allopurinol and Burns

Topics: Animals; Burns; Humans; Hyperuricemia; Superoxides; Uric Acid; Wounds and Injuries; Xanthine; Xanthine Oxidase

A skin burn is a common traumatic injury that results in both local tissue damage and a systemic mediator-induced response. There is evidence of both local and systemic oxidant changes manifested by lipid peroxidation in animal burn models and also in burned man. Both increased xanthine oxidase and neutrophil activation appear to be the oxidant sources. Animal studies have also demonstrated decreased burn edema, and also decreased distant organ dysfunction with the use of antioxidants, suggesting a cause-and-effect relationship, which needs to be tested in man. Smoke inhalation injury, a chemical injury to the airways caused by incomplete products of combustion, is frequently seen in conjunction with a body burn. Lipid peroxidation, both in lung and in distant organs, is also seen with this injury. The combined body burn and smoke inhalation injury lead to a marked increase in mortality rate and also an increase in the degree of generalized oxidant release and lipid peroxidation. Although data in man are limited, the available information, along with that from animal research on burns and smoke inhalation, indicates oxidants may well play a key role, and antioxidants may be of clinical therapeutic use.

Topics: Burns; Free Radicals; Hemodynamics; Humans; Lipid Peroxidation; Lung; Oxidants; Smoke Inhalation Injury; Xanthine Oxidase

Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis Syndrome (TENS) are severe and potentially lethal adverse drug reactions characterized by acute inflammation of the skin, mucous membranes, and ocular surface that typically occurs within weeks of a culprit drug ingestion. The purpose of this study is to report a retrospective trend analysis of SJS spectrum diagnoses and associated culprit drugs in patients admitted to the Loyola University Medical Center (LUMC) Burn Unit, the major referral center in the Chicagoland region for patients with SJS disease spectrum.. The electronic medical records (EMR) of 163 patients with a diagnosis of SJS/TENS admitted to the LUMC Burn Unit from 2000 to 2019 were reviewed. Clinical data in addition to the well-established algorithm of drug causality for epidermal necrolysis (ALDEN) allowed us to identify the single most probable culprit drug in 131 cases.. From 2000 to 2019, the most common spectrum classification was TENS (48.1%), followed by SJS (33.6%) and SJS-TEN Overlap Syndrome (18.3%). Anticonvulsants were found to be the most probable culprit class in 30% of cases followed by Trimethoprim-Sulfamethoxazole in 19% of cases. Beta-lactams were the most probable culprit class in 11% of cases while NSAIDs and allopurinol were each the most probable culprit class/drug in 8.4% of cases.. This is one of the largest single center series of SJS/TENS cases in the United States. Further study into culprit drug distribution by region as well as continuous monitoring of trends is crucial in order to advise prescribing practices.

Topics: Allopurinol; Anti-Inflammatory Agents, Non-Steroidal; Anticonvulsants; beta-Lactams; Burn Units; Burns; Humans; Retrospective Studies; Stevens-Johnson Syndrome; Trimethoprim, Sulfamethoxazole Drug Combination

In this study, we used a clinically relevant rat scald burn model to determine the treatment effects of cerium nitrate (CN) for stabilizing burn eschars through reduction of damage-associated molecular patterns (DAMPs), inflammatory cytokines, and bioburden. Forty-two male Sprague-Dawley rats were anesthetized before undergoing a scald burn at 99°C for 6 seconds to create a 10% full-thickness burn. The test groups included sham burn, burn with water bathing, and burn with CN bathing. End point parameters included circulating DAMPs, proinflammatory cytokines, tissue myeloperoxidase activity, and quantification of resident flora in burn skin. The high mobility group protein box 1 was found to be elevated in burn animals at postoperative days (POD) 1 and 7. CN significantly alleviated the increase (P < .05 at POD 1 and P < .01 at POD 7). CN also lessened the heightened levels of hyaluronan in burn animals (P < .05 at POD 7). Additionally, CN significantly reduced the burn-induced increases in interleukin-1β, growth-regulated oncogene/keratinocyte chemoattractant, and macrophage inflammatory protein-1α in burn wounds. The anti-inflammatory effect of CN was also demonstrated in its ability to mitigate the upregulated circulatory xanthine oxidase/dehydrogenase and increased tissue neutrophil infiltration in burn animals. Last, CN suppressed postburn proliferation of resident skin microbes, resulting in a significant 2-log reduction by POD 7. In conclusion, these results suggest that CN attenuates the burn-induced DAMPs, tissue inflammatory responses, and regrowth of resident skin flora, all of which collectively could improve the quality of burn eschar when applied at the point of injury in prolonged field care situations.

Topics: Alarmins; Animals; Biomarkers; Burns; Cerium; Cytokines; Disease Models, Animal; Male; Neutrophils; Rats; Rats, Sprague-Dawley; Stem Cells; Xanthine Oxidase

Toxic epidermal necrolysis (TEN) is a serious drug eruption that results in death in approximately 25% to 50% of patients. There is controversy over whether SCORTEN accurately predicts mortality or if treatment interventions such as intravenous immunoglobulin (IVIg) can alter mortality.. We sought to determine whether SCORTEN accurately predicts mortality in this cohort, whether IVIg improved survival, and which drugs and medical comorbidities impacted mortality.. We summarize our experience prospectively over 5 years and 82 patients. Patients either received supportive care, intravenous immunoglobulin, or cyclosporine as treatment. All patients had a SCORTEN on admission, an offending drug on record, and a list of medical comorbidities.. Of the 82 patients, 29% died from TEN. SCORTEN accurately predicted mortality in this cohort with an area under the curve (AUC) of 0.83 in a receiver operator curve (ROC) analysis. A Kaplan-Meier curve did not show improved mortality if patients received IVIg versus supportive care (P = .9). Medications most often responsible for TEN were trimethoprim/sulfamethoxazole, followed by anticonvulsants, nonsteroidal anti-inflammatories, and allopurinol.. This prospective cohort study design is not as ideal as patients presenting for a randomized controlled trial.. SCORTEN was an accurate predictor of mortality in this cohort. Age older than 40 years, the presence of metabolic syndrome and/or gout, higher body surface area involvement, higher SCORTEN, and higher number of medical comorbidities statistically significantly increased risk of death. IVIg did not significantly alter mortality. Although the highest number of cases was due to trimethoprim/sulfamethoxazole, the greatest proportion of deaths was due to allopurinol.

Topics: Adult; Aged; Allopurinol; Anti-Inflammatory Agents, Non-Steroidal; Anticonvulsants; Antimetabolites; Area Under Curve; Burn Units; Burns; Comorbidity; Drug Combinations; Female; Humans; Immunoglobulins, Intravenous; Kaplan-Meier Estimate; Male; Middle Aged; Predictive Value of Tests; Prospective Studies; ROC Curve; Stevens-Johnson Syndrome; Sulfadoxine; Trimethoprim; Young Adult

Nitric oxide (NO) is an important signal molecule in many types of cells and tissues. Efficiently balanced NO production was noted to play an important role in the healing of burns. However, the exact pathophysiological role of NO in burns and its potent relation with clinical and laboratory parameters has not been elucidated.. A cohort of 23 burn patients followed for 5 days were enrolled. NO, antioxidant capacity (AC), NO synthase (NOS) activity and xanthine oxidase (XO) activity were indirectly determined by fluorophotometer. Multiple regression against total burn surface area (TBSA), age, weight, height, proximity of septic episode, hemoglobin, white blood cells, percent of neutrophils, platelets, glucose, urea, potassium, sodium and albumin was performed.. Elevation of NO, XO and AC levels is observed from day 2 (p<0.00001), day 4 (p=0.005) and day 6 (p=0.036), respectively. At the end of follow-up period (day 6), NO production was found to independently correlate with TBSA, glucose levels and percent of neutrophils (p=0.0004), AC with age, hemoglobin and glucose levels (p=0.012), and NOS with proximity of septic episode and glucose levels (p=0.027).. NO production exerts its prophylactic effect from the first 24h after burn, and is independently correlated with severe injury, enhanced neutrophil motivation and augmented glucose levels, thus possibly representing a response to stress. This need might trigger induction of XO and salvage of antioxidants, as suggested by their rise at a later stage. These data underline that an effort to compromise stress and to administer antioxidants could be a priority in the treatment of these patients.

Topics: Adult; Antioxidants; Blood Glucose; Burns; Cohort Studies; Female; Follow-Up Studies; Humans; Leukocyte Count; Male; Middle Aged; Nitric Oxide; Nitric Oxide Synthase; Trauma Severity Indices; Xanthine Oxidase

Extensive burn injury leads to production of free radicals subsequent to massive fluid resuscitation, which in turn increases the risk of acute lung injury. Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one), a novel free radical scavenger, is clinically effective in improving the prognosis after cerebral infarction. However, the effect of edaravone against extensive burn injury has not been tested. Objected To evaluate whether edaravone can reduce free radical precursors in a 30% burn model in rats.. Prospective, randomized controlled experiment.. Animal basic science laboratory.. Male Wistar rats weighing 200 to 220 g.. All rats (n = 10) were given a 30% full-thickness burn according to the Walker and Mason method. Immediately after the burn, edaravone was injected into the rats (n = 5) intraperitoneally at a dose of 9 mg/kg. One hour after burn injury, blood and tissue samples were collected to analyze free radical changes of serum and tissue malondialdehyde (MDA) and xanthine oxidase (XOD) and lung white blood cells.. Statistical significance was found between nontreatment and edaravone treatment relative to serum MDA (mean +/- SD, 2.50 +/- 0.54 vs 1.74 +/- 0.29 nmol/mL), serum XOD (mean +/- SD, 5.04 +/- 1.67 vs 2.26 +/- 0.83 U/L), tissue MDA (mean +/- SD, 1268.7 +/- 289.9 vs 569.1 +/- 135.9 nmol/mg protein), tissue XOD (mean +/- SD, 256.3 +/- 58.1 vs 50.96 +/- 19.60 mU/g tissue), lung white blood cells (mean +/- SD, 3088 +/- 1144 vs 1542 +/- 575 mU/g tissue), and lung XOD (mean +/- SD, 428.3 +/- 210.5 vs 81.8 +/- 36.0 nmol/mg protein).. Edaravone treatment induces significant reduction of free radical precursors and their metabolites compared with controls in burn rats. This suggests that edaravone could be helpful in the clinical treatment of large burns.

Topics: Animals; Antipyrine; Burns; Disease Models, Animal; Edaravone; Free Radical Scavengers; Free Radicals; Lung; Male; Malondialdehyde; Prospective Studies; Random Allocation; Rats; Rats, Wistar; Xanthine Oxidase

Both experimental and clinical studies have shown that oxygen-derived free radicals rise in the plasma after thermal injury and participate in the pathogenesis of tissue damage. Hence, various antioxidant molecules have been used in treatment of burn injury both experimentally and clinically. Caffeic acid phenethyl ester (CAPE), an active component of propolis from honeybee hives, is known to have potent antioxidant property. The purpose of the present study was to investigate the effects of CAPE on oxidative stress in plasma of burned rats. Experiment was designed in three groups of rats with 20% full-thickness burn: (a) sham burn (n = 7); (b) burn only (n = 22); (c) burn + treatment with CAPE (n = 22). Plasma levels of malondialdehyde (MDA), nitric oxide (NO) and the activities of xanthine oxidase (XO), and superoxide dismutase (SOD) were used as both bio-indicators of oxidant status and determinant of antioxidant effect of CAPE. They were assessed by biochemical methods at 1st, 3rd, 7th, and 14th post-burn days. In conclusion, CAPE was shown to possess antioxidant activity by saving SOD activity, preventing XO activity and decreasing the levels of MDA, and NO. Our study showed that CAPE may be beneficial in burn injury.

Topics: Animals; Antioxidants; Burns; Caffeic Acids; Lipid Peroxidation; Male; Malondialdehyde; Nitric Oxide; Oxidative Stress; Phenylethyl Alcohol; Random Allocation; Rats; Rats, Wistar; Reactive Oxygen Species; Xanthine Oxidase

This study aimed to evaluate the relation between apoptosis of enterocytes and oxygen-free radical injury in scalded rats with delayed resuscitation as well as the role of antioxidants in the prevention of enterocyte apoptosis.. For this study, 150 male Wistar rats were divided randomly into four groups representing early resuscitation (ER), delayed resuscitation (DR), N-acetylcysteine (NAC) treatment, and allopurinol (Allo) treatment. The animals were subjected to a 30% total body surface area, full-thickness scald. Fluid therapy was started 6 hours after the injury in the DR and treatment groups. Apoptosis of enterocytes was identified by DNA fragmentation (ap%), DNA agarose gel electrophoresis, and terminal deoxynucleotidyl transferace (TdT)-mediated dUPT-biotin nick end labeling (TUNEL). The contents of malondialdehyde (MDA), total sulfhydryl (TSH), and nonprotein sulfhydryl (NPSH) and the activity of xanthine oxidase in intestinal mucosa were determined after the burn in the four groups.. Apoptosis of enterocytes increased significantly in all the groups. The animals in the DR group showed an earlier and greater increase in ap% than the animals in the ER group. Similar results were seen for electrophoresis, TUNEL assay, and levels of MDA, xanthine oxidase (XO), TSH, and NPSH. Treatment with NAC was associated with a decrease in ap% and MDA, but not XO, as compared with the levels in the DR group, whereas treatment with Allo was associated with a decrease in MDA and XO, but not ap%. Delayed resuscitation was associated with significant decreases in TSH and NPSH, as compared with the levels in the ER group, whereas both the NAC and Allo groups had significantly higher levels of TSH and NPSH than the DR group.. Significant apoptosis of enterocytes was induced by oxidative stress in the intestinal mucosa after a burn in rats. The findings show that NAC blunted intestinal apoptosis induced by oxygen-free radical, which was generated in the process of ischemia-reperfusion injury after a burn because of delayed resuscitation.

Topics: Acetylcysteine; Allopurinol; Animals; Apoptosis; Burns; DNA Fragmentation; Enterocytes; Glutathione; Ilium; In Situ Nick-End Labeling; Intestinal Mucosa; Male; Oxidative Stress; Rats; Rats, Wistar; Reactive Oxygen Species; Reperfusion Injury; Resuscitation; Shock; Xanthine Oxidase

To determine xanthine oxidase and superoxide dismutase activities, lipid peroxidation, protein carbonylation, and total radical-trapping antioxidant parameter in survivors and nonsurvivors patients with severe burn injury.. Prospective, comparative observational study in an intensive care unit, burn division, in a trauma hospital.. Twenty-five consecutive patients who met the established criteria for severe burn injury (total burn surface area of more than 30%).. Plasma thiobarbituric acid reactive species and protein carbonyls levels were significantly higher in nonsurvivors than in survivors at 0 and 6 h. Elevated xanthine oxidase activity at 0 h was associated with adverse outcome after burn injury. In contrast, plasma superoxide dismutase activity and total radical-trapping antioxidant parameter did not differ significantly between nonsurvivors and survivors at any time point.. For the first time we demonstrate the value of oxidative parameters, namely thiobarbituric acid reactive species, protein carbonyls, and xanthine oxidase activity, in identifying burn patients with a poor prognosis. Whether these parameters are merely markers of clinical course, or whether they signal specific deleterious effects of oxidative stress during the burn injury remains to be elucidated.

Topics: Adult; Biomarkers; Blood Proteins; Burns; Critical Care; Female; Humans; Lipid Peroxidation; Male; Oxidation-Reduction; Prognosis; Prospective Studies; Superoxide Dismutase; Thiobarbiturates; Xanthine Oxidase

We measured the amount of edema and the free radical production in burn-injured skin and the serum histamine levels, as well as changes in dermal interstitial fluid pressure.. Thirty-six Wistar rats with 20% total body surface area burns of different depth were resuscitated by lactated Ringer's solution intravenously. The rats were divided into a deep burn (DB) group (n = 12), a superficial dermal burn (SDB) group (n = 12), and a sham burn (Sham) group (n = 12). Dermal interstitial fluid hydrostatic pressure (Pif), total skin water and xanthine oxidase activity, and serum histamine levels were measured until 60 minutes postburn.. In the DB group, dermal Pif significantly fell to -35.9 +/- 11.0 and -40.9 +/- 7.0 mm Hg at 10 and 15 minutes postburn, respectively (p < 0.05); it returned to preburn values at 50 minutes postburn. In the SDB group, dermal Pif was slightly negative but did not markedly change. Total skin water was significantly higher than that of the DB and the Sham groups; however, in the SDB group, serum histamine and dermal xanthine oxidase were significantly higher than in the DB group at 15, 30, and 45 minutes postburn (p < 0.05).. The fluid-resuscitated DB produced a more negative dermal Pif than the SDB, but less dermal edema. In contrast, the SDB appeared to mainly generate dermal edema formation by wound free radical production and serum histamine release. The dermal Pif is one of the factors associated with edema formation immediately after deep burns. However, an increase in vascular permeability associated with oxygen radical production plays a more important role in dermal edema formation than does dermal Pif.

Topics: Animals; Body Water; Burns; Edema; Extracellular Space; Free Radicals; Histamine; Rats; Rats, Wistar; Xanthine Oxidase

Thermal trauma has a direct effect on mast cells, triggering the secretion of histamine. This secretion leads to an enhanced xanthine oxidase activity and an increased production of reactive oxygen species (ROS), the latter being produced after burns through differing mechanisms. As ROS have been shown to have deleterious effects on cellular membranes, a lesion of the mast cell membrane could close the circle of autoinjury due to the vasoactive actions of mast cell mediators. Our studies were designed to assess the potentiality of ROS as stimulators of mast cell degranulation after burns by comparing two groups of rats treated, respectively, with SOD and saline solution after a scald injury. Plasma levels of tryptase and histamine were analyzed as markers of mast cell activity. A comparison of the mean increases of tryptase between baseline and 3-h postburn levels in the two groups shows significant differences (p < 0.001) (control: 0.13+/-0.04, SOD: 0.03+/-0.01). When comparing the mean increases between the baseline and 3 h postburn levels of histamine in the two groups, significant differences were also found (p < 0.001) (control group: 2.70+/-0.57. SOD group: 1.22+/-0.32). The lower levels of histamine and tryptase induced by SOD provides indirect evidence that ROS are involved in the process, causing the release of such mediators by mast cells, which may in turn suggest that ROS can act as stimulators of mast cell degranulation in burns.

Topics: Animals; Biomarkers; Burns; Cell Degranulation; Chymases; Disease Models, Animal; Histamine; Male; Mast Cells; Rats; Rats, Wistar; Reactive Oxygen Species; Serine Endopeptidases; Superoxide Dismutase; Systemic Inflammatory Response Syndrome; Tryptases; Xanthine Oxidase

This experiment was designed to study the reactions in the surrounding area of burn injury that may lead to further necrosis in 24 h. To prevent extension of burn size into the tissue adjacent to burn injury, it was attempted to reduce progressive microvascular damage by different drugs (ibuprofen, allopurinol or cyclosporin A (CyA)) in a rat model. The burn model consisted of a row of four 10 x 20 mm burn areas separated by three unburned 5 x 20 mm skin bridges (interspaces). To evaluate microcirculation and perfusion of panniculus carnosus muscle which is beneath the burned area of skin, the radioactive agent, technetium-99m methoxyisobutylisonitrile (99Tc01-MIBI) was used 24 h after the burn. Capillary permeability of injured tissue was assessed by the wet and dry weight technique. In all study groups, interspaces showed higher uptakes of 99Tc01-MIBI between 40 and 95 per cent, in comparison with burn sites in the first 24 h following burn. Among the treated rats better results were obtained by allopurinol and CyA treatment that commenced before burn than ibuprofen. Wet and dry ratios were found to be significantly lower in interspaces in rats pretreated with allopurinol and CyA. Results of this experiment showed that neutrophils and free radical-mediated injury may be involved in the pathogenesis of local response to thermal injury, and allopurinol and CyA have some effects to prevent progressive ischemia, capillary compromise and oedema.

Topics: Allopurinol; Analysis of Variance; Animals; Anti-Inflammatory Agents, Non-Steroidal; Burns; Cyclosporine; Disease Models, Animal; Enzyme Inhibitors; Ibuprofen; Immunosuppressive Agents; Injury Severity Score; Male; Microcirculation; Rats; Rats, Wistar; Skin

Recent studies suggest that the cardiac dysfunction that occurs after a major burn is mediated by oxygen-derived free radicals. This hypothesis is based on the fact that superoxide dismutase and catalase, given with fluid resuscitation from burn injury, provided significant cardioprotection.. In this present study, rats received either enteral allopurinol or tungsten-enriched diets to determine if xanthine oxidase mediates postburn defects in cardiac contraction and relaxation. Polymorphonuclear neutrophil (PMN) were depleted to examine the contribution of PMN-derived factors to postburn cardiac dysfunction. Rats were divided into eight groups: groups 1 to 6 received regular chow, and groups 7 and 8 received tungsten-enriched diets for 14 days before study. Groups 2, 4, 6, and 8 were given a third-degree burn comprising 43 +/- 2 percent total body surface area and were resuscitated with Ringer's lactated solution for 24 hours (4 mL/kg/percent burn). In group 2, burned rats received fluid resuscitation alone; in group 4 (n = 10), rats were given allopurinol, 10 mg/kg daily by gastric lavage for five days preburn, group 6 (n = 11) received vinblastine (0.75 mg/kg) four days preburn, and group 8 (n = 11) received tungsten-enriched diets for 14 days before burn; sham burn controls included vehicle-treated (n = 10), allopurinol-treated (n = 8), PMN-depleted (n = 8), and tungsten-fed rats (n = 11) (groups 1, 3, 5, and 7, respectively).. Burn injury produced mild hypotension, hypothermia, bradycardia, and a significant decrease in left ventricular performance, despite aggressive fluid resuscitation (group 2). Allopurinol, tungsten-enriched diets, and PMN depletion partially attenuated burn-induced cardiac contractile dysfunction and improved left ventricular responsiveness to increases in preload, coronary flow rate and exogenous calcium.. Our data suggest that xanthine oxidase-derived oxygen metabolites and PMN-derived mediators contribute to postburn cardiac contractile deficits.

Topics: Allopurinol; Animals; Body Surface Area; Bradycardia; Burns; Coronary Circulation; Fluid Therapy; Heart Diseases; Hypotension; Hypothermia; Isotonic Solutions; Leukocyte Count; Male; Myocardial Contraction; Neutrophils; Rats; Rats, Sprague-Dawley; Ringer's Lactate; Tungsten; Ventricular Dysfunction, Left; Vinblastine; Xanthine Oxidase

We found that rats subjected to thermal skin injury (skin burn) had increased serum xanthine oxidase (XO) activities, increased serum complement activation (decreased serum CH50 levels), increased erythrocyte (RBC) fragility, increased lung neutrophil accumulation, and increased lung leak compared to sham-treated rats. Treatment of rats with allopurinol (an XO inhibitor) not only decreased serum XO activity, but also decreased complement activation, RBC fragility, lung neutrophil accumulation, and lung leak abnormalities in rats subjected to skin burn. We conclude that XO may contribute to acute lung injury and a number of events associated with the development of acute lung leak following skin burn.

Topics: Allopurinol; Animals; Burns; Capillary Permeability; Complement Activation; Erythrocyte Indices; Erythrocytes; Female; Lung; Neutrophils; Pulmonary Circulation; Rats; Rats, Sprague-Dawley; Skin; Xanthine Oxidase

51 burned patients with TBSA over 30% were studied prospectively. MOF developed in 17 of them. Postburn MOF occurred mainly in those with TBSA over 70%. Mortality of MOF was directly proportional to the number of organs involved. The incidence of pulmonary failure was the highest, and the highest mortality was attributed to renal failure. MOF occurring in the early stage was more related to burn shock, and those occurring in the late stage was predisposed mainly by infection. Oxygen free radicals play an important role in the genesis and development of postburn MOF. In this study, it was revealed that antiperoxidation ability declined, active oxygen was increased, and lipid peroxidation became excessive after the burn injury. It was also found that oxygen free radical-mediated effects produced more serious damages in patients with MOF than those without, and also more in those died than the survivors. The hypoxanthine-xanthine oxidase system was a significant source of oxygen radicals after the burn injury. There were also significant changes in plasma TXA2 and PGI2 levels postburn. The marked increase in TXA2/PGI2 ratio indicated imbalance between TXA2 and PGI2, which was correlated well with burn size and closely related to the development of postburn MOF. The excessive production of TXA2 might trigger or accelerate the formation of microaggregates and thromboxane, subsequently leading to visceral damages and failure.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Burns; Female; Humans; Male; Malondialdehyde; Multiple Organ Failure; Shock, Traumatic; Superoxide Dismutase; Thromboxane B2; Xanthine Oxidase

The role of oxygen-derived free radicals and lipid peroxidation in the pathogenesis of acute gastric mucosal erosion was investigated in rat models produced by burn shock stress, by treatment with regional hyperthermia, platelet activating factor, and compound 48/80, and by ischemia-reperfusion. In all experimental models, the increase in the gastric erosions and in TBA reactants in the gastric mucosa were significantly inhibited by the treatment with superoxide dismutase (SOD) and/or catalase. Pretreatment with allopurinol, a competitive inhibitor of xanthine oxidase, prevented considerably the gastric injury (a) induced by burn shock, (b) produced by treatment with compound 48/80, and (c) caused by ischemia-reperfusion. By the treatment with anti-rat neutrophil antibody, the gastric mucosal injuries induced by regional hyperthermia, platelet activating factor, and compound 48/80 were significantly inhibited; however, burn shock and ischemia-reperfusion injuries were not inhibited. These results suggest that oxygen-free radical and lipid peroxidation contribute to the formation of gastric mucosal lesions, and that the sources of oxygen radicals seem to be different among these experimental models.

Topics: Allopurinol; Animals; Burns; Female; Free Radical Scavengers; Free Radicals; Gastric Mucosa; Hyperthermia, Induced; Lipid Peroxidation; Male; Oxygen; p-Methoxy-N-methylphenethylamine; Platelet Activating Factor; Rats; Reperfusion Injury; Shock, Traumatic

Topics: Allopurinol; Animals; Burns; Deferoxamine; Hemodynamics; Ibuprofen; Lipid Peroxidation; Liver; Lung; Malondialdehyde; Sheep

Acute thermal injury of skin equivalent to second-degree injury and involving approximately 25% of total body surface results in a series of pathophysiologic events which lead to both local and distant tissue/organ injury. The distant effects involve intravascular hemolysis and acute lung injury, both of which can be attributed to complement activation and intravascular stimulation of neutrophils, resulting in oxygen radical production, which results in injury of red cells and pulmonary vascular endothelial cells. At the local site of thermal injury, the progressive increase in vascular permeability is linked to complement activation and histamine release, the outcome of which is interaction of histamine with xanthine oxidase, resulting in enhanced catalytic activity of the enzyme. Toxic oxygen products of xanthine oxidase, including H2O2 and its conversion product, the hydroxyl radical, appear to be linked to the damage of dermal vascular endothelial cells, resulting in progressive vascular permeability. The increased vascular permeability can be greatly attenuated by the use of inhibitors of xanthine oxidase, the inhibitor of histamine release (cromolyn), catalase, an iron chelator (deferoxamine), or scavengers of the hydroxyl radical. Interestingly, neutrophils appear to play little if any role in dermal vascular injury in this animal model of thermal trauma. Those studies suggest that pathophysiologic events following local thermal trauma are complex and involve a variety of mediator pathways.

Topics: Animals; Burns; Capillary Permeability; Complement Activation; Free Radicals; Models, Biological; Neutrophils; Rats; Skin; Xanthine Oxidase

We measured lipid peroxidation of plasma, lung, and liver in anaesthetized sheep after third-degree burns involving 30% of total body surface. Animals were resuscitated to baseline filling pressures with lactated Ringer's solution and killed 10 hours after burn. Six sheep were pretreated with ibuprofen (12.5 mg/kg) and five with allopurinol (50 mg/kg). We used conjugated dienes and malondialdehyde as measures of lipid peroxidation. Circulating conjugated dienes increased from a baseline of 0.48 +/- 0.06 to 0.64 +/- 0.05 after burn, while protein-rich burn tissue lymph flow increased up to eightfold. We also noted a significant increase in lung tissue malondialdehyde from 45 +/- 4 to 60 +/- 6 nmol/gm and liver malondialdehyde from 110 +/- 20 to 271 +/- 34 nmol/gm along with increased tissue neutrophil sequestration. Ibuprofen attenuated lung-tissue malondialdehyde but had no effect on lung inflammation, circulating lipid peroxides or burn edema, indicating that ibuprofen most likely decreased O2 radical release in lung tissue by the already-sequestered neutrophils. Allopurinol, possibly via xanthine oxidase inhibition, markedly attenuated burn QL and circulating lipid peroxides and prevented all pulmonary lipid peroxidation and inflammation, indicating that release of oxidant from burn tissue was in part responsible for local burn edema, as well as distant inflammation and oxidant release, the latter most likely from complement activation. Neither antioxidant decreased lipid peroxidation in the liver; this indicates that its mechanism of production was different from that seen in burn tissue, in plasma, or in the lung. An ischemic event resulting from a selective decrease in splanchnic blood flow may be the cause of the liver changes.

Topics: Allopurinol; Animals; Burns; Disease Models, Animal; Edema; Ibuprofen; Inflammation; Lipid Peroxidation; Liver; Lung; Malondialdehyde; Neutrophils; Oxygen Consumption; Reference Values; Sheep

Inasmuch as xanthine oxidase (XO)-derived O2* metabolites may contribute to vascular endothelial injury and Factor VIII antigen (F8Ag) is a component of endothelial cells, we hypothesized that XO-derived O2* might damage and cause distant organ endothelial cells to release F8Ag in rats subjected to skin burn. We found that serum F8Ag (ELISA) increased in the blood of rats subjected to skin burn (70 degrees C water to shaved dorsal skin for 30 seconds) but not in sham control rats (30 degrees C water). Coincidentally, F8Ag levels also decreased in lung and kidney tissue sections (immunofluorescent staining) of burned rats but not sham rats. Increases in circulating F8Ag levels and decreases in tissue F8Ag levels appeared to result from XO-derived O2* metabolites: F8Ag levels did not increase in the blood and did not decrease in the tissues of rats pretreated with allopurinol (a specific XO inhibitor, 50 mg/kg) or dimethylthiourea (DMTU) (a permeable O2* metabolite scavenger, 250 mg/kg). Lung injury as assessed by permeability studies (I125-albumin leak) paralleled changes in blood F8Ag levels in sham, burn, allopurinol-, and DMTU-treated groups. We conclude that skin burn causes a systemic vascular injury that can be inhibited by allopurinol or DMTU and is reflected by increased circulating and tissue decreased Factor VIII antigen levels. Release of Factor VIII antigen may serve as a valuable marker of distant organ injury in patients with skin burn.

Topics: Allopurinol; Animals; Antigens; Burns; Capillary Permeability; Endothelium; Factor VII; Kidney; Lung; Male; Osmolar Concentration; Pulmonary Circulation; Rats; Skin; Thiourea; von Willebrand Factor

The effect of free radicals scavengers (SOD and allopurinol) on the adherence of leukocytes and the blood flow of capillaries in spinotropizus muscle was observed in rats with burn shock. The changes in water content in heart, liver, lung, spleen, kidney and burned skin were measured. The survival time of the animals was recorded. The results showed that the number of the adherence of WBC decreased obviously, the amount of open capillaries increased, and the survival time of the animals with thermal injury prolonged by pretreating with SOD and allopurinol. The results of SOD were better than that of allopurinol. SOD also prevented the increase of water content in the lung and the burned skin, while allopurinol did not have this effect. It was shown that the therapeutic effect of SOD would appear if the medicine were given before or immediately after burn. However when SOD was administered half an hour after burn, there was no effect on adherence of WBC. These results confirm that superoxide free radical may be responsible for the adherence of WBC and hypoperfusion of microcirculation during burn shock. The scavengers have an important role in preventing microcirculatory disturbances, but it should be used as early as possible after thermal injury in order to block the response chain caused by free radicals.

Topics: Allopurinol; Animals; Burns; Female; Male; Microcirculation; Rats; Rats, Inbred Strains; Shock, Traumatic; Superoxide Dismutase

These studies were designed to assess pathophysiologic factors responsible for increased vascular permeability occurring in rat skin that has been thermally injured in vivo. Under the conditions employed, permeability changes and edema formation progressed over time, with peak changes occurring 60 minutes after thermal trauma. The plasma of thermally injured rats showed dramatic increases in levels of xanthine oxidase activity, with peak values appearing as early as 15 minutes after thermal trauma. Excision of the burned skin immediately after thermal injury significantly diminished the increase in plasma xanthine oxidase activity. The skin permeability changes were attenuated by treatment of animals with antioxidants (catalase, superoxide dismutase [SOD], dimethyl sulfoxide [DMSO], dimethylthiourea [DMTU]) or an iron chelator (deferoxamine), supporting the role of oxygen radicals in the development of vascular injury as defined by greatly increased vascular permeability. Studies employing laser Doppler velocimetry in thermally injured skin revealed a pronounced and sustained decrease in blood flow after thermal trauma, a pattern not affected by protective interventions. The failure of neutrophil depletion to protect against the vascular permeability changes and the protective effects of the xanthine oxidase inhibitors (allopurinol and lodoxamide tromethamine) suggest that xanthine oxidase is the most likely source of the oxygen radicals involved in edema formation. Lodoxamide was found to have some hydroxyl radical (HO.) scavenging ability (greater than that of allopurinol) but no iron chelating activity. Some of the protective effects of lodoxamide and allopurinol may be linked to their HO. scavenging ability. These data suggest that, in this model of thermal trauma, vascular injury defined by increased vascular permeability is, in part, related to the activation of xanthine oxidase and the generation of toxic oxygen metabolites that damage microvascular endothelial cells.

Topics: Animals; Burns; Edema; Enzyme Inhibitors; Free Radicals; Hydroxides; Hydroxyl Radical; Microcirculation; Oxygen; Rats; Skin; Xanthine Oxidase

The pathogenesis of burn edema in the skin of rats appears to be related to a role for histamine, xanthine oxidase and oxygen radicals. Histamine and its metabolic derivatives increase the catalytic activity of xanthine oxidase (but not xanthine dehydrogenase) in rat plasma and in rat pulmonary artery endothelial cells. In thermally injured rats levels of plasma histamine and xanthine oxidase rise in parallel, in association with increases in uric acid. Burn edema is greatly attenuated by treatment of rats with the mast cell stabilizer, cromolyn, by complement depletion and by treatment with the H2 receptor antagonist, cimetidine, but is unaffected by neutrophil depletion. These studies suggest the following pathogenesis of burn edema: thermal trauma causes complement activation with anaphylatoxin release and mast cell secretion of histamine, leading to enhancement of xanthine oxidase activity and increased production of oxygen radicals which damage endothelial cells.

Topics: Animals; Burns; Cimetidine; Complement Inactivator Proteins; Complement System Proteins; Cromolyn Sodium; Edema; Elapid Venoms; Endothelium, Vascular; Histamine; Histamine H1 Antagonists; Hydroxides; Hydroxyl Radical; Kinetics; Male; Radioimmunoassay; Rats; Skin; Superoxides; Uric Acid; Xanthine Oxidase

A scald burn injury was applied to 22-23 per cent of the body surface area of anaesthetized rats. The cardiac output was 38-60 per cent lower in the burn injury group than in the control group; heart rate and mean arterial blood pressure were only slightly affected, but burn injury caused a significant increase in total peripheral resistance. The involvement of oxygen-free radicals in this immediate fall in cardiac output was investigated. Pretreatment with a blocker of free radical production, allopurinol or the infusion of the free radical scavengers superoxide dismutase plus catalase caused no cardiovascular improvement, suggesting that oxygen free radicals are not involved in the fall in cardiac output after burn injury. Allopurinol treatment, however, prevented the rise in total peripheral resistance seen after burn injury.

Topics: Allopurinol; Animals; Blood Pressure; Burns; Cardiac Output; Catalase; Female; Free Radicals; Half-Life; Hemodynamics; Rats; Rats, Inbred Strains; Stroke Volume; Superoxide Dismutase; Vascular Resistance

Complement activation resulting from local burn injury of skin and other soft tissues can be linked to systemic complications, such as intravascular hemolysis, neutrophil activation, and acute lung injury. This study was designed to clarify the relationship between cutaneous thermal injury, oxygen radical formation, and complement activation in vivo. A model for "selective" venous sampling from the area of a partial-thickness cutaneous burn over 25% to 30% of the total body surface in the rat was developed. Interventions involving oxygen radical scavengers, antioxidant enzymes, xanthine oxidase inhibitors, an iron chelator, complement depletion, and neutrophil depletion were used to probe the nature of the oxygen products involved in complement activation. Plasma from the area of burn was examined for total hemolytic complement activity, content of C5a-related chemotactic peptide, and relationship of oxygen products to appearance of this peptide. Xanthine oxidase inhibitors, hydroxyl radical scavengers, and complement depletion diminished the generation of C5a activity at the burn site, whereas neutrophil depletion was without effect. These data suggest that C5a activity may be related to oxygen products from xanthine oxidase. The catalase sensitivity and iron dependency of C5a generation suggest that hydroxyl radical may be related to complement activation and C5a appearance. This is the first report to directly link oxygen radical generation and complement activation in vivo.

Topics: Animals; Antioxidants; Burns; Chemotactic Factors; Complement Activation; Complement C5; Complement C5a; Complement System Proteins; Lymphocyte Depletion; Male; Neutrophils; Rats; Rats, Inbred Strains; Superoxides; Xanthine Oxidase

When dehydration, infection, and mechanical trauma are prevented, procedures (such as cooling and/or oral antithromboxane) designed to diminish ischemia in experimental zone-of-stasis burns have been associated with no or only minor improvement in wound healing. To test the hypothesis that ongoing skin damage occurring postburn (PB) may in part be due to release of oxygen-derived free radicals during the 16-hour through 4-day PB period of reperfusion in such burns, beginning immediately and for a period of 5 days PB, equal numbers of guinea pigs received: allopurinol 150 mg/kg PO q 6 h vs. placebo, dimethylsulfoxide (DMSO) 75% applied topically q 12 h vs. placebo, or yeast-derived superoxide dismutase coupled with polyethylene glycol (PEG-SOD, Pharmacia) 10,000 U (Fridovich) given IV q 8 h producing a concentration of 16 U/cc of plasma 8 hr after injection vs. placebo. Gross and histologic examination of wounds by a 'blinded' investigator at 1 week and 3 weeks PB revealed no difference between treatment and control groups when rates of re-epithelialization and frequencies of hair-follicle retention were compared. Using the dosages, routes, and model described, treatment of a zone-of-stasis burn with PO allopurinol (a xanthine oxidase inhibitor), topical DMSO (a scavenger of the hydroxyl radical), or IV PEG-SOD (a scavenger of the superoxide radical) during the first 5 days PB was associated with no increase in the rate of re-epithelialization or frequency of hair follicle retention at 1 and 3 weeks PB when compared with controls.

Topics: Allopurinol; Animals; Burns; Free Radicals; Guinea Pigs; Male; Skin; Succimer; Superoxide Dismutase; Superoxides; Wound Healing

The pathogenesis of burn shock syndrome involves the production of superoxide radicals which are first generated in the burned skin. They are responsible for an increase in vascular permeability with loss of plasma, which results in hemoconcentration and hypovolemia. The resulting systemic hypoperfusion leads to a generalized production of superoxide radicals and subsequent cellular damage. Prior administration of allopurinol or superoxide dismutase increases the survival rates of mice subjected to burn shock.

Topics: Allopurinol; Animals; Burns; Female; Free Radicals; Hematocrit; Hemodynamics; Mice; Pigmentation; Shock; Superoxide Dismutase; Superoxides; Urinary Bladder

Topics: Adult; Allopurinol; Burns; Critical Care; Drug Combinations; Emergencies; Female; Humans; Middle Aged; Phenylbutazone; Stevens-Johnson Syndrome; Sulfamethoxazole; Trauma Centers; Trimethoprim; Trimethoprim, Sulfamethoxazole Drug Combination