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Biomedical subjects

W G Austen

Publications and source records attributed to W G Austen.

At least 19 recordsLinked to original sources
PubMed2001

Recombinant soluble P-selectin glycoprotein ligand 1 moderates local and remote injuries following experimental lower-torso ischaemia.

BACKGROUND: A central role for the polymorphonuclear leucocyte (PMN) in skeletal muscle ischaemia-reperfusion has been demonstrated by the observation that PMN depletion reduced local and remote pulmonary vascular permeability. This study investigated the role of recombinant soluble P-selectin glycoprotein ligand-immunoglobulin fusion protein (rPSGL-Ig), a P- and E-selectin antagonist, in moderating injury. METHODS: Mice underwent 2 h of hindlimb ischaemia and 3 h of reperfusion. Muscle and lung vascular permeability index (PI) was assessed by extravasation of (125)I-radiolabelled albumin. Lung myelo peroxidase (MPO) activity was also measured. RESULTS: In mice treated with rPSGL-Ig 1 mg/kg before reperfusion (n = 12) muscle PI was reduced by 40 per cent, whereas it was moderated by 20 per cent in animals treated 30 min after reperfusion (n = 15). Lung PI in mice treated with rPSGL-Ig before (n = 12) and 30 min after (n = 15) reperfusion was reduced by over 99 and 98 per cent respectively. Lung MPO activity in mice treated with rPSGL-Ig before (n = 10) and 30 min after (n = 12) reperfusion was reduced by 68 and 58 per cent respectively. Treatment with rPSGL-Ig 1 h after reperfusion, or with m20ek.Fc 1 mg/kg (n = 9; negative control for rPSGL-Ig which is inactive for selectin binding) before reperfusion failed significantly to moderate local or remote organ injury. CONCLUSION: Selectin blockade moderated local skeletal muscle and remote lung injury following hindlimb ischaemia--reperfusion. Significantly, delayed antiselectin therapy also decreased injury.

Animals↗
PubMed2001

Mast cells mediate complement activation after acid aspiration.

A significant role for the alternative complement pathway in acid aspiration has been demonstrated by the observation that C3 but not C4 genetic knockout mice are protected from permeability edema. Using mast cell-deficient mice (W/Wv), we tested the hypothesis that mast cells mediate complement activation after acid aspiration. Tracheostomy tubes were placed in anesthetized mice and 2 mL/kg 0.1 N HCL was instilled in the trachea. After 4 h, extravasation of 125I-albumin was used to calculate lung vascular permeability. The serum alternative complement pathway hemolytic activity was examined, and lung immunohistochemistry was performed. Lung permeability in W/Wv mice was 62% less than that of mast cell sufficient (+/+) animals and similar to +/+ mice treated with the chymase inhibitor chymostatin (65% decrease). Treatment of +/+ mice with D-PRO2,D-TRP(7,9)-Substance P, an antagonist to the neuropeptide substance P, reduced injury by 66%. Serum complement hemolytic activity was intact in injured w/wv mice and +/+ animals treated with chymostatin or dpdt-sp, but was decreased to 65% in the injured untreated +/+ group. Alveolar C3 deposition was intense in injured untreated +/+ mice but absent in the other groups. We interpret these data to indicate that mast cells mediate complement activation, via chymase degranulation, after acid aspiration. This mast cell activity likely is regulated by the release of substance P.

Animals↗
PubMed2001

Moderation of skeletal muscle reperfusion injury by a sLe(x)-glycosylated complement inhibitory protein.

The role of the sialyl Lewis(x) (sLe(x))-decorated version of soluble complement receptor type 1 (sCR1) in moderating skeletal muscle reperfusion injury, by antagonizing neutrophil endothelial selectin interaction and complement activation, is examined. Mice underwent 2 h of hindlimb ischemia and 3 h of reperfusion. Permeability index (PI) was assessed by extravasation of 125I-labeled albumin. Neutrophil depletion and complement inhibition with sCR1 reduced permeability by 72% (PI 0.81 +/- 0.10) compared with a 42% decrease (PI 1.53 +/- 0.08) observed in neutropenic mice, indicating that part of the complement-mediated injury is neutrophil independent. sCR1sLe(x) treatment reduced PI by 70% (PI 0.86 +/- 0.06), an additional 20% decrease compared with sCR1 treatment (PI 1.32 +/- 0.08). Treatment with sCR1sLe(x) 0.5 and 1 h after reperfusion reduced permeability by 63% (PI 0.09 +/- 0.07) and 52% (PI 1.24 +/- 0.09), respectively, compared with the respective decreases of 41% (PI 1.41 +/- 0.10) and 32% (PI 1.61 +/- 0.07) after sCR1 treatment. Muscle immunohistochemistry stained for sCR1 only on the vascular endothelium of sCR1sLe(x)-treated mice. In conclusion, sCR1sLe(x) is more effective than sCR1 in moderating skeletal muscle reperfusion injury.

Animals↗
PubMed2001

Sialyl Lewis(x) hybridized complement receptor type 1 moderates acid aspiration injury.

The potentially enhanced anti-inflammatory effects of the sialyl Lewis(x) (sLe(x))-decorated version of soluble complement receptor type 1 (sCR1) in moderating acid aspiration injury are examined. HCl was instilled in tracheostomy tubes placed in mice, and extravasation of (125)I-labeled albumin in bronchoalveolar lavage (BAL) fluid was used to calculate the vascular permeability index (PI). Neutrophil counts in BAL fluid and immunohistochemistry were performed. PI was moderated by 82% after treatment with sCR1sLe(x) compared with 54% in sCR1-untreated mice (P < 0.05). Respective reductions in PI in mice treated 0.5 and 1 h after acid aspiration with sCR1sLe(x) of 70 and 57% were greater than the decreases in PI of 45 and 38% observed in respective sCR1-treated groups (P < 0.05). BAL fluid neutrophil counts in sCR1sLe(x)-treated mice were significantly less than those in sCR1-treated animals, which were similar to those in untreated mice. Immunohistochemistry stained for sCR1 only on the pulmonary vascular endothelium of sCR1sLe(x)- but not sCR1-treated mice. In conclusion, sCR1sLe(x) moderates permeability by antagonizing complement activation and neutrophil adhesion. Delayed complement and neutrophil antagonism significantly reduces injury.

Animals↗
PubMed2000

Neutrophil mediated remote organ injury after lower torso ischemia and reperfusion is selectin and complement dependent.

BACKGROUND: Lower torso ischemia and reperfusion leads to remote organ leukosequestration and injury. We now examine the intermediary role of selectins and complement in mediating lung and liver injury after hindlimb ischemia. METHODS: Mice underwent a 2-hour bilateral tourniquet hind-limb ischemia followed by 3 hours of reperfusion. RESULTS: Neutrophil depletion significantly decreased lung vascular permeability index (PI), measured by the extravasation of 125I-albumin, and liver injury as assessed by serum alanine aminotransferse levels. Lung PI and serum alanine aminotransferse levels were also reduced in mice treated with recombinant soluble P-selectin glycoprotein ligand-immunoglobulin fusion protein. Complement inhibition with soluble complement receptor type 1 decreased lung PI and serum alanine aminotransferse levels. C5-deficient mice exhibited a similar decrease in lung PI and liver injury. Lung and liver injury were restored in C5-deficient mice reconstituted with wild-type serum. CONCLUSION: Remote organ injury after lower torso reperfusion is selectin and complement dependent.

Alanine Transaminase↗
PubMed2000

Soluble P-selectin moderates complement dependent injury.

P-selectin is an adhesion molecule expressed on activated endothelial and platelet membranes containing 9 short consensus repeats (SCRs) similar to the composition of complement regulatory proteins. In our murine model of intestinal ischemia and reperfusion where local injury is mediated by the classical complement pathway we hypothesized the SCRs would moderate the complement response. Confirmatory data were sought following hindlimb ischemia and reperfusion where injury is both complement- and neutrophil-mediated. Mice deficient in P-selectin (P-/-) were found to have similar intestinal and hindlimb permeability compared to normal wild types mice (P+/+). When reconstituted with P+/+ platelets, but not P-/- platelets, P-/- mice subjected to intestinal ischemia had a significant 29% decrease in permeability (P < 0.05) and after hindlimb ischemia the decrease was 33% (P<0.05). Reperfusion after intestinal ischemia led to a 76% fall in CH50 in P-/- compared to sham animals (P < 0.05) indicating complement activation and consumption, but only a 36% fall in animals reconstituted with P+/+ platelets (P < 0.05). Full-length, soluble P-selectin (sPsel) derived from processed platelets, but not the truncated version of sPsel has been shown to adhere to a heat labile fraction of serum and sensitized red blood cells thereby reducing Clq adherence to the sensitized red cell. From these data we conclude that sPsel moderates complement activation by competing with C1q binding to antibody, thereby limiting activation of the classical pathway that mediates murine reperfusion injury.

Animals↗
PubMed2000

Soluble P-selectin moderates complement-dependent reperfusion injury of ischemic skeletal muscle.

P-selectin is an adhesion molecule expressed on activated endothelial and platelet surfaces. The function of the short consensus repeats (SCRs) of P-selectin, homologous with the SCRs of complement regulatory proteins is largely unknown. In a model of murine hindlimb ischemia where local reperfusion injury is partly mediated by IgM natural antibody and classical complement pathway activation, we hypothesized that human soluble P-selectin (sP-sel) would moderate the complement component of the inflammatory response. Infusion of sP-sel supernatant or purified (p) sP-sel prepared from activated human platelets, reduced ischemic muscle vascular permeability by 48% and 43%, respectively, following reperfusion. Hindlimb immunohistochemistry demonstrated negligible C3 staining colocalized with IgM in these groups compared with intense staining in the untreated injured mice. In vitro studies of mouse serum complement hemolytic activity showed that psP-sel inhibited the classical but not alternative complement pathway. Flow cytometry demonstrated that psP-sel inhibited C1q adherence to sensitized red blood cells. From these data we conclude that sP-sel moderates skeletal muscle reperfusion injury by inhibition of the classical complement pathway.

Animals↗
PubMed1999

Intestinal ischemia-reperfusion injury is mediated by the membrane attack complex.

BACKGROUND: The dependence of intestinal ischemia-reperfusion injury on the classical complement pathway has been shown with the complement antagonist (sCR1) and complement-specific knockout mice. Using C5 deficient mice, we show that the membrane attack complex mediates local injury. METHODS: Mice underwent intestinal ischemia-reperfusion. Albumin leak and histologic evidence were compared in wildtype mice, wildtypes treated with sCR1, neutrophil-depleted wildtypes, C5-deficient mice, and C5-deficient mice reconstituted with wildtype serum. Neutrophil tissue levels in injured C5-deficient and wildtype intestines were compared. RESULTS: C5-deficient mice had a reduction in injury similar to mice treated with sCR1. Injury was restored by reconstitution with wildtype serum. Wildtype injury was unaffected by neutrophil depletion. Injured intestines of C5-deficient and wildtype mice had similar neutrophil levels. Immunohistochemistry of wildtype and reconstituted C5-deficient mice demonstrated injured intestinal epithelium although C5-deficient mice and sCr1-treated mice were similar to sham mice. CONCLUSIONS: C5-deficient animals are protected from local injury. Injury is unaffected by neutrophil depletion, and the presence of neutrophils in injured tissue is independent of C5. Local injury is C5 dependent, but the action of C5a on granulocytes is not required. Therefore the membrane attack complex mediates local injury.

Animals↗
PubMed1997

Intraaortic balloon pumping for cardiac support: trends in practice and outcome, 1968 to 1995.

OBJECTIVES: A total of 4756 cases of intraaortic balloon pump support have been recorded at the Massachusetts General Hospital since the first clinical insertion for cardiogenic shock in 1968. This report describes the patterns of intraaortic balloon use and associated outcomes over this time period. METHODS: A retrospective record review was conducted. RESULTS: Balloon use has increased to more than 300 cases a year at present. The practice of balloon placement for control of ischemia (2453 cases, 11.9% mortality) has become more frequent, whereas support for hemodynamic decompensation (congestive heart failure, hypotension, cardiogenic shock) has been relatively constant (1760 cases, 38.2% mortality). Mean patient age has increased from 54 to 66 years, and mortality has fallen from 41% to 20%. Sixty-five percent (3097/4756) of the total patient population receiving balloon support underwent cardiac surgery. Placement before the operation (2038 patients) was associated with a lower mortality (13.6%) than intraoperative (771 patients, 35.7% mortality) or postoperative use (276 patients, 35.9% mortality). Independent predictors of death with balloon pump support were insertion in the operating room or intensive care unit, transthoracic insertion, age, procedure other than angioplasty or coronary artery bypass, and insertion for cardiogenic shock. Independent predictors of death with intraoperative balloon insertion were age, mitral valve replacement, prolonged cardiopulmonary bypass, urgent or emergency operation, preoperative renal dysfunction, complex ventricular ectopy, right ventricular failure, and emergency reinstitution of cardiopulmonary bypass. CONCLUSIONS: Balloons are being used more frequently for control of ischemia in more patients who are elderly with lower mortality. An institutional bias toward preoperative use of the balloon pump appears to be associated with improved outcomes.

Age Distribution↗
PubMed1994

Mitral valve reconstruction versus replacement for degenerative or ischemic mitral regurgitation.

Between January 1985 and June 1992, 263 consecutive patients had mitral valve reconstruction (133 patients) or replacement (130 patients) for degenerative or ischemic mitral regurgitation. The two groups were similar in sex, age, prior infarctions or cardiac operations, hypertension, angina, and functional class. Both groups were similar in mean ejection fraction, pulmonary artery pressure, cardiac index, and incidence of coronary artery disease. More reconstruction than replacement patients had ischemic etiology (22 [16%] versus 12 [9%]; p = not significant), and fewer reconstruction patients had ruptured anterior leaflet chordae (9 [7%] versus 39 [30%]; p < 0.01). More reconstruction than replacement patients had concomitant cardiac procedures (67 [50%] versus 59 [45%]; p = not significant). Hospital death occurred in 4 reconstruction patients (3%) and 15 (12%) replacement patients (p < 0.01). Median postoperative stay was shorter in reconstruction patients (10 versus 12 days; p = 0.02). Late valve-related death occurred in 3 reconstruction patients (2%) and 8 (6%) replacement patients (p = 0.08). Six-year actuarial freedom from thromboembolism was 92% for the reconstruction group and 85% for the replacement group (p = 0.12). Freedom from all valve-related morbidity and mortality was 85% for the reconstruction patients and 73% for the replacement patients (p = 0.03). Significant multivariate predictors of hospital death were age, mitral valve replacement, functional class, congestive heart failure, no posterior chordal rupture, and nonelective operation. Mitral valve reconstruction, when technically feasible, is the procedure of choice for degenerative or ischemic mitral regurgitation because of significantly lower hospital mortality and late valve-related events.

Actuarial Analysis↗
PubMed1994

Reoperative coronary grafting: changing patient profiles, operative indications, techniques, and results.

To assess the changing trends in patient profiles, operative indications and techniques, and their impact on the results of reoperative myocardial revascularization, we reviewed the records of 750 consecutive patients who had an isolated first reoperation for coronary artery disease at the Massachusetts General Hospital from 1977 to 1992. The patients were chronologically grouped into three equal cohorts of 250 patients. Our assessment over time revealed a significantly (p < 0.03) increased incidence of the following: older age, peripheral vascular disease, grafts at the first revascularization, longer operative interval, interval infarctions and angioplasties, and congestive heart failure and unstable angina requiring greater use of preoperative intraaortic balloon pumping. At catheterization significantly more left main coronary disease, lower ejection fractions, and more patent but diseased grafts were found. The reoperations were significantly done more urgently, with more grafts placed and a greater use of mammary artery grafting. Despite these increased risks over time, median postoperative hospital stay was significantly shortened (p < 0.001), though hospital mortality (5.3%) and perioperative myocardial infarction (6.3%) did not change significantly. Significant multivariate predictors of hospital death were nonelective operation, perioperative myocardial infarction, prior myocardial infarction, and mammary artery grafting at the initial operation.

Adult↗
PubMed1992

Postinfarct ventricular septal defect repair: effect of coronary artery bypass grafting.

Between June 1968 and April 1991, 75 patients who had undergone coronary angiography underwent repair of a postinfarction ventricular septal defect. Group 1 (n = 33) includes patients who had two- or three-vessel serious (> 75% narrowing) proximal coronary artery disease and underwent complete revascularization in addition to repair of the ventricular septal defect. Group 2 (n = 19) patients also had two- or three-vessel coronary artery disease but bypass grafting was not performed; only the ventricular defect was repaired. Group 3 (n = 23) patients had only single-vessel coronary artery disease that corresponded to the region of the infarct; they underwent ventricular septal defect repair only. Follow-up of hospital survivors was 96% complete at a mean of 86.2 months (range, 1 to 288 months). Hospital mortality after ventricular septal defect repair was 21.2% in the cohort with bypassed coronary artery disease (group 1), 26.3% in those with unbypassed disease (group 2), and 26.1% in those with only single-vessel coronary artery disease (group 3) (p = 0.88). With follow-up after 5 and 10 years, the actuarial survival was 72.2% +/- 8% and 47.8% +/- 10%, respectively, in the bypassed group, 29.2% +/- 11% and 0%, respectively, in the unbypassed group, and 52.2% +/- 10% and 36.5% +/- 11%, respectively, in the cohort with single-vessel disease. Bypassing associated coronary artery disease significantly increased long-term survival when compared with patients with unbypassed coronary artery disease (p = 0.0015).

Aged↗
PubMed1992

Ultra-pure polymerized bovine hemoglobin blood substitute: effects on the coronary circulation.

The effects of stroma-free hemoglobin (SFHgb) on the coronary circulation remain unclear. An intact canine model utilizing intracoronary adenosine to abolish the confounding effect of autoregulation was used to study maximal myocardial oxygen delivery during progressive hemodilution with polymerized bovine SFHgb. The circumflex coronary artery was instrumented with a flow probe, hydraulic constrictor, and proximal and distal catheters for adenosine infusion and distal pressure measurement, respectively. This preparation was used to generate diastolic coronary pressure-flow relations during maximal vasodilation. Maximal coronary conductance and maximal myocardial oxygen delivery were determined in two groups of 7 dogs each following hemodilution, first with 6% hetastarch (Control), followed by further hemodilution with ultra-pure, polymerized, bovine SFHgb. After hemodilution with SFHgb, maximal coronary flow increased slightly without evidence of coronary vasoconstriction. Since hemodilution with this material increases oxygen carrying capacity, maximal oxygen delivery is greater than Control, despite the very low canine hematocrit. These findings suggest: 1) SFHgb can provide adequate oxygen delivery to the myocardium despite extreme degrees of hemodilution, and 2) in this intact model, there is no evidence of adverse coronary vasomotion.

Animals↗
PubMed1990

Late results with Carpentier-Edwards porcine bioprosthesis.

From 1977 to 1984, 429 patients underwent aortic valve replacement (AVR), and 339 underwent mitral valve replacement (MVR) with a Carpentier-Edwards bioprosthesis. Early mortality for AVR was 4.6% (isolated AVR, 1.9%) and for MVR was 5.3% (isolated MVR, 4.1%). Follow-up was 99.3% complete at a mean of 5.9 years. Actuarial event-free rates at 10 years for AVR and MVR were, respectively, 1) for structural valve deterioration, 91.4 +/- 3.2% versus 75.1 +/- 4.0% (p less than 0.01); 2) for nonstructural dysfunction, 100% versus 97.8 +/- 1.6% (p = NS); 3) for thromboembolism, 90.6 +/- 2.3% versus 87.3 +/- 2.6% (p = NS); 4) for anticoagulant-related bleeding, 95.3 +/- 1.1% versus 88.6 +/- 2.4% (p = 0.05); 5) for endocarditis, 87.8 +/- 5.7% versus 90.6 +/- 2.4% (p = NS); 6) for reoperation, 91.0 +/- 2.5% versus 74.4 +/- 3.7% (p less than 0.01); 7) for valve-related mortality, 76.1 +/- 6.9% versus 71.4 +/- 5.2% (p = 0.01); 8) for permanent physical impairment, 85.0 +/- 3.0% versus 71.5 +/- 3.6% (p less than 0.01); and 9) for combined operative mortality, valve-related mortality, and reoperation, 68.7 +/- 6.4% versus 51.5 +/- 4.9% (p = 0.01). No structural valve dysfunction was observed in any AVR patient whose valve was inserted after age 70. Age at operation was the only factor that predicted structural valve deterioration (p less than 0.01).

Actuarial Analysis↗
PubMed1990

Hemodynamic effects and oxygen transport properties of a new blood substitute in a model of massive blood replacement.

Recent concerns regarding the safety of the national blood supply have rekindled interest in the development of blood substitutes. Clinical studies have dampened the initial enthusiasm for fluorocarbon solutions as blood substitutes. The potential of hemoglobin solutions as blood substitutes has continued to stimulate investigations. However, the development of an ideal hemoglobin-derived blood substitute has eluded investigators for the past century. A persistent problem has been the inability to develop hemoglobin solutions that provide adequate oxygen and carbon dioxide exchange, while avoiding toxicity that precludes clinical safety and long-term survival. Traditionally, investigators have focused on human hemoglobin solutions. The use of outdated banked blood or pedigree human donor blood as a hemoglobin source poses continued disease transmission risks and a prohibitively limited supply. We evaluated the hemodynamic and gas transport effects of a new purified, polymerized bovine hemoglobin preparation. Bovine hemoglobin oxygen affinity is regulated by chloride ion. The concentration of chloride ions in human plasma results in excellent oxygen transport properties in a stroma-free environment. In addition, unlike human blood, bovine blood is a more disease-free hemoglobin source that is available in large supply. We exchange-transfused eight conscious sheep with this new polymerized bovine hemoglobin solution. All animals tolerated greater than or equal to 95% exchange transfusion to reach a final ovine hematocrit of 2.4 +/- 0.5% with stable hemodynamics and no clinical evidence of distress. The exchange transfusion with bovine hemoglobin polymer resulted in a final plasma hemoglobin concentration of 6.1 +/- 1.6 gm/dl, which supported oxygen consumption at baseline levels. All animals that were exchange transfused with this preparation survived long term with rapid resynthesis of ovine erythrocytes.

Animals↗
PubMed1989

Ultrapure, stroma-free, polymerized bovine hemoglobin solution: evaluation of renal toxicity.

Because of recent concern about the safety of our national blood supply, there is increased interest in finding safe and effective blood substitutes. One option is the use of stroma-free hemoglobin (SFH) solutions. Recently, a SFH solution based on ultrapure, polymerized bovine hemoglobin (UPPBHg) has been shown to be effective in oxygen transport. We examined the potential renal toxicity of this material. Sprague-Dawley rats were infused with UPPBHg at doses of 25, 50, 75, and 100 ml/kg. Additional groups of rats were infused with UPPBHg at these doses with the addition of bicarbonate at a dose adequate to alkalinize the urine. Further groups of rats received UPPBHg intentionally contaminated with raw bovine blood lysate. Renal function was examined by subsequent determination of serum creatinine. UPPBHg infusion up to 50 ml/kg caused no significant change in serum creatinine; at higher doses, there was a reversible rise in creatinine at 24 hr following infusion. Addition of bicarbonate diminished the amount of reversible toxicity seen, even at doses of 100 ml/kg. In contrast, with hemolysate-contaminated UPPBHg, there were sharp increases in creatinine 24 hr after infusion of all doses tested, even at 25 ml/kg; these did not decrease significantly by 48 hr following infusion. At the higher doses tested, death occurred. These observations were not affected by simultaneous bicarbonate infusion. This study shows that UPPBHg may be administered in very large doses with only mild, reversible renal toxicity. The observation that urine alkalinization ameliorates this toxicity suggests that this may occur by hemoglobin precipitation or by a toxic effect in the renal tubules.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗