allopurinol and Respiratory-Distress-Syndrome

The evolutionarily conserved, cofactor-dependent, enzyme xanthine oxidoreductase exists in both cell-associated and circulatory forms. The exact role of the circulating form is not known; however, several putative physiological and pathological functions have been suggested that range from purine catabolism to a mediator of acute respiratory distress syndrome. Regulation of gene expression, cofactor synthesis and insertion, post-translational conversion, entry into the circulation, and putative physiological and pathological roles for human circulating xanthine oxidoreductase are discussed.

Topics: Acute Disease; Amino Acid Sequence; Animals; Blood Circulation; Gene Expression Regulation, Enzymologic; Humans; Molecular Sequence Data; Protein Processing, Post-Translational; Respiratory Distress Syndrome; Xanthine Dehydrogenase; Xanthine Oxidase

Topics: Animals; Gout; Humans; Lung; NADPH Oxidases; Reactive Oxygen Species; Respiratory Distress Syndrome; Uric Acid; Xanthine Dehydrogenase; Xanthine Oxidase

Topics: Adolescent; Allopurinol; Anemia, Hemolytic, Autoimmune; Anti-Bacterial Agents; Antineoplastic Combined Chemotherapy Protocols; Betacoronavirus; Combined Modality Therapy; Coronavirus Infections; COVID-19; Cytokine Release Syndrome; Daunorubicin; Fluid Therapy; Humans; Male; Methylprednisolone; Nitriles; Pandemics; Pneumonia, Viral; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Pyrazoles; Pyrimidines; Respiration, Artificial; Respiratory Distress Syndrome; SARS-CoV-2; Vincristine

[corrected] The goal of this experimental study was to investigate whether erdosteine has a protective effect against lung injury as a remote organ after hind-limb ischemia-reperfusion (I/R).. The rats were divided into three groups: control, I/R, and I/R + erdosteine. After the experimental procedure, nitric oxide (NO) levels, myeloperoxidase (MPO), adenosine deaminase (ADA), and the activities of xanthine oxidase (XO) were determined on the lung tissue. The levels of NO and activities of MPO were also measured on the bronchial alveolar lavage (BAL). In addition, the lung tissue was examined by histopathology.. The lung tissue ADA and XO activities were increased in the I/R group compared with the control group (P < 0.05). In the I/R group, the levels of NO were higher than the control group (P < 0.05), whereas the erdosteine treatment did not alter the NO levels (P < 0.05). The MPO activities increased after I/R in the I/R group compared to both control and I/R + erdosteine group (P < 0.05). The activity of MPO increased in the IR group in comparison with the control group in BAL (P < 0.05). The activity of MPO in the I/R + erdosteine group was significantly lower than the I/R group in BAL (P < 0.05). NO levels increased in all I/R groups compared to control group in BAL (P < 0.05). However, treatment of erdosteine significantly decreased NO levels compared to I/R group (P < 0.05). The animals of the I/R group had total destruction of normal alveolar structure with the intense presence of infiltrating neutrophils and mononuclear phagocytes in histopathological examination. The rat lung exhibited mild degrees of destruction in the erdosteine group.. As a result, erdosteine may be a protective effect for lung injury, decreasing oxidative stress and neutrophil accumulation after hind-limb I/R in rats.

Topics: Adenosine Deaminase; Animals; Antioxidants; Bronchoalveolar Lavage Fluid; Hindlimb; Male; Neutrophils; Nitric Oxide; Oxidative Stress; Peroxidase; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Respiratory Distress Syndrome; Thioglycolates; Thiophenes; Xanthine Oxidase

Xanthine oxidoreductase (XOR) plays a prominent role in acute lung injury because of its ability to generate reactive oxygen species. We investigated the role of XOR in ventilator-induced lung injury (VILI). Male C57BL/6J mice were assigned to spontaneous ventilation (sham) or mechanical ventilation (MV) with low (7 ml/kg) and high tidal volume (20 ml/kg) for 2 h after which lung XOR activity and expression were measured and the effect of the specific XOR inhibitor allopurinol on pulmonary vascular leakage was examined. In separate experiments, rat pulmonary microvascular endothelial cells (RPMECs) were exposed to cyclic stretch (5% and 18% elongation, 20 cycles/min) for 2 h before intracellular XOR activity measurement. Lung XOR activity was significantly increased at 2 h of MV without changes in XOR expression. There was evidence of p38 MAP kinase, ERK1/2, and ERK5 phosphorylation, but no change in JNK phosphorylation. Evans blue dye extravasation and bronchoalveolar lavage protein concentration were significantly increased in response to MV, changes that were significantly attenuated by pretreatment with allopurinol. Cyclic stretch of RPMECs also caused MAP kinase phosphorylation and a 1.7-fold increase in XOR activity, which was completely abrogated by pretreatment of the cells with specific MAP kinase inhibitors. We conclude that XOR enzymatic activity is significantly increased by mechanical stress via activation of p38 MAP kinase and ERK and plays a critical role in the pathogenesis of pulmonary edema associated with VILI.

Topics: Animals; Capillary Permeability; Endothelium, Vascular; Enzyme Activation; Extracellular Signal-Regulated MAP Kinases; Lung; Lung Diseases; Male; MAP Kinase Signaling System; Mice; Mice, Inbred C57BL; p38 Mitogen-Activated Protein Kinases; Pulmonary Circulation; Respiratory Distress Syndrome; Stress, Mechanical; Transcription, Genetic; Ventilators, Mechanical; Xanthine Oxidase

Acute lung injury (ALI) is characterized by increased alveolar cytokines, inflammatory cell infiltration, oxidative stress, and alveolar cell apoptosis. Previous work suggested that xanthine oxidoreductase (XOR) may contribute to oxidative stress in ALI as a product of the vascular endothelial cell. We present evidence that cytokine induced lung inflammation and injury involves activation of XOR in the newly recruited mononuclear phagocytes (MNP). We found that XOR was increased predominantly in the MNP that increase rapidly in the lungs of rats that develop ALI following intratracheal cytokine insufflation. XOR was recovered from the MNP largely converted to its oxygen radical generating, reversible O-form, and alveolar MNP exhibited increased oxidative stress as evidenced by increased nitrotyrosine staining. Cytokine insufflation also increased alveolar cell apoptosis. A functional role for XOR in cytokine-induced inflammation was demonstrated when feeding rats two different XOR inhibitors, tungsten and allopurinol, decreased MNP XOR induction, nitrotyrosine staining, inflammatory cell infiltration, and alveolar cell apoptosis. Transfer of control or allopurinol treated MNP into rat lungs confirmed a specific role for MNP XOR in promoting lung inflammation. These data indicate that XOR can contribute to lung inflammation by its expression and conversion in a highly mobile inflammatory cell population.

Topics: Allopurinol; Animals; Apoptosis; Cell Differentiation; Cytokines; Enzyme Induction; Enzyme Inhibitors; Interferon-gamma; Interleukin-1; Lung; Male; Phagocytes; Pneumonia; Pulmonary Alveoli; Rats; Rats, Sprague-Dawley; Respiratory Distress Syndrome; Tungsten; Tyrosine; Xanthine Oxidase

To review the evidence and rationale that suggest that neutrophil elastase (NE) may contribute to the development of acute lung injury (ALI) and the acute respiratory distress syndrome. To review selected preliminary data regarding the effectiveness of NE inhibition in animals, in in vitro models, and in patients with ALI.. The published literature and observations provided by Ono Pharmaceutical and Eli Lilly investigators and their colleagues.. Taken en toto, the data suggest that NE could contribute to ALI and endothelial cell injury that is relevant to ALI. Moreover, the toxic effects of NE are greatly enhanced by increased oxidative stress, which commonly occurs in patients with ALI. In addition to neutrophils, xanthine oxidase, a constituent of endothelial cells, is a potential source of oxidative stress in ALI; xanthine oxidase-derived oxidants enhance NE toxicity in in vivo, isolated lung, and in vitro endothelial cell test systems. Not surprisingly, endogenous nonoxidatively sensitive NE inhibitors (e.g., eglin C) are more effective in combating the detrimental effects of NE than oxidatively sensitive NE inhibitors (e.g., alpha-1-proteinase inhibitor). In addition, a synthetic NE inhibitor, sivelestat (ONO-5046 and LY544349), is effective in reducing measures of inflammation and injury in multiple animal models of ALI. In a trial of ALI patients with systemic inflammatory response syndrome, conducted in Japan by Ono Pharmaceutical scientists, sivelestat treatment improved the investigator assessment of global improvement and the percentages of patients who were removed from ventilators and transferred out of the intensive care unit.. Further study of the role of NE inhibition as a treatment for ALI is warranted. Additional clinical and preclinical studies with sivelestat and various other NE inhibitors should not only clarify the clinical potential of this intervention strategy, but also better define the activities of NE in inflammatory disorders such as ALI and multiple organ failure.

Topics: Animals; Endothelium, Vascular; Glycine; Humans; Leukocyte Elastase; Oxidative Stress; Respiratory Distress Syndrome; Serine Proteinase Inhibitors; Sulfonamides; Xanthine Oxidase

The effects of nitric oxide (NO) from calcium-independent NO synthase (iNOS) on microvascular protein leak in acute lung injury (ALI) are uncertain, possibly because of disparate effects of iNOS-derived NO from different cells. We assessed the contribution of iNOS from inflammatory versus parenchymal cells to pulmonary protein leak in murine cecal ligation and perforation-induced ALI. We studied iNOS+/+, iNOS-/-, and two reciprocally bone marrow-transplanted iNOS chimeric mice groups: + to - (iNOS+/+ donor bone marrow-transplanted into iNOS-/- recipient mice) and - to +. Sepsis-induced ALI was characterized by pulmonary leukocyte infiltration, increased pulmonary iNOS activity, and increased pulmonary microvascular protein leak, as assessed by Evans blue (EB) dye. Despite equal neutrophil infiltration, sepsis-induced EB-protein leak was eliminated in iNOS-/- mice and in - to + iNOS chimeras (parenchymal cell-localized iNOS) but was preserved in + to - chimeric mice (inflammatory cell-localized iNOS). EB-protein leak was also prevented by pretreatment with allopurinol and superoxide dismutase. Microvascular protein leak in sepsis-induced ALI is uniquely dependent on iNOS in inflammatory cells with no obvious contribution of iNOS in pulmonary parenchymal cells. Pulmonary protein leak is also dependent on superoxide, suggesting an effect of peroxynitrite rather than NO itself.

Topics: Allopurinol; Animals; Bone Marrow Transplantation; Capillary Leak Syndrome; Chimera; Coloring Agents; Disease Models, Animal; Evans Blue; Free Radical Scavengers; Lung; Male; Mice; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Peritonitis; Pilot Projects; Polyethylene Glycols; Respiratory Distress Syndrome; Sepsis; Superoxide Dismutase

Hypoventilation, associated with hypercapnic acidosis (HCA), may improve outcome in acute lung injury (ALI). We have recently reported that HCA per se protects against ALI. The current study explored whether the mechanisms of protection with HCA were related to acidosis versus hypercapnia. Because CO(2) equilibrates rapidly across cell membranes, we hypothesized that (1) HCA would afford greater protection than metabolic acidosis. We further hypothesized that (2) buffering HCA would attenuate its protection. Forty isolated perfused rabbit lung preparations were randomized to: control (normal pH, PCO(2)); HCA; metabolic acidosis; or buffered hypercapnia. After ischemia-reperfusion (IR) injury wet:dry ratio was greatest with control and buffered hypercapnia, and rank order of capillary filtration coefficient was: control approximately buffered hypercapnia > metabolic acidosis > HCA. Isogravimetric pressure reduction was greatest with buffered hypercapnia. Despite comparable injury, pulmonary artery pressure elevation was less with buffered hypercapnia versus control. In vitro xanthine oxidase (XO) activity depended on pH, not PCO(2). We conclude that: (1) HCA and metabolic acidosis are protective, but HCA is the most protective; (2) buffering HCA attenuates its protection; (3) buffering HCA causes pulmonary vasodilation; (4) because metabolic acidosis and HCA similarly inhibit in vitro XO activity, the differential effects cannot be explained solely on the basis of extracellular XO activity.

Topics: Acidosis, Respiratory; Animals; Blood Gas Analysis; Capillary Permeability; Disease Models, Animal; Hydrogen-Ion Concentration; Hypercapnia; Hyperventilation; In Vitro Techniques; Lung; Male; Rabbits; Reperfusion Injury; Respiratory Distress Syndrome; Vasodilation; Xanthine Oxidase

P-selectin and circulating xanthine oxidase are involved in the process of neutrophil infiltration into the lung associated with acute pancreatitis. This study investigated the mediators that trigger the upregulation of P-selectin in this process. Pancreatitis was induced in rats by intraductal administration of 5% sodium taurocholate. P-selectin expression was measured using radiolabeled antibodies. Neutrophil infiltration and PAF levels were also evaluated. The role of superoxide radical, H(2)O(2), or the enzyme poly (ADP-ribose) synthetase (PARS) on these processes was determined in groups of animals treated with the corresponding inhibitors. Pancreatitis was associated with an increase in P-selectin expression in the lung. Inhibition of PARS or H(2)O(2) abrogated P-selectin upregulation, PAF generation, and neutrophil recruitment. Superoxide dismutation prevented neutrophil recruitment and PAF generation, but had no effect on P-selectin expression. We conclude that during acute pancreatitis, upregulation of P-selectin in the pulmonary endothelium is triggered by H(2)O(2) and PARS activity.

Topics: Acute Disease; Amylases; Animals; Benzamides; Catalase; Endothelium, Vascular; Enzyme Inhibitors; Free Radical Scavengers; Gene Expression Regulation; Hydrogen Peroxide; Lipase; Lung; Male; P-Selectin; Pancreatitis; Peroxidase; Platelet Activating Factor; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases; Rats; Rats, Wistar; Respiratory Distress Syndrome; Superoxide Dismutase; Taurocholic Acid; Xanthine Oxidase

Lung injury often occurs after hepatoenteric ischemia, with xanthine oxidase (XO, an oxidant-generating enzyme), released from reperfusing liver and intestines, mediating a significant component of this injury. Since pentastarch administration decreases intestinal reperfusion injury, we determined whether resuscitation with PentaLyte (a pentastarch-containing solution) would decrease hepatoenteric reperfusion injury, xanthine oxidase release, and concomitant lung injury after aortic occlusion- reperfusion. Aortic occlusion was established in rabbits for 40 min, and was followed by 3 h of reperfusion, during which either PentaLyte or lactated Ringer's solution-based resuscitation was administered. Sham-operated animals served as controls. Hepatoenteric reperfusion injury, as manifested by release of the enzyme aspartate aminotransferase and decreased gastric intramucosal pH, was significantly (p < 0.0167) attenuated by PentaLyte administration after aortic occlusion-reperfusion, as compared with its occurrence in animals given lactated Ringer's solution. The release of XO after aortic occlusion-reperfusion was 4-fold smaller after PentaLyte administration than after resuscitation with lactated Ringer's solution (p < 0.05). Pulmonary injury, as defined by an increase in bronchoalveolar lavage fluid (BALF) protein content and lactate dehydrogenase (LDH) activity, was 4-fold less after PentaLyte administration following aortic occlusion-reperfusion than after administration of lactated Ringer's solution (p < 0.05). We conclude that remote pulmonary injury is significantly decreased by concomitant PentaLyte-mediated reduction of hepatoenteric reperfusion injury and XO release.

Topics: Animals; Aorta, Thoracic; Aspartate Aminotransferases; Blood Proteins; Bronchoalveolar Lavage Fluid; Constriction; Electrolytes; Gastric Mucosa; Glucose; Hydrogen-Ion Concentration; Hydroxyethyl Starch Derivatives; Infusions, Intravenous; Intestines; Isotonic Solutions; L-Lactate Dehydrogenase; Liver; Male; Phenylephrine; Plasma Substitutes; Rabbits; Reperfusion Injury; Respiratory Distress Syndrome; Resuscitation; Ringer's Lactate; Sodium Bicarbonate; Xanthine Oxidase

To investigate the effect of methylene blue, an inhibitor of oxygen radicals, on lung injury caused by reperfusion of ischemic tissue.. Intestinal ischemia-reperfusion injury was induced in rats by clamping the superior mesenteric artery for 1 hour. Thereafter, the experimental group was administered 1% methylene blue intraperitoneally and the control group received saline. After 4 hours, pulmonary histopathologic features were assessed, and lung wet-weight to dry-weight ratios and tissue xanthine oxidase were determined.. The control group suffered from severe pulmonary parenchymal damage, compared with slight damage in the experimental group. The number of sequestered neutrophils was significantly higher in the control group (319 +/- 60 polymorphonuclear cells per 10 high-power fields) than in the methylene blue-treated group (91 +/- 8 polymorphonuclear cells per 10 high-power fields; p < 0.001). The wet-weight to dry-weight ratio was significantly increased in the saline-treated rats compared with the methylene blue-treated group (6.19 +/- 0.28 vs. 5.07 +/- 0.21; p < 0.001). Xanthine oxidase activity was similar in both groups.. Methylene blue attenuated lung injury after intestinal ischemia-reperfusion. Inhibition of oxygen free radicals may be the protective mechanism.

Topics: Animals; Antioxidants; Disease Models, Animal; Drug Evaluation, Preclinical; Intestines; Leukocyte Count; Male; Methylene Blue; Neutrophils; Organ Size; Random Allocation; Rats; Rats, Wistar; Reperfusion Injury; Respiratory Distress Syndrome; Xanthine Oxidase

Relative hypoventilation, involving passively-or "permissively"-generated hypercapnic acidosis (HCA), may improve outcome by reducing ventilator-induced lung injury. However, the effects of HCA per se on pulmonary microvascular permeability (Kf,c) in noninjured or injured lungs are unknown. We investigated the effects of HCA in the isolated buffer-perfused rabbit lung, under conditions of: (1) no injury; (2) injury induced by warm ischemia-reperfusion; and (3) injury induced by addition of purine and xanthine oxidase. HCA (fraction of inspired carbon dioxide [FICO2] 12%, 25% versus 5%) had no adverse microvascular effects in uninjured lungs, and prevented (FICO2 25% versus 5%) the increase in Kf,c following warm ischemia-reperfusion. HCA (FICO2 25% versus 5%) reduced the elevation in Kf,c, capillary (Pcap), and pulmonary artery (Ppa) pressures in lung injury induced by exogenous purine/xanthine oxidase; inhibition of endogenous NO synthase in the presence of 25% FICO2 had no effect on Kf,c, but attenuated the reduction of Pcap and Ppa. HCA inhibited the in vitro generation of uric acid from addition of xanthine oxidase to purine. We conclude that in the current models, HCA is not harmful in uninjured lungs, and attenuates injury in free-radical-mediated lung injury, possibly via inhibition of endogenous xanthine oxidase.

Topics: Acidosis; Analysis of Variance; Animals; Blood Pressure; Capillaries; Capillary Permeability; Carbon Dioxide; Free Radicals; Hydrostatic Pressure; Hypercapnia; Lung; Male; Microcirculation; Nitric Oxide Synthase; Pulmonary Artery; Purines; Rabbits; Reperfusion Injury; Respiration, Artificial; Respiratory Distress Syndrome; Uric Acid; Vascular Resistance; Xanthine Oxidase

The effects of methylprednisolone (MP) on the acute airway and pulmonary vascular responses induced by reactive oxygen species (ROS) were investigated in isolated, plasma-perfused rat lungs. ROS were generated by adding xanthine oxidase and hypoxanthine to the perfusate. MP was administered in 3 different ways: 1. Added to the perfusate (1 mg*ml-1) 5 min prior to xanthine oxidase and hypoxanthine, 2. Given as intraperitoneal injections (40 mg*kg-1) to lung donor rats 12 and 2 hours prior to the experiments, or 3. Combining 1 and 2. The lungs were perfused at constant volume inflow (15 ml*min-1). Pulmonary arterial pressure and transpulmonary pressure were followed for 30 min after addition of xanthine oxidase and hypoxanthine. ROS induced a powerful, acute broncho- and vasoconstriction, which was inhibited by addition of MP to the perfusate. Pretreatment with MP also inhibited the vascular and airway responses. Adding MP to the perfusate of pretreated lungs further reduced the ROS-induced smooth muscle constriction. In conclusion, MP inhibits vasoconstriction and bronchoconstriction induced by ROS in isolated rat lungs.

Topics: Animals; Blood Pressure; Bronchoconstriction; Hypoxanthine; Kinetics; Lung; Male; Methylprednisolone; Perfusion; Rats; Rats, Wistar; Reactive Oxygen Species; Respiratory Distress Syndrome; Vasoconstriction; Xanthine Oxidase

We investigated the role of free radicals, especially from activated neutrophils, in acute xanthine and xanthine oxidase-induced lung injury in rats. We evaluated the effects of intravenously administered intracellular and extracellular free radical scavengers (for O2-., H2O2, and .OH), methylprednisolone (MP), and Ulinastatin (UST, a protease inhibitor), on this animal model of lung injury. At 5 min prior to the intrabronchial injection of a mixture of xanthine (X, 100 nmol) and xanthine oxidase (XO, 1 unit) used to induce unilateral lung damage, rats were pretreated intravenously with superoxide dismutase (SOD, 40 mg/kg), SOD (40 mg/kg) plus catalase (CAT, 30 mg/kg), dimethylthiourea (DMTU, 500 mg/kg), N-2-mercaptopropionyl glycine (MPG, 20 mg/kg), MP, 30 mg/kg, and UST, 50,000 units/kg. Each scavenger was infused intravenously at one-half the initial dose for 20 min after intrabronchial injection; 3 hr later, we examined the wet/dry lung weight ratios and the levels of thiobarbituric acid-reactive substances (TBARS) in lung tissue. Intrabronchial injection of the X/XO mixture markedly increased wet/dry lung weight ratios and lung tissue content of TBARS. Histopathologic changes were observed in the injected lung as well. Pretreatment with SOD + CAT, DMTU, and UST significantly reduced the increases in wet/dry lung weight ratios and lung tissue content of TBARS induced by the intrabronchial injection of the X/XO mixture. Our data suggest indirectly that free radicals (H2O2, .OH) and proteases from activated neutrophils may contribute, in part, to the lung damage induced by the O2-.-generating system of xanthine and xanthine oxidase.

Topics: Animals; Disease Models, Animal; Free Radical Scavengers; Glycoproteins; Infusions, Intravenous; Lung; Male; Methylprednisolone; Organ Size; Rats; Rats, Wistar; Respiratory Distress Syndrome; Thiobarbituric Acid Reactive Substances; Xanthine; Xanthine Oxidase; Xanthines

Our purpose was to determine the effect of non-bacteria-dependent systemic inflammation on the degree and time course of lung oxidant activity and antioxidant defenses, comparing these changes with lung, physiologic, and histologic alterations. Adult male rats were given intraperitoneal zymosan (0.7 mg/g body weight) and were fluid resuscitated. Oxidant changes were measured as lung tissue oxidized glutathione (GSSG) and malondialdehyde (MDA) content, antioxidant defenses as tissue reduced glutathione (GSH), and catalase. Animals were killed at 4, 12, and 24 h, and at 5, 10, and 30 days. Lung data were compared with that found in liver. We noted a 45% mortality in the first 18 to 36 h with all remaining animals surviving. In the first 24 h, we noted a doubling of lung MDA and an 80% conversion of tissue GSH to GSSG compared with less than 5% in control animals, indicating a severe oxidant stress. These findings corresponded with marked increase in lung neutrophils. Arterial pressure (PaO2) was significantly decreased from a control of 95 +/- 4 mm Hg to 80 +/- 5 mm Hg and 75 +/- 4 mm Hg at Days 5 and 10, respectively, but returned toward control by 30 days. Lung GSSG and MDA remained significantly increased for the 30-day period, whereas amounts of the antioxidants, catalase, and GSH returned to control after 24 h. The ongoing oxidant stress corresponded with marked mononuclear cell infiltration and interstitial thickening, which persisted over the 30-day period even after peritonitis had completely resolved.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Blood Gas Analysis; Catalase; Disease Models, Animal; Evaluation Studies as Topic; Glutathione; Glutathione Disulfide; Inflammation; Lipid Peroxidation; Male; Malondialdehyde; Oxygen Consumption; Peritonitis; Rats; Rats, Sprague-Dawley; Respiratory Distress Syndrome; Time Factors; Xanthine Dehydrogenase; Xanthine Oxidase; Zymosan

We have previously shown that gut ischemia/reperfusion (I/R) causes simultaneous liver and lung dysfunction and that neutrophils play a critical role in this process. The purpose of this study was to ascertain whether xanthine oxidase (XO) was likewise operational. Normal and XO-inactivated rats (given a tungsten-enriched, molybdenum-depleted diet for 3 weeks) underwent 45 minutes of occlusion of the superior mesenteric artery, and control rats were subjected to a sham laparotomy. After zero and six hours of reperfusion, blood was sampled and livers and lungs harvested. Iodine-125-labeled albumin leak was used as a marker for pulmonary and liver capillary permeability barrier function, and serum acetoacetate/3-hydroxybutyrate (AcAc/3-OHB) levels as an index of hepatic mitochondrial redox state. Gut ischemia/six hours of reperfusion (I/R) increased the 125I albumin lung/blood ratio and the 125I albumin liver/blood ratio; AcAc/3-OHB levels decreased significantly. Xanthine oxidase activation eliminated the observed lung and liver capillary leak as well as the hepatic metabolic derangement induced by gut I/R. In conclusion, the simultaneous lung and liver dysfunction produced by gut I/R is mediated by XO.

Topics: Animals; Disease Models, Animal; Evaluation Studies as Topic; Ischemia; Liver; Lung; Male; Mesentery; Multiple Organ Failure; Neutrophils; Rats; Rats, Inbred Strains; Reperfusion Injury; Respiratory Distress Syndrome; Serum Albumin, Radio-Iodinated; Xanthine Oxidase

Because platelets contain active antioxidant systems, the capacity of platelets to attenuate oxidant lung injury was investigated. Purine and xanthine oxidase were infused into isolated perfused rabbit lungs (IPL) to generate H2O2, thereby causing increased membrane permeability edema. The coinfusion of washed human platelets (1.20 +/- 0.07 x 10(10) cells) attenuated the degree of edema formation as measured by lung weight gain and lung lavage albumin concentration. Electron microscopy of lung preparations demonstrated platelet adherence to capillary endothelial luminal surfaces of oxidant-injured lungs, but there was no evidence of vascular plugging with platelet macroaggregates. The platelet glutathione redox cycle or platelet catalase were inhibited before infusion of platelets into the IPL with purine and xanthine oxidase. Inhibition of the glutathione redox cycle with 1,3-bis(2-chloroethyl)-1-nitrosourea, 1-chloro-2,4-dinitrobenzene, or buthionine sulfoximine prevented platelet attenuation of lung injury. Inactivation of platelet catalase with 3-amino-1,2,4-triazole, however, did not significantly reduce the platelet-induced lung protection. We conclude that the platelet glutathione redox cycle plays a major role in reducing enzymatically generated toxic O2 metabolites and attenuating lung injury.

Topics: Animals; Blood Platelets; Blood Pressure; Glutathione; Humans; In Vitro Techniques; Lung; Oxidation-Reduction; Pulmonary Edema; Purines; Rabbits; Respiratory Distress Syndrome; Xanthine Oxidase

Topics: Animals; Free Radicals; Guinea Pigs; Lung Compliance; Oxygen; Pulmonary Surfactants; Rabbits; Respiratory Distress Syndrome; Respiratory Insufficiency; Superoxide Dismutase; Xanthine Oxidase

Topics: Acute Kidney Injury; Adult; Allopurinol; Chemical and Drug Induced Liver Injury; Drug Hypersensitivity; Gout; Humans; Male; Respiratory Distress Syndrome; Stevens-Johnson Syndrome

Activation of the kallikrein-kinin system was demonstrated in experimental lung failure in dogs and respiratory distress syndrome (RDS) in newborns. Further lung damage was found in rats after intravenous infusion of hypoxanthine during exposure to 100% oxygen for 48 h. It is discussed whether such damage was mediated through free oxygen radicals produced by the hypoxanthine-xanthine oxidase system. Newborn babies with RDS had high serum myoinositol levels and the role of myoinositol as regulator of surfactant synthesis is discussed. These three different approaches demonstrate the complexity of pathogenesis of RDS in newborn babies and adults.

Topics: Adult; Animals; Dogs; Female; Free Radicals; Humans; Hyaline Membrane Disease; Infant, Newborn; Inositol; Kallikreins; Kininogens; Kinins; Prekallikrein; Rats; Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn; Xanthine Oxidase