Generation Of Reactive Oxygen Metabolites Research Articles

Functional response difference between diabetic/normal cancerous patients to inflammatory cytokines and oxidative stresses after radiotherapy.

Diabetes, which is considered as a chronic metabolic disorder leads to an increase in inflammatory cytokines and oxidative stresses. Studies have shown several functional differences in the oxidative stress and inflammatory cytokines responses in diabetic/normal cancerous patients candidate for radiotherapy. Also, radiotherapy as a cancer treatment modality is known as a carcinogen due to oxidative damage via generation of reactive oxygen metabolites and also causing inflammation of the tissue by increasing the inflammatory cytokines. Therefore, the consequence of diabetes on oxidative stress and increased inflammatory factors and synergistic effects of radiotherapy on these factors cause complications in diabetics undergoing radiotherapy. It is considered as one of the most interesting objectives to control inflammation and oxidative stress in these patients. This review aims to concentrate on the influence of factors such as MPO, MDA, IL-1β, and TNF-α in diabetic patients by emphasizing the effects related to radiation-induced toxicity and inflammation by proposing therapeutic approaches which could be helpful in reduction of the complications.

Halofuginone Alleviates Burn-Induced Hepatic and Renal Damage in Rats.

The aim of this study was to evaluate the possible protective effects of halofuginone on burn-induced oxidative injury of the liver and kidney. For the induction of burn, backs of Wistar albino rats were shaved and exposed for 10 seconds to water bath at 90°C, whereas rats in the control group were exposed for 10 seconds at 25°C. Rats were then administered either saline (1 ml/kg) or halofuginone (100 μg/kg/day) intraperitoneally and decapitated at the 24th hour (early burn) or on the 7th day (late burn). Serum concentrations of creatinine, blood urea nitrogen, alanine aminotransferase, and aspartate aminotransferase were determined. Renal and hepatic tissue samples were used for microscopic analysis, and glutathione, malondialdehyde, and myeloperoxidase activity and chemiluminescence levels were measured. Halofuginone treatment improved renal functions in late burn group and hepatic functions in early burn group as demonstrated by decreased serum creatinine, blood urea nitrogen, and alanine aminotransferase levels. Increased serum lactate dehydrogenase level measured in late phase was reduced by halofuginone treatment. Generation of reactive oxygen metabolites measured by chemiluminescence, indicating burn-induced renal and hepatic oxidative injury in both the early and late burn groups, was reduced by halofuginone. Increased hepatic malondialdehyde levels accompanied with high microscopic damage scores were reversed by halofuginone in early burn group, while depleted renal glutathione levels were replenished. The present findings demonstrate that halofuginone preserved renal and hepatic functions and alleviated oxidative tissue damage insulted by burn trauma, suggesting an anti-inflammatory and antioxidant potential for halofuginone in providing protection against burn-induced renal and hepatic injury.

Detection of reactive oxygen metabolites in malignant and adjacent normal tissues of patients with lung cancer

BackgroundDifferent types of reactive oxygen metabolites (ROMs) are known to be involved in carcinogenesis. Several studies have emphasized the formation of ROMs in ischemic tissues and in cases of inflammation. The increased amounts of ROMs in tumor tissues can either be because of their causative effects or because they are produced by the tumor itself. Our study aimed to investigate and compare the levels of ROMs in tumor tissue and adjacent lung parenchyma obtained from patients with lung cancer.MethodsFifteen patients (all male, mean age 63.6 ± 9 years) with non-small cell lung cancer were enrolled in the study. All patients were smokers. Of the patients with lung cancer, twelve had epidermoid carcinoma and three had adenocarcinoma. During anatomical resection of the lung, tumor tissue and macroscopically adjacent healthy lung parenchyma (control) that was 5 cm away from the tumor were obtained. The tissues were freshly frozen and stored at −20°C. The generation of ROMs was monitored using luminol- and lucigenin-enhanced chemiluminescence (CL) techniques.ResultsBoth luminol (specific for .OH, H2O2, and HOCl-) and lucigenin (selective for O2.-) CL measurements were significantly higher in tumor tissues than in control tissues (P <0.001). Luminol and lucigenin CL measurements were 1.93 ± 0.71 and 2.5 ± 0.84 times brighter, respectively, in tumor tissues than in the adjacent parenchyma (P = 0.07).ConclusionIn patients with lung cancer, all ROM levels were increased in tumor tissues when compared with the adjacent lung tissue. Because the increase in lucigenin concentration, which is due to tissue ischemia, is higher than the increase in luminol, which is directly related to the presence and severity of inflammation, ischemia may be more important than inflammation for tumor development in patients with lung cancer.

Status of Systemic Oxidative Stress during Therapeutic Hypothermia in Patients with Post-Cardiac Arrest Syndrome

Therapeutic hypothermia (TH) is thought to be due to the downregulation of free radical production, although the details of this process remain unclear. Here, we investigate changes in oxidative stress and endogenous biological antioxidant potential during TH in patients with post-cardiac arrest syndrome (PCAS). Nineteen PCAS patients were enrolled in the study. Brain temperature was decreased to the target temperature of 33°C, and it was maintained for 24 h. Patients were rewarmed slowly (0.1°C/h, <1°C/day). The generation of reactive oxygen metabolites (ROMs) was evaluated in plasma samples by d-ROM test. Plasma antioxidant capacity was measured by the biological antioxidant potential (BAP) test. Levels of d-ROMs and BAP levels during the hypothermic stage (33°C) were suppressed significantly compared with pre-TH induction levels (P < 0.05), while both d-ROM and BAP levels increased with rewarming (33–36°C) and were correlated with brain temperature. Clinical monitoring of oxidative stress and antioxidant potential is useful for evaluating the redox state of patients undergoing TH after PCAS. Additional therapy to support the antioxidant potential in the rewarming stage following TH may reduce some of the observed side effects associated with the use of TH.

Heme Oxygenase-1 Expresion in Gastric Mucosa and Liver after Burns: Preliminary Immunohistochemical Study

Objective: Generation of reactive oxygen metabolites (ROM) and oxidative stress are crucial in pathogenesis of thermal skin injury. Heat shock proteins such as HSP32 known as heme oxygenase-1 (HO-1) possesses antioxidant, anti-inflammatory, and vasodilative properties and play an important role in the protecting of tissues from several stresses. In this immunohistochemical study, we have assessed the constitutive expression of HO-1 in normal gastric mucosa and liver and tested the hypothesis that its expression in these tissues is upregulated in thermal skin injury characterized by increased production of ROMs and other pro-inflammatory mediators. We used malondialdehyde (MDA) as a marker of oxidative stress and tumor necrosis factor (TNF) α as a marker of inflammatory response in burn rat model. Methods: HO-1 expression in formalin-fixed sections was assessed by peroxidase anti-peroxidase immunohistochemistry using a polyclonal rabbit anti-HO-1 as primary antibody. TNF-α in plasma was quantified using enzyme-linked immunosorbent assay (ELISA) kit. Spectrometric method was used for plasma and tissue MDA assay. Results:Immunohistochemical staining revealed HO-1 expression in all groups. Staining scores for HO-1 in endothelial cells in both gastric mucosa and liver were increased with 32% (p

Effects of Hydrogen Sulfide on Oxidative Stress, TNF- and #945; Level and Kidney Histological Changes in Cisplatin Nephrotoxicity in Rat

Cisplatin (CP) is an anticancer drug that enhances renal generation of reactive oxygen metabolites, lipid peroxidation and inflammation. This study examined the effect of hydrogen sulfide on lipid peroxidation content, tissue antioxidant enzyme activities and tumor necrosis factor (TNF-α) in cisplatin nephrotoxic rats. Thirty male Sprague-Dawley rats were divided into three groups of 10 rats in each group: control, nephrotoxic and nephrotoxic groups that received single dose 100 µmol/kg NaHS (i.p.). Nephrotoxicity was induced by a single intraperitoneally injection of cisplatin (6 mg/kg b.w.). Five days after cisplatin injection kidney tissue samples removed for laboratory analyses and light microscopy evaluation. Lipid peroxidation content and activities of catalase, superoxide dismutase, glutathione peroxidase and TNF-α were measured in kidney homogenate supernatants. Statistical differences were assessed with one-way ANOVA by SPSS followed by Tukey\'s t-test. P

Cation dyshomeostasis and cardiomyocyte necrosis: the Fleckenstein hypothesis revisited

An ongoing loss of cardiomyocytes to apoptotic and necrotic cell death pathways contributes to the progressive nature of heart failure. The pathophysiological origins of necrotic cell loss relate to the neurohormonal activation that accompanies acute and chronic stressor states and which includes effector hormones of the adrenergic nervous system. Fifty years ago, Albrecht Fleckenstein and coworkers hypothesized the hyperadrenergic state, which accompanies such stressors, causes cardiomyocyte necrosis based on catecholamine-initiated excessive intracellular Ca(2+) accumulation (EICA), and mitochondrial Ca(2+) overloading in particular, in which the ensuing dysfunction and structural degeneration of these organelles leads to necrosis. In recent years, two downstream factors have been identified which, together with EICA, constitute a signal-transducer-effector pathway: (i) mitochondria-based induction of oxidative stress, in which the rate of reactive oxygen metabolite generation exceeds their rate of detoxification by endogenous antioxidant defences; and (ii) the opening of the mitochondrial inner membrane permeability transition pore (mPTP) followed by organellar swelling and degeneration. The pathogenesis of stress-related cardiomyopathy syndromes is likely related to this pathway. Other factors which can account for cytotoxicity in stressor states include: hypokalaemia; ionized hypocalcaemia and hypomagnesaemia with resultant elevations in parathyroid hormone serving as a potent mediator of EICA; and hypozincaemia with hyposelenaemia, which compromise antioxidant defences. Herein, we revisit the Fleckenstein hypothesis of EICA in leading to cardiomyocyte necrosis and the central role played by mitochondria.

The effects of β-glucan on iron levels and lipid peroxidation in intra-abdominal sepsis in rats

Sepsis is defined as a systemic response of organisms to microorganisms and toxins. Sepsis is associated with the enhanced generation of reactive oxygen metabolites, leading to multiple organ dysfunctions. β-glucan is accepted to be one of the most powerful immune response modifiers. The aim of this study was to investigate the putative protective effect of β-glucan on changes of iron and malondialdehyde (MDA) levels in various tissue and blood after experimental sepsis in rats. Sepsis was induced by cecal ligation and perforation (CLP) in 32 male Wistar albino rat. To evaluate this, rats were divided into four groups as sham operated, β-glucan treated sham operated, CLP and β-glucan treated CLP. Sixteen hours after operation, rats were decapitated and MDA and iron levels were measured in the liver, kidney, heart, diaphragm tissues and blood. Also, whole tissue histopathology was evaluated by a light microscope. The results demonstrate that sepsis significantly decreased iron levels of all tissues and blood. The decrease in tissue iron levels and the increase MDA levels demonstrate the role of trace elements and free radicals in sepsis-induced tissue damage. Our results indicate that the given dose of β-glucan was probably insufficient to prevent sepsis-induced organ injury.

Genetic Dissection of a Mitochondria-Vacuole Signaling Pathway in Yeast Reveals a Link between Chronic Oxidative Stress and Vacuolar Iron Transport

Deletion of two homologous genes, MRS3 and MRS4, that encode mitochondrial iron transporters affects the activity of the vacuolar iron importer Ccc1. Ccc1 levels are decreased in Deltamrs3Deltamrs4 cells, but the activity of the transporter is increased, resulting is reduced cytosolic iron. Overexpression of CCC1 in Deltamrs3Deltamrs4 cells results in a severe growth defect due to decreased cytosolic iron, referred to as the mitochondria-vacuole signaling (MVS) phenotype. Mutants were identified that suppress the MVS growth defect, and FRA1 was identified as a gene that suppresses the MVS phenotype. Overexpression of FRA1 suppresses altered transition metal metabolism in Deltamrs3Deltamrs4 cells, whereas deletion of FRA1 is synthetically lethal with Deltamrs3Deltamrs4. Fra1 binds to Tsa1, which encodes a thioredoxin-dependent peroxidase. Deletion of TSA1 or TRR1 is synthetically lethal in Deltamrs3Deltamrs4 cells, suggesting that Deltamrs3Deltamrs4 cells generate reactive oxygen metabolites. The generation of reactive oxygen metabolites in Deltamrs3Deltamrs4 cells was confirmed by use of the reporter molecule 2',7'-dichlorodihydrofluorescein diacetate. These results suggest that mitochondria-induced oxidant damage is responsible for activating Ccc1 and that Fra1 and Tsa1 can reduce oxidant damage.

Increased oxidative stress in barn swallows from the Chernobyl region

The Chernobyl nuclear accident produced the largest unintended release of radionuclides in history, with dramatic consequences for humans and other organisms. Exposure to ionizing radiation is known to reduce circulating and stored levels of specific antioxidants in birds and humans, thus potentially increasing oxidative stress. However, overall effects of radioactive exposure on oxidative status have never been investigated in any free ranging vertebrate. We measured plasma antioxidant capacity and concentration of reactive oxygen metabolites in adult barn swallows (Hirundo rustica) from colonies with variable background radiation levels in the Chernobyl region in Ukraine and Belarus. We predicted that antioxidants would decrease while reactive oxygen metabolites would increase with exposure to increasing levels of radiation at the breeding sites. Consistent with this expectation, radiation level positively predicted plasma concentration of reactive oxygen metabolites, whereas no significant covariation was found with non-enzymatic plasma antioxidant capacity. An index of oxidative stress was also larger in barn swallows exposed to high contamination levels. Thus, radioactive contamination appeared to be responsible for the increased generation of reactive oxygen metabolites and the imbalance between reactive oxygen metabolites and non-enzymatic plasma antioxidant capacity.

Amelioration of Cisplatin-Induced Nephrotoxicity in Rats by Tetramethylpyrazine, a Major Constituent of the Chinese Herb Ligusticum wallichi

Nephrotoxicity of the anticancer drug, cisplatin (CP) involves enhanced renal generation of reactive oxygen metabolites and lipid peroxidation caused by decreased levels of antioxidants and antioxidant enzymes. Tetramethylpyrazine (TMP) is known to act as a strong antioxidant. Therefore, in the present work, we aimed at testing the possible protective or palliative effect of TMP on CP nephrotoxicity in rats. TMP was given orally at a dose of 80 mg . kg(- 1) . day(- 1) for 7 days. Some of these rats were given a single intraperitoneal injection of CP (or vehicle) at a dose of 6 mg/kg on Day 6 of treatment. Animals were sacrificed 6 days after CP (or vehicle) treatment, and blood, urine, and kidneys were obtained. Nephrotoxicity was assessed biochemically by measuring creatinine and urea in serum, reduced glutathione (GSH) concentration in renal cortex, by urinalysis, and histopathologically by light microscopy. CP significantly increased the concentration of urea and creatinine (P < 0.05) by about 128% and 170%, respectively; increased urine volume and N-acetyl-beta-D-glucosaminidase (NAG) activity; and significantly decreased osmolality and protein concentrations. CP treatment reduced GSH by about 34% (P < 0.05) and superoxide dismutase (SOD) and total antioxidant activity (TOX) by about 28% and 21%, respectively (P < 0.05). TMP pretreatment significantly mitigated all of these effects. Sections from saline- and TMP-treated rats showed apparently normal proximal tubules. However, kidneys of CP-treated rats had a moderate degree of necrosis. This was markedly reduced when CP was given after pretreatment with TMP. CP cortical concentration was not significantly altered by TMP treatment. The results suggest that TMP ameliorated the histological, physiological, and biochemical indices of nephrotoxicity in rats. Pending further pharmacological and toxicological studies, TMP may potentially be useful as a nephroprotective agent.

Oxytocin alleviates hepatic ischemia–reperfusion injury in rats

Various mechanisms have been proposed for the pathogenesis of postischemic hepatic injury, including the generation of reactive oxygen metabolites. Oxytocin (OT) possesses antisecretory, antiulcer effects, facilitates wound healing and has anti-inflammatory properties. Hepatic ischemia-reperfusion (I/R)-injury was induced by inflow occlusion to median and left liver lobes ( approximately 70%) for 30 min of ischemia followed by 1h reperfusion in female Sprague-Dawley rats under anesthesia. I/R group (n=8) was administered intraperitoneally either OT (500 microg/kg) or saline at 24 and 12 h before I/R and immediately before reperfusion. Sham-operated group that underwent laparotomy without hepatic ischemia served as the control. Rats were decapitated at the end of reperfusion period. Hepatic samples were obtained for the measurement of myeloperoxidase (MPO) activity, malondialdehyde (MDA), glutathione (GSH) and collagen levels and histopathological analysis. Tumor necrosis factor-alfa (TNF-alpha) and transaminases (SGOT, SGPT) were assayed in serum samples. I/R injury caused significant increases in hepatic microscopic damage scores, MPO activity, collagen levels, transaminase, serum TNF-alpha levels. Oxytocin treatment significantly reversed the I/R-induced elevations in serum transaminase and TNF-alpha levels and in hepatic MPO and collagen levels, and reduced the hepatic damage scores. OT treatment had tendency to abolish I/R-induced increase in MDA levels, while GSH levels were not altered. These results suggest that OT has a protective role in hepatic I/R injury and its protective effect in the liver appears to be dependent on its inhibitory effect on neutrophil infiltration.

Pro-inflammatory feedback activation cycle evoked by attack of Vibrio cholerae cytolysin on human neutrophil granulocytes

Vibrio cholerae cytolysin (VCC) is a pore-forming toxin that is secreted in precursor form (pro-VCC) and requires proteolytic cleavage in order to attain membrane-permeabilizing properties. Pro-VCC can be activated both in solution and membrane-bound state. Processing of membrane-bound pro-VCC can in turn be achieved through the action of both cell-associated and soluble proteases. The current investigation describes the interaction of VCC with human neutrophil granulocytes. It is shown that pro-VCC binds to these cells and is cleaved by cell-bound serine proteases. Membrane permeabilization leads to granulocyte activation, as witnessed by the generation of reactive oxygen metabolites and liberation of granule constituents. A mutant toxin with unaltered binding properties but devoid of pore-forming activity did not elicit these effects. The secreted proteases cleave and activate further bound- and non-bound pro-VCC. A positive feedback loop is thus created that results in enhanced cytotoxicity towards both the targeted granulocytes and towards bystander cells that are not primarily killed by the protoxin. Thus, activation of neutrophil granulocytes by VCC fuels a positive feedback cycle that will cripple immune defence, augment inflammation, and enhance the cytotoxic action of the toxin on neighbouring tissue cells.

Inhibitory effect of stobadine on FMLP‐induced chemiluminescence in human whole blood and isolated polymorphonuclear leukocytes

The chemiluminescence (CL) technique with luminol and isoluminol was used to characterize the effect of stobadine on reactive oxygen metabolites (ROM) generation in human whole blood and in isolated polymorphonuclear leukocytes (PMNL) stimulated with N-formyl-methionyl-leucyl-phenyl-alanine (FMLP). In whole blood and in isolated PMNL, stobadine in the concentrations of 1, 10 and 100 micromol/L significantly inhibited the CL signal after FMLP, which activated predominantly extracellular generation of ROM. The same concentrations of stobadine were effective on CL in a cell-free system. On the other hand, myeloperoxidase (MPO) liberation was decreased by stobadine only in the concentration of 100 micromol/L. The results showed stobadine to act as a potent inhibitor/scavenger of extracellularly produced ROM in human PMNL and indicated interference of stobadine with ROM as well as with signalling events resulting in NADPH-oxidase activation and MPO liberation.

Protection against cisplatin-induced nephrotoxicity by Spirulina in rats

Cisplatin (CP)-induced nephrotoxicity is associated with the increased generation of reactive oxygen metabolites and lipid peroxidation in kidney, caused by the decreased levels of antioxidants and antioxidant enzymes. The purpose of this study was to evaluate the role of Spirulina, blue-green alga with antioxidant properties, in the protection of cisplatin-induced nephrotoxicity in rat. Rats were treated with CP (6 mg/kg bw, single dose, intraperitoneally). Spirulina (1,000 mg/kg) was administered orally for 8 days and CP treatment was given on day 4. Nephrotoxicity was assessed, 6 days after the CP treatment, by measuring plasma urea, creatinine, urinary N-acetyl-(D-glucose-aminidase) (beta-NAG) and histopathology of kidney. Rats treated with CP showed marked nephrotoxicity as evidenced from the significant elevation in plasma urea, creatinine and urinary beta-NAG. Histological assessment revealed marked proximal tubular necrosis and extensive epithelial vacuolization in the kidney of CP-treated rats. Superoxide dismutase, catalase and glutathione peroxidase were decreased and lipid peroxidation was increased in kidney tissue. Pretreatment with Spirulina protected the rats from CP-induced nephrotoxicity. The rise in plasma urea, creatinine, urinary beta-NAG, plasma and kidney tissue MDA and histomorphological changes were significantly attenuated by Spirulina. In vitro studies using human ovarian cancer cells revealed that Spirulina did not interfere with the cytotoxic effects of CP on tumor cells. In summary, Spirulina significantly protected the CP-induced nephrotoxicity through its antioxidant properties.

Counteraction of Adriamycin-Induced Oxidative Damage in Rat Heart by Selenium Dietary Supplementation

Many reports indicate that dietary selenium, potentially increasing the activity of glutathione peroxidase, could offer protection against free-radical-induced damage. The effects of diets moderately enriched in selenium, as sodium selenite or as a lyophilized selenium-rich food, were studied in rats. Adriamycin, an anticancer drug causing a free-radical-mediated cardiotoxicity, was administered intraperitoneally to some rats. The onset of an oxidative damage was indicated by the increase in the plasma level of reactive oxygen metabolites coupled to a decrease in the total antioxidant activity but without modification of glutathione peroxidase activity, which were observed in all rats, independent of the dietary treatment. On the contrary, in the heart, selenium supplementation caused an increase in the total antioxidant activity, glutathione concentration, and glutathione peroxidase and catalase activities leading to a decreased generation of reactive oxygen metabolites. These results clearly indicate that a moderate Se dietary supplementation counteracts adriamycin-induced cardiotoxicity by preservation of endogenous antioxidants.

Streptococcus pyogenes bacteria modulate membrane traffic in human neutrophils and selectively inhibit azurophilic granule fusion with phagosomes

We recently reported that the human pathogen Streptococcus pyogenes of the M1 serotype survives and replicates intracellularly after being phagocytosed by human neutrophils. These data raised the possibility that the generation of reactive oxygen metabolites by neutrophils, and the release of microbicidal molecules from their azurophilic and specific granules into phagosomes, can be modulated by S. pyogenes bacteria expressing surface-associated M and/or M-like proteins. We now demonstrate, using flow cytometry, immunofluorescence microscopy and transmission electron microscopy, that live wild-type S. pyogenes, after internalization by human neutrophils, inhibits the fusion of azurophilic granules with phagosomes. In contrast, azurophilic granule-content is efficiently delivered to phagosomes containing bacteria not expressing M and/or M-like proteins. Also, when heat-killed wild-type bacteria are used as the phagocytic prey, fusion of azurophilic granules with phagosomes is observed. The inhibition caused by live wild-type S. pyogenes is specific for azurophilic granule-phagosome fusion, because the mobilization of specific granules and the production of reactive oxygen species are induced to a similar extent by all strains tested. In conclusion, our results demonstrate that viable S. pyogenes bacteria expressing M and M-like proteins selectively prevent the fusion of azurophilic granules with phagosomes.

Endoplasmic Reticulum Stress–Associated Caspase 12 Mediates Cisplatin-Induced LLC-PK1 Cell Apoptosis

Reactive oxygen metabolites are important mediators in cisplatin-induced apoptosis in renal tubular epithelial cells (LLC-PK1). Mitochondria have been implicated to play a principal role in cisplatin-induced apoptosis. Caspase 12, an endoplasmic reticulum (ER)-specific caspase, participates in apoptosis under ER stress. Cytochrome P450 system is crucial to the generation of reactive oxygen metabolites and is present at high concentration in the ER. The direct role of caspase 12 in any model of renal injury has not previously been described. In this study, cleavage of procaspase 12 preceded that of caspases 3 and 9 after cisplatin treatment of LLC-PK1 cells. The active form of caspase 8 was not detected throughout the course of study. Preincubation of the LLC-PK1 cells with the caspase 9 inhibitor did not attenuate caspase 3 activation and provided no significant protection. Caspase 3 inhibitor provided only modest protection against cisplatin-induced apoptosis. LLC-PK1 cells that were transfected with anti-caspase 12 antibody significantly attenuated cisplatin-induced apoptosis. Taken together, these data indicate that caspase 12 plays a pivotal role in cisplatin-induced apoptosis. It is proposed that the oxidative stress that results from the interaction of cisplatin with the ER cytochrome P450 leads to activation of procaspase 12, resulting in apoptosis.

Estrogen Protects the Liver and Intestines Against Sepsis-Induced Injury in Rats

Sepsis is commonly associated with enhanced generation of reactive oxygen metabolites, leading to multiple organ dysfunctions. The aim of this study was to examine the putative protective role of estradiol against sepsis-induced oxidative organ damage. Sepsis was induced by cecal ligation and puncture method in Wistar albino rats. Sham-operated (control) and sepsis groups received saline or estradiol propionate (10 mg/kg) intraperitoneally immediately after the operation and at 12 h. Twenty-four hours after the surgery, rats were decapitated and malondialdehyde, glutathione levels, and myeloperoxidase activity were determined in the liver and ileum, while oxidant-induced tissue fibrosis was determined by collagen contents. Tissues were also examined microscopically. Serum aspartate aminotransferase, alanine aminotransferase levels, and lactate dehydrogenase were measured for the evaluation of liver functions and tissue damage, respectively. Tumor necrosis factor-alpha was also assayed in serum samples. In the saline-treated sepsis group, glutathione levels were decreased significantly, while the malondialdehyde levels, myeloperoxidase activity, and collagen content were increased in the tissues (P < 0.01 to P < 0.001), suggesting oxidative organ damage, which was also verified histologically. In the estradiol-treated sepsis group, all of these oxidant responses were reversed significantly (P < 0.05 to P < 0.01). Liver function tests and tumor necrosis factor-alpha levels, which were increased significantly (P < 0.001) following sepsis, were decreased (P < 0.05 to P < 0.001) with estradiol treatment. The results demonstrate the role of oxidative mechanisms in sepsis-induced tissue damage, and estradiol, by its antioxidant properties, ameliorates oxidative organ injury, implicating that treatment with estrogens might be applicable in clinical situations to ameliorate multiple organ damage induced by sepsis.

Oxytocin Protects Against Sepsis-Induced Multiple Organ Damage: Role of Neutrophils

Sepsis, commonly associated with enhanced generation of reactive oxygen metabolites, leads to multiple organ dysfunctions. The neurohypophyseal hormone oxytocin (OT), released during social contact, was recently shown to modulate the immune and inflammatory processes. We investigated the protective role of OT against sepsis-induced pelvic inflammation. Under anesthesia, sepsis was induced in female Sprague-Dawley rats (200-250 g) by cecal ligation and perforation method. Sham-operated rats served as controls. Either saline or OT (1 mg/kg) was given subcutaneously immediately after and at the 16th hour, and rats were decapitated at the 24th hour of sepsis induction. Colon, uterus, and liver samples were obtained for the histopathological analysis of damage and for the measurement of myeloperoxidase (MPO) activity, indicating neutrophil infiltration, malondialdehyde (MDA), indicating lipid peroxidation, and glutathione (GSH), a key antioxidant, levels. Colonic, uterine and liver MDA levels in the sepsis group were significantly increased (P < 0.01-P < 0.001), while colonic and uterine GSH levels were decreased (P < 0.05-P < 0.01) when compared to the control group. OT treatment reversed the MDA and GSH levels back to the control levels, while hepatic GSH levels were not altered. MPO activity in the colon and liver was increased by sepsis (P < 0.05-P < 0.001) while OT treatment abolished the elevated MPO activity. Collagen levels in the uterus and liver were increased by sepsis (P < 0.01) and OT treatment reduced the collagen levels in both tissues (P < 0.01-P < 0.05). Serum TNF-alpha levels were significantly increased by sepsis (P < 0.001) and OT treatment abolished the sepsis-induced increase in TNF-alpha levels. OT protects against sepsis-induced oxidative damage by acting as an antioxidant agent and its protective effect in the colon and liver appears to be dependent on its inhibitory effect on neutrophil infiltration. Our results suggest that OT may have a therapeutic value in limiting sepsis-associated multiple organ damage.