Oxidant stress increases susceptibility of porcine endothelial cells to injury by xenoreactive antibody and complement.
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Animals↗
Biomedical subjects
K T Oldham
Publications and source records attributed to K T Oldham.
Decreased oxidized glutathione with aerosolized cyclosporine delivery.
Cyclosporine immunosuppression remains vital for successful lung transplantation. Cyclosporine also functions as a membrane active biological response modifier and has been noted to have a variable effect on ischemia-reperfusion (I/R) injury in various tissues. Glutathione plays an important role in the endogenous antioxidant defense system; plasma oxidized glutathione (GSSG) levels are useful as a sensitive indicator of in vivo oxidant stress and I/R injury. Lung transplantation results in ischemia, followed by a period of reperfusion, potentially producing functional injury. This study was designed to evaluate the effect of cyclosporine on oxygen radical generation in a model of single-lung transplantation. Single-lung transplantation was performed in 12 mongrel puppies, with animals assigned to receive either intravenous or aerosolized cyclosporine. Arterial blood and bronchoalveolar lavage fluid (BALF) samples were obtained to determine GSSG levels via a spectrophotometric technique. Samples were obtained both prior to and following the revascularization of the transplanted lung. Whole blood and tissue cyclosporine levels were determined via an high-performance liquid chromatography technique 3 hr following the completion of the transplant. Aerosolized cyclosporine administration resulted in greatly decreased arterial plasma and BALF GSSG levels, whole blood cyclosporine levels, and equivalent tissue cyclosporine levels when compared to intravenous cyclosporine delivery. These findings support the hypothesis that the transplanted lung is a source of GSSG production and release into plasma. Additionally, these findings suggest that cyclosporine may have a direct antioxidant effect on pulmonary tissue, with this activity occurring at the epithelial surface, an area susceptible to oxidant injury.
Aerosols↗
Perforation associated with barium enema in acute appendicitis.
A child with the suspected diagnosis of atypical acute appendicitis underwent a diagnostic barium enema. The study was complicated by perforation with leakage of a large amount of barium into the peritoneal cavity. The complex hospital course that resulted has prompted us to reevaluate the barium enema in the diagnosis of appendicitis and review the literature for contraindications. We conclude that this particular complication is extremely rare and that barium enema still has a part to play in some patients where the clinical diagnosis is uncertain.
Acute Disease↗
Reperfusion injury following single-lung transplantation: the tissue glutathione response.
Parenchymal injury following reperfusion of the donor lung remains a significant problem in clinical lung transplantation. It has been postulated that free oxygen radicals act as local mediators of this event, and that tissue oxidized glutathione levels which reflect local free oxygen radical production, may be useful as an indicator of this regional ischemia-reperfusion injury. The glutathione redox cycle plays a physiologically important role in the endogenous antioxidant defense system. Intracellular glutathione depletion has been shown to render cells vulnerable to oxidant mediated injury. Adequate glutathione stores may be vital in protecting the cell from oxidant injury, especially the relatively exposed pulmonary epithelial cells. Single lung transplantation was carried out in 10 3- to 5-kg mongrel puppies, with a standard 2-hour ischemic time for the donor lung prior to reimplantation. Four hours following transplantation, lung tissue was harvested from both the transplanted and native lung of the recipient animal, and compared to normal lung tissue from the donor animal. Tissue was prepared for histological evaluation and glutathione assay. Tissue glutathione levels were determined via a spectrophotometric assay. For determination of oxidized glutathione (GSSG), samples were prepared with 2-vinylpyridine and N-ethylmaleimide (NEM) to derivatize all reduced glutathione and leave only GSSG for measurement by the fluorometric assay.(ABSTRACT TRUNCATED AT 250 WORDS)
Analysis of Variance↗
Intestinal ischemia-reperfusion injury causes pulmonary endothelial cell ATP depletion.
Intestinal ischemia-reperfusion is a common clinical event associated with both clinical and experimental distant organ injury. In particular, the pulmonary microvasculature appears to be susceptible to injury resulting from systemic inflammatory mediator activation. This study was designed to evaluate the hypothesis that noncellular humoral factors associated with intestinal ischemia-reperfusion result in pulmonary endothelial cell adenosine triphosphate (ATP) depletion. Male Sprague-Dawley rats had intestinal ischemia induced by microvascular clip occlusion of the superior mesenteric artery (SMA) for 120 minutes. Reperfusion resulted from superior mesenteric artery clip removal. After reperfusion for 0, 15, or 30 minutes, plasma samples were obtained from the portal vein. Monolayers of cultured rat pulmonary artery endothelial cells then were incubated with the plasma samples. Adenosine triphosphate levels were determined using a luciferin-luciferase assay. A 51Cr-release assay using labeled endothelial cells was performed under identical conditions to assess cytotoxicity. Potential mechanisms of ATP depletion were evaluated by analysis of cellular energy charge and assessment of microfilament architecture. Endothelial cell ATP levels decreased from 2.23 +/- 0.16 x 10(-11) moles/microgram DNA in sham preparations to 1.23 +/- 0.09 x 10(-11) moles/microgram DNA (p < 0.001) after 4 hours in plasma from animals undergoing 120 minutes of intestinal ischemia. For plasma obtained after 15 minutes of reperfusion, the decrease in cellular ATP concentration persisted (1.23 +/- 0.27 x 10(-11) moles/microgram DNA, p < 0.001 vs. sham). After 30 minutes' reperfusion, cellular ATP levels increased only slightly after the 4-hour incubation (1.39 +/- 0.26 x 10(-11) moles/microgram DNA, p < 0.005 vs. sham). No significant cytotoxic injury occurred in any group when compared with controls. Cellular energy charge was unchanged, and microfilament architecture was preserved. These data confirm the hypothesis that humoral factors, independent of the neutrophil, result in endothelial cell ATP depletion without metabolic inhibition or cell death. Depletion of energy stores by noncellular humoral factors may represent an early event that predisposes the cell to more severe injury by other mediators of the endogenous inflammatory response.
Actin Cytoskeleton↗
Mycotic thromboaneurysmal disease of the abdominal aorta in preterm infants: its natural history and its management.
Five infants with mycotic complications of umbilical artery catheterization were evaluated with abdominal ultrasound and followed serially to document their natural history. Methicillin-resistant Staphylococcus aureus was always the infecting organism. There were one female and four male infants and they weighed between 900 and 1,200 g at birth. While two of the catheters were positioned in the abdominal aorta, three were located above the diaphragm. The predominate signs and symptoms included: thrombocytopenia, unexplained anemia, renal failure, hypertension, and embolic phenomena to the toes. Real-time ultrasound always proved sufficient for diagnosis. Serial studies detected the initial aortic thrombosis in three patients and accurately documented its progression to aneurysmal disease over 10 days in one patient and 17 days in another. Three of the infants were diagnosed with aneurysms at their initial examination. Of the five patients, three were treated nonoperatively and died of complications of their aortic disease. One patient was discovered at operation to have necrotic ischemic intestine. Aortic repair was postponed and he died of septic complications. The remaining patient underwent a PTFE interposition graft and survived for 6 months, dying of pulmonary failure with autopsy confirmed graft patency.
Aneurysm, Infected↗
Pulmonary endothelial cell ATP depletion following intestinal ischemia.
Multiple organ failure (MOF) is known to follow systemic inflammatory mediator activation associated with intestinal ischemia-reperfusion injury. In particular, the pulmonary microvasculature appears to be susceptible to MOF-related injury. This study was designed to evaluate the hypothesis that non-cellular plasma factors associated with intestinal ischemia without reperfusion also mediate pulmonary endothelial cell injury. Male Sprague-Dawley rats had intestinal ischemia induced by microvascular clip occlusion of the superior mesenteric artery for 30, 60, 90, or 120 min. Following each period of ischemia, plasma samples were obtained from the protal vein. Time-matched sham-operated animals served as controls. Monolayers of cultured rat pulmonary artery endothelial cells were then incubated with the plasma samples and ATP levels determined using a luciferin-luciferase assay. A 51Cr-release assay using labeled endothelial cells was performed under identical conditions to assess cytotoxicity. Endothelial cell ATP levels were 1.99 +/- 0.23 x 10(-11) mole/micrograms DNA in sham preparations. After a 4-hr incubation in plasma from the 90 and 120 min ischemia groups, cellular ATP levels fell significantly to 1.07 +/- 0.23 x 10(-11) mole/micrograms DNA, respectively (P less than 0.005). No significant cytotoxic injury resulted from incubation with plasma from the 120 min group (1.0 +/- 0.4% versus 0.8 +/- 0.4% in sham group, P = NS). All animals survived 24 hr in the sham, 30, and 60 min groups. However, survival was 40 and 0% in the 90 and 120 min groups, respectively (P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)
Adenosine Triphosphate↗
Redo fundoplication in infants and children with recurrent gastroesophageal reflux.
The Nissen fundoplication is well established as the surgical treatment for medically refractory gastroesophageal reflux (GER) in childhood. Recurrent GER following fundoplication is a challenging problem with a reported incidence ranging from 0% to 12%. From January 1974 to January 1989, 286 children have been treated for GER with Nissen fundoplication and gastrostomy tube placement at the University of Michigan C.S. Mott Children's Hospital; 242 of these children have been followed for an average of 30 months, the remaining 44 have been lost to follow-up. Twenty-nine children (12%) have developed recurrent reflux following fundoplication. Medical management with thickened upright feelings, gastrostomy feedings, or gastrojejunostomy tube feedings has been successful for 11 children with control of reflux symptoms. Five additional children who were treated nonoperatively died of coexistant medical problems within 2 months following documentation or recurrent reflux. The remaining 13 children have required redo fundoplication for wrap disruption or herniation, and an additional six children, initially treated at other institutions, have also undergone redo fundoplications. One other child treated at this hospital required redo fundoplication for a postoperative partial gastric volvulus causing gastric outlet obstruction. Of the 20 children who have undergone a second Nissen fundoplication, 16 (80%) are doing well without recurrent GER. Four children have developed recurrent GER with wrap disruption; 1 is doing well following a third fundoplication, 2 have been managed successfully with continuous feedings via gastrojejunostomy feeding tubes, and a fourth child died of complications related to a recurrent tracheoesophageal fistula. Conservative management with gastrojejunal tube feedings should be considered in the initial management of children with recurrent GER following fundoplication.(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
Hepatocellular oxidant stress following intestinal ischemia-reperfusion injury.
Reperfusion of ischemic intestine results in acute liver dysfunction characterized by hepatocellular enzyme release into plasma, reduction in bile flow rate, and neutrophil sequestration within the liver. The pathophysiology underlying this acute hepatic injury is unknown. This study was undertaken to determine whether oxidants are associated with the hepatic injury and to determine the relative value of several indirect methods of assessing oxidant exposure in vivo. Rats were subjected to a standardized intestinal ischemia-reperfusion injury. Hepatic tissue was assayed for lipid peroxidation products and oxidized and reduced glutathione. There was no change in hepatic tissue total glutathione following intestinal ischemia-reperfusion injury. Oxidized glutathione (GSSG) increased significantly following 30 and 60 min of reperfusion. There was no increase in any of the products of lipid peroxidation associated with this injury. An increase in GSSG within hepatic tissue during intestinal reperfusion suggests exposure of hepatocytes to an oxidant stress. The lack of a significant increase in products of lipid peroxidation suggests that the oxidant stress is of insufficient magnitude to result in irreversible injury to hepatocyte cell membranes. These data also suggest that the measurement of tissue GSSG may be a more sensitive indicator of oxidant stress than measurement of products of lipid peroxidation.
Animals↗
Anti-tumor necrosis factor antibody augments edema formation in caerulein-induced acute pancreatitis.
The pathogenesis of acute pancreatitis is incompletely defined, but the outcome is determined in part by an acute inflammatory process. Pancreatitis-associated inflammation appears to play a role in the local retroperitoneal injury as well as in the associated dysfunction of remote organs such as the lung. Tumor necrosis factor (TNF) appears to be a proximal mediator of the inflammatory response. In this study, anti-TNF antibody was administered to rats with caerulein-induced pancreatitis to determine if the observed increases in pancreatic and pulmonary microvascular permeability were related to plasma TNF activity. In contrast to the expected findings, blockade of TNF activity was found to increase the amount of edema formation in both the pulmonary and pancreatic microvascular beds. The mechanism is not known; however, blockade of TNF-induced down regulation of phagocytic cell activity, ablation of TNF-dependent feedback inhibition of other cytokines, failure of induction of endogenous antioxidant systems, or inactivation of the TNF control of microvascular tone are all possible explanations. This is potentially an important observation as clinical strategies are now being developed to modify the inflammatory response in ways presumed advantageous to an injured host.
Acute Disease↗
Experimental obliterative cholangitis. A model for the study of biliary atresia.
Noninfectious obliterative cholangitis results from biliary tract inflammation in clinical conditions such as biliary atresia and sclerosing cholangitis. The purpose of this study was to develop an animal model of noninfectious biliary tract inflammation and fibrosis. An implantable osmotic pump was connected to a catheter placed into the gallbladder of hamsters. Phorbol myristate acetate (PMA) was infused into the biliary tract for periods of 6 hours to 28 days. After 7 days the animals developed neutrophil infiltration, cellular necrosis, and edema of the biliary ducts. After 14 days, the animals demonstrated intrahepatic cholestasis with bile duct fibrosis and acute and chronic inflammatory cell infiltration. By 28 days pronounced portal fibrosis was present, some of which created an early bridging cirrhosis pattern. In addition there was evidence of neocholangiogenesis. We conclude that long-term PMA infusion into the biliary tract generates an inflammatory response characterized by obliterative cholangitis and fibrosis, sharing many of the histologic features of human biliary atresia. This model may provide a relatively simple technique for investigating the process of nonpyogenic biliary tract inflammation.
Animals↗
A long-term experience with biliary atresia. Reassessment of prognostic factors.
Thirty-four infants with biliary atresia were primarily treated at our institution between 1974 and 1987. The mean age at diagnosis was 8.8 weeks. The Kasai portoenterostomy was used in 11 patients (32%) and the Sawaguchi modification in 23 infants (68%). Overall survival was 47% (16/34), with a mean follow-up of 45 months. Fifteen survivors (94%) are jaundice free, with two having undergone liver transplantation. Survival was not influenced by earlier age at operation, size of ductal remnants, or the use of an external biliary vent. Good bile flow was predictive of a favorable outcome. The incidence of cholangitis was increased in the Kasai (87%) versus the Sawaguchi groups (45%) (p less than 0.05), but 1-year survival rates were similar (55% vs 64%). The authors conclude that portoenterostomy offers a reasonable chance for success and should be the initial procedure for biliary atresia.
Bile↗
Histamine: a promoter of xanthine oxidase activity in intestinal ischemia/reperfusion.
Xanthine oxidase (XO)-derived oxygen radicals are thought to play an important role in the intestinal injury resulting from ischemia and reperfusion. In vitro data shows enhanced XO activity in the presence of histamine. Histamine is known to be released during intestinal ischemia and reperfusion. The purpose of this study was to evaluate the relationship between histamine and XO in vivo in intestinal ischemia/reperfusion injury. Using an established model of gut ischemia and reperfusion, portal venous plasma was obtained and assayed for histamine levels, XO activity, and xanthine dehydrogenase (XD) activity following injury. Intestinal ischemia for 120 minutes resulted in a 200% increase in plasma histamine levels (263.4 +/- 36.9 nmol/mL control, v 548.7 +/- 35.1 nmol/mL experimental, P less than .05). Reperfusion for 15 minutes resulted in a further increase in plasma histamine (to 658.3 +/- 33.9 nmol/mL), compared with 120 minutes of ischemia alone. No significant change in plasma XO activity resulted after simple ischemia for 120 minutes. However, XO activity doubled within 15 minutes of reperfusion of the ischemic intestine (6.37 +/- 0.53 nmol O2- per milliliter per minute v 3.12 +/- 0.25 nmol O2- per milliliter per minute, P less than .05). Reperfusion for 60 minutes resulted in the maximal observed increase in plasma XO activity (9.49 +/- 0.67 nmol O2- per milliliter per minute). Analysis of XD activity demonstrated no significant decrease compared with controls until 120 minutes of ischemia and 60 minutes of reperfusion (1.62 +/- 0.49 nmol uric acid per milliliter per minute at 60 minutes of reperfusion, versus 5.02 +/- 0.52 nmol uric acid per milliliter per minute control, P less than .05).(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Use of high-frequency jet ventilation in the management of congenital tracheoesophageal fistula associated with respiratory distress syndrome.
Two preterm infants (28 weeks, 960 g; 32 weeks, 1,870 g) with very large tracheoesophageal fistulas suffered from respiratory distress syndrome and failed to respond to conventional mechanical ventilation despite placement of a decompressive gastrostomy. Pulmonary air leaks developed in both, resulting in transdiaphragmatic pneumoperitoneum, and significant gas flow occurred through the gastrostomy tube despite placement under water-seal. High-frequency jet ventilation was instituted in each case and resulted in improved pulmonary gas exchange at lower mean airway pressure (12.0 to 6.7 cm H2O; 11.0 to 8.0 cm H2O) and in prompt resolution of air leaks. Both patients remained refractory to reinstitution of conventional ventilation until division of the fistula in the first patient and complete resolution of the respiratory distress syndrome in the second.
Female↗
Embryonal rhabdomyosarcoma of the ampulla of Vater with long-term survival following pancreaticoduodenectomy.
Rhabdomyosarcoma of the biliary tree is a rare cause of biliary tract obstruction in childhood. A 3-year-old child is reported here after presenting with obstructive jaundice secondary to an embryonal rhabdomyosarcoma of the ampulla of Vater. He underwent pancreaticoduodenectomy followed by adjuvant chemotherapy and irradiation. He is now well and free of disease 5 years following treatment. This child appears to be the first long-term survivor who has required pancreaticoduodenal resection for this lesion.
Ampulla of Vater↗
Arterial levels of oxidized glutathione (GSSG) reflect oxidant stress in vivo.
Neutrophil-related, oxidant-mediated injury to the pulmonary microvasculature appears to follow endotoxemia, cutaneous thermal injury, and ischemia-reperfusion injury to the liver or intestine. Glutathione is an important endogenous intracellular oxygen radical scavenger. Plasma concentrations of oxidized glutathione (GSSG) reflect oxidant injury resulting from an overdose of certain oxidatively metabolized drugs. The purpose of this investigation was to evaluate plasma GSSG as an indicator of oxidant stress resulting from activation of the endogenous inflammatory response. An established model of neutrophil- and oxidant-related acute lung injury following intestinal ischemia and reperfusion in rats was used. Intestinal ischemia was induced by clip occlusion of the superior mesenteric artery (SMA) for 120 min. Reperfusion resulted from SMA clip removal. Following reperfusion for 0, 15, or 120 min, plasma GSSG levels in portal vein, inferior vena cava (IVC), and aorta were obtained. Plasma GSSG was undetectable in sham animals and those with intestinal ischemia alone. Following reperfusion, all plasma samples had significant elevations in GSSG. Aortic plasma GSSG after 15 min of reperfusion was significantly elevated compared to both portal vein and IVC plasma GSSG. These data suggest that oxidant stress after intestinal reperfusion is reflected by elevations in plasma GSSG. The step up in plasma GSSG across the pulmonary vascular bed, a site of known oxidant injury, suggests that plasma GSSG may be a useful marker of oxidant stress in vivo, particularly with regard to the pulmonary microvasculature. This simple in vivo approach to assessing oxidant stress related to inflammatory tissue injury may have the potential to be of significant use in the clinical setting.
Animals↗
Evidence for tumor necrosis factor-induced pulmonary microvascular injury after intestinal ischemia-reperfusion injury.
Acute lung injury characterized by increased microvascular permeability is one feature of multiple-organ system failure and the adult respiratory distress syndrome. Intestinal ischemia-reperfusion injury has been linked to this type of acute lung injury. The purpose of these experiments was to examine the pathogenic mediators that link the two processes, with particular emphasis on the roles of endotoxin and tumor necrosis factor alpha (TNF alpha). Previously described characteristics of the acute lung injury in this rat model of intestinal ischemia-reperfusion include pulmonary neutrophil sequestration, depletion of lung tissue ATP, alveolar endothelial cell disruption, and increased microvascular permeability. Plasma levels of TNF in the systemic circulation of sham-operated animals and those with intestinal ischemic injury less than 60 minutes in duration were very low or undetectable. Intestinal ischemia for 120 minutes was associated with TNF elevation to 1.19 +/- 0.50 U/mL. Reperfusion for periods of 15 and 30 minutes generated 5- to 10-fold increases in circulating TNF levels (6.61 +/- 3.11 U/mL, p greater than 0.05 and 10.41 +/- 5.41 U/mL, p = 0.004 compared to sham); however this increase in circulating TNF was transient and largely cleared within 60 minutes after initiating reperfusion. Portal vein endotoxin levels were found to increase significantly before the appearance of TNF in systemic plasma, suggesting that gut-derived endotoxin may induce TNF release from hepatic macrophages into the systemic circulation. Anti-TNF antibody attenuated the increase in pulmonary microvascular permeability in this preparation but did not prevent pulmonary neutrophil sequestration. These observations suggest that endotoxin and TNF have pathogenic roles in this acute lung injury, but that mechanisms of adherence of neutrophils to endothelial cells independent of TNF may be involved. The accumulation of neutrophils in the lung but the prevention of a vascular permeability increase in the presence of antibody to TNF may imply an in vivo role for TNF in the process of neutrophil activation. These studies provide additional evidence of the importance of the endogenous inflammatory mediators in the development of systemic injury in response to local tissue injury.
Animals↗
The production of tumor necrosis factor alpha and the development of a pulmonary capillary injury following hepatic ischemia/reperfusion.
The large mass of fixed macrophages resident in the liver make it a potentially rich source of cytokines. We have previously demonstrated that an isolated and severe ischemia/reperfusion injury to the liver results in cytokine release, specifically tumor necrosis factor alpha, and that TNF is then involved in the development of pulmonary pathology. This study was designed to determine the kinetics of TNF release following varying periods of hepatic ischemia and to further investigate the acute lung injury that follows. Suprahepatic blood samples were obtained at serial time points following a 45-, 60-, 75-, or 90-min ischemic insult to a segment of the rat liver with subsequent reperfusion. Using a bioassay based on the WEHI 164 cell line, plasma TNF levels were measured in all experimental animals; sham-operated control animals had undetectable levels. Changes in pulmonary capillary permeability were then measured using a standard 125I-labeled albumin washout technique following a 90-min ischemic insult with subsequent reperfusion. A significant increase in the mean permeability index was observed 9 to 12 hr following hepatic reperfusion (.601 +/- 102 as compared with .114 +/- .085 in sham-operated controls, P less than 0.005). Animals treated with anti-TNF antiserum prior to the induction of hepatic ischemia had a significantly reduced pulmonary capillary leak compared to animals pretreated with rabbit serum without TNF-blocking properties (.184 +/- .029 versus .694 +/- 052 for the control serum, P less than 0.005). TNF release follows both moderate and severe ischemic injury to the liver and the results reported here implicate TNF as an important mediator of increased pulmonary capillary permeability. These experiments confirm previous histologic studies that demonstrated pulmonary edema and intra-alveolar hemorrhage following hepatic ischemia/reperfusion, with subsequent blockade of the histologic injury by pretreatment with anti-TNF antiserum.
Animals↗