Effects of a dual endothelin-1 receptor antagonist on airway obstruction and acute lung injury in sheep following smoke inhalation and burn injury

2005 ◽  
Vol 108 (3) ◽  
pp. 265-272 ◽  
Author(s):  
Robert A. COX ◽  
Perenlei ENKHABAATAR ◽  
Ann S. BURKE ◽  
Jiro KATAHIRA ◽  
Katahiro SHIMODA ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Airway Obstruction ◽  
Receptor Antagonist ◽  
Burn Injury ◽  
Lymph Flow ◽  
Smoke Inhalation ◽  
Endothelin 1 ◽  
Lung Lymph ◽  
Lung Lymph Flow

Studies have suggested that ET-1 (endothelin-1) is associated with lung injury, airway inflammation and increased vascular permeability. In the present study we have tested the hypothesis that treatment with a dual ET-1 receptor antagonist will decrease airway obstruction and improve pulmonary function in sheep with combined S+B (smoke inhalation and burn) injury. Twelve sheep received S+B injury using the following protocol: six sheep were treated with tezosentan, an ETA and ETB receptor antagonist, and six sheep received an equivalent volume of vehicle. Physiological and morphological variables were assessed during the 48 h study period and at the end of the study. There was no statistically significant difference in the PaO2/FiO2 (partial pressure of O2 in arterial blood/fraction of O2 in the inspired gas) ratio of the tezosentan-treated animals compared with controls; however, lung lymph flow was significantly higher (P<0.05) in the treated animals. PVRI (pulmonary vascular resistance index) was significantly reduced (P<0.05) in the tezosentan-treated animals. Assessment of NOx (nitric oxide metabolite) levels in plasma and lymph showed significantly elevated (P<0.05) levels in the tezosentan-treated animals compared with levels in untreated sheep. The degree of bronchial obstruction was similar in both treated and control sheep; however, bronchiolar obstruction was reduced in sheep treated with tezosentan. Histopathologically, no difference in the degree of parenchymal injury was detected. In conclusion, administration of a dual ET-1 receptor antagonist prevented an increase in PVRI after injury and reduced the degree of bronchiolar obstruction in sheep with S+B; however, treated sheep showed higher levels of NOx and increased lung lymph flow. Tezosentan treatment was ineffective in protecting against acute lung injury in this model.

Increasing duration of smoke exposure induces more severe lung injury in sheep

1988 ◽  
Vol 64 (3) ◽  
pp. 1107-1113 ◽  
Author(s):  
R. Kimura ◽  
L. D. Traber ◽  
D. N. Herndon ◽  
H. A. Linares ◽  
H. J. Lubbesmeyer ◽  
...  
Keyword(s):  
Lung Injury ◽  
Inhalation Injury ◽  
Lymph Flow ◽  
Smoke Inhalation ◽  
Lung Water ◽  
Arterial Blood ◽  
Chronic Study ◽  
Lung Lymph ◽  
Severe Lung ◽  
Lung Lymph Flow

Eighteen sheep previously prepared for chronic study were divided into three groups of six animals each. These were given graded inhalation injury utilizing smoke obtained from burning cotton-toweling material. Smoke was insufflated into animals with a modified bee smoker at temperatures less than 40 degrees C. Group H, which received 64 breaths of smoke, showed the most pronounced changes in pulmonary function. The changes consisted mainly of a profound increase in lung lymph flow following a reduced P/F ratio (PO2 in arterial blood/inspired O2 fraction) and an elevation in both thermal and gravimetrically measured extravascular lung water. Similar changes were seen in group M (48 breaths of smoke) and group L (32 breaths of smoke). However, the injury was graded based on the changes in gravimetrically measured lung water and lung lymph flow. These were highest in group H and lowest in group L. These studies confirm our ability to accurately quantitate the injury induced by smoke inhalation. In addition, it demonstrates that lung injury associated with the inhalation of smoke can be graded depending on the duration of exposure.

Role of anti-L-selectin antibody in burn and smoke inhalation injury in sheep

2002 ◽  
Vol 283 (5) ◽  
pp. L1043-L1050 ◽  
Author(s):  
Jiro Katahira ◽  
Kazunori Murakami ◽  
Frank C. Schmalstieg ◽  
Robert Cox ◽  
Hal Hawkins ◽  
...  
Keyword(s):  
Leukocyte Adhesion ◽  
Experimental Period ◽  
Inhalation Injury ◽  
Lymph Flow ◽  
Smoke Inhalation ◽  
Control Group ◽  
Fluid Flux ◽  
Smoke Inhalation Injury ◽  
Lung Lymph ◽  
Lung Lymph Flow

We hypothesized that the antibody neutralization of L-selectin would decrease the pulmonary abnormalities characteristic of burn and smoke inhalation injury. Three groups of sheep ( n = 18) were prepared and randomized: the LAM-(1–3) group ( n = 6) was injected intravenously with 1 mg/kg of leukocyte adhesion molecule (LAM)-(1-3) (mouse monoclonal antibody against L-selectin) 1 h after the injury, the control group ( n = 6) was not injured or treated, and the nontreatment group ( n = 6) was injured but not treated. All animals were mechanically ventilated during the 48-h experimental period. The ratio of arterial Po 2 to inspired O2 fraction decreased in the LAM-(1–3) and nontreatment groups. Lung lymph flow and pulmonary microvascular permeability were elevated after injury. This elevation was significantly reduced when LAM-(1–3) was administered 1 h after injury. Nitrate/nitrite (NO x ) amounts in plasma and lung lymph increased significantly after the combined injury. These changes were attenuated by posttreatment with LAM-(1–3). These results suggest that the changes in pulmonary transvascular fluid flux result from injury of lung endothelium by polymorphonuclear leukocytes. In conclusion, posttreatment with the antibody for L-selectin improved lung lymph flow and permeability index. L-selectin appears to be principally involved in the increased pulmonary transvascular fluid flux observed with burn/smoke insult. L-selectin may be a useful target in the treatment of acute lung injury after burn and smoke inhalation.

Inspiratory airway obstruction does not affect lung fluid balance in lambs

1985 ◽  
Vol 58 (4) ◽  
pp. 1314-1318 ◽  
Author(s):  
T. N. Hansen ◽  
A. L. Gest ◽  
S. Landers
Keyword(s):  
Airway Obstruction ◽  
Endotracheal Tube ◽  
Fluid Balance ◽  
Left Atrial ◽  
Lymph Flow ◽  
Lung Fluid ◽  
Lung Fluid Balance ◽  
Pulmonary Arterial ◽  
Lung Lymph ◽  
Lung Lymph Flow

The purpose of this study was to examine the effects of inspiratory airway obstruction on lung fluid balance in newborn lambs. We studied seven 2- to 4-wk-old lambs that were sedated with chloral hydrate and allowed to breathe 30–40% O2 spontaneously through an endotracheal tube. We measured lung lymph flow, lymph and plasma protein concentrations, pulmonary arterial and left atrial pressures, mean and phasic pleural pressures and airway pressures, and cardiac output during a 2-h base-line period and then during a 2- to 3-h period of inspiratory airway obstruction produced by partially occluding the inspiratory limb of a nonrebreathing valve attached to the endotracheal tube. During inspiratory airway obstruction, both pleural and airway pressures decreased 5 Torr, whereas pulmonary arterial and left atrial pressures each decreased 4 Torr. As a result, calculated filtration pressure remained unchanged. Inspiratory airway obstruction had no effect on steady-state lung lymph flow or the lymph protein concentration relative to that of plasma. We conclude that in the spontaneously breathing lamb, any decrease in interstitial pressure resulting from inspiratory airway obstruction is offset by a decrease in microvascular hydrostatic pressure so that net fluid filtration remains unchanged.

Oleic acid lung injury in sheep

1986 ◽  
Vol 60 (2) ◽  
pp. 433-440 ◽  
Author(s):  
M. Julien ◽  
J. M. Hoeffel ◽  
M. R. Flick
Keyword(s):  
Oleic Acid ◽  
Lung Injury ◽  
Pulmonary Edema ◽  
Fluid Balance ◽  
Lymph Flow ◽  
Lung Fluid ◽  
Lung Fluid Balance ◽  
Pulmonary Arterial ◽  
Lung Lymph ◽  
Lung Lymph Flow

Intravenous infusion of oleic acid into experimental animals causes acute lung injury resulting in pulmonary edema. We investigated the mechanism of oleic acid lung injury in sheep. In experiments with anesthetized and unanesthetized sheep with lung lymph fistulas, we measured pulmonary arterial and left atrial pressures, cardiac output, lung lymph flow, and lymph and plasma protein concentrations. We injured the lungs with intravenous infusions of oleic acid at doses ranging from 0.015 to 0.120 ml/kg. We found that oleic acid caused reproducible dose-related increases in pulmonary arterial pressure and pulmonary vascular resistance, arterial hypoxemia, and increased protein-rich lung lymph flow and extravascular lung water. The lung fluid balance changes were characteristic of increased permeability pulmonary edema. Infusion of the esterified fat triolein had no hemodynamic or lung fluid balance effects. Depletion of leukocytes with a nitrogen mustard or platelets with an antiplatelet serum had no effect on oleic acid lung injury. Treatment of sheep before injury with methylprednisolone 30 mg/kg or ibuprofen 12.5–15.0 mg/kg also had no effects. Unlike other well-characterized sheep lung injuries, injury caused by oleic acid does not require participation of leukocytes.

L-ARGININE ATTENUATES ACUTE LUNG INJURY AFTER SMOKE INHALATION AND BURN INJURY IN SHEEP

Shock ◽  
2007 ◽  
Vol 28 (4) ◽  
pp. 477-483 ◽  
Author(s):  
Kazunori Murakami ◽  
Perenlei Enkhbaatar ◽  
Yong-Ming Yu ◽  
Lillian D. Traber ◽  
Robert A. Cox ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Burn Injury ◽  
Smoke Inhalation

Role of sulfidopeptide leukotrienes in synthetic smoke inhalation injury in sheep

1990 ◽  
Vol 68 (5) ◽  
pp. 1962-1969 ◽  
Author(s):  
D. A. Quinn ◽  
D. Robinson ◽  
W. Jung ◽  
C. A. Hales
Keyword(s):  
Systemic Vascular Resistance ◽  
Vascular Resistance ◽  
Weight Ratio ◽  
Inhalation Injury ◽  
Lymph Flow ◽  
Smoke Inhalation ◽  
Lung Water ◽  
Smoke Inhalation Injury ◽  
Lung Lymph ◽  
Lung Lymph Flow

Acute lung injury with smoke inhalation results in significant morbidity and mortality. Previously we have shown that synthetic smoke composed of carbon and acrolein, a common component of smoke, causes delayed-onset noncardiogenic pulmonary edema. To study the possible role of the vasoactive and edemagenic sulfidopeptide leukotrienes (SPLT) in smoke inhalation injury, we measured pulmonary hemodynamics, lung lymph flow, and SPLT and leukotriene (LT) B4 in lung lymph before and after 10 min of synthetic acrolein smoke exposure. After smoke exposure there was a significant rise in pulmonary vascular resistance caused by a rise in pulmonary arterial pressure, a fall in cardiac output, and no change in pulmonary capillary wedge pressure. This was accompanied by an increase in total systemic vascular resistance (P less than 0.05), lung lymph flow (P less than 0.05), and extravascular lung water-to-lung dry weight ratio (P less than 0.05). Both SPLT and LTB4 clearance rose significantly (P less than 0.05), but there was a 10-fold increase in SPLT over LTB4 clearance. In sheep pretreated with FPL55712, a SPLT antagonist, the early rise in pulmonary vascular resistance was attenuated, and the rise in systemic vascular resistance was blocked. This was associated with an attenuated and delayed fall in cardiac output. FPL55712 had no effect on lung lymph flow or extravascular lung water-to-dry weight ratio. SPLT, and especially LTD4, may have a role in increased pulmonary and systemic vascular resistance after smoke inhalation injury but does not appear to affect vascular permeability.

Alpha-adrenergic agents have little effect during air embolism lung injury in awake sheep

1987 ◽  
Vol 62 (6) ◽  
pp. 2147-2153
Author(s):  
M. R. Bonsignore ◽  
E. H. Jerome ◽  
N. C. Staub
Keyword(s):  
Lung Injury ◽  
Adrenergic Receptors ◽  
Adrenergic Receptor ◽  
Air Embolism ◽  
Lymph Flow ◽  
Receptor Stimulation ◽  
Alpha Adrenergic Receptors ◽  
Alpha Adrenergic Receptor ◽  
Lung Lymph ◽  
Lung Lymph Flow

Since it is not clear whether alpha-adrenergic receptors can modulate lung microvascular liquid and protein leakiness, we studied the effects of alpha-adrenergic receptor stimulation or blockade on lung filtration under base-line conditions and during the acute lung injury caused by a 4-h infusion of venous air emboli in six unanesthetized, chronically instrumented sheep with lung lymph fistulas. During the experiments we continuously infused the alpha-adrenergic receptor agonist phenylephrine hydrochloride (1.0 microgram X kg-1 X min-1 iv) or the alpha-adrenergic receptor antagonist phentolamine mesylate (1.0 mg X kg-1 X min-1 iv), and we measured pulmonary vascular pressures, cardiac output, lung lymph flow, and the lymph-to-plasma protein concentration ratio. During air embolism, alpha-receptor stimulation increased pulmonary vascular resistance and decreased lung lymph flow by 25%; alpha-receptor blockade had the opposite effects. During recovery, neither agent significantly affected pulmonary hemodynamics or lymph flow. Our results indicate that alpha-adrenergic receptors are active during air embolism and modulate pulmonary filtration by causing arteriolar constriction, which reduces the surface area or the perfusion pressure in the pulmonary microvascular bed. They may also affect venous smooth muscle tone. We found no evidence that alpha-adrenergic receptors modulate lung microvascular liquid or protein leakiness directly.

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.

Pathophysiology of acute lung injury in combined burn and smoke inhalation injury

2004 ◽  
Vol 107 (2) ◽  
pp. 137-143 ◽  
Author(s):  
Perenlei ENKHBAATAR ◽  
Daniel L. TRABER
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Burn Injury ◽  
Surgical Excision ◽  
Inhalation Injury ◽  
Burn Injuries ◽  
Morbidity And Mortality ◽  
Smoke Inhalation ◽  
Therapeutic Approaches ◽  
Smoke Inhalation Injury

In the U.S.A., more than 1 million burn injuries occur every year. Although the survival from burn injury has increased in recent years with the development of effective fluid resuscitation management and early surgical excision of burned tissue, the mortality of burn injury is still high. In these fire victims, progressive pulmonary failure and cardiovascular dysfunction are important determinants of morbidity and mortality. The morbidity and mortality increases when burn injury is associated with smoke inhalation. In the present review, we will describe the pathophysiological aspects of acute lung injury induced by combined burn and smoke inhalation and examine various therapeutic approaches.

EFFECTS OF MANGANESE SUPEROXIDE DISMUTASE NEBULIZATION ON LUNG LYMPH FLOW AFTER OVINE SMOKE INHALATION INJURY

2004 ◽  
Vol 32 (Supplement) ◽  
pp. A24
Author(s):  
Marc O Maybauer ◽  
Dirk M Maybauer ◽  
Yuji Kikuchi ◽  
Martin Westphal ◽  
Lillian D Traber ◽  
...  
Keyword(s):  
Superoxide Dismutase ◽  
Manganese Superoxide Dismutase ◽  
Inhalation Injury ◽  
Lymph Flow ◽  
Smoke Inhalation ◽  
Smoke Inhalation Injury ◽  
Manganese Superoxide ◽  
Lung Lymph ◽  
Lung Lymph Flow
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