and control mice at baseline and with endotoxin (LPS) intraperitoneal injection to determine whether a proinflammatory state truly exists. At baseline, sickle mice had elevated levels of circulating leukocytes and soluble vascular cell adhesion molecule 1 (sVCAM-1). No other differences were observed at baseline or in response to saline. However, LPS challenge was associated with significant increases in mortality (p<0.05), airway tone (p<0.03), serum and bronchoalveolar lavage levels of cytokines tumor necrosis factor-alpha (p<0.03), interleukin-1beta (p<0.02), and sVCAM-1 (p<0.01) in sickle mice compared with control subjects. Furthermore, 4 hours after LPS, microarray analysis identified 413 genes differentially expressed in the sickle mice (n=5) compared with only 7 in the control subjects (n=5). No difference in lung parenchyma was observed by light microscopy. This enhanced response to LPS suggests that the sickle red blood cell confers a subclinical "proinflammatory state." This enhanced response to inflammatory insult, particularly by adhesion molecules such as sVCAM-1, could play a role in the increased susceptibility to pulmonary dysfunction that has been observed clinically in SCD.     

Relationship between endotoxin antibody levels and portal systemic shunt evaluated by per-rectal portal scintigraphy

Abstract The reasons for the high frequency of endotoxaemia in cirrhosis, whether poor liver function or abnormal portal circulation, are not known. Accurate measurement of endotoxin itself is difficult. Instead, in this study an enzyme-linked immunosorbent assay was used to measure levels of IgA, IgG and IgM antibodies to endotoxin in patients with chronic liver disease and underlying hepatic viral infection. The relationships between the results and clinical symptoms or the presence of a portal systemic shunt were investigated. The median level of IgA antibodies was not different in patients with chronic hepatitis and those with cirrhosis, and the same was found for IgM, but the median level of IgG antibodies was significantly higher in the patients with cirrhosis. When patients with cirrhosis were grouped by the presence or absence of ascites or hepatocellular carcinoma, no significant difference was observed in any of these antibody levels. However, in cirrhotic patients with varices, the level of IgG antibodies to endotoxin was significantly higher than in patients without varices. For evaluation of the portal systemic shunt, the per-rectal portal shunt index was calculated. There was a significant correlation ( R = 0.431, P < 0.001) between the per-rectal portal shunt index and the level of IgG antibodies to endotoxin. That is, the degree of abnormality in the portal haemodynamics was correlated with the level of IgG antibodies to endotoxin in patients with liver disease.     

Aging and the kidney: adjusting treatment to physiologic change

Changes in renal physiology and function with aging--eg, morphologic changes, decreased renal blood flow, altered glomerular filtration rate, and blunted tubule response--put the elderly patient at higher risk for adverse effects of drug therapy and for undertreatment. A thorough understanding of the many age-related alterations in kidney function will lead to the selection of appropriate therapy for elderly patients and, thus, the prevention of common problems such as volume depletion, infection, hyponatremia, metabolic acidosis, and excessive dosing.     

Relationship between advanced glycation end products and increased lipid peroxidation in semen of diabetic men

Aims

Majority of diabetic male patients have disturbances in their reproductive systems. However, the mechanisms underlying these disturbances are largely unknown. Since advanced glycation end products (AGE) have a key role in oxidative stress and cell damage in diabetic complications, we hypothesize that AGEs may be involved sperm lipid peroxidation.

Methods

Total AGEs in seminal plasma of 32 diabetic and 35 non-diabetic men was determined by spectrofluorimetric method and carboxy methyl lysine (CML) level was assayed using ELISA. Contents of lipid peroxidation in sperm and seminal plasma were determined by thiobarbituric acid reaction. Total antioxidant capacity (TAC) was measured by a colorimetric assay.

Results

Total AGEs were found significantly higher in seminal plasma of diabetic men than non-diabetic group (p < 0.001) whereas no significant differences in seminal plasma CML values between two groups was observed. Moreover, sperm and seminal plasma lipid peroxidation were significantly higher in diabetic subjects than non-diabetic men and a significantly lower TAC was detected in diabetic group compare to non-diabetics.

Conclusions

These results showed an increment in AGEs in seminal plasma of diabetic subjects and may suggest a key role for glycation process and increased oxidative stress in reproductive system dysfunction.     

Association between lipid peroxidation and inflammation in obstructive sleep apnoea.

In the present study, the authors examined the relationship between lipid peroxidation and inflammation in patients with obstructive sleep apnoea (OSA). A total of 40 obese patients with OSA were studied, along with 18 obese and 12 lean subjects without OSA. Overnight excretion of 8-isoprostane in urine and serum levels of high-sensitivity C-reactive protein (hsCRP) were measured. In addition, the effects of 3 months' treatment with nasal continuous positive airway pressure (nCPAP) were studied in 20 obese patients with moderate-to-severe OSA. Overnight urinary excretion of 8-isoprostane and serum levels of hsCRP were significantly higher in patients with moderate-to-severe OSA compared with patients with mild OSA and obese or lean subjects without OSA. Overnight urinary excretion of 8-isoprostane significantly correlated with apnoea-hypopnoea index, duration of hypoxia during sleep, body mass index, and serum levels of hsCRP in patients with OSA. The severity of OSA was an independent factor predicting the urinary excretion of 8-isoprostane. nCPAP significantly decreased urinary excretion of 8-isoprostane and serum levels of hsCRP. In conclusion, these results suggest that both obstructive sleep apnoea severity and obesity can independently contribute to elevations in urinary excretion of 8-isoprostane. Therefore, obstructive sleep apnoea may increase the risks of cardiovascular morbidity in obese patients.     

Impaired response of VLDL lipid and apoB secretion to endotoxin in the fasted rat liver

Bacterial infection elicits hypertriglyceridemia attributed to increased hepatic production of very low-density lipoprotein (VLDL) particles and decreased peripheral metabolism. The mechanisms underlying VLDL overproduction in sepsis are as yet unclear, but seem to be fed/fasted state-dependent. To learn more about this, we investigated hepatocytes isolated from fasted rats, made endotoxic by 1 mg/kg lipopolysaccharide (LPS) injection, for their ability to secrete the VLDL protein and lipid components. The results were then related to lipogenesis markers and expression of genes critical to VLDL biogenesis. Endotoxic rats showed increased levels of serum VLDL-apoB (10-fold), -triglyceride (2-fold), and -cholesterol (2-fold), whereby circulating VLDL were lipid-poor particles. Similarly, VLDL-apoB secretion by isolated endotoxic hepatocytes was approximately 85% above control, whereas marginal changes in the output of VLDL-lipid classes occurred. This was accompanied by a substantial rise in apoB and a moderate rise in MTP mRNA levels, but with basal de novo formation and efficiency of secretion of triglycerides, cholesterol and cholesteryl esters. These results indicate that during periods of food restriction, endotoxin does not enhance lipid provision to accomplish normal lipidation of overproduced apoB molecules, though this does occur to a sufficient extent to pass the proteasome checkpoint and secretion of lipid-poor, type 2 VLDL takes place.     

Evaluation of the causal relationship between crocidolite asbestos-induced lipid peroxidation and toxicity to macrophages

In vitro, crocidolite asbestos toxicity to macrophages is mediated by the production of reactive oxygen metabolites. We examined whether exposure of macrophages to crocidolite asbestos induced lipid peroxidation as measured by the thiobarbituric acid assay. When elicited mouse peritoneal macrophages were exposed to crocidolite, a dose- and time-dependent increase in lipid peroxidation breakdown products accompanied cell death. Superoxide dismutase plus catalase or deferoxamine prevented both lipid peroxidation and loss of viability caused by crocidolite. We tested whether crocidolite-induced lipid peroxidation was causally responsible for cell death. Macrophages were not killed by crocidolite when incubated with 10 mM 3-aminobenzamide. The level of thiobarbituric acid-reactive material was the same, however, for cells incubated with crocidolite in the presence or absence of 3-aminobenzamide. When macrophagaes were pretreated for 24 h with 25 microM vitamin E and then incubated with crocidolite, no thiobarbituric acid-reactive products were detected. Vitamin E, however, did not prevent crocidolite cytotoxicity. These results suggest that exposure of macrophages to crocidolite asbestos produces lipid peroxidation as measured by thiobarbituric acid-reactive products. This reaction, however, is not directly responsible for irreversible injury in this model system.     

Early pulmonary disease in systemic sclerosis: a comparison between carbon monoxide transfer factor and static lung compliance.

OBJECTIVES--Pulmonary disease is responsible for considerable morbidity and mortality in systemic sclerosis (SSc). Static lung compliance (Cst) has been observed to be decreased more often in SSc than the vital capacity, indicating that it is a sensitive measure of lung restriction. In this study Cst was compared with the carbon monoxide transfer factor (TLCO), a widely used measure of the function of the alveolar capillary unit, and with lung volumes in 59 patients with confirmed or suspected SSc. METHODS--Cst was calculated from the oesophageal pressure at different lung volumes and the TLCO was measured with the single breath method. RESULTS--The TLCO was found to be the earliest sign of pulmonary disease and was already decreased at a disease duration of one year or less. Surprisingly, no relation was found between the TLCO and smoking habits, nor the degree of peripheral vascular disease. The TLCO correlated with the Cst and vital capacity. CONCLUSIONS--An early pulmonary lesion can be identified in patients with SSc with decreased TLCO at a time when no fibrotic changes are manifested.     

Relationship between acute physiologic derangement and risk of death

Initial evidence from 481 acutely ill patients with 12 major life-threatening diseases suggests a consistent relationship between the magnitude of physiologic derangement and the patient's risk of death. These results were found in postoperative and nonoperative diseases, including gastrointestinal bleeding, intracranial bleeding, pneumonia, congestive heart failure, trauma and hemorrhagic shock. There appear to be substantial differences in the inherent risk of these diseases, but within each diagnosis, the impact of incremental increases in physiologic derangement on mortality appears to be similar. The existence of a uniform relationship in a variety of diagnoses could have important implications for the researcher and clinician wishing to evaluate outcome from intense medical care. It would allow more reproducible and precise stratification of patients by risk of death prior to therapy, thereby improving our understanding of the efficacy of new and existing treatments.     

Pentafraction reduces the lung lymph response after endotoxin administration in the ovine model.

For the past half-century, several high molecular weight compounds have been used for volume expansion during cardiopulmonary resuscitation. However, the effectiveness and side effects of these different expanders are varied. We have compared plasma, pentastarch, and a new product, pentafraction, for effective plasma volume expansion before and after tissue injury with endotoxin administration. In each group, eight range ewes instrumented with a Swan-Ganz, arterial, and venous catheters, and lung and flank lymphatic cannulas were compared. Each group received 15 ml/kg of either 6% pentafraction, 6% pentastarch, or plasma followed two hours later by 1.5 micrograms/kg/0.5 hr E. Coli endotoxin over 30 min. Data were collected for an additional 24 hr after endotoxin administration. Our results indicated a plasma volume expansion in all three groups. However, the prior administration of pentafraction significantly attenuated the increase in the lung lymph flow and early evaluation of systemic vascular resistance noted with endotoxin in comparison to the other two groups.     

Malondialdehyde in dried blood spots: a biomarker of systemic lipid peroxidation linked to cardiopulmonary symptoms and risk factors

BackgroundThere are few oxidative biomarkers that can be used in resource-limited settings (e.g., rural Africa) where blood collection facilities are lacking. This study aims to evaluate the potential of malondialdehyde (MDA) in dried blood spots (DBS) as a useful biomarker to monitor cardiopulmonary health.MethodsWe first conducted a cross-validation comparison of matched capillary DBS, plasma, and whole venous blood collected from nine healthy volunteers for the measurement of total MDA (free + conjugated) and C-reactive protein (CRP), a well-established biomarker of systemic inflammation. Then a field study was conducted in a rural Senegal with a population of 441 women routinely exposed to severe household air pollution, examining associations of MDA and CRP levels in 882 DBS with self-reported cardiopulmonary symptoms.ResultsIn the cross-validation study, CRP levels were strongly correlated across DBS, plasma, and whole blood. MDA levels were correlated between DBS and whole blood and were 1–2 orders of magnitude lower in plasma, suggesting that DBS MDA may reflect total oxidation levels in intracellular and extracellular compartments. In the field study, we observed significantly higher MDA levels in women with secondhand smoke exposure. An interquartile range increase in MDA concentration was associated with 27.0% (95% CI: 3.1–56.5%) and 21.1% (95% CI: −3.5% to 52.0%) increases in the incidence of chest tightness and breath difficulty, respectively. In contrast, CRP levels were not associated with worse outcomes or risk factors.ConclusionsThese results support the use of DBS as a convenient alternative to venous blood when MDA is measured as a biomarker for cardiopulmonary health risk.