Superoxide dismutase with heparin prevents increased lung vascular permeability during air emboli in sheep

1983 ◽  
Vol 55 (4) ◽  
pp. 1284-1291 ◽  
Author(s):  
M. R. Flick ◽  
J. M. Hoeffel ◽  
N. C. Staub
Keyword(s):  
Superoxide Dismutase ◽  
Pulmonary Vascular Resistance ◽  
Vascular Resistance ◽  
Lymph Flow ◽  
Microvascular Permeability ◽  
Base Line ◽  
Pulmonary Arterial ◽  
The Right ◽  
Protein Rich ◽  
Lung Lymph

We studied the effects of bovine superoxide dismutase on the increased lung microvascular permeability to fluid and protein during air emboli in unanesthetized sheep. We measured pulmonary arterial and left atrial pressures, cardiac output, lung lymph flow, and lymph and plasma protein concentrations. In air emboli experiments we continuously infused the same dose of air bubbles 1 mm in diameter into the right atrium of each sheep to increase pulmonary vascular resistance to 2-4 times base-line values. We did experiments in pairs so that each sheep served as its own control. We found an increase in protein-rich lymph flow from the lung during embolization in untreated sheep, indicating an increase in microvascular permeability to both fluid and protein. When we pretreated the sheep with heparin (300 U/kg) and infused them with intravenous bovine superoxide dismutase (1 mg X kg-1 X h-1 beginning before the air infusion), we found that vascular pressures and pulmonary vascular resistance were not different from untreated sheep but that the expected increases in transvascular fluid and protein flow during emboli were significantly decreased (P less than 0.0005). Heparin alone did not significantly attenuate the increased microvascular permeability but we found that it greatly enhanced the effectiveness of superoxide dismutase in preserving microvascular functional integrity during air emboli. We conclude that superoxide anion, probably produced and released by leukocytes, is a central factor in the microvascular injury that results in increased permeability in the lungs of sheep during air microembolization.

Verapamil attenuates lung vascular responses to endotoxin in sheep

1988 ◽  
Vol 65 (5) ◽  
pp. 2138-2143 ◽  
Author(s):  
R. E. Parker ◽  
J. R. Hardin ◽  
K. L. Brigham
Keyword(s):  
Flow Rate ◽  
Lymph Flow ◽  
Microvascular Permeability ◽  
Base Line ◽  
Pulmonary Hemodynamic ◽  
Pulmonary Arterial ◽  
Lung Lymph ◽  
Lung Lymph Flow

Experiments were conducted on five chronically instrumented unanesthetized sheep to determine the effects of verapamil, a calcium channel inhibitor, on the pulmonary hemodynamic and microvascular permeability responses to endotoxemia. Paired control endotoxemia experiments (E) and endotoxemia with verapamil treatment (30-60 micrograms.kg-1.min-1) experiments (V + E) were conducted on each sheep in random order. In the V + E experiments sheep were pretreated with a continuous intravenous infusion of verapamil 1.5-2.0 h before endotoxin infusion (1.0 microgram/kg, given over 15 min). Verapamil significantly increased base-line pulmonary arterial pressure, left atrial pressure, lung lymph flow rate, and circulating blood leukocyte levels and significantly decreased base-line cardiac output. During the endotoxin response, verapamil significantly attenuated both phase I pulmonary arterial hypertension and phase II lung lymph flow rate compared with control endotoxin experiments. The results indicate that verapamil attenuates both the pulmonary hemodynamic and increased lung microvascular permeability response to endotoxin in sheep. In a series of in vitro experiments, verapamil was found to be a potent inhibitor of phorbol myristate acetate-induced superoxide production in isolated sheep granulocytes. These data suggest that the beneficial in vivo effects of verapamil during endotoxemia may in part be due to its inhibition of increased free cytosol calcium concentration and/or inhibition of toxic O2 metabolite production.

Effect of progressive exercise on lung fluid balance in sheep

1988 ◽  
Vol 64 (5) ◽  
pp. 2125-2131 ◽  
Author(s):  
J. H. Newman ◽  
B. J. Butka ◽  
R. E. Parker ◽  
R. J. Roselli
Keyword(s):  
Cardiac Output ◽  
Fluid Balance ◽  
Lymph Flow ◽  
Base Line ◽  
Lung Fluid ◽  
Lung Fluid Balance ◽  
Progressive Exercise ◽  
Pulmonary Arterial ◽  
Lung Lymph ◽  
Lung Lymph Flow

The purpose of this study is to determine the roles of cardiac output and microvascular pressure on changes in lung fluid balance during exercise in awake sheep. We studied seven sheep during progressive treadmill exercise to exhaustion (10% grade), six sheep during prolonged constant-rate exercise for 45–60 min, and five sheep during hypoxia (fraction of inspired O2 = 0.12) and hypoxic exercise. We made continuous measurements of pulmonary arterial, left atrial, and systemic arterial pressures, lung lymph flow, and cardiac output. Exercise more than doubled cardiac output and increased pulmonary arterial pressures from 19.2 +/- 1 to 34.8 +/- 3.5 (SE) cmH2O. Lung lymph flow increased rapidly fivefold during progressive exercise and returned immediately to base-line levels when exercise was stopped. Lymph-to-plasma protein concentration ratios decreased slightly but steadily. Lymph flows correlated closely with changes in cardiac output and with calculated microvascular pressures. The drop in lymph-to-plasma protein ratio during exercise suggests that microvascular pressure rises during exercise, perhaps due to increased pulmonary venous pressure. Lymph flow and protein content were unaffected by hypoxia, and hypoxia did not alter the lymph changes seen during normoxic exercise. Lung lymph flow did not immediately return to base line after prolonged exercise, suggesting hydration of the lung interstitium.

Effects of ONO-5046, a specific neutrophil elastase inhibitor, on endotoxin-induced lung injury in sheep

1994 ◽  
Vol 77 (3) ◽  
pp. 1333-1340 ◽  
Author(s):  
K. Kubo ◽  
T. Kobayashi ◽  
T. Hayano ◽  
T. Koizumi ◽  
T. Honda ◽  
...  
Keyword(s):  
Lung Injury ◽  
Arterial Pressure ◽  
Pulmonary Vascular Resistance ◽  
Vascular Resistance ◽  
Neutrophil Elastase ◽  
Pulmonary Arterial Pressure ◽  
Pulmonary Vascular Permeability ◽  
Lung Dysfunction ◽  
Pulmonary Arterial ◽  
Lung Lymph

The purpose of the present study was to assess the role of polymorphonuclear leukocyte (neutrophil) elastase in endotoxin-induced acute lung injury in sheep with lung lymph fistula. We studied the effects of ONO-5046, a specific inhibitor of neutrophil elastase, on the lung dysfunction induced by the intravenous infusion of 1 microgram/kg of Escherichia coli endotoxin. Endotoxin alone produced a biphasic response as previously reported. Early (0.5–1 h) after endotoxin, pulmonary arterial pressure increased from 19.5 +/- 0.9 cmH2O at baseline to a peak of 46.8 +/- 2.4 cmH2O (P > 0.05). Pulmonary vascular resistance increased from 3.03 +/- 0.17 cmH2O.l–1.min at baseline to a peak of 9.77 +/- 0.70 cmH2O.l–1.min (P < 0.05). Circulating neutrophils decreased from 7,355 +/- 434/mm3 at baseline to a nadir of 1,762 +/- 32/mm3 (P < 0.05). Thromboxane B2 and 6-ketoprostaglandin F1 alpha concentrations in plasma and lung lymph were significantly increased. Late (3–5 h) after endotoxin, pulmonary arterial pressure and pulmonary vascular resistance returned to baseline levels, but lung lymph flow remained increased from 4.2 +/- 0.3 ml/0.5 h at baseline to 7.3 +/- 0.7 ml/0.5 h (P < 0.05), with a slight increase in lung lymph-to-plasma protein concentration ratio, suggesting increased pulmonary vascular permeability. The histopathological features of the lungs during the early period in sheep treated with endotoxin alone revealed a large increase in neutrophils per 100 alveoli and changes of pulmonary edema such as thickening of the interstitium of the lung and alveolar flooding.(ABSTRACT TRUNCATED AT 250 WORDS)

Potentiation of lung vascular response to endotoxin by superoxide dismutase

1985 ◽  
Vol 58 (3) ◽  
pp. 1005-1009 ◽  
Author(s):  
D. L. Traber ◽  
T. Adams ◽  
L. Sziebert ◽  
M. Stein ◽  
L. Traber
Keyword(s):  
Superoxide Dismutase ◽  
Lymph Flow ◽  
Halothane Anesthesia ◽  
Protein Ratio ◽  
Hydroxyl Ion ◽  
Before And After ◽  
Blood Neutrophils ◽  
Pulmonary Arterial ◽  
Lung Lymph ◽  
Lung Lymph Flow

We studied the effects of superoxide dismutase (SOD), an enzyme that converts superoxide into peroxide, on the cardiopulmonary response to endotoxin in sheep. Sheep (n = 18) were prepared for chronic measurement of cardiopulmonary variables, including lung lymph flow, by surgically implanting catheters under halothane anesthesia. Nine of the animals were studied before and after the administration of endotoxin (0.75 microgram/kg) with and without SOD. An additional nine animals received SOD without the lipopolysaccharide. Endotoxin produced an increase in lung lymph flow that was initially associated with a marked pulmonary arterial (PA) hypertension and reduced lymph-to-plasma protein ratio (L/P). The lymph flow remained elevated later in the response, but there was only a mild increase in PA pressure, and the L/P was normal. There was also a fall in blood neutrophils and in cardiac index. SOD increased this secondary elevation in lung lymph flow, and the corresponding L/P was greater than the preendotoxin value. The fall in neutrophil count, cardiac output, and the elevation in PA pressure seen with endotoxin were not affected by SOD. When administered in the absence of endotoxin, SOD produced no perceptible change in the cardiopulmonary and lymph values. We conclude that peroxide, hydroxyl ion, and/or other free radicals formed by the action of SOD must be responsible for a portion of the endotoxin response rather than superoxide itself.

Simultaneous comparison of tracheobronchial and right duct lymph dynamics in dogs

1983 ◽  
Vol 54 (1) ◽  
pp. 199-207 ◽  
Author(s):  
D. J. Martin ◽  
J. C. Parker ◽  
A. E. Taylor
Keyword(s):  
Left Atrial ◽  
Protein Concentration ◽  
Lymph Flow ◽  
Base Line ◽  
Pulmonary Vascular Permeability ◽  
Endogenous Protein ◽  
Duct Lymph ◽  
The Right ◽  
Lung Lymph ◽  
Capillary Pore

The simultaneous responses of lymph flow and protein concentration were compared using lymph from the right duct (RD) and small afferent tracheobronchial (TB) lymphatics cannulated in the same dog. Lymph was collected during a base-line period and following steady-state left atrial pressure (Pla) elevations. For a mean increase in Pla of 14.8 cmH2O, RD flow increased 1.1 times control and TB flow by 2.5 times control. Total protein lymph-to-plasma ratios decreased significantly for TB lymph but not for RD lymph. Assuming TB represented pure lung lymph, the right duct was estimated to drain 4% of the total lung lymph and consist of 11% lung lymph with 89% extrapulmonary lymph at normal lymph flows. The lung lymph contribution to RD flow increased to 24% with increased Pla. Equivalent capillary pore dimensions calculated using endogenous protein fractions in both RD and TB lymph resulted in small pores of 100 and 90 A and large pores of 220 and 225 A, respectively. The fraction filtered through the large-pore population estimated using RD lymph was half that predicted using TB lymph. These data indicate that RD lymph data cannot accurately reflect pulmonary vascular permeability, since extrapulmonary lymph provided a major component of RD lymph flow at both base-line and increased filtration states.

Venous air emboli in sheep: reversible increase in lung microvascular permeability

1981 ◽  
Vol 51 (4) ◽  
pp. 887-894 ◽  
Author(s):  
K. Ohkuda ◽  
K. Nakahara ◽  
A. Binder ◽  
N. C. Staub
Keyword(s):  
Vascular Resistance ◽  
Elevated Pressure ◽  
Lymph Flow ◽  
Base Line ◽  
Air Bubbles ◽  
Lung Fluid ◽  
Average Decrease ◽  
Protein Clearance ◽  
Lung Fluid Balance ◽  
Lung Lymph

We studied the effects of continuous intravenous air embolization on lung fluid balance in unanesthetized sheep. Following a 2-h base line, we infused 300-micrometers-diam air bubbles into the pulmonary artery at a rate sufficient to increase pulmonary vascular resistance by 60–300% and for periods of 0.25–3 h. Air emboli produced a dose- and duration-dependent increase in lung lymph and protein flow due mainly to an increase in endothelial barrier permeability but also to elevated pressure in the over-perfused microcirculation. When we stopped the air infusion, the vascular resistance fell as the air emboli were reabsorbed. Lung lymph and protein flow increased further and then returned slowly to base line with a half-time proportional to the duration of embolization. Increasing left atrial pressure during air embolization caused an increase in lymph flow and protein clearance and an average decrease of 15 Torr in arterial O2 tension, all changes in excess of that caused by either increased pressure or air emboli alone.

Unilateral smoke inhalation in sheep: effect on left lung lymph flow with right lung injury

1996 ◽  
Vol 271 (6) ◽  
pp. R1620-R1624 ◽  
Author(s):  
Y. Kikuchi ◽  
L. D. Traber ◽  
D. N. Herndon ◽  
D. L. Traber
Keyword(s):  
Reflection Coefficient ◽  
Pulmonary Veins ◽  
Left Lung ◽  
Lymph Flow ◽  
Microvascular Permeability ◽  
Smoke Inhalation ◽  
Fourfold Increase ◽  
The Right ◽  
Lung Lymph ◽  
Lung Lymph Flow

We previously reported that smoke inhalation to the right lung will result in damage to the air-insufflated left lung. In this study we confirm these findings and determine whether this injury is associated with an elevation in lung lymph flow and pulmonary microvascular permeability to protein as indexed by changes in reflection coefficient. Sheep (n = 12) were surgically prepared by placement of a Swan-Ganz catheter and pneumatic occluders on all pulmonary veins and the left pulmonary artery. The left lung lymphatic was selectively cannulated as shown previously (Y. Kikuchi, H. Nakazawa, and D. Traber. Am. J. Physiol. 269 (Regulatory Integrative Comp. Physiol. 38): R943-R947, 1995). All afferent lymphatics from the right lung were severed, and the right pulmonary ligament was sectioned. The caudal end of the lymph node was sectioned to remove systemic lymph contamination. The sheep were studied in the unanesthetized state 7 days later. To ensure that lymph flow was exclusively from the left lung (QLL), right pulmonary microvascular pressure was increased, a procedure that resulted in little or no change in QLL, as was previously shown. The sheep were then anesthetized, and a Carlens tube was positioned to allow separate ventilation of the right and left lung. The right lungs of five sheep and the left lungs of two sheep were insufflated with cotton smoke. Insufflation of the left lung with cotton smoke produced a fourfold increase in QLL that began 4 h after insult. Insufflation of the right lung with smoke led to a doubling of QLL that began 12 h after insult. Changes in QLL were associated with increased microvascular permeability, as indexed by the reflection coefficient. Control sheep (air insufflated into both lungs, n = 5) showed no change in QLL. Injury to the right lung resulted in damage to the left air-insufflated lung, suggesting a hematogenous mediation of the response.

Effect of isoproterenol or exercise on pulmonary lymph flow and hemodynamics

1986 ◽  
Vol 60 (1) ◽  
pp. 38-44 ◽  
Author(s):  
H. O'Brodovich ◽  
G. Coates
Keyword(s):  
Cardiac Output ◽  
Pulmonary Vascular Resistance ◽  
Vascular Resistance ◽  
Lymph Flow ◽  
Pulmonary Hemodynamic ◽  
Vascular Catheters ◽  
Exercise Induced ◽  
Response To Exercise ◽  
Lung Lymph ◽  
Lung Lymph Flow

Experiments were performed to determine whether different methods of increasing cardiac output would have similar effects on lung lymph flow, and to assess the contribution of the microvasculature (fluid-exchanging vessels) to the total calculated pulmonary vascular resistance. Yearling unanesthetized sheep with chronic vascular catheters and lung lymph fistulas underwent intravenous infusions of isoproterenol at 0.2 micrograms X kg-1. min-1 (n = 8) or were exercised on a treadmill (n = 16). Both isoproterenol and exercise increased cardiac output, lowered calculated total pulmonary and systemic vascular resistances, and had no effect on the calculated pulmonary microvascular pressure. Isoproterenol infusions did not affect lung lymph flow, whereas exercise increased lung lymph flow in proportion to the increase in cardiac output. We conclude that 1) the sheep has a different pulmonary hemodynamic response to exercise than dogs and man, 2) the microvasculature is recruited during exercise-induced but not isoproterenol-induced increases in cardiac output, and 3) the microvasculature represents only a small proportion of the total calculated pulmonary vascular resistance.

Catalase prevents increased lung vascular permeability during air emboli in unanesthetized sheep

1988 ◽  
Vol 64 (3) ◽  
pp. 929-935 ◽  
Author(s):  
M. R. Flick ◽  
S. A. Milligan ◽  
J. M. Hoeffel ◽  
I. M. Goldstein
Keyword(s):  
Vascular Permeability ◽  
Lymph Flow ◽  
Leukocyte Counts ◽  
Pulmonary Arterial ◽  
Protein Rich ◽  
Arterial Po2 ◽  
Lung Lymph ◽  
Lung Vascular Permeability ◽  
Lung Lymph Flow

We studied the effects of bovine catalase on increased lung vascular permeability to fluid and protein during air emboli in unanesthetized sheep. Pulmonary arterial and left atrial pressures, cardiac output, lung lymph flow, lymph and plasma protein concentrations, arterial PO2, and numbers of arterial leukocytes were measured in paired experiments in which each sheep served as its own control. We found an increase in protein-rich lung lymph flow during embolization in untreated sheep, indicating an increase in microvascular permeability. When sheep were pretreated with intraperitoneal injections of catalase (50 mg/kg divided over the 24 h before air infusion), vascular pressures, arterial PO2, and leukocyte counts were not different from when the sheep were untreated, but the expected increases in transvascular fluid and protein flow during emboli were significantly attenuated (by approximately 50%). This effect required catalase enzyme activity, as demonstrated by the failure of enzymatically inactivated catalase (by reaction in vitro with aminotriazole in the presence of H2O2) or catalase vehicle (0.1% thymol in water) to affect the lung lymph response to air emboli. We conclude that H2O2 plays a role in the pathogenesis of the acute lung injury caused by intravenous air infusions into unanesthetized sheep. Because both catalase and superoxide dismutase have protected sheep lungs from air emboli-induced increased vascular permeability, a possible specific cause of microvascular barrier injury could be hydroxyl radicals formed from reactions between H2O2 and superoxide anion.

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