BACKGROUND AND METHODS: Tissue oxygenation during ischemia and hypoxia is critical to cellular viability. Adequate tissue oxygenation reflects a balance between oxygen delivery (DO2) and oxygen demand. At critical levels of DO2, oxygen consumption (VO2) declines due to supply dependency, indicating inadequate tissue oxygenation and impaired cellular metabolism. The mechanism by which DO2 is compromised (hypoxia vs. ischemia) determines the level of delivery at which VO2 becomes supply dependent. Tonometry is a method used to assess the adequacy of gut oxygenation. RESULTS: Studies using tonometric monitoring of intramural pH have shown that tonometry detects early tissue anaerobiosis and net adenosine triphosphate (ATP) hydrolysis. A decrease in intramural pH strongly correlates with the onset of supply dependency in tissue VO2. Inadequate intestinal oxygenation determined by tonometry has predicted clinical outcomes and complications in patients at risk. CONCLUSIONS: Gut tonometry may provide an early indication of inadequate tissue oxygenation. This early recognition is necessary to mitigate adverse consequences, including ATP catabolism, the production of reactive oxygen metabolites, and the activation of the inflammatory process, which can lead to progressive cellular dysfunction and cell death.

Animals↗

PubMed1992

Spirometry and chest roentgenographic appearance in adults with cystic fibrosis.

The pathophysiologic manifestations of cystic fibrosis are continually evolving as more patients survive into their adult years. Although the correlation between chest roentgenographic appearance and pulmonary function testing is well described in children with cystic fibrosis, to our knowledge, there are no data that evaluate this relationship in adults. We analyzed 66 paired studies of chest roentgenographic appearance (Brasfield score) and spirometry in 27 adults with cystic fibrosis between the ages of 18 and 40 years. There was a very good correlation between spirometry and the Brasfield score in adults with cystic fibrosis. The strongest correlation was between the percent predicted FEV1 and the Brasfield score (r = 0.68, p less than 0.001). These correlations were found to remain significant in the patients in whom longitudinal data were available. The FEV1 declined 104 +/- 26 ml/yr in 11 patients who were followed up for a mean duration of 5.8 +/- 0.5 years. The decline in FEV1 per year in adults with cystic fibrosis was significantly greater than in nonsmoking or smoking adults of similar age.

Adolescent↗

PubMed1992

Cells in crisis. Cellular bioenergetics and inadequate oxygenation in the intensive care unit.

Explore the source record for details and available documents.

Adenosine Triphosphate↗

PubMed1992

Chest radiographic findings in cystic fibrosis.

Radiographic imaging modalities that have been applied to the staging and prognostication of the lung lesion in cystic fibrosis (CF) include conventional chest radiographs, computed tomography (CT), and magnetic resonance imaging (MRI). Conventional chest radiographs are usually adequate to detect the salient radiographic features of CF and provide objective parameters for longitudinal disease progression. Although the lung manifestations of CF can be highly variable most patients with CF demonstrate some of the classic chest radiographic findings that reflect chronic bronchiectasis: hyperinflation, bronchial thickening and dilatation, peribronchial cuffing, mucoid impaction, cystic radiolucencies, an increase in interstitial markings, and scattered nodular densities. Complications of advanced CF include atelectasis, mucoid impaction, pneumothorax, pneumomediastinum, pulmonary hemorrhage, cardiomegaly, and enlargement of the pulmonary artery with cor pulmonale. Scoring systems have been developed to grade the chest radiograph in CF and to more accurately quantitate the severity of disease. Currently, the Brasfield system is in widest use. These radiographic scoring systems correlate well with pulmonary function data in both the pediatric and adult CF populations. High-resolution computed tomography (HRCT) is clearly more sensitive and accurate than conventional chest radiography in delineating the extent and severity of bronchiectasis and other parenchymal and airway lesions in CF. Quantifiable scoring systems using HRCT have been developed to assess disease severity in CF. The use of MRI in the clinical management of CF has been limited. MRI may be helpful in determining the cause of linear lung markings, differentiating mucous plugging, and peribronchial thickening from normal pulmonary blood vessels. MRI is an excellent imaging modality to differentiate hilar or mediastinal adenopathy from blood vessels or mediastinal fat.

Adult↗

PubMed1991

Xanthine oxidase inhibition does not limit canine infarct size.

BACKGROUND: Evidence supporting the role of xanthine oxidase in myocardial reperfusion injury is based on studies with pharmacological interventions used to inhibit enzyme function. Controversy exists, however, regarding the true role of xanthine oxidase in reperfusion injury. This study was performed to determine whether xanthine oxidase inhibition limits myocardial injury due to coronary artery occlusion and reperfusion. METHODS AND RESULTS: Anesthetized dogs underwent coronary artery occlusion (90 minutes) and reperfusion (6 hours). Oxypurinol (28 mg/kg) or amflutizole (30 mg/kg), chemically unrelated inhibitors of xanthine oxidase, or vehicle was infused intravenously 15 minutes before and 3 hours after reperfusion. Regional myocardial blood flow was determined with radiolabeled microspheres. Infarct size was determined with the tetrazolium method. Myocardial infarct size (percent of risk region) was less in oxypurinol-treated dogs, 32 +/- 16%, compared with that of the control group, 46 +/- 15%. Infarct size for the amflutizole-treated dogs, 40 +/- 21%, was not significantly different from that of the control group. There were no differences in rate-pressure product or collateral blood flow to account for differences in infarct size. Uric acid concentration in the coronary venous plasma increased after reperfusion in the dogs treated with vehicle but not in the drug-treated dogs. Xanthine oxidase inhibition was demonstrated in each of the drug treatment groups, but only oxypurinol limited the extent of myocardial injury. CONCLUSIONS: Previously reported cardioprotective effects of allopurinol, noted to occur only when the drug was administered chronically, may be related to a property of oxypurinol, a major metabolite of allopurinol. The beneficial effect of oxypurinol is unrelated to inhibition of superoxide formation during xanthine oxidase-catalyzed oxidation of xanthine and hypoxanthine.

Animals↗

PubMed1991

Inhibition of cyclooxygenase metabolite production attenuates ischemia-reperfusion lung injury.

We investigated if cyclooxygenase metabolites of arachidonic acid were involved in ischemia-reperfusion lung injury by determining if inhibition of their production attenuated the injury. Isolated rat lungs were perfused with physiologic salt solution osmotically stabilized with Ficoll until circulating blood elements were not detected in lung effluent. Ischemia was induced by stopping ventilation and perfusion for 90 min. Lung ventilation and perfusion were then resumed. Ischemia-reperfusion resulted in the production of prostacyclin and thromboxane assessed by lung effluent and tissue measurements of their respective stable metabolites, 6-keto-PGF1 alpha thromboxane B2 (TxB2). In contrast, prostaglandin F2 alpha did not increase. Ischemia-reperfusion also caused lung injury as assessed by increased lung 125I-BSA accumulation compared with nonischemic control lungs. Addition of the cyclooxygenase inhibitors, indomethacin, or flubiprofen to the lung perfusate before and after ischemia inhibited lung injury as well as the production of 6-keto-PGF1 alpha and TxB2. Addition of a thromboxane synthetase inhibitor (U 63557A) reduced lung injury as well as TxB2 formation without affecting the production of 6-keto-PGF1 alpha. The attenuation of lung injury was not explained by direct H2O2 removal by indomethacin, flubiprofen, or U 63557A because the concentrations of the inhibitors used in the isolated lung experiments did not remove exogenously added H2O2 from buffer in vitro. We conclude that cyclooxygenase metabolites of arachidonic acid are involved in ischemia-reperfusion injury to isolated rat lungs.

6-Ketoprostaglandin F1 alpha↗

PubMed1990

Cerium chloride as a histochemical marker of hydrogen peroxide in reperfused ischemic hearts.

Hydrogen peroxide (H2O2) has been implicated in cardiac damage due to ischemia and reperfusion. We adapted an electron microscopic, histochemical method for demonstrating H2O2 produced by isolated cells to isolated, buffer-perfused rabbit hearts. The method involves formation of an electron-dense precipitate when H2O2 reacts with cerium chloride (CeCl3). We perfused hearts retrograde via the aorta with well-oxygenated bicarbonate-buffered solution, followed by one in which bicarbonate was replaced with imidazole (IPSS) to prevent precipitation of bicarbonate and CeCl3. Some hearts were made globally ischemic (30 min, 37 degrees C), reperfused 5 min with well-oxygenated IPSS containing 1 mM CeCl3, then processed for electron microscopy. Others were perfused with IPSS containing catalase (300 U/ml) or albumin before ischemia and upon reperfusion, followed by CeCl3 administration. Nonischemic control hearts perfused with IPSS (+/- catalase) were also studied. Electron micrographs were assessed visually and by computer for precipitate localization and amount. There was abundant precipitate on the luminal face of the coronary vascular endothelium in ischemic-reperfused, cerium-treated hearts, including those treated with albumin. There was significantly less in reperfused catalase-treated or nonischemic control hearts. X-ray microbeam analysis of the endothelial precipitate indicated the presence of Ce. This appears to be the first visual demonstration of a CeCl3-H2O2-dependent reaction product in intact isolated ischemic hearts. The data indicate that at the time of reperfusion some H2O2 is accessible to the vascular space, and that its amount can be reduced by perfused catalase. Further modifications this technique may be useful for assessing the sites and pathways by which H2O2 is generated by hearts or other buffer-perfused organs subjected to stresses such as ischemia or hypoxia.

Animals↗

PubMed1990

Neutrophils are not necessary for induction of ischemia-reperfusion lung injury.

Ischemia-reperfusion lung injury limits lung transplantation. Neutrophil activation and/or xanthine oxidase-mediated purine degradation may cause toxic oxygen metabolite production and lung injury. We investigated whether circulating blood elements are involved in the pathogenesis of ischemia-reperfusion lung injury. Isolated rat lungs were perfused with physiological salt solution (PSS) stabilized with Ficoll until circulating blood elements were not detected in the lung effluent. Lungs were then rendered ischemic by stopping ventilation and perfusion for 45 min at room temperature. Lung injury occurred and was quantitated by the accumulation of 125I-bovine serum albumin into lung parenchyma and alveolar lavage fluid during reperfusion. Lung injury occurred, in the absence of circulating blood elements, when ischemic lungs were reperfused with PSS-Ficoll solution alone. Reperfusion with whole blood or PSS-Ficoll supplemented with human or rat neutrophils did not increase lung injury. Furthermore, during lung ischemia, the presence of neutrophils did not enhance injury. Experiments using PSS-albumin perfusate and quantitating lung injury by permeability-surface area product yielded similar results. Microvascular pressures were not different and could not account for the results. Toxic O2 metabolites were involved in the injury because addition of erythrocytes or catalase to the perfusate attenuated the injury. Thus reperfusion after lung ischemia causes injury that is dependent on a nonneutrophil source of toxic O2 metabolites.

Animals↗

PubMed1990

Tissue release of adenosine triphosphate degradation products during shock in dogs.

Clinical monitoring of cellular metabolism during shock, based largely on traditional metabolic indicators, remains unsatisfactory. The purpose of this study was to compare venous oxygen tension and blood lactate gradients with blood gradients of purine nucleotide degradation products which are derived from tissue ATP catabolism during hypovolemic shock. Sixteen dogs were instrumented to sample arterial and venous blood. Measurements of arteriovenous lactate and PNDP gradients during spontaneous respiration were examined at four tissue sites: gut, kidney, hindlimb, and diaphragm. Hypovolemic shock (mean arterial blood pressure 35 to 40 mm Hg) was induced and maintained for one hour. The above parameters were remeasured at 30 and 60 minutes after induction of shock. Hypoxanthine gradients were greater than that of other PNDP, and so were used as the primary indicator of tissue ATP metabolism. In the hindlimb, the mean AV gradients for hypoxanthine (1 +/- 1 microM) were not significantly greater than baseline, while the lactate gradient (700 +/- 300 microM) rose markedly. In contrast, across the kidney there was a significantly greater AV hypoxanthine gradient (16 +/- 3 microM, p less than 0.002) but no lactate gradient (-400 +/- 200 microM). Both the hypoxanthine and lactate AV gradients were significantly elevated across the diaphragm and gut. Venous PO2 values less than 35 mm Hg predicted an increased hypoxanthine gradient across the kidney, but not across the hindlimb. We conclude that the metabolic response to hypovolemic shock as assessed by PNDP gradients, lactate gradients, and venous PO2 differs among tissues. Although resting muscle such as the hindlimb may be an important source of blood lactate, the viscera and working skeletal muscle (the diaphragm) are major contributors to circulating PNDP.

Adenosine↗

PubMed1990

The correlation of subcarinal density visualized on plain chest roentgenograms with computed tomographic scans.

A prospective evaluation of 212 paired chest roentgenograms and computed tomographic (CT) scans was performed to determine the predictive value of detecting subcarinal adenopathy by finding increased subcarinal density on routine roentgenograms. Based on CT criteria for subcarinal lymphadenopathy, 37 true-positive and 124 true-negative cases of subcarinal adenopathy were found in 161 patients. Evaluation of density in the subcarinal area on the routine posteroanterior (PA) chest roentgenograms in these patients demonstrated a sensitivity of 72 percent and specificity of 96 percent for the detection of adenopathy when compared with established CT criteria. False-positive and false-negative appraisals of central mediastinal density on routine roentgenograms appear to be due to the super-imposition of other masses, bullae, or lack of appropriate roentgenographic contrast. The accuracy of predicting the presence or absence of subcarinal adenopathy from routine chest roentgenograms suggests that this observation is clinically useful and should be routinely evaluated.

False Negative Reactions↗

PubMed1990

Expression of xanthine oxidase activity by murine leukocytes.

The enzyme xanthine oxidase participates in the pathogenesis of tissue ischemia-reperfusion injury by depleting purine pools and generating toxic oxygen metabolites. The role of xanthine oxidase in inflammatory cell populations has not been defined. We examined the level of xanthine oxidase activity expressed by murine leukocytes both in the resting state, and after in vivo and in vitro exposure to inflammatory stimuli. The contribution of xanthine oxidase to inflammation may vary among tissue compartments, so leukocytes harvested from several tissues were studied. Resident murine peritoneal macrophages consistently expressed xanthine oxidase activity (291 +/- 55 microIU/10(6) cells). Thioglycolate-elicited peritoneal macrophages contained similar levels of xanthine oxidase activity (265 +/- 42 microIU/10(6) cells). By contrast, resident murine alveolar macrophages expressed one tenth the xanthine oxidase activity (24 +/- 4 microIU/10(6) cells). Xanthine oxidase activity was also consistently found in murine peritoneal neutrophils (127 +/- 28 microIU/10(6) cells) but not in splenic lymphocytes. In vitro studies were performed to determine whether xanthine oxidase activity of resident peritoneal macrophages could be modulated by exogenous stimuli relevant to the pathogenesis of inflammation. Lipopolysaccharide caused a 62% +/- 9% reduction in cellular xanthine oxidase activity (p less than 0.02). Interferon-gamma alone had no effect on xanthine oxidase activity; however, interferon-gamma and lipopolysaccharide together caused a striking reduction in cellular xanthine oxidase activity, reaching 25% +/- 2% of unstimulated control cells (p less than 0.001). We conclude that murine macrophages and neutrophils are potentially important sources of xanthine oxidase activity in inflamed tissues. In addition, the activity of xanthine oxidase in macrophages is tissue specific and is modulated in vitro by proinflammatory stimuli.

Animals↗

PubMed1989

Absence of detectable xanthine oxidase in human myocardium.

The enzyme xanthine oxidase has been implicated as a generator of toxic oxygen metabolites that contribute to ischemic injury. Because substantial species variability has been demonstrated and because there are minimal human data available, the relevance of xanthine oxidase to human heart damage has been in doubt. We report the absence of xanthine oxidase activity in nine human heart biopsy specimens obtained during cardiac surgery, and in two larger samples obtained during heart transplantation. A sensitive radiochemical assay was used to assess enzyme activity. Our findings imply that oxygen free radicals generated by xanthine oxidase are not relevant in terms of human myocardial injury.

Animals↗