The effect of dextran solution on pulmonary plasma-lymph barrier in awake sheep

We investigated the effect of dextran solution on lung lymph flow in awake sheep with chronic lung lymph fistulas. Ten percent of dextran (molecular weight 40,000) solution or normal saline were infused at 1000 ml/h for 2 h through left atrial catheter. We measured pulmonary arterial pressure (Ppa), left atrial pressure (Pla), aortic pressure (Psa), cardiac output (CO), oncotic pressures of both plasma (IImv) and lung lymph (IIpmv), lung lymph flow rate (Qlym), and lymph-to-plasma ratio of total protein (L/P). Infusion of dextran solution caused significant increases in Ppa, Pla and CO and decrease in plasma-lung lymph oncotic pressure gradient (IImv-IIpmv), without changes in L/P. Infusion of normal saline caused significant increases in Ppa and Pla and no changes in IImv-IIpmv and CO, and slight decrease in L/P. The calculated filtration coefficients increased by 2.2 fold after dextran infusion and 1.7 fold after normal saline infusion. Moreover, an apparent increase in protein transport across microvessels as evidenced by the normal L/P despite increases in hydrostatic pressure occurred after dextran solution infusion. These results suggest that dextran solution may increase permeability of microvascular wall, as well as effective net pressure gradient across microvessels, both of which result in a large net fluid filtration from microvessels to perimicrovascular compartment.     

Effects of plasmapheresis and of hypoproteinemia on lung liquid conductance in awake sheep

The Starling equation, which describes net transvascular liquid flow, does not include the possibility that a reduction in plasma protein concentration may have a direct effect on lung liquid conductance or microvascular protein permeability. Nevertheless, both effects have been reported. Since these results were not predictable, we wondered whether the changes were due to the decrease in plasma protein concentration or to the process by which protein depletion was accomplished (batch plasmapheresis which involves considerable handling of blood). To separate these factors, we did control (sham) and protein removal plasmapheresis in awake sheep by two plasmapheresis methods (batch and continuous-flow). We monitored pulmonary hemodynamics, measured lung lymph flow, and determined protein concentrations in lymph and plasma. We calculated or measured the protein osmotic pressures of plasma and lymph. After control plasmapheresis, lymph flow increased and lymph:plasma protein concentration decreased but had returned to baseline levels by 4 hours. After protein removal plasmapheresis, the changes persisted for 24 hours. However, lung microvascular conductance (filtration coefficient) was not increased, except during the first 4-hour period. The changes in lymph flow and protein concentration ratio are explained using a simple two-pore model. We conclude that, over the range studied, hypoproteinemia does not increase lung microvascular liquid conductance or protein permeability.     

Effect of catalase on endotoxin-induced acute lung injury in unanesthetized sheep

Administration of endotoxin intravenously to unanesthetized sheep causes an acute lung injury characterized by increased microvascular barrier permeability and subsequent pulmonary edema. Endotoxin-induced sheep lung injury can be attenuated by leukocyte depletion, and may be mediated by toxic metabolites of oxygen. We studied effects of administering catalase, which catalyzes conversion of hydrogen peroxide to oxygen and water, to sheep subsequently infused with endotoxin to test the hypothesis that hydrogen peroxide plays a role in the pathogenesis of lung injury. We found that infusions of endotoxin (1 microgram/kg) into untreated sheep caused the expected biphasic response, a transient, early, marked pulmonary arterial hypertension followed by a prolonged increase in protein-rich lung lymph flow characteristic of increased microvascular permeability filtration in the lungs. Intraperitoneal injections of catalase (50 mg/kg) prior to infusing endotoxin in these same sheep resulted in substantial catalase activity in plasma and in lung lymph, and attenuated the expected changes in pulmonary arterial pressure, lung lymph flow, and arterial leukocyte counts and oxygen tension after endotoxin infusions. Furthermore, mechanical elevation of hydrostatic pressure in the lungs of a catalase-treated sheep infused with endotoxin resulted in increased lung lymph flow with a decreased protein concentration, indicating that the microvascular barrier to fluid and protein was functionally intact. Administration of catalase that was inactivated by reaction with hydrogen peroxide in the presence of aminotriazole or administration of the catalase vehicle, thymol, had no effects on the sheep responses to endotoxin. We conclude that hydrogen peroxide plays a role in the pathogenesis of endotoxin-induced acute lung injury in sheep.     

Pulmonary oxygen toxicity: increased microvascular permeability to protein in unanesthetized lambs

To study transvascular filtration of fluid and microvascular permeability to protein in the lung during prolonged hyperoxia, we measured lung lymph flow, protein transport, and simultaneous pulmonary vascular pressures of six lambs breathing 100 percent O2 for five days. Lymph flow doubled, protein flow increased by 131 percent, and radioactive tracer studies demonstrated a clearcut increase in pulmonary microvascular permeability to protein after five days of continuous O2 breathing.     

Effects of dextran 70 on hemodynamics and lung liquid and protein exchange in awake sheep.

We studied the effect of intravenous dextran 70 infusion on lung liquid and protein exchange to determine whether its effects were due to altered hemodynamics or to altered microvascular permeability. In each of six instrumented awake sheep with chronic lung lymph fistulas, we performed three experiments: 1) control, 2) a 30-minute infusion of 1 l of 6% dextran 70, and 3) an infusion of 1 l of 0.9% NaCl. In addition to pulmonary hemodynamics and lymph dynamics, we measured the plasma-to-lung lymph equilibration rate of [125I] albumin. We followed all the sheep for 10 hours, including a 2-hour baseline period. Dextran was more effective in expanding plasma volume (63 +/- 15% [mean +/- SD]) than saline (11 +/- 6%) at the end of the 30-minute infusion. Pulmonary vascular pressures increased after dextran and remained elevated for 8 hours, whereas after saline the pressures returned to baseline within 1 hour. After dextran, lung lymph flow increased and remained elevated. It was only transiently increased after saline. We confirmed that dextran equilibrated rapidly with lung lymph (half-time, less than 0.6 hour), even though it maintained plasma volume expansion for the whole body (half-time, 11.1 +/- 2.7 hours). The dextran increased both plasma and lymph total macromolecular osmotic pressure but did not increase the plasma-interstitial (lymph) osmotic pressure difference in the lung, except transiently during the infusion. The lymph/plasma protein concentration ratio increased after dextran due mainly to plasma protein dilution. There were no differences in the half-time of tracer albumin equilibration between plasma and lung lymph (control, 2.2 +/- 0.6 hours; saline, 2.0 +/- 0.6 hours; dextran, 2.3 +/- 0.6 hours). Dextran 70 increased liquid filtration mainly by increasing microvascular pressure and possibly filtration surface area. There was no evidence for a change in the leakiness of the lung microvascular barrier to albumin.     

Effects of alveolar hypoxia during partial mitral valve obstruction in unanesthetized sheep

The effects of elevated left atrial pressure (Pla) on the pulmonary hemodynamic responses to hypoxia and infused prostaglandin-H2 analog (PGH2-A) were studied in 10 chronically instrumented unanesthetized sheep. Sheep were studied with isocapnic hypoxia (fraction of inspired O2, 0.12) or infused PGH2-A (0.2 to 1.0 micrograms X kg-1 X min-1 adjusted to increase pulmonary artery pressure (Ppa) by approximately 15 cm H2O) when Pla was normal or elevated to 10 or 20 cm H2O. The Pla was elevated by inflating a Foley catheter positioned in the mitral valve orifice. Elevation of Pla did not block the increase in Ppa or cardiac output (CO) caused by hypoxia but did block the increase in pulmonary vascular resistance (PVR). When Pla was elevated to 10 or 20 cm H2O, hypoxia caused Pla to increase further, and PGH2-A caused Ppa and PVR to increase whether Pla was elevated or not; PGH2-A did not cause CO to increase or Pla to increase further under any experimental condition. Neither hypoxia nor PGH2-A had any effect on left ventricular end-diastolic pressure under any experimental condition. We hypothesize that when Pla is elevated, the increase in CO may dilate the pulmonary circulation, obscuring hypoxic vasoconstriction. When Pla is elevated, the direct effects of hypoxic pulmonary vasoconstriction cannot overcome the increased intraluminal pressure, and PVR does not increase. The pulmonary vessels are still able to respond to a potent vasoconstrictor such as PGH2-A when Pla is elevated. We conclude that the further increase in Pla caused by hypoxia when Pla is elevated is primarily due to increased flow across a mitral valve behaving as a relatively fixed resistor.     

Recombinant tumor necrosis factor increases pulmonary vascular permeability independent of neutrophils.

We studied the effects of intravenous infusion of recombinant human tumor necrosis factor type alpha (rTNF-alpha; 12 micrograms/kg) on lung fluid balance in sheep prepared with chronic lung lymph fistulas. The role of neutrophils was examined in sheep made neutropenic with hydroxyurea (200 mg/kg for 4 or 5 days) before receiving rTNF-alpha. Infusion of rTNF-alpha resulted in respiratory distress and 3-fold increases in pulmonary arterial pressure and pulmonary vascular resistance within 15 min, indicating intense pulmonary vasoconstriction. Pulmonary lymph flow (i.e., net transvascular fluid filtration rate) and transvascular protein clearance rate (a measure of vascular permeability to protein) increased 2-fold within 30 min. The increased permeability was associated with leukopenia and neutropenia. The pulmonary hypertension and vasoconstriction subsided but fluid filtration and vascular permeability continued to increase. Sheep made neutropenic had similar increases in pulmonary transvascular fluid filtration and vascular permeability. rTNF-alpha also produced concentration-dependent increases in permeability of 125I-labeled albumin across ovine endothelial cell monolayers in the absence of neutrophils or other inflammatory mediators. The results indicate that rTNF-alpha increases pulmonary vascular permeability to protein by an effect on the endothelium.     

Lactic dehydrogenase activity in lung lymph during hemorrhagic shock, resuscitation and recovery

Lactic dehydrogenase activity was determined in lung lymph before, during and after hemorrhagic shock to determine if this insult produced pulmonary cellular damage. Lung lymph flow and lymph protein content, reliable indices of fluids filtration rate and microvascular protein permeability were also monitored. The experiment was performed in unanesthetized sheep with a chronic lung lymph fistula. Lymph flow, lymph LDH and protein content did not change during the period of shock. Lymph flow increased significantly during resuscitation but lymph LDH and protein content decreased in relation to plasma values indicating the sieving effect of the microvascular membrane for protein to be intact. The increased flow was most likely caused by an increase in microvascular hydrostatic pressure. Plasma LDH was significantly increased during the 72 hour recovery period with lymph flow, lymph protein and lymph LDH being normal. We therefore found that hemorrhagic shock produced a systemic cellular injury reflected in an increased plasma LDH activity. No pulmonary cellular damage was noted.     

Left atrial pressure can be accurately transmitted to the pulmonary artery despite zone 1 conditions

Pulmonary arterial occlusion pressure is not thought to reflect left atrial pressure (Pla) when alveolar pressure (PA) exceeds pulmonary venous pressure because alveolar capillaries collapse and the required continuous fluid column between the pulmonary artery and left atrium is interrupted. However, arterial-to-venous flow can occur when PA exceeds both the pulmonary arterial pressure (Ppa) and pulmonary venous pressure (i.e., in Zone 1 conditions), indicating the existence of a continuous patent vascular channel. Accordingly, Ppa should reflect Pla under these conditions. To investigate this connection cannulas were placed in the pulmonary arteries and left atria of eight excised rabbit lungs. Ppa and Pla were set 5 cm H2O above PA, which ranged from 0 to 25 cm H2O. Pla was then reduced in 2 to 4 cm H2O decrements while recording Ppa when arterial-to-venous flow ceased. At all PAs greater than 0 cm H2O, Pla was accurately reflected by the Ppa when both were exceeded by PA. The greater the PA, the lower the Ppa could track Pla below PA. Pla can be accurately measured by a pulmonary arterial catheter under Zone 1 conditions.     

Effects of intravenous amphotericin B infusion on hemodynamics and airway mechanics in awake sheep

To gain a better understanding of the adverse pulmonary response to amphotericin B administration reported in humans, we examined the effects of this agent in the chronically instrumented awake sheep. We measured pulmonary artery and left atrial pressures (Ppa and Pla), lung lymph flow (Qlymph), dynamic lung compliance (Cdyn), resistance to airflow across the lung (RL), lymph thromboxane B2 (TxB2), lymph 6-keto-PGF1 alpha, peripheral leukocyte counts, and arterial blood gases. After at least one hour of stable baseline (BL) observation, amphotericin B (Fungizone, Squibb, 1 mg/kg) was infused intravenously over 1 h. Measurements were continued for 3 h after the start of infusion. Amphotericin caused an immediate decrease in Cdyn nadiring at 55 percent of BL and an increase in Ppa from 21 +/- 1 mm Hg at BL to 44 +/- 4 at 30 minutes. RL increased to 5.5-fold over BL by 30 minutes into infusion, and lung lymph TxB2 concentrations were increased tenfold compared with BL by the end of the 1-h infusion (p less than 0.05). In this same time interval, there were increases in Qlymph (1.5 ml/15 min at BL to 4.9 +/- 0.8), but 6-keto-PGF1 alpha concentrations did not reach maximum until 2 h after the start of infusion. There was a decrease in peripheral leukocyte count and PaO2 (80 +/- 3 mm Hg at BL to 69 +/- 4 at 1 h) that returned to BL over the remaining 2 h. The temporal relationship of the TxB2 peak with these pathophysiologic changes and previous data describing the effects of thromboxane in the sheep lung suggest that a component of these alterations is due to thromboxane release. We conclude that several pulmonary system abnormalities occur following amphotericin infusion in sheep and that these findings provide a better physiologic basis for explaining the human pulmonary response to amphotericin.     

The pulmonary microvascular response to infusion of live Escherichia coli in sheep with acutely or chronically prepared lung lymph fistula

The effects of infusion of live Escherichia coli bacteria in awake sheep with a chronic lung lymph fistula (n = 15) were compared to anesthetized animals (n = 7) receiving the same septic insult after surgical trauma including bilateral thoracotomies for lung lymph cannulation (acute group). During preseptic baseline conditions, pulmonary arterial pressure (Ppa) and central venous pressure (Pcv) were increased and leukocytes decreased in the newly operated animals compared to the sheep with a chronic lung lymph fistula. After i.v. infusion of live E. coli 10(9) X kg-1 b.w. over 20 min, arterial pressure (Psa), cardiac output (Qt), leukocytes, and partial pressure of arterial oxygen (PaO2) decreased in both groups. Ppa peaked after 15 min at 37.2 +/- 2.5 in the chronic and 33.4 +/- 3.3 mm Hg in the acute group. In the chronic group, Ppa remained elevated but not in the acute group during the rest of experiment. Lung lymph flow (QL) increased significantly in both groups during the initial high Ppa, but it increased to a higher level in the chronic group. After 150 min, QL did not differ between the groups but remained elevated over baseline. Lymph-to-plasma concentration ratio (L/P) for total protein decreased in the chronic group during the initial high QL. This decrease was not seen in the acute group that had a significantly higher L/P between 30 and 120 min after sepsis. The high QL with unchanged L/P compared to baseline indicated increased permeability in the pulmonary microvessels in both groups but the changes in permeability, hemodynamics, or respiratory parameters after sepsis were not aggravated by the surgical trauma.     

Effects of hypoxia and complement activation on lung hemodynamics and fluid exchanges in unanesthetized goats

The effects of hypoxia and zymosan-activated plasma (ZAP) on lung hemodynamics and fluid exchange were studied in unanesthetized goats. Hypoxia produced a sustained increase in pulmonary arterial pressure (PPA), but had no effect on lung lymph flow and protein content. 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. When ZAP was infused at a simulated altitude of 4,000 m, there was a further increase in PPA followed by pulmonary vasodilatation, and about 1 h later it was almost back to the control level. No obvious difference in lung lymph flow and protein content was observed between the groups treated with ZAP alone and ZAP plus hypoxia. We conclude that infusion of ZAP into hypoxic animals reduces pulmonary vasoconstriction and that the increase in pulmonary microvascular permeability associated with ZAP is not enhanced by hypoxic conditions occurring at a simulated altitude of 4,000 m.     

Lung edema caused by high peak inspiratory pressures in dogs. Role of increased microvascular filtration pressure and permeability

Mechanical ventilation with high peak airway pressures (Paw) has been shown to induce pulmonary edema in animal experiments, but the relative contributions of transvascular filtration pressure and microvascular permeability are unclear. Therefore, we examined the effects of positive-pressure ventilation on two groups of open-chest dogs ventilated for 30 min with a peak Paw of 21.8 +/- 2.3 cm H2O (Low Paw) or 64.3 +/- 3.5 cm H2O (High Paw). No hemodynamic changes were observed in the Low Paw group during ventilation, but mean pulmonary artery pressure (Ppa) increased by 9.9 cm H2O, peak inspiratory Ppa by 24.6 cm H2O, and estimated mean microvascular pressure by 12.5 cm H2O during High Paw ventilation. During the same period, lung lymph flow increased by 435% in the High Paw and 35% in the Low Paw groups, and the terminal extravascular lung water/blood-free dry weight ratios were 5.65 +/- 0.27 and 4.43 +/- 0.13 g/g, respectively, for the two groups. Lung lymph protein clearances and minimal lymph/plasma ratios of total protein were significantly higher (p less than 0.05) after 2 h of increased left atrial pressure (PLA) in the High Paw group versus the Low Paw group, which indicates a significant increase in microvascular permeability. Lymph prostacyclin concentration in pulmonary lymph, measured as the stable metabolite 6-0-PGF1 alpha, was increased significantly by 70 to 150% from baseline (p less than 0.05) in both groups during the periods of increased Paw and increased PLA, but it was not significantly different between the groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

Prostaglandin E1 prevents increased lung microvascular permeability during intravascular complement activation in sheep

Prostaglandin E1 (PGE1) inhibits a variety of functions of activated neutrophils including respiratory burst, release of leukotriene B4, and adherence to endothelial cells. To determine if PGE, alters the pathophysiology of complement-induced lung vascular injury, experiments were conducted in anesthetized sheep with lung lymph fistulas given a 1-hour infusion of zymosan-activated plasma. PGE1 (30 ng/min/kg) or its saline vehicle was infused intravenously for 90 minutes beginning 30 minutes before the infusion of activated plasma. PGE1 had no effect on leukocyte count, the initial hypoxemia and thromboxane A2 release, or the development of acute pulmonary hypertension. However, PGE1 prevented steady-state increases in lung lymph flow that in vehicle-treated sheep signaled an increase in lung microvascular permeability. Furthermore, extraction of PGE1 by pulmonary endothelial cells was unaffected by the infusion of activated plasma. We propose that PGE1 prevented the increase in lung vascular permeability by inhibiting adherence of activated neutrophils to endothelial cells.     

An experimental research on the acute lung injury induced by endotoxin]

Using a goat endotoxin model with chronic lung lymph fistula, we continuously measured lung lymph flow (QL), lymph to plasma protein ratio (L/P), pulmonary arterial pressure (Ppa) and the level of thromboxane B2 in plasma and lymph. We also observed the changes of ultrastructure in leukocyte and pulmonary parenchyma. It showed that the alteration can be divided into two intervals: phase I is characterized by the abrupt onset of pulmonary hypertension and in phase II, the capillary permeability increased predominantly. It was suggested that this model is a good research tool for studying adult respiratory distress syndrome (ARDS).     

Changes and significance of chemiluminescence of polymorphonuclear leukocytes in endotoxin-induced lung injury in conscious sheep]

The chemiluminescence (CL) of polymorphonuclear leukocytes and its relation with pulmonary microvascular permeability after endotoxin-induced lung injury in conscious sheep with lung lymph fistula were observed. Four hours after the injury the CL of PMNs increased from 0.27 cpm/PMN of baseline to 0.69 cpm/PMN (P < 0.05). The increment of the CL had positive correlation with the increment of lung lymph flow or permeability index (r = 0.632 0.638 P < 0.05), suggesting that the increase of pulmonary microvascular permeability after the endotoxin injury had relation with the increase of the respiratory tract of PMNs.     

Effect of increased vascular pressure on lung fluid balance in unanesthetized sheep.

In 20 unanesthetized sheep, we measured lung lymph flow and lymph and plasma protein concentrations during steady-state base-line conditions and during steady-state elevations of pulmonary microvascular hydrostatic pressure (range 3 to 23 cm H2O). In every sheep there was a base-line lung lymph flow (average 5.7 +/- 2.5 (SD) ml/hour), demonstrating that net fluid filtration occurred. The base-line lymph-plasma total protein ratio averaged 0.69 +/- 0.05, indicating a high protein osmotic pressure in the interstitial fluid at the filtration site. Lymph flow increased and lymph protein concentration decreased approximately linearly whenever hydrostatic pressure rose. A new steady-state condition was reached in 1-2 hours. The difference in plasma-to-lymph protein osmotic pressure increased by half the hydrostatic pressure increment (50% negative feedback regulation). Extravascular lung water content, measured post-mortem, did not change significantly until microvascular hydrostatic pressure more than doubled, indicating a large safety factor that protects the lungs against fluid accumulation normally. The major contributions to the safety factor appeared to be a sensitive and efficient lymph pump coupled to a washout of interstitial protein. The fluid filtration coefficient, whose calculation required many assumptions, averaged 1.64 +/- 2.65 ml/(cm H2O times hour) in the base-line condition and did not change significantly over the pressure range studied.     

The effect of glucagon on the pulmonary transvascular fluid filtration rate

Administration of glucagon has been shown to decrease pulmonary vascular resistance, but its primary site of action is undetermined. Whether this is on the arterial or venous side of the capillary would be reflected in the microvascular hydrostatic pressure. We used the pulmonary flow of lymph, a sensitive index of the transvascular fluid filtration rate, to monitor the microvascular hydrostatic pressure. Eight unanesthetized sheep with a surgically created long-term fistula for monitoring pulmonary lymph were given a 3-mg bolus of glucagon after a baseline period. We found no change in pulmonary arterial or left atrial pressures but noted a significant increase in cardiac output and a decrease in pulmonary resistance. The flow of pulmonary lymph increased by 50 percent for 30 minutes after administration of glucagon, and the protein content of the lymph decreased by 15 percent, indicating a large increase in the microvascular hydrostatic pressure. From these data, we calculated a decrease in arterial resistance from 60 percent to 30 percent of the total and, subsequently, an increase of 6 cm H2O in the microvascular hydrostatic pressure. Administration of glucagon, therefore, decreases the arterial resistance while increasing microvascular pressure in the process.     

Increased sheep lung vascular permeability caused by histamine.

To see whether histamine increases lung vascular permeability to protein, we compared the effects of steady-state histamine infusions on lung vascular pressures, lung lymph flow, and lung lymph protein content with the effects of mechanically elevated lung vascular pressures on these variables in the same unanesthetized sheep. We surgically implanted catheters in the pulmonary artery, the left atrium, the superior vena cava, and a main lung lymphatic. After the sheep had recovered from surgery, we carried out steady-state experiments without anesthesia. Histamine induced a dose-related, quickly reversible increase in lung lymph flow without affecting pulmonary artery pressure, and it caused left atrial pressure to fall. During 4-hour intravenous 4-mug/kg min-1 histamine infusions, lymph flow and lymph protein clearance (lymph flow X lymph-plasma protein concentration ratio) increased more than they did with mechanically elevated pressure even though vascular pressures fell. Lymph-plasma protein ratios decreased linearly with increasing lymph flow during increased pressure experiments, but during histamine infusions the ratios did not decrease even though lymph flow increased 2-6-fold. Lymph clearance and permeability-surface area products (PS) for eight protein fractions with molecular radii ranging from 36 to 100 A decreased with increasing molecular size in base-line, increased pressure, and histamine studies. PS values for all eight fractions were significantly higher than base line in histamine experiments but not in increased pressure experiments. Four-hour intravenous histamine infusions caused moderate increases in lung water content. Left atrial infusions had less effect on lymph flow than did intravenous infusions. We conclude that histamine causes pulmonary vascular permeability to protein to increase but that the effects on exchanging vessel porosity are more modest than those suggested for systemic microvessels. Histamine should be considered a possible mediator of increased lung vascular permeability.     

Effects of recombinant human tumor necrosis factor alpha, lymphotoxin, and Escherichia coli lipopolysaccharide on hemodynamics, lung microvascular permeability, and eicosanoid synthesis in anesthetized sheep

We infused recombinant human tumor necrosis factor alpha (rhTNF alpha), lymphotoxin (rhLT), and Escherichia coli 0111:B4 lipopolysaccharide (LPS) into anesthetized sheep with a lung lymph fistula to compare their effects on systemic and pulmonary hemodynamics, lung lymph dynamics, and eicosanoid release. rhTNF alpha (25-150 micrograms/kg, n = 6 sheep), but not rhLT (25 micrograms/kg, n = 3), rapidly increased lung lymph and plasma levels of 6-keto-prostaglandin F1 alpha (6-k-PGF1 alpha) and caused profound systemic vasodilation and hypotension. Meclofenamate pretreatment (10 mg/kg) of three other sheep given 25 micrograms/kg rhTNF alpha prevented the increase of lymph and plasma 6-k-PGF1 alpha levels, systemic vasodilation, and the early (less than 2 hrs) but not the late (4-6 hours) hypotension caused by rhTNF alpha. LPS (1 micrograms/kg, n = 11) induced a briefer increase of lymph 6-k-PGF1 alpha levels than did rhTNF alpha while plasma 6-k-PGF1 alpha levels did not increase. LPS induced more gradual hypotension than did rhTNF alpha but did not cause systemic vasodilation. LPS and rhTNF alpha, but not rhLT, increased lymph thromboxane B2 (TXB2) levels during the first hour of study, whereas only LPS acutely increased plasma TXB2 levels. LPS caused acute pulmonary vasoconstriction and greater acute pulmonary artery hypertension than did either rhTNF alpha or rhLT. Whereas LPS-treated sheep required less fluid transfusion than rhTNF alpha-treated sheep to maintain mean systemic arterial pressure greater than 50 mm Hg, LPS infusion caused a greater increase of lung lymph protein clearance. rhTNF alpha caused minimal alterations of lung microvascular permeability. We conclude that eicosanoid mediators contribute importantly to differences of systemic and pulmonary hemodynamics caused by these agents in sheep. rhTNF alpha cannot account for all of the LPS-induced hemodynamic, lung lymph, and eicosanoid responses in sheep.