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Biomedical subjects

K L Brigham

Publications and source records attributed to K L Brigham.

At least 127 records · Page 7Linked to original sources
PubMed1984

Facilitation of granulocyte migration into bovine pulmonary artery intimal explants by intact viable endothelium.

To characterize the role of normal endothelium in granulocyte chemotaxis, the authors measured granulocyte adherence to and migration into bovine pulmonary artery intimal explants. Explants were placed, endothelium uppermost, in chemotaxis chambers with zymosan-activated plasma in the lower well and 5 X 10(6)/ml 51Cr-labeled granulocytes in the upper well. After 15, 30, 60, 120, 180, or 240 minutes incubation at 37 C, granulocyte adherence was measured by removal of adherent granulocytes from the endothelial layer with a 0.1% trypsin wash and counting of radioactivity in the wash. Scanning electron microscopy confirmed that this technique removed the majority of adherent cells from the endothelial surface without disrupting its continuity. Migration was calculated by counting of the remaining radioactivity in the explant. Granulocyte migration with Medium 199 alone in the lower well (random migration) was 36 +/- 3% by 3 hours. Chemotaxis-induced migration at each time studied was 1.5-2 times random migration. Granulocyte adherence was between 4% and 9% in both groups at all times examined. In some experiments, either endothelium was removed from explants or explants were fixed with glutaraldehyde prior to experimentation. Removal of endothelium resulted in a two-fold increase in granulocyte adherence but no significant difference in migration, compared with intact intimal explants. Glutaraldehyde fixation of explants resulted in more tightly adherent granulocytes and significantly less migration. With lactate dehydrogenase as a marker of endothelial cell damage, granulocyte migration in response to zymosan-activated plasma did not injure endothelium. It is concluded that, in blood vessels, chemotaxis is an interactive process between granulocytes and endothelium and that intact, viable endothelium facilitates granulocyte migration.

Animals↗
PubMed1984

Pulmonary vascular and hemodynamic effects of prostaglandin E1 in unanesthetized sheep.

We prepared fully instrumented sheep with chronic lung lymph fistulas and measured lung lymph and hemodynamic responses to intravenous infusions of prostaglandin (PG) E1. PGE1 decreased lung lymph flow from 8.0 +/- 0.8 S.E.M. ml/h during baseline to 6.5 +/- 0.7 ml/h (p less than 0.05) and 5.4 +/- 0.8 ml/h (p less than 0.05) at 50 and 250 micrograms/min, respectively. Lymph to plasma protein concentration ratio (L/P) did not change during PGE1 infusion and increased after PGE1 was stopped. Systemic and pulmonary vascular pressures decreased without producing reflex tachycardia. PGE1 consistently caused hypoxemia and hemoconcentration. Multiple indicator dilution studies showed consistent decreases in the 14C-urea permeability surface area product (PS urea) during PGE1 infusion. To distinguish effects of PGE1 on perfused lung vascular surface area from effects on vascular permeability, we mechanically increased lung vascular pressures, achieved a steady state lung lymph response, and infused PGE1 (50 micrograms/min) while maintaining constant left atrial pressure. PGE1 decreased lung lymph flow from 14.1 +/- 2.0 ml/h to 10.0 +/- 1.8 ml/h (p less than 0.05). Systemic and pulmonary arterial pressures fell. Cardiac output did not change and heart rate decreased. L/P increased significantly, indicating that the decrease in lymph flow could be attributed to decreased lung microvascular pressure without obligate change in microvascular permeability. During increased lung vascular permeability caused by E. coli endotoxin, PGE1 (250 micrograms/min) decreased lung lymph flow, and systemic and pulmonary vascular pressures fell. Although PGE1 decreased lymph protein clearance, L/P did not change. Decreased lymph flow with PGE1 could be attributed to decreased lung vascular pressure, decreased exchanging vessel surface area, or both.

Alprostadil↗
PubMed1984

The effect of a single infusion of zymosan-activated plasma on the pulmonary microcirculation of sheep. Structure-function relationships.

Activation of the complement cascade is one of the mechanisms through which endotoxin may cause acute lung damage. The structural and functional changes following infusion of complement-activated plasma are described. In five anesthetized open-chest sheep, the authors monitored pulmonary and systemic artery pressures for 1 hour before and for 4 hours following the start of zymosan-activated plasma (ZAP) infusion (2 ml/min over a 20-minute period). Cardiac output, blood gases, and the number of circulating white cells were also measured. In addition, we took lung biopsy tissue at baseline, 7.5, 15, 30, 60, 120, 180, and 240 minutes following the start of infusion. Lung lymph flow and protein concentration were also monitored in 2 sheep. Following ZAP infusion there was an early phase of leukopenia and marked pulmonary hypertension, followed by a phase characterized by a modest increase in the flow of protein-rich lung lymph. By light microscopy pulmonary sequestration of granulocytes was evident just 7.5 minutes following the start of ZAP infusion. Peripheral lung granulocytes increased threefold above control values by 7.5 minutes, increasing to sevenfold by 30 minutes. Electron-microscopic studies showed that some of the granulocytes were disrupted, and specific and azurophilic granules were seen in the lumen. By 15 minutes endothelial damage was apparent, and intravascular monocytes were surrounded by a proteinaceous coat. Edema accumulation and an infiltration of inflammatory cells in the lungs' connective tissue regions increased to 2 hours. From 2 hours, lung injury was less marked, and the number of peripheral lung granulocytes, fewer. Sequestration of granulocytes occurred with the onset of pulmonary hypertension and leukopenia, and was most marked when lung injury was most severe. Transient endothelial damage and edema preceded the physiologic changes interpreted as an increase in pulmonary vascular permeability. Although pulmonary sequestration of granulocytes was at least as great as that with endotoxemia, unlike endotoxemia, ZAP caused only transient endothelial injury and modest changes in vascular permeability.

Animals↗
PubMed1983

Effects of 100% oxygen on lung vascular function in awake sheep.

The purpose of this study was to define the time course of pulmonary toxicity during continuous breathing of 100% oxygen in adult sheep. Sheep were prepared for chronic measurement of vascular pressures, cardiac output, gas exchange, and for collection of lung lymph. Tracheostomies allowed accurate delivery of either 100% oxygen, compressed air, or hypoxic gas. Six sheep breathed 100% oxygen for 72-96 h, and four sheep breathed compressed air for 96 h. In addition to hypoxic challenges [fractional concentration of inspired O2 (FIo2) = 0.12], some sheep received prostaglandin H2 (PGH2)-analogue infusions to further assess pulmonary vascular reactivity. Lung lymph and blood chemotactic activity were measured by granulocyte migration in modified Boyden chambers. Postmortem lung water content and light microscopy were used to measure pulmonary edema. All sheep breathing 100% oxygen died between 72 (n = 2) and 96 h (n = 4). Sheep breathing oxygen demonstrated lung toxicity by measurements of 1) a fourfold increase in flow of protein-rich lung lymph, 2) increased alveolar-arterial difference in Po2 (greater than 20 Torr on FIo2 = 0.21) and hypercapnic acidemia, and 3) a mean extravascular lung water/dry lung weight of 5.7 (controls = 3.3), and histological evidence of interstitial and alveolar edema. Chemotactic activity in lung lymph at base line increased eightfold within 72-96 h of oxygen breathing. In sheep breathing oxygen, the hypoxic pressor response decreased by 50% at 48 h, and by 72-96 h there was a total absence of hypoxic vasoconstriction. There was no increase in lung lymph prostacyclin metabolite, and sodium meclofenamate did not restore the pressor response. In sheep breathing compressed air none of these changes in pulmonary vascular reactivity, lymph flow, or chemotactic activity occurred. We conclude that prolonged breathing of pure oxygen causes pulmonary edema by increasing lung vascular permeability and that respiratory failure results from both edema and loss of pulmonary vascular reactivity.

Animals↗
PubMed1983

Effect of endotoxin on airway responsiveness to aerosol histamine in sheep.

This study tested the hypothesis that in the awake sheep, airway responsiveness to aerosol histamine would be increased acutely by endotoxemia. Eleven sheep were chronically instrumented to allow for measurements of lung lymph flow, vascular pressures, and lung mechanics. Awake sheep were studied in a whole-body plethysmograph designed to measure dynamic compliance (Cdyn), resistance of the lung (RL), and functional residual capacity (FRC). Pulmonary responsiveness to aerosol histamine was assessed by giving five breaths of increasing concentrations of histamine (0.1-50 mg/ml) until Cdyn decreased to 65% (of control) or until 50 mg/ml of histamine had been given. Escherichia coli endotoxin (0.2-0.5 microgram/kg) was then infused, and at 5 h after endotoxemia pulmonary responsiveness to aerosol histamine was remeasured. After endotoxin, 9 of the 11 sheep exhibited decreased Cdyn at a lower concentration of histamine compared with the preendotoxin level (P less than 0.05). The mean of the log dose of histamine necessary to reduce Cdyn to 65% of control was 1.00 +/- 0.16 (SE) before endotoxin and 0.027 +/- 0.29 5 h after endotoxin; i.e., histamine responsiveness was increased. In the last 3 sheep studied, atropine (0.1 mg/kg iv) was given after the second aerosol histamine challenge, and a third dose-response curve was performed. Atropine did not return the endotoxin-induced increase in histamine responsiveness to base line. There was no correlation between the change in histamine responsiveness and the endotoxin-induced changes in Cdyn, FRC, RL, alveolar-arterial O2 difference, pulmonary arterial pressure, or lung lymph flow.

Aerosols↗
PubMed1983

Effect of granulocyte depletion on altered lung mechanics after endotoxemia in sheep.

To examine the role of circulating granulocytes in the airway changes caused by endotoxemia, we measured the response of chronically instrumented unanesthetized sheep to endotoxemia before and after granulocyte depletion with hydroxyurea. Granulocyte depletion did not affect the increases in mean pulmonary arterial pressure caused by endotoxin [peak pressure 59 +/- 8 cmH2O +/- (SE) control, 51 +/- 8 cmH2O granulocyte depleted]. However, the early (30-60 min after endotoxin) airway response to endotoxemia was markedly attenuated. Without granulocyte depletion, endotoxin caused dynamic compliance (Cdyn) to decrease to 41 +/- 10% of the base-line value and total lung resistance (RL) to increase to 283 +/- 61% of base line. When animals were granulocyte depleted, endotoxin decreased Cdyn to 69 +/- 6% (P less than 0.05) of base line and increased RL to 141 +/- 20% of base line (P less than 0.05). Granulocyte depletion also attenuated the effect of endotoxin on arterial oxygenation. During the maximum airway response to endotoxin, the alveolar-to-arterial oxygen gradient was 47 +/- 5 Torr in control studies and 32 +/- 2 Torr in granulocyte depleted studies (P less than 0.05). We conclude that interaction of granulocytes with the lung contributes to the changes in lung mechanics observed following endotoxemia and that the early pulmonary hypertension and the early alterations in lung mechanics caused by endotoxemia are caused by separate processes.

Agranulocytosis↗
PubMed1983

Effect of naloxone on the pulmonary vascular responses to graded levels of intracranial hypertension in anesthetized sheep.

UNLABELLED: We increased intracranial pressure (ICP) in anesthetized sheep for 3 h by connecting the cisterna magna to an elevated reservoir of buffered saline. We monitored systemic and pulmonary vascular pressures, pulmonary blood flow, and the flow of lymph from the lungs. The volume and protein concentration of the lymph were used to assess changes in lung vascular permeability-surface area. Extravascular lung water was measured postmortem, and in vivo indicator dilution studies were used to measure permeability-surface area product (PS urea) of the lung circulation for a small hydrophillic molecule (14C-urea) and extravascular water volume (VH2O). These studies were done in 16 sheep with ICP raised to 0, 60, or 100 mmHg. Thirteen other sheep received naloxone before and during elevation of ICP to 0, 60, or 100 mmHg. Elevation of ICP increased pulmonary artery pressure ( CONTROL: 16 +/- 3 cmH2O; ICP: 60 mmHg = 16 +/- 2 cmH2O; ICP: 100 mmHg = 23 +/- 2 cmH2O), cardiac output ( CONTROL: 2.7 +/- 0.1 L/min; ICP: 60 mmHg = 3.3 +/- 0.05, p less than 0.05; ICP: 100 mmHg = 5.3 +/- 1.0, p less than 0.05), lung lymph flow ( CONTROL: 94 +/- 8% baseline; ICP: 60 mmHg = 193 +/- 25% baseline, p less than 0.05; ICP: 100 mmHg = 285 +/- 38% baseline, p less than 0.05), PS urea ( CONTROL: 7.0 +/- 0.5 ml/s; ICP: 60 mmHg = 11.0 +/- 3.7 ml/s; ICP: 100 mmHg = 12.4 +/- 1.3 ml/s, p less than 0.05), and VH2O (CONTROL: 93 +/- 8% baseline; ICP: 60 mmHg = 112 +/- 6% of baseline; ICP: 100 mmHg = 129 +/- 13% of baseline, p less than 0.05) proportional to the level of ICP. Sheep with ICP raised to 100 mmHg had modestly increased lung water (pulmonary edema).(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthesia↗
PubMed1983

Correlation of oxygenation with vascular permeability-surface area but not with lung water in humans with acute respiratory failure and pulmonary edema.

We used a single-pass multiple tracer technique to measure cardiac output, extravascular lung water (EVLW) and lung vascular [14C]urea permeability-surface area (PSu) in 14 patients with acute respiratory failure and pulmonary edema. All patients had increased EVLW, but EVLW in the 10 surviving patients (0.26 +/- 0.06 SE ml/ml total lung capacity [TLC]) was not significantly different from that in the five patients who died (0.22 +/- 0.05). EVLW did not correlate with intravascular pressures or with alveolar-arterial oxygen pressure difference (A-aDO2). PSu was lower in surviving patients (0.50 +/- 0.16 SE ml/s X liter TLC) than in patients who died (3.44 +/- 0.36; P less than 0.05) and also lower than in previously reported data in patients with normal PSu. PSu correlated significantly with A-aDO2. Serial studies showed that PSu returned from a low value toward normal in a patient who survived but remained high in a patient who died. We conclude that the amount of edema in the lungs measured by indicator methods was not the principal determinant of either the magnitude of oxygenation defect or survival in the patients studied. We interpret the low PSu in surviving patients as decreased surface area and infer that the ability of the lung circulation to reduce perfusion of damaged and edematous areas was important in preserving oxygenation. A high PSu, presumably reflecting perfusion of areas with increased permeability, was a sign of especially poor prognosis. Multiple tracer techniques for measuring lung vascular PSu may help to define the pathogenesis and to evaluate therapies of acute lung injury in humans. Such measurements may be a more useful clinical tool than measurements of lung water in patients with acute respiratory failure and pulmonary edema.

Adult↗
PubMed1983

Effects of cyclooxygenase inhibitors on the alterations in lung mechanics caused by endotoxemia in the unanesthetized sheep.

The effects of Escherichia coli endotoxin on lung mechanics, hemodynamics, gas exchange, and lung fluid and solute exchange were studied in 12 chronically instrumented unanesthetized sheep. A possible role for cyclooxygenase products of arachidonate metabolism as mediators of the endotoxin-induced alterations in lung mechanics was investigated by studying sheep before and after cyclooxygenase inhibition with sodium meclofenamate and ibuprofen. Sheep were studied three times in random order: (a) sodium meclofenamate (or ibuprofen) infusion alone; (b) E. coli endotoxin alone; and (c) meclofenamate (or ibuprofen) and endotoxin. Meclofenamate alone had no effect on any of the variables measured. Endotoxin alone caused early marked changes in lung mechanics: resistance to airflow across the lungs (RL) increased 10-fold, dynamic lung compliance (Cdyn) decreased 80% and functional residual capacity (FRC) decreased by greater than 30%. The alveolar-to-arterial oxygen difference (delta AaPO2) increased markedly following endotoxemia. In the presence of sufficient meclofenamate to inhibit accumulation of thromboxane-B2 and 6-keto-prostaglandin F1 alpha in lung lymph, endotoxin caused no increase in RL, Cdyn decreased by less than 40%, and FRC decreased by only 6%. Meclofenamate significantly attenuated the hypoxemia and early pulmonary hypertension caused by endotoxemia but had no effect on the late increases in lung fluid and solute exchange. Ibuprofen had similar effects to those observed with meclofenamate. We conclude that both the pulmonary hypertension and changes in lung mechanics observed after endotoxemia may be mediated, at least in part, by constrictor prostaglandins or thromboxanes and that gas exchange may be improved by preventing endogenous synthesis of these mediators.

6-Ketoprostaglandin F1 alpha↗
PubMed1983

Effects of cyclooxygenase inhibition on the response to group B streptococcal toxin in sheep.

The effects of cyclooxygenase inhibition on the reaction to a toxin isolated from group B beta-hemolytic streptococci, type III, were studied in seven sheep instrumented for chronic measurement of pulmonary lymph flow, pulmonary artery and left atrial pressures. Each sheep was infused with toxin alone on one day and with indomethacin plus toxin on a different day in random order. The toxin alone caused a two-phased reaction. After the infusion of toxin, alone, in the initial phase, pulmonary artery pressure increased from 16.5 +/- 1.2 mmHg to 47.1 +/- 4.8 mmHg and the rectal temperature rose from 39.7 +/- 0.13 degree C to 40.9 +/- 0.16 degree C. During the second phase, the granulocyte count decreased to less than 10% of baseline values and the lymph protein clearance increased from 4.8 +/- 1.2 ml/h to 10.02 +/- 1.4 ml/h, suggesting increased pulmonary vascular permeability. Indomethacin pretreatment prevented the initial phase of pulmonary hypertension, the increases in thromboxane and prostacyclin metabolites in lung lymph, and the febrile response to toxin infusion but did not modify the granulocytopenia or the increased pulmonary vascular permeability. It appears that the hemodynamic changes are independent from the pulmonary vascular changes, and that prostaglandin endoperoxides or their metabolites are necessary for the fever and the acute pulmonary hypertension.

Animals↗
PubMed1983

Pulmonary hemodynamic and ultrastructural changes associated with Group B streptococcal toxemia in adult sheep and newborn lambs.

A toxin isolated from Group B beta-hemolytic streptococci, Type III was infused into adult sheep and newborn lambs. A two-phased reaction was observed. There was an initial phase of pulmonary hypertension and high flow of protein-poor lymph. This was followed by a second phase when pressures returned to baseline but lymph flow remained twice the baseline values and protein concentration in lymph increased. During the second phase there was a significant increase in lymph protein clearance, suggestive of increased microvascular permeability to protein. The absolute granulocyte count decreased to 10% of baseline values by 60 min after the infusion, and was followed by a variable return to baseline. The sheep with the largest changes in protein clearance were those who had the slowest return to baseline values. Pathologic examination of lung tissue revealed there was capillary dilation, interstitial edema, and large numbers of granulocytes in the lungs. The basement membranes of both capillaries and arterioles showed disruption and widening, along with fragmentation of the internal elastic membrane. This study provides morphologic and physiologic evidence of increased pulmonary vascular permeability after injection of streptococcal toxin associated with granulocyte trapping in the lung. We postulate that granulocytes may be involved as mediators of the pulmonary vascular injury.

Animals↗
PubMed1983

Comparison of sodium and urea as indicators of pulmonary vascular permeability.

The objective of this work was to compare the blood-tissue transport properties of 14C-urea and 24Na in the lung circulation. The extraction of both substances was measured relative to intravascular reference tracers (125I-albumin for 24Na, 51Cr red cells and 125I-albumin for 14C-urea) in single-pass transpulmonary multiple indicator curves measured in awake sheep. Sheep were studied in baseline condition, after infusion of histamine solution (4 micrograms/kg-min for 4 hr), and after microvascular pressure was elevated. Permeability-surface area was computed for both sodium (PSn) and urea (PSu) by the Crone extraction model and by a mathematical model. In spite of the fact that the free diffusion coefficients of sodium and urea are approximately equal, the mean ratio of Crone PSn/PSu for baseline studies was 0.76. PSu was significantly increased by histamine infusion but PSn was not. The variation in PSn with histamine and increased pressure was marked. Thus, neither manipulation altered the ratio PSn/PSu in a consistent fashion. Correction of PS for extravascular distribution volumes of urea and Na did not change the PS ratio significantly. We concluded that the diffusional resistance to sodium is higher than expected from its diffusivity, possibly because of charge, and that PS for urea is more sensitive to changes in lung vascular permeability.

Animals↗
PubMed1983

Septicemia and lung injury.

The results of investigations undertaken by the authors which deal with the functional and structural changes in the lungs resulting from gram-negative bacterial endotoxemia and the mechanisms of these changes are analyzed. The authors emphasize the major roles played by granulocytes and metabolites of arachidonic acid in mediating endotoxin-induced lung injury.

Adult↗
PubMed1983

Effects of endotoxemia on cyclic nucleotides in the unanesthetized sheep.

The effects of endotoxemia on hemodynamics, pulmonary fluid, and solute exchange and cGMP and cAMP concentrations in lung lymph and pulmonary artery and left atrial blood were studied in six unanesthetized sheep. Cyclic AMP levels increased early in the endotoxin reaction, reaching peak concentration 1 hr after endotoxemia (during the period of pulmonary hypertension). Cyclic GMP levels increased gradually during the endotoxin reaction, reaching peak concentrations 5 hr after endotoxemia (during the period of "increased pulmonary vascular permeability"). The changes observed in cyclic nucleotide levels in lung lymph and pulmonary artery and left atrial blood suggested pulmonary production of cGMP but not cAMP. Cyclic AMP concentrations correlated with PPA, Qlymph, and a drop in the L/P ratio, whereas lung lymph cGMP correlated with an increased clearance of protein in the lymph. These results further characterize the sheep endotoxin reaction and suggest a possible role for cyclic nucleotides in the pathogenesis of the changes in lung vascular function that follow endotoxin infusion in sheep.

Animals↗
PubMed1983

Acute effects of Escherichia coli endotoxin on the pulmonary microcirculation of anesthetized sheep structure:function relationships.

Infusion of Escherichia coli endotoxin into sheep causes a syndrome analogous to the adult respiratory distress syndrome. Physiologic measurements show an initial phase of marked pulmonary hypertension followed by a phase characterized by the production of large quantities of protein-rich lung lymph. The present study relates the structural changes that occur during endotoxemia to concomitant functional changes. In five anesthetized open-chest sheep, we monitored pulmonary and systemic artery pressure for a 1 hour baseline period and for 4 hours after the start of E. coli endotoxin infusion (1.25 microgram/kg, intravenously). We also measured cardiac output, arterial blood gases and pH, and number of circulating leukocytes. In addition, we sequentially biopsied random lobes from the lungs of each sheep at baseline and at 15, 30, 60, 120, 180, and 240 minutes after the start of endotoxin. Five control sheep were treated identically except that they received saline instead of endotoxin. By 15 minutes after the start of endotoxin infusion, light microscopy revealed margination and accumulation of leukocytes in the lungs' microcirculation. Counts of the number of peripheral lung granulocytes in biopsy specimens showed a 3-fold increase above baseline by 15 minutes and a 6-fold increase by 4 hours. By electron microscopy, the leukocytes were identified as both granulocytes and lymphocytes, present in approximately equal numbers. Some granulocytes were fragmented, and specific granules were found free in the vessel lumen. By 30 minutes, some leukocytes were migrating into the interstitium. By 60 minutes, interstitial edema was seen, and there was focal endothelial cell damage. Correlation of the structural with the physiologic changes shows that the initial accumulation of leukocytes in the microcirculation occurs when pulmonary hypertension develops. The migration of leukocytes into the interstitium and endothelial cell damage precedes the physiologic changes that we interpret as increased pulmonary vascular permeability. Since gram negative septicemia is a frequent occurrence in the adult respiratory distress syndrome the changes described here may be similar to the alterations that occur early in the development of the syndrome in man.

Animals↗