Effects of hyperoxia on neutrophil adhesion.
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Animals↗
Biomedical subjects
S R Thom
Publications and source records attributed to S R Thom.
Blood flow and ionic responses in the awake brain due to carbon monoxide.
This study examined the effect of 2000 ppm CO on the brain of an awake rat. Measurements of regional perfusion as well as metabolic, ionic and electrical activities were used to examine whether mechanisms responsible for changes in brain perfusion were separable from those attributable to compromises in neuronal metabolism. Exposure to 2000 ppm CO resulted in elevation of cerebral blood flow. The stability of mitochondrial NADH redox level during CO exposure indicated that tissue hypoxia did not develop. The elevation in blood flow was inhibited by L-nitroarginine methyl ester, indicating that nitric oxide was responsible for the CO-induced elevation in blood flow. Exposure to 2000 ppm CO also triggered a significant decrease in pH and rise in extracellular potassium ion, possibly due to ion-pump inhibition. The amplitude of the electrocorticogram wave activity decreased, indicative of a compromise to physiological activity. These changes were not observed in rats anesthetized with pentobarbital during CO exposure, although anesthesia had no effect on the CO-induced elevation in blood flow and there was still no change in mitochondrial NADH redox level. We concluded that CO acts by separate mechanisms to alter cerebral vasoactivity and neuronal metabolic responses and that both processes are independent of hypoxic stress.
Anesthetics↗
Hyperbaric oxygenation affects rat brain function after carbon monoxide exposure.
The application of hyperbaric oxygenation (HBO2) has been recommended for correction of neurological injury in severely CO-poisoned patients. However, the mechanisms of HBO2 action on brain mitochondrial function under the circumstances is not yet understood completely. In the present study, the effect of HBO2 on the rat brain after CO exposure was evaluated by measuring the intramitochondrial NADH and its responses to anoxic test or repetitive induction spreading depression (SD) leading to brain activation. A unique monitoring system for bilateral monitoring of brain NADH redox state was used. Rats were exposed to 3000 ppm CO for 30 (group A) or 60 min (C). In groups B and D, after CO exposure, the rats were exposed to HBO2 (3 atm abs for 30 min). Following CO exposure in groups A and C, a definite decrease in the amplitude of the NADH response and significant increase in the number of waves of NADH was noted during induced cortical SD. Anoxic test in these two groups led to a significant decrease of maximum levels of NADH (reduction) at the end of observation. The amplitude, and the number of SD waves and magnitude of NADH deviation during anoxic test in group B after application of HBO2, was not significantly different from the values measured under the initial conditions. However, in group D, tendency of maintenance of the parameter's initial level was weaker or absent. The results obtained indicated that suppression of brain energy metabolism is a characteristic manifestation of CO poisoning in rats. Restoration of cerebral energy metabolism by adequate dosage of HBO2 may become an important factor for recovery of brain activities after CO poisoning.
Animals↗
Roles for platelet-activating factor and *NO-derived oxidants causing neutrophil adherence after CO poisoning.
Studies were conducted with rats to investigate whether platelet activating factor (PAF) and nitric oxide (*NO)-derived oxidants played roles in the initial adherence of neutrophils to vasculature in the brain after carbon monoxide (CO) poisoning. Before CO poisoning, rats were treated with the competitive PAF receptor antagonist WEB-2170 or with the peroxynitrite scavenger selenomethionine. Both agents caused significantly lower concentrations of myeloperoxidase in the brain after poisoning, indicating fewer sequestered neutrophils. Similarly, both agents reduced the concentration of nitrotyrosine, indicating less oxidative stress due to *NO-derived oxidants. There were no alterations in whole brain homogenate PAF concentration measured by immunoassay and bioassay, nor were there changes in phosphatidylcholine concentration. Immunohistochemical imaging showed PAF to be more heavily localized within perivascular zones after CO poisoning. Neutrophils colocalized with both PAF and nitrotyrosine in brains of rats killed immediately after CO poisoning. We conclude that qualitative changes in brain PAF are responsible for neutrophil adherence immediately after CO poisoning and that activated neutrophils trigger the initial rise in brain nitrotyrosine. Persistent PAF-mediated neutrophil adherence required production of *NO-derived oxidants because when oxidants were scavenged, neutrophil adherence was not maintained.
Animals↗
[Hyperbaric oxygen inhibits neutrophil infiltration and reduces postischemic brain injury in rats].
Reversible occlusion of the middle cerebral artery (MCA) was used to test hypothesis that hyperbaric oxygen inhibits the neutrophile infiltration into the ischemic brain thus reducing the brain injury. Treatment with hyperbaric oxygen prior to ischemia or during MCA occlusion significantly reduced neutrophile infiltration, motor disorders, and cerebral infarction volume.
Animals↗
Carbon monoxide poisoning: interpretation of randomized clinical trials and unresolved treatment issues.
Since hyperbaric oxygen therapy (HBO2) appeared as a treatment for CO poisoning in 1960, whether and when to use it for CO poisoning have often been debated. HBO2 has been advocated to treat severe CO poisoning to limit delayed and permanent neurologic sequelae. Initially, inferences about efficacy were based on clinical experience and uncontrolled studies, but since1989, six prospective clinical trials have been reported comparing HBO2 and normobaric O2 administration to treat patients with acute CO poisoning. Of the six trials, four found better clinical outcomes among patients receiving HBO2 while two have shown no treatment effect. The most recent and best-designed randomized controlled clinical trial, performed in Salt Lake City, supports the efficacy of HBO2 in severe acute CO poisoning in accordance with scientific rationale and clinical experience. However, a number of important issues remain for future investigation, which could be addressed in a large multi-center trial. Such a trial should attempt to determine the optimal number of HBO2 treatments and the maximum treatment delay from CO poisoning for HBO2 to provide efficacy in patients with specific risk factors for a poor outcome.
Carbon Monoxide Poisoning↗
Smoke inhalation-induced alveolar lung injury is inhibited by hyperbaric oxygen.
Smoke-induced lung injury in rats was assessed in terms of histopathology, gross mortality, neutrophil accumulation and as capillary leak. Administration of hyperbaric oxygen (HBO2), 2.8 atm abs for 45 min, inhibited adhesion of circulating neutrophils subsequent to smoke inhalation. HBO2 reduced pulmonary neutrophil accumulation whether used in a prophylactic manner, 24 h before smoke inhalation, or as treatment immediately after the smoke insult Emphasis was placed on prophylactic administration of HBO2 to avoid the possibility that beneficial effects may be related to hastened removal of carbon monoxide. Based on all parameters tested, smoke inhalation injury was reduced by prophylactic aadministration of HBO2. The beneficial effect appears related to inhibition of neutroophil adhesion to the vasculature.
Animals↗
Carbon monoxide poisoning--a public health perspective.
Carbon monoxide (CO) may be the cause of more than one-half of the fatal poisonings reported in many countries; fatal cases also are grossly under-reported or misdiagnosed by medical professionals. Therefore, the precise number of individuals who have suffered from CO intoxication is not known. The health effects associated with exposure to CO range from the more subtle cardiovascular and neurobehavioral effects at low concentrations to unconsciousness and death after acute or chronic exposure to higher concentrations of CO. The morbidity and mortality resulting from the latter exposures are described briefly to complete the picture of CO exposure in present-day society. The symptoms, signs, and prognosis of acute CO poisoning correlate poorly with the level of carboxyhemoglobin (COHb) measured at the time of hospital admission; however, because CO poisoning is a diagnosis frequently overlooked, the importance of measuring COHb in suspicious settings cannot be overstated. The early symptoms (headache, dizziness, weakness, nausea, confusion, disorientation, and visual disturbances) also have to be emphasized, especially if they recur with a regular periodicity or in the same environment. Complications occur frequently in CO poisoning. Immediate death is most likely cardiac in origin because myocardial tissues are most sensitive to the hypoxic effects of CO. Severe poisoning results in marked hypotension, lethal arrhythmias, and electrocardiographic changes. Pulmonary edema may occur. Neurological manifestation of acute CO poisoning includes disorientation, confusion, and coma. Perhaps the most insidious effect of CO poisoning is the development of delayed neuropsychiatric impairment within 2-28 days after poisoning and the slow resolution of neurobehavioral consequences. Carbon monoxide poisoning during pregnancy results in high risk for the mother by increasing the short-term complication rate and for the fetus by causing fetal death, developmental disorders, and chronic cerebral lesions. In conclusion, CO poisoning occurs frequently; has severe consequences, including immediate death; involves complications and late sequelae; and often is overlooked. Efforts in prevention and in public and medical education should be encouraged.
Carbon Monoxide Poisoning↗
Adaptive responses and apoptosis in endothelial cells exposed to carbon monoxide.
Prior studies have shown that exposure to carbon monoxide (CO) will elevate the steady-state concentration of nitric oxide ((.)NO) in several cell types and body organs and that some toxic effects of CO are directed toward endothelial cells. Studies reported in this paper were conducted with bovine pulmonary artery endothelial cells exposed to 10 to 100 ppm CO to achieve concentrations between 11 and 110 nM in air-saturated buffer. Exposure to 11 nM CO increased synthesis of manganous superoxide dismutase and conferred resistance against the lethal effects of 110 nM CO. At concentrations of 88 nM CO or more, exposures for 1 h or longer caused cell death that became apparent 18 h after the exposure ceased. Caspase-1 was activated in response to CO, and cell death was inhibited by a caspase-1 inhibitor. Alteration of proteolytic pathways by CO was indicated by the presence of ubiquitin-containing intracellular inclusion bodies. Morphological changes and caspase activation indicated that cell death was an apoptotic process. Cells exposed to 110 nM CO had higher concentrations of manganous superoxide dismutase and heme oxygenase-1 but no changes in glutathione peroxidase, glucose-6-phosphate dehydrogenase, thiols, or catalase. Elevated levels of antioxidant enzymes and apoptosis were inhibited by the nitric oxide synthase inhibitor, S-isopropylisothiourea, and the peroxynitrite scavenger, selenomethionine. These results show that biochemical effects of CO occur at environmentally relevant concentrations, that apoptotic cell death follows exposure to relatively high concentrations of CO, and that these actions of CO are mediated by nitric oxide.
Adaptation, Physiological↗
Neutrophil sequestration and the effect of hyperbaric oxygen in a rat model of temporary middle cerebral artery occlusion.
A rat model of reversible occlusion of the middle cerebral artery was developed to assess the role of neutrophils and prophylactic hyperbaric oxygen (HBO2) on cerebral injury. Blood flow to the ipsilateral caudate putamen nucleus was reduced by approximately 50% during 2 h of arterial occlusion, but unaffected on the contralateral side. Neutrophil accumulation in brain was documented as myeloperoxidase concentration, which was elevated in both ipsilateral and contralateral cerebral hemispheres at 1 and 46 h after occlusion/reperfusion. HBO2 administered before ischemia at 2.8 atm abs for 45 min, as well as antibody-induced neutropenia, reduced neutrophil accumulation, functional neurologic deficits, and cerebral infarct volume. These data demonstrate that one mechanism for benefit of HBO2 is related to its ability to ameliorate post-ischemic injury by inhibiting neutrophil sequestration. This mechanism should be taken into consideration when choosing partial pressures of oxygen for investigational clinical protocols.
Analysis of Variance↗
Ventriculo-peritoneal shunt performance under hyperbaric conditions.
A novice scuba diver with an implanted ventriculo-peritoneal (VP) shunt inquired about the performance characteristics of his shunt while diving. A literature search revealed no information regarding shunt performance under hyperbaric conditions. The manufacturer could not certify that the shunt would function under pressure. Therefore, four VP shunts were tested according to the manufacturer's testing protocol at 1 and 4 atm abs in a multiplace hyperbaric chamber. The pressure (in mm of H2O) required to establish flow through the shunts was recorded. Trials at 1 atm abs (n = 12) and 4 atm abs (n = 12) show that all shunts performed within the pressure range specified by the manufacturer.
Atmospheric Pressure↗
Pulmonary vascular stress from carbon monoxide.
Studies were conducted with rats to investigate whether exposure to carbon monoxide (CO) at concentrations frequently found in the environment caused lung injury mediated by nitric oxide (*NO)-derived oxidants. Lung capillary leakage was significantly increased 18 h after rats had been exposed to CO at concentrations of 50 ppm or more for 1 h. An elevation of *NO during CO exposure was demonstrated by electron paramagnetic resonance spectroscopy. There was a 2.6-fold increase of *NO over control in the lungs of rats exposed to 100 ppm CO. A qualitative increase in the concentration of H2O2 was also detected in lungs during CO exposure, and this change was caused by *NO as it was inhibited in rats pretreated with the nitric oxide synthase inhibitor, Nomega nitro-l-arginine methyl ester (l-NAME). Production of *NO-derived oxidants during CO exposure was indicated by an elevated concentration of nitrotyrosine in lung homogenates. The CO-associated elevations in lung capillary leakage and nitrotyrosine concentration did not occur when rats were pretreated with l-NAME. CO exposure did not change the concentrations of endothelial or inducible nitric oxide synthase in lung and leukocyte sequestration was not detected as a consequence of CO exposure. CO-mediated lung leak and nitrotyrosine elevation were not affected by neutropenia. We conclude that CO exposure elevates the steady-state concentration of *NO in lungs. Consequences from this change include increases in the concentration of reactive oxygen species, production of *NO-derived oxidants such as peroxynitrite, and physiological evidence of lung injury.
Animals↗
Detection of reactive nitrogen species using 2,7-dichlorodihydrofluorescein and dihydrorhodamine 123.
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Animals↗
Role of nitric oxide-derived oxidants in vascular injury from carbon monoxide in the rat.
Studies were conducted with rats to investigate whether exposure to CO at concentrations frequently found in the environment caused nitric oxide (NO)-mediated vessel wall changes. Exposure to CO at concentrations of 50 parts per million or higher for 1 h increased the concentration of nitrotyrosine in the aorta. Immunologically reactive nitrotyrosine was localized in a discrete fashion along the endothelial lining, and this was inhibited by pretreatment with the NO synthase (NOS) inhibitor Nomega-nitro-L-arginine methyl ester (L-NAME). The CO-induced elevations of aortic nitrotyrosine were not altered by neutropenia or thrombocytopenia, and CO caused no change in the concentration of endothelial NOS. Consequences from NO-derived stress on the vasculature included an enhanced transcapillary efflux of albumin within the first 3 h after CO exposure and leukocyte sequestration that became apparent 18 h after CO exposure. Oxidized plasma low-density lipoprotein was found immediately after CO exposure, but this was not inhibited by L-NAME pretreatment. We conclude that exposure to relatively low CO concentrations can alter vascular status by several mechanisms and that many changes are linked to NO-derived oxidants.
Animals↗
A model of wound healing in chronically radiation-damaged rat skin.
The aim of this investigation was to develop a model for studying the chronic effects of radiation on wound healing in the rat. Six months after rats received a single radiation exposure of 20 Gy, a random-pattern dorsal skin flap was elevated. Two weeks after the flap was elevated, irradiated animals showed diminished scar formation and wound breaking strength, as compared with controls (P < 0.05). The effect of hyperbaric oxygen treatment was investigated in some rats who received 20 sessions at 2.4 atmospheres absolute for 90 min daily, 5 days per week, prior to flap elevation and 10 sessions after creation of the flap. Treated animals showed a trend toward improvements in wound breaking strength and scar formation (P = 0.06). A reproducible model of chronic radiation damage in the rat was established. Further studies involving investigations at times more that 2 weeks post-wounding are needed.
Animals↗
Nitric oxide and peroxynitrite-mediated pulmonary cell death.
Nitric oxide (.NO) can be produced within the lung, and recently inhaled nitric oxide has been used as a therapeutic agent. Peroxynitrite1 (ONOO-), the product of the nearly diffusion-limited reaction between .NO and superoxide, may represent the proximal reactive species mediating .NO injury to pulmonary cells. To investigate the physiological and pathological reactivities of .NO and ONOO- at the molecular and cellular levels, bovine pulmonary artery endothelial cells (BPAEC) and rat type II epithelial cells were exposed to .NO (0.01-2.5 microM/min for 2 h) generated by spermine-NONOate and papa-NONOate and to the same fluxes of ONOO- generated by 1,3-morpholinosydnonimine (SIN-1). Exposure to SIN-1 resulted in cellular injury and death in both cell types. Epithelial cells displayed a concentration-dependent loss of cellular viability within 8 h of exposure. In contrast, BPAEC loss of cellular viability was evident after 18 h postexposure. Events preceding cell death in BPAEC include depolarization of the mitochondrial membrane, evident as early as 6 h postexposure, loss of cellular redox activity at 16 h, and DNA fragmentation detected by in situ staining at 18 h after exposure. Exposure of BPAEC to .NO did not affect the cellular viability, but type II cells were injured in a manner similar to ONOO- exposure. .NO-mediated cellular injury within type II cells was reduced by preincubation with N-acetylcysteine. The data imply that the pathological and physiological effects of .NO may be regulated by its reactions with superoxide and reduced thiols.
Acetylcysteine↗
Nitric oxide inhibits neutrophil beta 2 integrin function by inhibiting membrane-associated cyclic GMP synthesis.
The aim of this investigation was to identify the mechanism by which nitric oxide inhibits neutrophil beta 2 integrin dependent adherence. Isolated rat neutrophils from blood and peritoneal exudates were exposed for 2 min to nitric oxide generated by diethylamine-NO at rates between 1.6 and 138 nmol/min. Exposure to nitric oxide at rates less than 14 nmol/min had no effect on adherence. Exposure to 14 to 56 nmol nitric oxide/min inhibited beta 2 integrin dependent adherence to endothelial cells, nylon columns, and fibrinogen-coated plates, but higher concentrations had no significant effect on adherence. Adherence by beta 2 integrins could be restored by incubating cells with dithioerythritol, phorbol 12-myristate 13-acetate, or 8-bromo cyclic GMP. Elevations in cellular cyclic GMP concentration were associated with adherence, but this did not occur after cells were exposed to concentrations of nitric oxide that inhibited beta 2 integrin-dependent adherence. Elevations in cyclic GMP did occur after cells were incubated with dithioerythritol or phorbol 12-myristate 13-acetate. Concentrations of nitric oxide that inhibited beta 2 integrin-dependent adherence also inhibited catalytic activity of membrane associated guanylate cyclase and binding of atrial natriuretic peptide, but were insufficient to activate cytosolic guanylate cyclase. Nitric oxide did not inhibit neutrophil oxidative burst or degranulation, nor effect beta 2 integrin expression or adherence that did not depend on beta 2 integrins, nor cause oxidative stress identified in terms of cellular glutathione concentration or protein nitrotyrosine. The results indicate that nitric oxide inhibited beta 2 integrins in a concentration-dependent fashion by inhibiting cell-surface transduction of signals linked to the activity of membrane-bound guanylate cyclase. The inhibitory effect could be overcome by providing cells with cyclic GMP exogenously or by stimulating cytosolic guanylate cyclase.
Animals↗
Impaired neutrophil adherence as an early marker of systemic inflammatory response syndrome and severe sepsis.
STUDY OBJECTIVE: To determine whether neutrophil adherence was altered in the presence of systemic inflammatory response syndrome (SIRS) and infection or severe sepsis. METHODS: We conducted a prospective study of a convenience sample of adults presenting to an academic urban ED to be admitted with SIRS and infection or with severe sepsis. Serial phlebotomy was performed in the ED and 12 and 24 hours into the hospital stay. We used an adherence assay that involves adding 1-mL aliquots of heparinized blood to pipettes packed with nylon. Cell count and differential on the eluates and a control tube were carried out to determine the percentage of adhering neutrophils. We reviewed charts for parameters of clinical progression. RESULTS: Adherence values among patients with SIRS and severe sepsis were 27% +/- 17% (n = 19) and 13% +/- 16% (n = 4), respectively, significantly less than mean adherence in normal controls (47% +/- 10%; P = .0006 and .0007, ANOVA). Adherence among patients with severe sepsis and those who clinically progressed were not significantly different from that in all SIRS cases. Serial values did not differ from initial values. CONCLUSION: Neutrophil adherence was significantly decreased in patients with SIRS and severe sepsis compared with that in normal controls. A larger study enrolling consecutive SIRS subject at risk for severe sepsis may demonstrate whether this assay could be useful in managing sepsis in the ED.
Adult↗