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T Lindsay

Publications and source records attributed to T Lindsay.

13 recordsLinked to original sources
PubMed2000

Involvement of cytosolic phospholipase A2 and secretory phospholipase A2 in arachidonic acid release from human neutrophils.

The purpose of this study was to define the role of secretory phospholipase A2 (sPLA2), calcium-independent PLA2, and cytosolic PLA2 (cPLA2) in arachidonic acid (AA) release from fMLP-stimulated human neutrophils. While fMLP induced the release of extracellular sPLA2 activity and AA, 70% of sPLA2 activity remained associated with the cell. Treatment with the cell-impermeable sPLA2 inhibitors DTT or LY311-727, or the anti-sPLA2 Ab 3F10 all inactivated extracellular sPLA2 activity, but had minimal effect on neutrophil AA mass release. In contrast, coincubation of streptolysin-O toxin-permeabilized neutrophils with DTT, LY311-727, or 3F10 all decreased [3H8]AA release from [3H8]AA-labeled, fMLP-stimulated cells. Exposure to fMLP resulted in a decrease in the electrophoretic mobility of cPLA2, a finding consistent with cPLA2 phosphorylation, and stimulated the translocation of cPLA2 from cytosolic to microsomal and nuclear compartments. The role of cPLA2 was further evaluated with the cPLA2 inhibitor methyl arachidonyl fluorophosphonate, which attenuated cPLA2 activity in vitro and decreased fMLP-stimulated AA mass release by intact neutrophils, but had no effect on neutrophil sPLA2 activity. Inhibition of calcium-independent PLA2 with haloenol lactone suicide substrate had no effect on neutrophil cPLA2 activity or AA mass release. These results indicate a role for cPLA2 and an intracellular or cell-associated sPLA2 in the release of AA from fMLP-stimulated human neutrophils.

Arachidonic Acid↗
PubMed2000

Therapeutic hypercapnia reduces pulmonary and systemic injury following in vivo lung reperfusion.

Permissive hypercapnia, involving tolerance to elevated Pa(CO(2)), is associated with reduced acute lung injury (ALI), thought to result from reduced mechanical stretch, and improved outcome in ARDS. However, deliberately elevating inspired CO(2) concentration alone (therapeutic hypercapnia, TH) protects against ALI in ex vivo models. We investigated whether TH would protect against ALI in an in vivo model of lung ischemia-reperfusion (IR). Anesthetized open chest rabbits were ventilated (standard eucapnic settings), and were randomized to TH (FI(CO(2)) 0.12) versus control (FI(CO(2)) 0.00). Pa(CO(2)) and arterial pH values achieved in the TH versus CON groups were 101 +/- 3 versus 44.4 +/- 4 mm Hg and 7.10 +/- 0.03 versus 7.37 +/- 0.03, respectively. Following left lung ischemia and reperfusion, TH versus control was associated with preservation of lung mechanics, attenuation of protein leakage, reduction in pulmonary edema, and improved oxygenation. Indices of systemic protection included improved acid-base and lactate profile, in the absence of systemic hypoxemia. In the TH group, mean BALF TNF-alpha levels were 3.5% of CON levels (p < 0.01), and mean 8-isoprostane levels were 30% of CON levels (p = 0.02). Western blot analysis demonstrated reduced lung tissue nitrotyrosine in TH, indicating attenuation of tissue nitration. Finally, preliminary data suggest that TH may attenuate apoptosis following lung IR. We conclude that in the current model TH is protective versus IR lung injury and mechanisms of protection include preservation of lung mechanics, attenuation of pulmonary inflammation, and reduction of free radical mediated injury. If these findings are confirmed in additional models, TH may become a candidate for clinical testing in critical care.

Animals↗
PubMed1999

Impact of red cell salvage on transfusion requirements during elective abdominal aortic aneurysm repair.

Elective abdominal aortic aneurysm (AAA) surgery may result in substantial blood loss. Concerns regarding the safety, availability, and acceptability of homologous blood have led to initiatives toward reducing transfusion requirements at the time of aneurysm repair. This study was designed to determine if the routine use of intraoperative red cell salvage and autotransfusion resulted in a reduction in homologous transfusion at our institution. A retrospective review of elective AAA repairs in the years 1987, 1992, and 1997 was carried out. Demographic data, operative details, blood loss, hemoglobin levels, red cell salvage and return volumes, and transfusion requirements were recorded and compared across the study years. From this study we conclude that routine use of red cell salvage and autotransfusion is an effective means for reducing transfusion requirements in elective AAA repair.

Aged↗
PubMed1993

A CD18 antibody prevents lung injury but not hypotension after intestinal ischemia-reperfusion.

Antibodies to the neutrophil CD18 integrin have been shown to ameliorate the local effects of intestinal ischemia and reperfusion (I/R). In addition to local mucosal injury, intestinal I/R results in systemic hypotension and injury to the lungs with lung leukosequestration. This study tests the effect of a CD18 monoclonal antibody on the hypotension and lung injury after intestinal I/R. In anesthetized rabbits, the superior mesenteric artery was clamped for 60 min followed by 3 h of reperfusion. Animals were treated with saline, an anti-CD18 monoclonal antibody (R15.7 MAb), or nonspecific immunoglobulin G. Another non-ischemic group were sham controls. Neutrophil sequestration was assessed by measure of lung myeloperoxidase (MPO) and permeability by lung-to-blood concentration ratio of 125I-labeled bovine serum albumin and wet-to-dry weight ratio. Immediately after reperfusion, mean arterial pressure fell to 49 +/- 2.1 mmHg and remained at this level. The hypotension was unaffected by treatment with R15.7 MAb. Thirty minutes after reperfusion, the circulating white blood cell count fell to 2.91 +/- 0.53 x 10(3)/mm3 vs. sham 6.40 +/- 0.66 x 10(3)/mm3 (P < 0.05). Treatment with R15.7 MAb prevented this fall in white blood cell count (5.75 +/- 1.59 x 10(3)/mm3). At 3 h of reperfusion in saline-treated animals there was increased MPO, 74.8 +/- 4.9 U/g vs. 42.0 +/- 4.8 U/g in sham animals (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

A Mac-1 antibody reduces liver and lung injury but not neutrophil sequestration after intestinal ischemia-reperfusion.

BACKGROUND: Intestinal ischemia and reperfusion (I/R) result in leukosequestration and injury to the liver and lungs. The adherence-dependent oxidative burst of neutrophils requires cell adhesion through the Mac-1 integrin. Neutrophil-mediated tissue injury may depend on this specific cell adhesion event. This study tests the effect of a Mac-1 (CD 11b) monoclonal antibody (MAb) (R17) on liver and lung injury after intestinal I/R. METHODS: After collaterals were ligated in anesthetized rats, the superior mesenteric artery was clamped for 60 minutes followed by 3 hours of reperfusion. Animals were treated with saline solution, R17, or nonspecific immunoglobulin M. Another nonischemic group of rats were sham controls. Lung and intestinal polymorphonuclear leukocyte sequestration was assessed by measurement of myeloperoxidase and lung permeability by bronchoalveolar lavage blood concentration ratio of 125I-labeled bovine serum albumin. RESULTS: At 3 hours of reperfusion lung and intestinal myeloperoxidase and lung permeability were increased. Treatment with R17 MAb did not reduce intestinal or lung myeloperoxidase but prevented increased lung permeability. Similarly, after treatment with saline solution, liver polymorphonuclear leukocyte sequestration increased after 3 hours of reperfusion, and serum alanine aminotransferase level rose eightfold. R17 MAb did not significantly reduce liver neutrophil sequestration; however, it reduced alanine aminotransferase level more than 50% when compared to saline solution controls. At 3 hours of reperfusion there was a leukocytosis (white blood cell count, 14.9 +/- 1.0 x 10(3)/mm3 vs 6.0 +/- 0.8 in sham [p less than 0.05]). The white blood cell count was unaffected by R17 MAb. CONCLUSIONS: These data indicate that a MAb to the neutrophil Mac-1 integrin reduces lung and liver injury after intestinal I/R but does not reduce lung or intestinal leukosequestration.

Animals↗
PubMed1990

Ascending cholangitis: surgery versus endoscopic or percutaneous drainage.

A retrospective review of 61 patients with calculous cholangitis was carried out. There were 31 men and 30 women and their mean age was 75.8 years. All patients had abdominal pain, 87% had chills and fever, 65% had clinical jaundice, 23% were in shock, and 54% had positive blood cultures. Because intravenous hydration and antibiotics did not help, 33 patients underwent surgery, 25 patients underwent endoscopic papillotomy (EP), and three patients underwent percutaneous transhepatic drainage of the common bile duct (PTD). Morbidity in the surgery group included two wound infections, one respiratory failure, and one renal failure. Morbidity in the EP-PTD group was one case of arterial bleeding requiring surgery and one of pancreatitis treated conservatively. Two patients (6%) died in the surgery group, one of sepsis and the other of cardiorespiratory arrest. In the EP-PTD group nine patients (32%) died of sepsis and multisystem organ failure. These patients were considered too ill to undergo surgery and thus repeat EP-PTD was carried out. Cholangitis persisted, and retained common bile duct stones with sepsis was the cause of death. Thus when initial EP or PTD is unsuccessful, surgical exploration of the common bile duct should be carried out to control sepsis.

Adult↗
PubMed1989

The rate and distribution of muscle blood flow after prolonged ischemia.

The magnitude and distribution of muscle blood flow in the lower extremity after relief of an acute arterial occlusion may influence the extent of the resulting necrosis. The object of this study was to document the distribution of blood flow in the resting state and after prolonged periods of complete ischemia, and to assess the relationship between the degree of reactive hyperemia and subsequent necrosis. The isolated bilateral canine gracilis muscle preparation that we have previously characterized was used for microsphere studies. Total blood flow was measured by means of timed venous collections, and the distribution of flow was determined by means of a multiple microsphere injection technique. Measurements of microsphere distribution and blood flow were made before ischemia and during the initial 48 minutes of reperfusion after both 4 and 5 hours of normothermic ischemia, which resulted in 46.7% +/- 6% and 71.2% +/- 7% necrosis, respectively. The muscle was harvested and sectioned transversely into six slices approximately 1.5 cm thick, and the extent of necrosis was quantified by means of nitroblue tetrazolium staining 48 hours after reperfusion. Blood flow distribution during the early reperfusion phase was determined in each muscle slice and in both the alive and dead portions of each slice by use of the microsphere injection technique. Preischemic blood flow was distributed homogeneously throughout the muscle and was 4.5 +/- 0.8 ml/100 gm/min (mean +/- SEM, n = 8). On reperfusion total flow was 6 to 10 times higher than it was before ischemia and was distributed predominantly to the middle slices (p less than 0.05, n = 12).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Quantitation of postischemic skeletal muscle necrosis: histochemical and radioisotope techniques.

Skeletal muscle necrosis will result from prolonged periods of ischemia. The purpose of this study was to develop a method to estimate the extent of necrosis using nitroblue tetrazolium staining and technetium scanning. The bilateral canine gracilis muscle preparation with total vascular isolation was exposed to 4 hr of complete normothermic ischemia followed by reperfusion. After 45 hr of reperfusion 99mTc pyrophosphate (PYP) was injected and 3 hr later the muscles were harvested, cut into six slices, and stained with nitroblue tetrazolium. Biopsies were taken from tetrazolium-positive and -negative areas for electron microscopy to confirm the ability of the stain to distinguish viable from necrotic muscle. Computerized planimetry of the staining pattern was used to estimate the extent of necrosis as a percentage of the total muscle. Electron microscopy confirmed the validity of nitroblue tetrazolium to discriminate between viable and necrotic skeletal muscle in this experimental model. After 4 hr of ischemia the percentage necrosis was 30.2 +/- 6.1% (mean +/- SEM, n = 12), there was no difference in the extent of necrosis in left vs right paired muscles, using tetrazolium staining or technetium PYP uptake. There was a statistically significant correlation between the percentage necrosis and the density of 99mTc PYP uptake per muscle (r = 0.83, P less than 0.001) and per slice (r = 0.94, P less than 0.001). This study demonstrates the ability of tetrazolium staining to accurately differentiate between viable and necrotic skeletal muscle and provides a reproducible method for estimating the extent of necrosis in the gracilis muscle model.

Animals↗
PubMed1988

Measurement of hydroxy-conjugated dienes after ischemia-reperfusion in canine skeletal muscle.

Recent studies have suggested that oxygen-derived free radicals are involved in the reperfusion injury of ischemic skeletal muscle. Although postischemic necrosis and increased vascular permeability have been attenuated with the addition of free radical scavengers, no unequivocal chemical evidence for free radical injury in skeletal muscle is available. The purpose of this study was to identify products of free radical-mediated membrane injury by isolation of lipid oxidation products (hydroxy-conjugated dienes) from postischemic skeletal muscle. The bilateral canine gracilis muscle model was used, and in each pair one muscle was exposed to 3 and the other to 5 h of normothermic ischemia. Muscle biopsies were taken before and at end ischemia, as well as during the first 3 h of reperfusion. Phospholipids were extracted from the muscle biopsies and the fatty acids hydrolyzed from the 2 position. After methylation, the oxidized fatty acid esters were separated by high-performance liquid chromatography. Hydroxy diene peaks absorbing at 235 nm were collected and subjected to gas chromatography-mass spectrometry (GC-MS) for positive structural identification. No significant increase in the level of conjugated dienes occurred during ischemia. Significant increases, however, were detected during the period of reperfusion, although the time when peak levels were achieved varied between animals. The cumulative sum of dienes produced during reperfusion in both 3- and 5-h muscles was significantly increased over pre- and end-ischemic values. The hydroxy-conjugated diene isomers of 18:2 and 20:4 were positively identified in reperfusion biopsies by GC-MS. These studies provide chemical evidence of free radical-mediated lipid oxidation during reperfusion of ischemic skeletal muscle.

Animals↗
PubMed1987

The extent and distribution of skeletal muscle necrosis after graded periods of complete ischemia.

The management of an acutely ischemic extremity requires knowledge of the response of skeletal muscle (the largest component of the lower limb) to prolonged periods of complete normothermic ischemia. We have used the canine gracilis muscle model to evaluate the extent and distribution of ischemic necrosis after 3 and 5 hours of ischemia and 48 hours of reperfusion. Each muscle was cut into six slices, and the extent and distribution of postischemic necrosis identified by means of nitroblue tetrazolium staining and 99mTc pyrophosphate uptake. After 3, 4, and 5 hours of ischemia the extent of necrosis was 2.0% +/- 0.9%, 30.3% +/- 6.0%, and 90.1% +/- 3.5% (mean +/- SEM), respectively. A statistically significant correlation exists between the extent of necrosis and the uptake of 99mTc pyrophosphate uptake per gram of tissue (y = 1574.9x - 8.4, r = 0.84, p less than 0.001). Most necrosis was centrally located and found in the thickest portion of the muscle. We conclude that there is a graded response in the extent of skeletal muscle necrosis related to the length of ischemic stress rather than an "all-or-none" phenomenon. This central distribution of necrosis makes the usual external evaluation of ischemic damage clinically unreliable. In addition, since there was no enveloping fascia in this model, a compartment release alone may not prevent the development of skeletal muscle necrosis. This knowledge of the response of skeletal muscle to ischemia may lead to an improved clinical approach to an extremity suffering a prolonged ischemic insult.

Animals↗
PubMedDate not supplied

The impact of energy depletion on skeletal muscle.

Changes in the skeletal muscle adenine nucleotide pool during prolonged periods of normothermic ischemia, followed by reperfusion are a result of an exaggerated breakdown to lipid soluble precursors, the degree of reactive hyperemia, and activities of the salvage and direct pathways for resynthesis. We show that the degree of breakdown of ATP, ADP and AMP, is time dependent, and with restoration of circulation there is washout of these lipid soluble precursors, and no resynthesis of ATP. We demonstrated a relationship between the loss of energy during ischemia, and the degree of resultant necrosis, suggesting that a limit on the effectiveness of therapeutic interventions during reperfusion in reducing the extent of necrosis may exist.

Adenine Nucleotides↗
PubMedDate not supplied

Free radical mediated damage in skeletal muscle.

Skeletal muscle subjected to prolonged ischemia will develop significant injury, however it can withstand periods of ischemia that would be irreversible in other tissues such as brain and heart. Reperfusion injury has been measured and suggested to occur secondary to oxygen free radicals. The increases in vascular permeability and resistance following ischemia/reperfusion can be blunted using free radical scavengers. Also skeletal muscle necrosis can be reduced if these scavengers are provided in high concentration during reperfusion. Recently increases in hydroxy-conjugated dienes, a marker of lipid peroxidation, have been found in reperfused skeletal muscle, providing chemical evidence for free radical injury during reperfusion. These studies have provided some insight into ischemia/reperfusion injury in skeletal muscle, but more investigations are required to detail the mechanisms involved in this injury.

Animals↗