Biomedical subjects

S R Thom

Publications and source records attributed to S R Thom.

At least 37 records · Page 2Linked to original sources

PubMed1997

Vascular endothelial cells generate peroxynitrite in response to carbon monoxide exposure.

Carbon monoxide causes a perivascular oxidative injury in animals, and we tested the hypothesis that endothelial cells could be a source of the injurious oxidants. Studies were undertaken to assess whether exposure to carbon monoxide would cause cultured bovine pulmonary artery endothelial cells to liberate reactive species. Concentrations of carbon monoxide between 11 and 110 nM caused progressively higher concentrations of nitric oxide to be released by endothelial cells based on measurements of nitrite and nitrate. Intracellular production of peroxynitrite was indicated by elevated concentrations of nitrotyrosine, and extracellular liberation of peroxynitrite was indicated by oxidation of p-hydroxyphenylacetic acid and dihydrorhodamine-123. Carbon monoxide did not disturb mitochondrial function based on the rate of oxygen consumption, intracellular production of hydrogen peroxide, and the ability of cells to reduce 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide. Carbon monoxide also did not alter arginine transport by cells or nitric oxide synthase activity, but it was found to increase steady state levels of nitric oxide by competing for intracellular binding sites. Acute cytotoxicity from carbon monoxide, assessed as radioactive chromium leakage, was due to nitric oxide-derived oxidants. A delayed cell death, whose mechanism is not entirely clear, was also demonstrated by chromium leakage and uptake of vital stain. These findings offer a possible mechanism for adverse health effects caused by carbon monoxide at concentrations ranging from the relatively low levels in polluted environments to levels typically encountered with life-threatening poisoning. Carbon monoxide causes oxidative stress by a novel mechanism involving a competition for intracellular binding sites which increases steady state levels of nitric oxide and allows for generation of peroxynitrite by endothelium.

Animals↗

PubMed1997

Inhibition of human neutrophil beta2-integrin-dependent adherence by hyperbaric O2.

Animal and clinical investigations have reported that exposure to hyperbaric O(2) improved the outcome of some reperfusion injuries. Animal studies have suggested that this may be due to an inhibition of leukocyte adherence to injured endothelium. This investigation tested the hypothesis that exposure to hyperbaric O(2) would inhibit beta2-integrin-dependent adherence of human neutrophils. Subjects were exposed to O(2) at partial pressures of up to 3 atmospheres absolute (ATA; 1 ATA = 0.1 MPa) for 45 min, and neutrophil binding to nylon columns and to fibrinogen-coated surfaces was measured. Exposure to O(2) at 2.8 or 3.0 ATA inhibited beta2-integrin-dependent neutrophil adherence but had no effect on the cell-surface expression of beta2-integrins, respiratory burst in response to phorbol ester, or non-beta2-integrin-dependent adherence to plastic plates coated with a fibronectin-like protein. beta2-Integrin adherence was restored by incubating blood with 8-bromoguanosine 3',5'-cyclic monophosphate (cGMP) and hyperbaric O(2) inhibited synthesis of cGMP by neutrophils stimulated with N-formyl-Met-Leu-Phe (FMLP). In studies of cell fractions, the activity of membrane guanylate cyclase was found to be increased by incubation with FMLP as well as by atrial natriuretic peptide (ANP) plus ATP. Hyperbaric O(2) had no effect on the basal activity of soluble or membrane-bound guanylate cyclase. However, hyperbaric O(2) inhibited the function of both the extracellular binding domain of membrane guanylate cyclase as well as intracellular catalytic activity. There are approximately 7,300 membrane guanylate cyclase molecules per cell, based on binding studies with ANP, with a dissociation constant of approximately 450 pM. Hyperbaric O(2) inhibits the function of human neutrophil beta2-integrins by a process linked to impaired synthesis of cGMP.

Adult↗

PubMed1997

Release of glutathione from erythrocytes and other markers of oxidative stress in carbon monoxide poisoning.

Rats exposed to CO in a manner known to cause oxidative stress in brain exhibited a twofold increase in plasma levels of oxidized proteins, thiobarbituric acid-reactive substances (TBARS), oxidized glutathione (GSSG), and reduced glutathione (GSH). Changes were neither directly related to hypoxic stress from carboxyhemoglobin nor significantly influenced by circulating platelets or neutrophils. Treatment with the nitric oxide synthase inhibitor N omega-nitro-L-arginine methyl ester inhibited elevations in GSH and GSSG but not changes in oxidized proteins or TBARS, suggesting that two oxidative mechanisms may be operating in this model and that GSH and GSSG elevations involved nitric oxide-derived oxidants. Elevations of blood GSH and GSSG occurred at different anatomic sites, indicating that no single organ was the source of the increased peptides. Animals that underwent exchange transfusion with a hemoglobin-containing saline solution did not exhibit elevations in GSH and GSSG, suggesting that blood-borne cells released these peptides in response to oxidative stress. In in vitro studies, erythrocytes, but not platelets and leukocytes, responded to oxidative stress from peroxynitrite by releasing GSH, whereas no release was observed in response to nitric oxide or superoxide. Glucose, maltose, and cytochalasin B, agents that protect extracellular components of the hexose transport protein complex from oxidative stress, prevented GSH release. The data indicate that nitric oxide-derived oxidants are involved in CO-mediated oxidative stress within the vascular compartment and that elevations of several compounds may be useful for identifying exposures to CO likely to precipitate brain injury.

Animals↗

PubMed1997

Mechanism of oxidative stress from low levels of carbon monoxide.

The purpose of this study was to determine whether platelets and vascular endothelial cells would liberate nitric oxide free radical (NO)* and NO-derived oxidant species after exposure to carbon monoxide (CO) at concentrations up to 100 parts per million (ppm). We hypothesized that exposure to environmentally relevant concentrations of CO would increase production of agents that may be involved in human pathological processes, such as atherosclerosis. Platelets obtained from rats released NO when incubated with CO, but CO did not increase platelet nitric oxide synthase activity. Platelets released comparable NO levels when they were exposed to CO in vitro and when taken from rats that had been exposed to CO. Partial pressures of CO as low as 10 ppm could successfully compete with NO for intraplatelet binding sites in in vitro studies. We conclude that CO enhanced the release of NO from platelets because it inhibited NO sequestration by intraplatelet binding sites, and that this phenomenon can occur with exposure to CO concentrations found in the environment. Bovine pulmonary artery endothelial cells released NO in response to CO exposure. Carbon monoxide did not affect the transport of L-arginine across the plasma membrane or nitric oxide synthase activity; therefore, the mechanism appeared to be based on a disturbance of intracellular NO sequestration. Cells incubated with CO also released into the surrounding medium peroxynitrite, an NO-derived oxidant, based on oxidation of dihydrorhodamine 123 and p-hydroxyphenylacetic acid. Peroxynitrite-mediated oxidative stress to endothelial cells was identified as increased concentrations of nitrotyrosine in cell lysates, and by measuring the release of radioactive chromium. Carbon monoxide caused an acute injury when cells were continuously exposed for 4 hours, and a delayed injury when cells were exposed for 2 hours. Delayed injury was documented by leakage of radioactive chromium and by uptake of a vital fluorescent stain, ethidium homodimer-1, between 6 and 20 hours after CO exposure. Oxidative stress caused by CO exhibited several unique aspects because CO exposure did not alter the cellular content of reduced sulfhydryls nor did CO augment oxidative stress caused by superoxide, hydrogen peroxide, or a flux of NO. We concluded that concentrations of CO achieved in vivo when humans are exposed to CO concentrations found in the environment can cause endothelial cells to liberate NO and NO-derived oxidants, and that these products can adversely affect cell physiology.

Air Pollutants↗

PubMed1996

Carbon dioxide enhancement of peroxynitrite-mediated protein tyrosine nitration.

Production of reactive species has been associated with tissue injury in diverse human disorders and experimental models of disease. Peroxynitrite is a strong oxidant with multiple pathways of reactivity. One protein modification reaction that may be specific to peroxynitrite is the nitration of the ortho position of tyrosine residues and nitrotyrosine has been used as a marker for peroxynitrite-mediated oxidative stress. Nitrotyrosine was formed when peroxynitrite was reacted at physiological pH with fatty acid-free bovine serum albumin or with human plasma proteins. Nitrotyrosine was not formed when proteins were incubated with nitric oxide, nitrogen dioxide, or nitric oxide plus hydrogen peroxide in the presence of ferrous iron or ferrihorseradish peroxidase. Low-molecular-weight molecules such as uric acid, ascorbate, and sulfhydryls inhibited protein tyrosine nitration in the absence of bicarbonate. Addition of bicarbonate catalytically enhanced the yield of nitration and overcame the inhibition of these antioxidants. Bicarbonate/CO2 enhanced the yield of protein nitrotyrosine in a concentration-dependent manner. Catalysis of nitration is achieved by the interaction of CO2 with the peroxynitrite anion. A mechanism is proposed involving an ONOO(O)CO- intermediate, which readily nitrates tyrosine residues in a non-radical-dependent manner. Thus, peroxynitrite nitrates tyrosine residues by a mechanism that is catalyzed by CO2 under normal physiological conditions.

Adult↗

PubMed1996

Hyperbaric oxygen therapy for the treatment of radiation-induced sequelae in children. The University of Pennsylvania experience.

BACKGROUND: The role of hyperbaric oxygen (HBO) therapy in the treatment of radiation-related sequelae in adults is well known. In contrast, its role in the management of radiation-related sequelae in children has not been well studied. In an effort to define its value better, the authors reviewed the University of Pennsylvania experience and hereby report the results of their analysis. METHODS: Between 1989 and 1994, ten patients who underwent radiation therapy for cancer as children were referred for HBO therapy. Six patients underwent HBO therapy as a prophylactic measure prior to maxillofacial procedures; dental extractions and/or root canals (four patients), bilateral coronoidectomies for mandibular ankylosis (one patient), and wound dehiscence (one patient). Therapeutic HBO was administered to four other patients; one patient for vasculitis resulting in acute seventh cranial nerve palsy and the other three after sequestrectomy for osteoradionecrosis (mastoid bone, temporal bone, and sacrum, respectively). Osteoradionecrosis was diagnosed both radiologically and histologically after exclusion of tumor recurrence. The number of treatments ranged between 9-40 "dives" (median, 30 dives). Treatments were given once daily at 2 atmosphere absolutes for 2 hours each. Adjunctive therapy in the form of debridement, antibiotics, and placement of tympanotomy tubes was administered to two patients. Ages at HBO treatment ranged from 3.5 to 26 years (median, 14 years). Six patients were male and four were female. The most commonly irradiated site was the head and neck region (eight patients; brain stem gliomas [one], posterior fossa primitive neuroectodermal tumor [one], rhabdomyosarcomas [three], nasopharyngeal cancer [one], carcinoma of the parotid gland [one], and Hodgkin's disease [one]). The remaining two patients received radiation therapy for pelvic tumors [Ewings's sarcoma and rhabdomyosarcoma). Radiation doses ranged between 4000 and 6660 centigray (cGy) (median, 5500 cGy). The interval between the end of radiation therapy and HBO treatment ranged between 2 months and 11 years (median, 15 years). The median follow-up interval after HBO therapy was 2.5 years (range, 2 months-4 years). RESULTS: Except for two patients who had initial anxiety, nausea, and vomiting, the HBO treatments were well tolerated. In all but one patient, the outcome was excellent. In the six patients who had prophylactic HBO, all continued to demonstrate complete healing of their orthodontal scars at last follow-up. In the four patients who received HBO as a therapeutic modality, all 4 had documented disappearance of signs and symptoms of radionecrosis and two patients demonstrated new bone growth on follow-up computed tomography scan. One patient with vasculitis and seventh cranial nerve palsy had transient improvement of hearing; however, subsequent audiograms returned to baseline. CONCLUSIONS: The use of hyperbaric oxygen for children with radiation-induced bone and soft tissue complications is safe and results in few significant adverse effects. It is a potentially valuable tool both in the prevention and treatment of radiation-related complications.

Adolescent↗

PubMed1996

Nitric oxide production and perivascular nitration in brain after carbon monoxide poisoning in the rat.

Nitric oxide is a short-lived free radical and physiological mediator which has the potential to cause cytotoxicity. Studies were conducted to investigate whether nitric oxide, and the potent oxidant peroxynitrite, were generated in brain during experimental carbon monoxide (CO) poisoning in the rat. Nitric oxide production was documented by electron paramagnetic resonance spectroscopy, and found to be increased by ninefold immediately after CO poisoning. Evidence that peroxynitrite was generated was sought by looking for nitrotyrosine in the brains of CO-poisoned rats. Nitrotyrosine was found deposited in vascular walls, and also diffusely throughout the parenchyma in inummocytochemical studies. The affinity and specificity of an anti-nitrotyrosine antibody was investigated and a solid phase immunoradiochemical assay was developed to quantity nitrotyrosine in brain homogenates. A 10-fold increase in nitrotyrosine was found in the brains of CO-poisoned rats. Platelets were involved with production of nitrotyrosine in the early phase of exposure to CO. However, nitrotyrosine formation and leukocyte sequestration were not decreased in thrombocytopenic rats poisoned with CO according to the standard model. When rats were pre-treated with the nitric oxide synthase inhibitor, L-nitroarginine methyl ester, formation of both nitric oxide and nitrotyrosine in response to CO poisoning were abolished, as well as leukocyte sequestration in the microvasculature, endothelial xanthine dehydrogenase conversion to xanthine oxidase, and brain lipid peroxidation. We conclude that perivascular reactions mediated by peroxynitrite are important in the cascade of events which lead to brain oxidative stress in CO poisoning.

Animals↗

PubMed1996

Effects of carbon monoxide on the brain may be mediated by nitric oxide.

Carbon monoxide (CO) is known to be a toxic molecule due to the high affinity of hemoglobin for it. However, it has recently been shown that low doses of CO may play a physiological role. The aim of the present study was to examine processes occurring in the brain during exposure to 1,000 parts per million CO that result in an increase in cerebral blood flow (CBF) but are not accompanied by changes in oxidation metabolism. This study was carried out in awake rats with the multiprobe assembly developed in this laboratory for the simultaneous continuous measurement of CBF, intramitochondrial NADH redox levels, direct current potential, and extracellular concentrations of K+, Ca2+, and H+ as well as the electrocorticogram. Exposure to 1,000 parts per million CO in air resulted in an increased CBF without any concomitant changes in any of the other metabolic or ionic parameters measured. This indicates that tissue hypoxia was not the trigger for this vasodilation. Injection of N omega-nitro-L-arginine (L-NNA), a nitric oxide synthase inhibitor, before exposure to CO effectively blocked the increase in CBF that was observed when the animal was exposed to CO without prior injection of L-NNA. Furthermore, electrocorticographic depression was observed after the combined treatment of L-NNA and CO. In conclusion, exposure to relatively low doses of CO apparently does not have a deleterious effect on oxidative metabolism because the increase in CBF after this exposure is sufficient to prevent changes in oxidative metabolism, as indicated by the fact that NADH levels remained constant. This protective autoregulatory effect may be mediated by nitric oxide.

Animals↗

PubMed1996

Functional inhibition of rat polymorphonuclear leukocyte B2 integrins by hyperbaric oxygen is associated with impaired cGMP synthesis.

We hypothesized that hyperbaric oxygen caused a metabolic derangement in polymorphonuclear leukocytes that impaired the function of B2 integrins. Isolated neutrophils from rats that had been exposed to 3 atm oxygen for 45 min failed to exhibit B2 integrin-dependent adherence to nylon columns or to fibrinogen-coated plates. Adherence was restored after cells were incubated with 8-bromo-cGMP, phorbol 12-myristate 13-acetate (PMA) or the reducing agent dithioerythritol. Hyperbaric oxygen was found to inhibit cGMP synthesis that normally occurred when cells were stimulated by passage through nylon columns, and exposure to PMA or dithioerythritol reestablished cGMP synthesis. Cells adherent to plastic plates synthesized cGMP when they were exposed to N-formyl-methionyl-leucine-phenylalanine (FMLP) or PMA. Neutrophils from rats exposed to hyperbaric oxygen synthesized cGMP in response to PMA but failed to respond to FMLP, although hyperbaric oxygen did not alter the affinity of the FMLP receptor or its associated G protein. Dithioerythritol restored the cGMP synthetic ability of adherent neutrophils in response to FMLP. We conclude that hyperbaric oxygen inhibits B2 integrin-dependent adherence because it impairs cGMP synthesis by activated neutrophils.

Animals↗

PubMed1995

Delayed neuropsychologic sequelae after carbon monoxide poisoning: prevention by treatment with hyperbaric oxygen.

STUDY OBJECTIVE: Carbon monoxide (CO) poisoning is a major clinical problem. The risk of morbidity and the most effective treatment have not been clearly established. We measured the incidence of delayed neurologic sequelae (DNS) in a group of patients acutely poisoned with CO and tested the null hypothesis that the incidence would not be affected by treatment with hyperbaric oxygen (HBO). DESIGN: We conducted a prospective, randomized study in patients with mild to moderate CO poisoning who presented within 6 hours. Patients had no history of loss of consciousness or cardiac instability. INTERVENTIONS: The incidence of DNS was compared between groups treated with ambient pressure 100% oxygen or HBO (2.8 ATA for 30 minutes followed by 2.0 ATA oxygen for 90 minutes). DNS were defined as development of new symptoms after oxygen treatment plus deterioration on one or more subtests of a standardized neuropsychologic screening battery. RESULTS: In 7 of 30 patients (23%), DNS developed after treatment with ambient-pressure oxygen, whereas no sequelae developed in 30 patients after HBO treatment (P < .05). DNS occurred 6 +/- 1 (mean +/- SE) days after poisoning and persisted 41 +/- 8 days. At follow-up 4 weeks after poisoning, patients who had been treated with ambient pressure oxygen and had not sustained DNS exhibited a worse mean score on one subtest, Trail Making, compared with the group treated with HBO and with a control group matched according to age and education level. There were no differences in scores between the control group and the hyperbaric oxygen group. CONCLUSION: DNS after CO poisoning cannot be predicted on the basis of a patient's clinical history or CO level. HBO treatment decreased the incidence of DNS after CO poisoning.

Adolescent↗

PubMed1995

Multiparametric monitoring of the awake brain exposed to carbon monoxide.

We have applied in vivo real-time techniques to monitor the physiological changes associated with exposure to a pattern of carbon monoxide (CO) known to cause brain oxidative stress. Using a multiparametric monitoring device connected to the brain, we exposed unanesthetized rats to two levels of CO, 0.1 and 0.3% in air. Energy metabolism was evaluated by the optical monitoring of relative cerebral blood flow (CBF) and intramitochondrial redox state. Ionic homeostasis was assessed by measurements of K+,Ca2+, and H+ or Na+ levels in the extracellular space. The electrical parameters monitored were the electrocorticogram and direct current steady potential. Under 1,000 ppm of CO, the CBF was increased significantly without any measurable change in the NADH redox state, suggesting that the cause for the increased CBF was not hypoxia. Exposing the awake rat to 1,000 ppm of CO (40 min) followed by 3,000 ppm of CO (20 min) led to an increase in CBF followed by episodes of spontaneous brain depolarizations characterized by changes in ionic homeostasis and blood flow. These changes were similar to those recorded under cortical spreading depression. In most animals exposed to 3,000 ppm of CO, spontaneous oscillations in CBF and NADH redox state that were negatively correlated were recorded. The results indicate that an inspired CO level of 0.1% had effects largely restricted to blood flow, whereas at a higher CO level an additional impairment in energy supply resulted in a complex pattern of effects similar to that caused by brain ischemia.

Animals↗

PubMed1994

Nitric oxide released by platelets inhibits neutrophil B2 integrin function following acute carbon monoxide poisoning.

Carbon monoxide (CO) poisoning has been reported to temporarily inhibit B2 integrin adherence molecules on leukocytes in previous studies in a rat model. The aim of this study was to investigate the mechanism for this effect. Studies were conducted using blood obtained from rats after they were exposed to CO and also with blood cells exposed to CO in vitro. Initial investigations indicated that inhibition of neutrophil (polymorphonuclear leukocyte, PMN) B2 integrin function was linked to the platelets in blood, as the effect was resolved by decreasing platelet number before PMN adherence was tested. The platelet effect could also be shown by incubating either platelet-rich plasma or whole blood with CO in vitro. The effect of platelets was blocked by superoxide radicals and by NG-nitro-L-arginine methyl ester, an inhibitor of nitric oxide (NO) synthase. These observations suggested that CO caused platelets to release NO, an agent known to inhibit the function of B2 integrins. The concentration of NO measured in suspensions of platelets from rats poisoned with CO according to the established model (exposure to 1000 ppm CO for 40 min and 3000 ppm CO for 20 min) was 47 nmol/10(8) platelets, in contrast to only 0.3 nmol NO/10(8) platelets from control rats. Enhanced NO release occurred despite a 60% inhibition of NO synthase activity, assessed by measuring conversion of [14C]L-arginine to citrulline. Exposure to only 1000 ppm CO for 1 hr caused platelets to release 74 nmol NO/10(8) platelets, and no inhibition of NO synthase occurred. Enhanced NO release, and inhibition of PMN adherence, did not occur after platelets were exposed to light from a quartz lamp to photodissociate CO from heme proteins. The data suggest that the NO flux from platelets increased when CO became bound to heme-containing platelet proteins, which normally scavage intraplatelet NO and thus prevent diffusion beyond the platelet membrane.

Amino Acid Oxidoreductases↗

PubMed1994

Smoke inhalation with a concurrent systemic stress results in lung alveolar injury.

Smoke inhalation causes injuries to lung airways, and, at times, alveolar inflammation also develops over approximately 24 h. The pathophysiology of parenchymal lung injuries is unknown, and it is often fatal. We hypothesized that an inflammatory stress remote from the smoke-related lung insult was required for development of alveolar injuries. Spontaneously breathing rats were exposed, head only, to smoke generated by nonflaming pyrolysis (smoldering) of Douglas fir wood (DF), polyvinylchloride (PVC), or the combination of DF+PVC. Intraperitoneal injection of sterile oyster shell glycogen 4 h before smoke inhalation was used as an extra inflammatory stimulus. Histologic examinations revealed extensive airway inflammation in all smoke-exposed groups. Glycogen peritonitis alone caused no lung injuries, and in the absence of glycogen, smoke inhalation caused neither parenchymal lung injuries, assessed by [125I]bovine serum albumin (BSA) leakage, nor neutrophil infiltration, quantified by myeloperoxidase (MPO) activity. However, in rats pretreated with glycogen and studied 24 h after exposure to smoke from burning DF+PVC, [125I]BSA permeability was increased by 232 +/- 41% (SE; n = 13), MPO activity was increased 5-fold, from 2.6 +/- 0.4 (n = 7) to 13.9 +/- 1.4 (n = 19) A460/min/g lung, and histopathologic findings included extensive pulmonary inflammation. We conclude that inhalation of certain types of smoke will trigger pulmonary injury when an inflammatory process remote from the lungs is present.

Analysis of Variance↗

PubMed1994

Role of neutrophils and nitric oxide in lung alveolar injury from smoke inhalation.

We examined potential mechanisms responsible for the parenchymal lung injury seen in an animal model of smoke inhalation with concurrent inflammation. Rats injected with sterile glycogen and exposed to smoke generated by the nonflaming pyrolysis of combined Douglas fir wood and polyvinylchloride showed a 74% increase in 125I-albumin lung permeability and a fivefold increase in lung myeloperoxidase (MPO) compared with control rats. There was also a significant increase in plasma indices of oxidative injury in these animals. Compared with control animals, plasma concentrations of thiobarbituric acid reactive substances (TBARS) were elevated by 62%, the concentrations of reduced sulfhydryl groups declined by 37%, and the levels of dinitrophenylhydrazine-reactive proteins (DNPH-RP) were doubled. In addition, the plasma concentrations of nitrate (NO3-) in rats exposed to glycogen plus smoke were increased three times that of control animals. Injection of the nitric oxide synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), immediately after smoke exposure or induction of neutropenia using either nitrogen mustard or antineutrophil antiserum, abolished the increase in concentrations of circulating NO3-, and prevented changes in plasma concentrations of TBARS, DNPH-RP, lung MPO activity, and tissue permeability index. These data suggest that neutrophil activation and the production of nitric oxide-derived oxidants contribute to the lung and plasma indices of oxidative injury in this smoke inhalation model.

2,4-Dinitrophenol↗

PubMed1994

Pathophysiology and treatment of carbon monoxide poisoning.

Carbon monoxide poisoning is the leading cause of poisoning deaths in the US, and published reports of carbon monoxide related morbidity and mortality can vary widely. Common morbidity involves myocardial and/or neurologic injury including delayed neurologic sequelae. The pathophysiology of this entity is complex, involving hypoxic stress on the basis of interference with oxygen transport to the cells and possibly impairing electron transport. Carbon monoxide can also affect leukocytes, platelets and the endothelium, inducing a cascade of effects resulting in oxidative injury. Carboxyhemoglobin levels are valuable for confirming carbon monoxide exposure but cannot be used to stratify severity of poisoning, predict prognosis, or indicate a specific treatment plan. Oxygen therapy is the key treatment of carbon monoxide intoxication, and hyperbaric oxygen has been shown to interdict and improve clinical outcome in some patients. Immediate treatment with a high fraction of inspired oxygen and careful clinical evaluation are mandatory. Timely referral for hyperbaric oxygen is indicated for patients with any history of unconsciousness, cardiovascular instability or ischemia, and persistent mental and/or neurologic deficits. Hyperbaric oxygen should also be considered in certain other patient subsets.

Animals↗

PubMed1994

Use of hyperbaric oxygen in toxicology.

HBO has become recognized as a potential treatment for a variety of toxins. HBO is helpful because it provides an excess of dissolved oxygen, which not only can sustain life in the absence of hemoglobin, but in some cases can actually increase the clearance of toxins. In addition, it is now apparent that HBO serves more complex roles in toxicological injuries, such as modifying PMN-endothelial interactions and preventing oxidative tissue injury. The major drawback of HBO therapy is the lack of controlled clinical trials, partly due to the rarity of most of the toxins discussed. In fact, the field of hyperbaric medicine has come under increasing criticism for this failure. There is a physiologic basis for use of HBO in the toxins discussed. Unfortunately, only for CO is patient volume adequate for studies to document efficacy. Regarding the other toxins mentioned, the use of HBO should be reserved for carefully selected cases in which patients have failed routine care or are at risk for delayed effects.

Animals↗

PubMed1993

Involvement of platelet-endothelial cell adhesion molecule-1 in neutrophil recruitment in vivo.

During inflammation, neutrophils migrate from the vascular lumen into extravascular sites. In vitro assays have suggested that platelet-endothelial cell adhesion molecule-1 [PECAM-1 (CD31)], a member of the immunoglobulin superfamily, is required for the transmigration of neutrophils across endothelial monolayers. Antibody to human PECAM-1, which cross-reacts with rat PECAM-1, was found to block not only in vivo accumulation of rat neutrophils into the peritoneal cavity and the alveolar compartment of the lung but also neutrophil accumulation in human skin grafts transplanted onto immunodeficient mice. On the basis of these findings in three different models of inflammation, it appears that PECAM-1 is required for neutrophil transmigration in vivo and may thus be a potential therapeutic target.

Animals↗

PubMed1993

Leukocytes in carbon monoxide-mediated brain oxidative injury.

This study was conducted with rats to assess the involvement of leukocytes in a model of CO-mediated brain injury. Myeloperoxidase activity, measured as an index of leukocyte sequestration, was found to be increased 10-fold in brain microvessel segments prepared from rats immediately or 90 min after exposure to CO. Fluorescence and light microscopic examinations revealed leukocytes in microvessels taken from CO-poisoned rats, but not in that from control rats. Studies were then conducted with rats that had been made leukopenic or treated with monoclonal anti-CD-18 F(ab')2 fragments to inhibit leukocyte adherence to the vasculature. Neither of these groups of animals exhibited the biochemical changes observed in the brains of sham-treated rats: conversion of xanthine dehydrogenase (XD) to sulfhydryl-irreversible xanthine oxidase (XO), and lipid peroxidation, at 90 min following CO poisoning. Treatment with a synthetic serine protease inhibitor, gabexate mesylate, also prevented these biochemical changes if administered immediately after CO poisoning, but the agent did not inhibit leukocyte sequestration. Rats depleted of XD and XO by a tungsten diet, and those treated with allopurinol to inhibit XD and XO, also exhibited at least a 10-fold increase in myeloperoxidase activity in microvessels immediately after CO poisoning, but only a 5-fold increase at 90 min. In vitro studies demonstrated that B2 integrin-dependent polymorphonuclear leukocyte adherence was impaired immediately following CO poisoning although the adherence molecules were expressed on the membrane surface. Adherence function normalized by 45 min. The results suggest that leukocytes are responsible for the development of biochemical changes in brain following CO poisoning, and the sequence of events is as follows: leukocyte sequestration in the microvasculature, B2 integrin-dependent adherence, protease-mediated conversion of XD to XO, O2 radical-dependent lipid peroxidation.

Allopurinol↗