Biomedical subjects

K L Brigham

Publications and source records attributed to K L Brigham.

At least 91 records · Page 5Linked to original sources

PubMed1986

Thromboxane A2 and prostacyclin do not modulate pulmonary hemodynamics during exercise in sheep.

The purpose of this study was to determine the role of thromboxane and prostacyclin in modulating pulmonary hemodynamics during maximal cardiopulmonary stress in the healthy lung. We studied 11 yearling sheep in paired studies during progressive maximal treadmill exercise with and without meclofenamate (n = 5), ibuprofen (n = 6), or UK38485 (n = 2). We also studied five sheep during hypoxia and hypoxic exercise, and six sheep during prolonged steady-state treadmill exercise for 45-60 min with and without drug treatment. We measured the metabolites of thromboxane A2 (thromboxane B2, TxB2) and prostacyclin (6-ketoprostaglandin F1 alpha, 6-keto-PGF1 alpha) in blood plasma and lung lymph in each protocol. We found that progressive exercise significantly reduced pulmonary vascular resistance but that cyclooxygenase or thromboxane synthesis blockade did not alter the change. Plasma TxB2 rose minimally but significantly during maximal exercise, but 6-keto-PGF1 alpha did not change. During continuous hypoxia, exercise reduced pulmonary vascular resistance nearly to base-line levels, but the degree of reduction was also unchanged by drug treatment. There were also no significant changes in lymph or plasma TxB2 or 6-keto-PGF1 alpha during 45-60 min of continuous moderate exercise. We conclude that neither TxB2 nor prostacyclin modulate pulmonary hemodynamics in the normal lung during maximal exercise, prolonged moderate exercise, or exercise-induced reductions in vascular resistance during hypoxia.

6-Ketoprostaglandin F1 alpha↗

PubMed1986

Increased vasoreactivity and chronic pulmonary hypertension following thoracic irradiation in sheep.

Six chronically catheterized sheep were exposed to 1,500-rad whole-lung irradiation and followed for a four-week period. Pulmonary arterial, left atrial and systemic arterial pressures, cardiac output, arterial blood gases, and pH were measured at base line and biweekly following radiation. Pulmonary vasoreactivity to 12% O2, 100% O2, and an analogue of prostaglandin H2 (PGH2-A) was also assessed. Five nonirradiated sheep served as controls. By the 2nd wk following irradiation, pulmonary vascular resistance had doubled. Final pulmonary arterial pressure was increased 50% over the base-line value (base line = 14 +/- 1 cm H2O; final 22 +/- 2; mean +/- SE; P less than 0.05). Arterial PO2 was decreased to approximately 70 Torr throughout the study. In addition, pulmonary vasoreactivity to PGH2-A, but not to breathing 12 or 100% O2, was significantly increased above base line in the irradiated animals (P less than 0.05). Morphometric techniques applied to the lungs in which the pulmonary arterial circulation was distended with barium gelatin mixture, showed extension of muscle into the distal intra-acinar arteries, and a reduction in both the external diameter and the number of barium-filled peripheral arteries in the irradiated animals. Thus thoracic irradiation results in functional and structural changes of chronic pulmonary hypertension and increased pulmonary vasoreactivity to PGH2-A. The structural changes in the peripheral pulmonary arterial bed may contribute to the increased pulmonary vascular reactivity following thoracic irradiation.

Animals↗

PubMed1986

Influence of steroidal and nonsteroidal anti-inflammatory agents on the accumulation of arachidonic acid metabolites in plasma and lung lymph after endotoxemia in awake sheep. Measurements of prostacyclin and thromboxane metabolites and 12-HETE.

The influence of methylprednisolone and meclofenamate on endotoxin-induced release of 3 arachidonic acid metabolites was studied in unanesthetized sheep. Concentrations in plasma and lung lymph of prostacyclin and thromboxane (Tx) A2 metabolites (6-keto-PGF1 alpha and TxB2, respectively) were measured by radioimmunoassay. Concentrations of 12-HETE in lung lymph were measured by stable isotope dilution assay employing gas chromatography-mass spectroscopy. Thromboxane B2 concentrations increased quickly to peak values during the first hour after endotoxin infusion, then decreased to baseline by 1.5 hr. 6-keto-PGF1 alpha concentrations increased more gradually to peak values between 1 and 2 h after endotoxin infusion and remained elevated at 2.5 h. Lymph concentrations of both cyclooxygenase metabolites exceeded those in blood plasma. Methylprednisolone significantly inhibited accumulation of 6-keto-PGF1 alpha in lymph and plasma, but did not significantly inhibit accumulation of TxB2 in lymph or plasma. The combination of meclofenamate and methylprednisolone completely inhibited accumulation of TxB2 and 6-keto-PGF1 alpha in lymph and plasma. The concentration of 12-HETE in lung lymph increased significantly to peak values by 2.5 h after endotoxemia, and methylprednisolone, with or without meclofenamate, inhibited accumulation of 12-HETE in lung lymph. These data support participation of TxA2 in acute pulmonary hypertension after endotoxemia. That methylprednisolone treatment inhibited accumulation of 6-keto-PGF1 alpha and prevented the increase in lung vascular permeability suggests that prostacyclin production is a consequence of lung vascular injury. Increased lung lymph concentrations of the lipoxygenation product, 12-HETE, were coincident with physiologic evidence of increased lung vascular permeability, but whether release of lipoxygenase products after endotoxemia contributes to or results from lung vascular injury remains to be established.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗

PubMed1986

Pulmonary edema. Pathophysiologic mechanisms and new approaches to therapy.

Since the first report by Ashbaugh and Petty in 1967 categorizing patients with acute respiratory failure and labelling the process the adult respiratory distress syndrome (ARDS), this illness has been recognized with increasing frequency. Adult respiratory distress syndrome now afflicts more than 150,000 people a year and the mortality remains in the 70 percent range in spite of significant advances in critical care medicine. As a consequence, research in the area of acute lung injury has intensified resulting in the elucidation of many of the pathophysiologic mechanisms operative in the process. As long as the mortality of ARDS remains high, research of this kind will be needed especially with regard to clinical trials of pharmacologic agents which have appeared promising in the laboratory. An aggressive approach, possibly utilizing multiple drug regimens, seems justified considering the morbidity and mortality with which are dealing. Until success is achieved, supportive intensive care with diligent attention to oxygen and ventilator management, infection control, and fluid therapy will be the mainstay of treatment for ARDS.

Animals↗

PubMed1986

Role of free radicals in lung injury.

Free radicals (and other toxic metabolites of oxygen) are generated in most cells as a consequence of normal metabolic processes, but cells are protected from injury by antioxidant mechanisms. Several forms of lung injury appear to result from generation of toxic metabolites of oxygen in quantities which exceed the antioxidant capacity of lung cells. Several manipulations which prevent free radical production or accumulation or enhance antioxidant capacity of lung tissue may prove to be useful therapeutically in acute and chronic diseases of the lungs.

Animals↗

PubMed1986

The effect of steroidal and nonsteroidal anti-inflammatory agents on granulocyte migration into bovine pulmonary artery intimal explants.

To determine whether steroidal or non-steroidal anti-inflammatory agents inhibit granulocyte migration, we measured granulocyte adherence to and migration across the intact endothelial layer of bovine pulmonary artery intimal explants. Explants were placed endothelium uppermost in chemotaxis chamber with either fetal calf serum (FCS) or zymosan activated plasma (ZAP) in medium 199 in the lower well and 5 X 10(6) separated 51Cr labelled granulocytes/ml in medium 199 + FCS in the upper well. Methylprednisolone (0.3 and 3.0 mg/ml), indomethacin (5 and 50 microM) and ibuprofen (10 and 100 microM) were also added to the upper well of some chambers. After 30, 60, 120 or 180 minutes of incubation the chambers were dismantled. Granulocyte adherence was assessed by rinsing the explant in 0.1% trypsin; the number of radioactive counts in the trypsin wash represented the number of adherent cells. Those remaining in the explant represented the number of granulocytes that migrated into the explant. At each time studied, chemotaxin-induced granulocyte migration was 2-3 times that of unstimulated or random migration (180 min incubation with FCS = 30.5% +/- S.E. 2.1; with ZAP in lower well = 61.6 +/- 3.4). Both unstimulated and chemotaxin-induced migration was significantly decreased from 30 minutes by 3.0 mg/ml of methylprednisolone (180 min incubation with ZAP in lower well = 22.3 +/- 5.8), but not by 0.3 mg/ml. However, one hour pretreatment of either the granulocytes or the explant with 3.0 mg/ml methylprednisolone had no significant effect on granulocyte migration. In contrast, granulocyte migration was unaltered by treatment with either indomethacin or ibuprofen. Methylprednisolone, indomethacin and ibuprofen had little effect on granulocyte adherence. We conclude that granulocyte migration across an intact endothelial layer is inhibited by high dose corticosteroids but not by cyclooxygenase inhibitors. This suggests a plausible rationale for use of high doses of corticosteroids in clinical states where granulocytes may mediate tissue injury.

Animals↗

PubMed1986

Endotoxin and lung injury.

Two things are certain: endotoxin has dramatic effects on the structure and function of the lungs in intact animals and also on isolated lung cells, and both the in vivo and in vitro effects of endotoxin are complex. In whole animals, endotoxin causes obvious and subtle effects on functions of both airways and the pulmonary circulation. These effects include diffuse lung inflammation and injury of pulmonary vascular endothelium. Endotoxin can also directly injure endothelial cells in vitro. In vivo, lung injury caused by endotoxin is at least partly dependent on the presence of granulocytes, and some evidence also suggests that both lymphocytes and macrophages may participate in the response either directly or by directing cell traffic. At least in the sheep preparation, platelets do not seem to play a major role in the lungs' response to endotoxemia. Although endotoxin can activate complement and activated complement infused into whole animals affects the lungs, it seems unlikely that complement activation alone is sufficient to explain the severe and prolonged lung injury caused by endotoxin. Cyclooxygenase metabolites of arachidonic acid appear to mediate both changes in lung mechanics and pulmonary vasoconstriction after endotoxemia. Lipoxygenase products may play a role in these responses as well as the inflammatory response and increases in vascular permeability, although evidence for these latter speculations is not firm. Lung cell injury caused by endotoxin probably is mediated at least in part by generation of free radicals. Inflammatory cells, especially neutrophils, are one source of these toxic oxygen species, but intracellular generation of free radicals within lung cells per se may also be stimulated by endotoxin and account for some of the lung injury. Likewise, inflammatory-cell-derived proteinases may mediate endotoxin-induced injury of lung cells and, as with chronic lung diseases, balance between proteinases and antiproteinases could be important. The fact that free radicals can inactivate antiproteinases, and antiproteinases can act as free radical scavengers, may suggest a complex relationship among the several possible mediators of toxicity. Cyclic nucleotide metabolism is affected in whole animals and isolated lung cells by endotoxin and these classic second messengers could be involved in the pathogenetic sequence, but exactly how is unclear. Chronic effects of endotoxin on the lungs may provide a pathogenetic link between acute lung injury and chronic changes in lung structure and function.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1986

Direct effects of E coli endotoxin on structure and permeability of pulmonary endothelial monolayers and the endothelial layer of intimal explants.

The direct structural, metabolic, and physiologic effects of Escherichia coli endotoxin on bovine pulmonary endothelial monolayers and on the intact endothelial layer of bovine pulmonary artery intimal explants were examined. Endothelial monolayers exposed to E coli endotoxin (0.001, 0.01, 0.1, 1.0, and 10 micrograms/ml) for 24 hours in the absence of bovine fetal calf serum (FCS) showed a dose-dependent response, as demonstrated by number of pyknotic cells and lactate dehydrogenase release that was enhanced by addition of FCS. Prostacyclin production was increased only in the presence of FCS. Endotoxin also caused an increase in permeability. Endothelial cells on nitrocellulose filters placed in chemotaxis chambers with radioactive tracers in the upper well showed a significant 25% increase in rate of equilibration (counts in lower well/counts in upper well) of 3H-water after 2 and 3 hours' incubation with endotoxin (3 hours' endotoxin = 0.89 +/- 0.03 m +/- SE; no endotoxin = 0.69 +/- 0.05) and a 40% increase in equilibration of 125I-albumin at three hours (3 hours' endotoxin = 0.40 +/- 0.03; no endotoxin = 0.27 +/- 0.02). An increase in hydraulic conductance was also seen at 1 hour. Electron microscopy of the endothelial layer of intimal explants showed dilatations in the intercellular junctions and cellular changes representing contraction--increased prominence of cytoplasmic filaments, nuclear crenation, and cytoplasmic protrusions--at 30 and 60 minutes. From 2 hours evidence of cell death was found. Thus, endotoxin causes structural and metabolic changes in pulmonary endothelial cells and an increase in permeability of the endothelial layer. The injury occurs in the absence of FCS but is enhanced by its addition.

Animals↗

PubMed1986

Repeated Escherichia coli endotoxin-induced pulmonary inflammation causes chronic pulmonary hypertension in sheep. Structural and functional changes.

Chronic pulmonary hypertension occurs in several human diseases in which there is evidence of chronic or repeated bouts of pulmonary inflammation. To determine whether prolonged lung inflammation causes persistent pulmonary hypertension Escherichia coli endotoxin was given to seven chronically instrumented awake sheep three times a week for 10 to 14 weeks. Pulmonary artery, left atrial and systemic arterial pressures, cardiac output, arterial blood gases and pH were monitored before starting endotoxin treatment and twice weekly, immediately before endotoxin infusion. Three sheep receiving saline over a similar time period served as controls. Pulmonary vasoreactivity to breathing 12% oxygen and a bolus infusion of an analog of prostaglandin H2 was also assessed. Peripheral lung biopsy tissue was taken at baseline and at periods throughout the experiment to assess pulmonary inflammation. Repeated endotoxin infusions resulted in a significant increase in mean pulmonary artery pressure from the 8th week of treatment and more than a 50% increase from week 10 (baseline = 18.4 cm H2O +/- 1.0 (mean +/- SE); 10 weeks endotoxin = 27.8 +/- 4.3; p less than 0.05). Pulmonary vasoreactivity to both an analog of prostaglandin H2 and 12% oxygen decreased in the period from 4 to 8 weeks of endotoxin treatment. Light microscopic assessment of lung biopsy tissue showed a persistent four-fold increase above baseline in number of peripheral lung granulocytes. Electron microscopy revealed that granulocytes, lymphocytes, and monocytes sequestered in the lungs of these animals, and that structural damage to the endothelium was minimal. Morphometry of lungs obtained at autopsy in which the pulmonary arteries had been distended with barium-gelatin showed extension of muscle into the walls of smaller intra-acinar arteries (than normal) and a reduction in number of filled peripheral arteries. We conclude that repeated infusions of endotoxin into sheep cause persistent lung inflammation, altered pulmonary vasoreactivity, sustained pulmonary hypertension, and some of the structural changes characteristic of this disease. Chronic inflammation may play a role in the pathogenesis of chronic pulmonary hypertension.

Animals↗

PubMed1986

Noncardiac pulmonary edema.

ARDS is a severe disorder affecting over 150,000 patients per year in the United States alone. The syndrome has multiple etiologies that to a larger extent determine the 60% to 70% mortality associated with the process. In spite of intense research, there is still no specific therapy of proven benefit that we can offer patients. Supportive measures designed to keep the patient alive long enough to allow the pulmonary lesion to heal are the mainstay of therapy. These measures are constantly being improved and increasingly require invasive high technology. Even with advances in treating established ARDS, careful attention toward prevention and day-to-day management of ARDS patients will be required to reduce the excessive mortality.

Adult↗

PubMed1985

Plasma 6-keto prostaglandin F1 alpha and thromboxane B2 in sick preterm neonates.

To determine if vascular abnormalities in preterm neonates might be related to vasoactive prostaglandins, stable prostacyclin (6-KPGF1 alpha) and thromboxane A2 (T X B2) metabolites in arterial blood were measured at less than or equal to 6 hours after birth and at 24, 48, and 72 hours using a radioimmunoassay. Neonates of less than 32 weeks gestation (N = 26) were diagnosed as having either the idiopathic respiratory distress syndrome (IRDS, N = 15) or pulmonary edema (PE, N = 11), and were also grouped according to the presence or absence of intracranial hemorrhage (ICH, N = 11) or patent ductus arteriosus (PDA, N = 10). Initial plasma 6-KPGF1 alpha was greater in neonates with ICH (0.23 +/- 0.04 ng/ml, mean +/- SE) than without ICH (0.11 +/- 0.04, p less than 0.05). Neonates with both ICH and IRDS (N = 8) had significantly elevated T X B2 at all sampling times compared to neonates with IRDS and no ICH (N = 7). Both T X B2 and 6-KPGF1 alpha increased with time in those with major ICH. Among neonates without ICH, 7 with IRDS had higher initial 6-KPGF1 alpha (0.19 +/- 0.07 ng/ml) and lower T X B2 (0.15 +/- 0.04 ng/ml) than 8 with PE (0.04 +/- 0.01 and 0.37 +/- 0.09 ng/ml, respectively). The initial 6-KPGF1 alpha (0.024 + 0.003 ng/ml), measured in neonates with PE and without PDA or ICH (N = 6), was significantly less than the corresponding value in the other neonates (0.201 +/- 0.036 ng/ml) (N = 20).

6-Ketoprostaglandin F1 alpha↗

PubMed1985

The adult respiratory distress syndrome.

The Adult Respiratory Distress Syndrome is a complication of many illnesses such as sepsis, pneumonia and trauma afflicting over 150,000 patients per year. While progress in intensive care medicine has increased the survival rates in many of these underlying illnesses, major obstacles remain in the successful therapy of ARDS. Animal and human investigations shed light on the pathophysiology of the illness that is allowing researchers to formulate promising new treatment strategies.

Adrenal Cortex Hormones↗

PubMed1985

Effects of prolonged elevated microvascular pressure on lung fluid balance in sheep.

Experiments were conducted in seven chronically instrumented unanesthetized sheep to estimate the osmotic reflection coefficient (sigma d) for total proteins and the solvent-drag reflection coefficients (sigma f) for six endogenous protein fractions. We measured the lymph-to-plasma ratio of total proteins (CL/CP) and six protein fractions during base-line conditions and after left atrial pressure elevations of 24-26 h per elevation. We also monitored pulmonary arterial pressure, left atrial pressure, systemic arterial pressure, and lung lymph flow at the various levels of pulmonary microvascular pressure. Our results indicate the CL/CP may require up to 24 h to reach a true steady state. It was found that sigma d is at least 0.89 for total proteins and sigma f is at least 0.84, 0.87, 0.86, 0.92, 0.95, and 0.96 for protein fractions with effective molecular radii of 36, 39.5, 44, 66, 105, and 123 A, respectively. In addition, the sigma f values for various protein fractions obtained from this investigation are compared with the predicted values of various mathematical models of the lung microcirculation.

Animals↗

PubMed1985

Effect of endotoxemia on hypoxic pulmonary vasoconstriction in unanesthetized sheep.

This study examined the effect of acute endotoxemia on hypoxic pulmonary vasoconstriction (HPV) in awake sheep. Thirteen sheep were chronically instrumented with Silastic catheters in the pulmonary artery, left atrium, jugular vein, and carotid artery; with a Swan-Ganz catheter in the main pulmonary artery; with a chronic lung lymph fistula; and with a tracheostomy. Base-line HPV was determined by measuring the change in pulmonary vascular resistance (PVR) while sheep breathed 12% O2 for 7 min. Concentrations of immunoreactive 6-keto-PGF1 alpha and thromboxane B2 (TXB2) were measured in lung lymph during the hypoxic challenge. Escherichia coli endotoxin (0.2-0.5 micrograms/kg) was infused intravenously. Four hours after endotoxemia, HPV was measured. In five sheep, meclofenamate was infused at 4.5 h after endotoxemia and HPV measured again. During the base-line hypoxic challenge, PVR increased by 36 +/- 9% (mean +/- SE). There was no significant change in lung lymph 6-keto-PGF1 alpha or TXB2 levels with hypoxia. Twelve of the 13 sheep showed a decrease in HPV 4 h after endotoxemia; the mean change in PVR with hypoxia was -8 +/- 5%, which was significantly (P less than 0.05) reduced compared with base-line HPV. The infusion of meclofenamate at 4.5 h after endotoxin did not restore HPV.

6-Ketoprostaglandin F1 alpha↗

PubMed1985

Pulmonary hypertension and increased vasoreactivity caused by repeated indomethacin in sheep.

Six chronically catheterized awake sheep were given the cyclooxygenase inhibitor indomethacin (5 mg/kg) twice a day over a 3-wk period. Three sheep receiving vehicle alone served as controls. Pulmonary arterial, left atrial, and systemic arterial pressures, cardiac output, blood gases, and pH were measured biweekly. Pulmonary vasoreactivity to 12% O2 and an analogue of prostaglandin H2 (PGH2-A) was also assessed. As a percent of base line, indomethacin caused a doubling in pulmonary vascular resistance (3 wk = 190 +/- 26%, mean +/- SE) and a 50% increase in pulmonary arterial pressure (3 wk = 151 +/- 9%). Vasoreactivity to 12% O2 increased approximately fourfold during the 1st wk of treatment and then declined. Vasoreactivity to PGH2-A increased steadily, nearly doubling by 3 wk. Light-microscopic counts of peripheral lung biopsy tissue revealed marked sequestration of granulocytes. Morphometric techniques applied to lungs removed at autopsy and fixed with the pulmonary arteries distended with barium gelatin mixture showed a significant reduction in number of barium-filled peripheral arteries and reduction in their external diameter. We conclude that repeated administration of indomethacin alters pulmonary vasoreactivity and causes sustained pulmonary hypertension. Structural studies reveal peripheral lung inflammation and changes in the arterial circulation that are perhaps more consistent with maintained vasoconstriction than chronic pulmonary hypertension.

Animals↗

PubMed1985

Relation of blood-free to blood-inclusive postmortem lung water measurements in sheep.

Our purpose was to see if the postmortem weight ratio of extravascular lung water to blood-free dry lung (blood-free ratio) was related to similar ratios in blood-inclusive lung and in blood. We developed linear regressions of blood-free ratio on ratios for blood-inclusive lung and blood together and for blood-inclusive lung alone for 73 sheep studied under 11 different protocols and for two subgroups of sheep, one with plasma space expansion and the other without expansion. The relation of ratios of blood-free to blood-inclusive lungs was different between the two subgroups. Although all regressions were highly correlated, the fits of the blood-free ratio on ratios for blood-inclusive lung and blood together were better than for blood-inclusive lung alone. The mean error of prediction of extravascular lung water for all sheep was significantly less for the regression of blood-free ratio on ratios for blood and blood-inclusive lung together (11 g) than for blood-inclusive lung alone (18 g). This study shows that weights of lung homogenate and blood samples before and after simple oven drying can be used to provide accurate inexpensive estimates of postmortem extravascular lung water.

Animals↗

PubMed1985

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.

Animals↗

PubMed1985

Vasoconstriction and remodeling in pulmonary hypertension.

In one group of sheep, Escherichia coli endotoxin was given intravenously three times per week for ten weeks, and in another group the cyclooxygenase inhibitor indomethacin was given subcutaneously two times per day for three weeks. Both groups developed the structural and functional changes of modest but sustained pulmonary hypertension and showed granulocyte sequestration in the peripheral lung. Indomethacin enhanced pulmonary vasoreactivity, but endotoxin depressed reactivity transiently. Prolonged inflammation of the lung may be associated with alterations in vasoreactivity and the development of chronic pulmonary hypertension.

Animals↗