PubMed Health⌕ Search

Biomedical subjects

B Meyrick

Publications and source records attributed to B Meyrick.

At least 37 records · Page 2Linked to original sources
PubMed1992

Insulin-like growth factor I and pulmonary hypertension induced by continuous air embolization in sheep.

Chronic pulmonary hypertension is associated with arterial structural remodeling. Insulin-like growth factor I (IGF-I) has been proposed as one of the mediators of vascular change because of its ability to stimulate proliferation in, and elastin production by, cultured vascular smooth muscle cells. We have shown previously that 12 days of continuous air embolization into the pulmonary arterial circulation of sheep results in the functional and structural changes of chronic pulmonary hypertension. In the present study, measurements of IGF-I (by radioimmunoassay) and IGF-I binding protein activity in sheep lung lymph and plasma were made before and during the 12 days of air embolization in six sheep. Two untreated animals served as controls. Baseline lung lymph contained 23.5 +/- 3.6 ng/ml (mean +/- SEM) of IGF-I, and there was a slight increase to 36.7 +/- 9.8 on day 3, but by day 6 levels were back to baseline. The flux of IGF-I from the lung (concentration times lymph flow) increased significantly by day 2 embolization and remained elevated through day 12 (baseline = 37.2 +/- 11.1 ng/15 min; day 2 = 237.7 +/- 55.8; day 5 = 190.2 +/- 53.4; day 6 = 82.6 +/- 21.9; day 12 = 78.7 +/- 12.5). IGF-I binding protein activity was also present in lung lymph at baseline (29.6 +/- 3.0%) and was unchanged during air embolization. Plasma levels of IGF-I and plasma binding protein activity remained at baseline throughout the 12 days of embolization (71.51 +/- 34.48 ng/ml and 36.4 +/- 3.5%, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Endotoxin enhancement of lymphocyte adherence to cultured sheep lung microvascular endothelial cells.

The most common predisposing factor for development of the adult respiratory distress syndrome is gram-negative sepsis. Our previous studies have shown that a single infusion of Escherichia coli endotoxin into sheep causes early sequestration of lymphocytes in the lungs' microcirculation. In this report, we examined the effects of endotoxin on sheep lymphocyte adherence to sheep pulmonary microvascular endothelial cells in vitro. Endothelial cells were exposed to endotoxin, and subsequent adherence of 51Cr-labeled lymphocytes was measured in a monolayer adhesion assay. Endotoxin enhanced adherence of lymphocytes isolated from blood and caudal mediastinal node (CMN) lymph in a time- and dose-dependent manner. Adherence of CMN lymphocytes increased from a control value of 13.6 +/- 1.6% to 29.9 +/- 3.1% after 4 h of treatment with 1 microgram/ml endotoxin. Both B and T lymphocytes contributed to the increased adherence. Pretreatment of the endothelial cells with cycloheximide revealed that the endotoxin-enhanced adherence was partially dependent upon protein synthesis. Morphologic studies revealed that enhanced adherence was accompanied by a 5-fold increase in migration of lymphocytes between endothelial cells. In contrast to human umbilical vein endothelial cells, antibodies to the known lymphocyte adherence molecules, lymphocyte function-associated antigen (LFA-1), CD-44, and the lymphocyte homing receptor (LECAM-1), were ineffective in blocking adherence to the sheep pulmonary endothelial cells. We conclude that the acute sequestration of lymphocytes in the pulmonary microcirculation of sheep after endotoxin administration is due to increased adhesive properties of the endothelial cells. Our data suggest that this adherence is mediated by as yet undescribed mechanisms that may be unique to pulmonary microvascular endothelium.

Animals↗
PubMed1991

Role of pulmonary inflammation in altered airway responsiveness in three sheep models of acute lung injury.

Pulmonary inflammation may contribute to increased airway responsiveness in experimental models of acute lung injury. Infusions of endotoxin, phorbol myristate acetate (PMA), or zymosan-activated plasma (ZAP) all result in the accumulation of polymorphonuclear leukocytes (PMNs) in the lung and alterations in lung mechanics. These three interventions have strikingly different effects on airway responses to aerosol histamine: ZAP does not increase airway responsiveness, whereas endotoxin causes a greater increase in airway responsiveness than does PMA. The present histologic study examines the question of whether the pattern and severity of PMN and mast cell accumulation in large- and medium-sized airways and lung periphery could contribute to the differences in airway responsiveness to histamine. Minimally instrumented sheep were given either an infusion of endotoxin (0.5 microgram/kg over 20 min), a bolus injection of PMA (5 micrograms/kg), or repetitive boluses of autologous ZAP (5 ml). Four and a half hours later, the animals were killed, and the left lung was removed and fixed in the distended state. Three levels of the left lung were examined by light microscopy: the large hilar bronchus, a medium-sized bronchus, and peripheral lung. The number of PMNs and mast cells in the airway wall were expressed as cells/mm length of airway circumference and in the lung periphery as cells/100 alveolar profiles. Both endotoxin and PMA caused a significant 2- to 3-fold increase in number of PMNs/mm of large airway circumference, the majority of PMNs being in the blood vessels of the lamina propria and submucosa; ZAP caused only minimal PMN accumulation in the blood vessels of the submucosa.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Morphologic changes in lungs of anesthetized sheep following intravenous infusion of recombinant tumor necrosis factor alpha.

Tumor necrosis factor alpha (TNF alpha) is a monokine released in response to endotoxin and has been suggested as a primary mediator of endotoxic shock. We have recently demonstrated that infusion of recombinant human tumor necrosis factor alpha (rTNF alpha) into sheep elicits a physiologic response in the lung that closely resembles endotoxemia. The present study examines the morphologic changes that accompany these alterations in pulmonary physiology. Five anesthetized, open-chest sheep received 0.01 mg/kg of protein (2.24 x 10(7) U rTNF alpha/mg) intravenously over 30 min. Lung biopsy tissue for light and electron microscopy was obtained from random lobes 7.5, 15, 30, 60, 120, 180, and 240 min after beginning the infusion. Pulmonary (Ppa) and systemic arterial pressures, cardiac output, and peripheral blood leukocyte number and differential counts were monitored throughout the study. Three control animals were treated in a similar manner but received either saline (n = 1) or rTNF alpha denatured by boiling for 30 min (n = 2). rTNF alpha caused an early increase in Ppa and peripheral blood leukopenia. Light microscopy revealed a threefold increase in the number of granulocytes per 100 alveolar profiles by 30 min and a fivefold increase by 2 h. From 60 min, increased alveolar wall thickness, red cell congestion, and peribronchovascular edema were apparent; from 2 h, there was increased cellularity of the alveolar walls and mononuclear cell infiltration of perivascular connective tissue. Electron microscopy revealed damage to alveolar Type I and II pneumonocytes and progressive endothelial injury from 30 min.(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthesia↗
PubMed1991

Simultaneous exposure of sheep to endotoxin and 100% oxygen.

The purpose of this study was to determine the effect of endotoxin on the development of vascular and airway dysfunction during O2 toxicity. Sheep were prepared for chronic measurement of vascular pressures, cardiac output, gas exchange, and collection of lung lymph. Tracheostomies were made for accurate delivery of gas mixtures. Sheep were placed in one of three experimental groups: those receiving endotoxin (n = 9), those breathing 100% O2 and receiving endotoxin (n = 7), and those exposed to 100% O2 alone (n = 6). Sheep had daily measurements of hypoxic vasoconstriction (FIO2 = 0.12), gas exchange, circulating white blood cell counts, lymph flow, and lymph and plasma protein concentrations. Lung neutrophils were counted, and copper-zinc superoxide dismutase and manganous superoxide dismutase were measured in lung samples from some sheep biopsies taken at baseline surgery and postmortem. Endotoxin markedly prolonged survival time and partially protected against the increased lung vascular permeability in sheep breathing 100% oxygen, but impairment of gas exchange, loss of hypoxic pulmonary vasoconstriction, and ultimate progression of respiratory failure were not prevented. Induction of MnSOD occurred in sheep breathing 100% O2, in sheep receiving endotoxin alone, and in those exposed to 100% O2 plus endotoxin. We conclude that endotoxin markedly increases tolerance to O2 toxicity but that some of the pathophysiology of O2 toxicity is unaltered. The role of superoxide dismutase in the observed protection is unclear.

Animals↗
PubMed1991

Structure function correlates in the pulmonary vasculature during acute lung injury and chronic pulmonary hypertension.

Arteries, veins, and capillaries comprise the pulmonary vasculature. Three structural types of artery and vein are identified, the most muscular vessels being the largest. For example, arteries that accompany the preacinar arteries are muscular in structure while those within the acinus may be either, muscular, partially muscular or non-muscular. These small intra-acinar arteries contribute much to the hemodynamic behavior of the lung. Pulmonary edema results from damage to the capillary endothelium while chronic pulmonary hypertension is characterized by structural alterations in the pulmonary arteries. Correlation of the structural and functional changes of chronic pulmonary hypertension suggest that the increases in medial and adventitial thickness of the muscular preacinar arteries are secondary to the onset of this disease, while the changes in the peripheral arteries--appearance of muscle in smaller intra-acinar arteries than normal and reduction in arterial volume--contribute to the rise in pulmonary artery pressure and pulmonary vascular resistance. Such correlations of structure and hemodynamic measurements demand that the lung be fixed in a simple and standardized manner. Available methodology to evaluate the structural changes that occur during the development of pulmonary edema and chronic pulmonary hypertension are described.

Acute Disease↗
PubMed1991

Sequence of structural changes and elastin peptide release during vascular remodelling in sheep with chronic pulmonary hypertension induced by air embolization.

The progression of structural changes in the pulmonary arterial bed were followed in a model of chronic pulmonary hypertension. Chronically instrumented awake sheep received continuous air embolization for 0 (controls), 1, 4, 8, or 12 days (n = 5-6/group). After the period of embolization, the lungs were removed, the pulmonary arteries were distended with barium-gelatin, and the lungs were fixed via the airways with formal-saline. Quantitative techniques were applied to sections from random blocks from the lungs of each animal. One day of embolization resulted in granulocyte sequestration in the lung interstitium and in small vessels; additionally, intraalveolar and perivascular edema was present. By 4 days, increased medial thickness, appearance of muscle in smaller arteries than normal (e.g., muscular arteries at alveolar duct level: control = 1.2 +/- 1.2%; day 4 = 22.7 +/- 7.7) and reduction in number of barium-filled intraacinar arteries was found. The arterial changes progressed in severity to day 8 and were similar at day 12. Since arterial remodelling involves increased elastin deposition, the concentration of elastin peptides was measured in lung lymph. Increased flux of elastin peptides was apparent from day 2 of embolization and continued to increase to a level 20 x baseline by day 12 (baseline 351 +/- 86 micrograms/15 min; day 12 = 6338 +/- 2999). Comparison of the onset of the structural changes with previous findings shows that the arterial remodelling parallels the onset of sustained pulmonary hypertension. The increase in lung-lymph elastin peptides by day 2 provides evidence that vascular remodelling is initiated before day 4 of embolization. The early sequestration of granulocytes and appearance of edema suggest that these may be part of the trigger to the development of the structural changes.

Angiography↗
PubMed1991

Effects of recombinant tumor necrosis factor-alpha on cultured pulmonary artery and lung microvascular endothelial monolayers.

Whole animal studies suggest that tumor necrosis factor-alpha (TNF alpha) plays a central role in the endotoxin response. In vitro studies show that TNF alpha and endotoxin induce a similar range of metabolic changes to endothelial cells. However both endotoxin- and TNF alpha-induced cytotoxicity is not a feature of all endothelial cells lines. In recent studies, the authors have shown that endotoxin causes different responses in endothelial cells taken from two levels of the lung's circulation--main pulmonary artery and lung microvasculature. Endotoxin exposure caused cell death for cells cultured from the large pulmonary artery but not for those taken from lung periphery. The present study examined the effect of TNF alpha on endothelial cells cultured from two levels of the lungs' circulation--the main pulmonary artery and the lung microvasculature. End points examined included lactate dehydrogenase (LDH), prostacyclin, and prostaglandin E2 (PGE2) release and phase contrast microscopy. Exposure to TNF alpha resulted in a dose-dependent increase in LDH release and number of detached cells for cells of the pulmonary artery, whereas cells from the microvasculature seemed unaffected. At both levels, however, TNF alpha caused increased release of both prostacyclin and PGE2. The authors conclude that TNF alpha causes different effects in endothelial cells cultured from two levels of the same organ.

Animals↗
PubMed1990

Granulocyte depletion attenuates sustained pulmonary hypertension and increased pulmonary vasoreactivity caused by continuous air embolization in sheep.

Chronic pulmonary hypertension can develop in diseases associated with acute or repeated inflammation in the lungs, e.g., adult respiratory distress syndrome, chronic bronchitis. Inflammation has also been associated with some animal models of chronic pulmonary hypertension. We have previously shown that 12 days of continuous air embolization into sheep results in the functional and structural changes of chronic pulmonary hypertension. To determine whether granulocytes contribute to these changes, five sheep were granulocyte-depleted with hydroxyurea immediately before and during air embolization (AIR-PMN) and were compared with sheep receiving air embolization (AIR only). Air embolization was discontinued briefly every 4 days for monitoring of pulmonary vascular pressures and assessment of pulmonary vasoreactivity to a bolus injection of PGH2-A. After 12 days of air embolization, the lungs were removed for structural studies. AIR-PMN sheep did not develop the sustained increase in pulmonary artery pressure seen in the AIR sheep (Day 12, AIR-PMN = 20 +/- 3 cm H2O; AIR = 29 +/- 2; mean +/- SE). Similarly, the increased pulmonary pressor response to PGH2-A seen in AIR sheep was not found in the AIR-PMN group. Structural studies of the barium-injected lungs of AIR-PMN sheep revealed a twofold increase in medial thickness of normally muscular arteries and a significant increase in the percent of muscular intraacinar arteries (similar to findings in lungs from AIR sheep). The number of barium-filled arteries was increased in AIR-PMN sheep when compared with that in AIR sheep, but the number was still less than in the control sheep. We conclude that granulocytes may contribute to the functional changes of chronic pulmonary hypertension after continuous air embolization in sheep, but they do not play a role in structural changes involving pulmonary arterial smooth muscle cells and their precursors. The present data also suggest that the reduction in peripheral arterial filling is the structural alteration that contributes most to the sustained rise in pulmonary artery pressure. The data further suggest that pulmonary hypertension after air embolization may have a vasoconstrictive component that is granulocyte-dependent.

Animals↗
PubMed1990

Transforming growth factor-beta activity in sheep lung lymph during the development of pulmonary hypertension.

Chronic pulmonary hypertension is associated with extensive structural remodeling of the pulmonary arterial bed. The structural changes in the arterial walls include increased production of extracellular matrix components and smooth muscle cell hypertrophy, changes that have been similarly induced by transforming growth factor-beta (TGF-beta) in culture. In the present study, experiments were performed to determine whether TGF-beta is present in sheep lung lymph, and whether TGF-beta levels were altered in an animal model of chronic pulmonary hypertension induced by continuous air embolization. Several standard biological assays for TGF-beta activity were used for these determinations including soft agar assays, inhibition of epithelial cell proliferation, and a TGF-beta-specific radioreceptor assay. In each case, control lung lymph contained high concentrations of TGF-beta (100 ng/ml) which required transient acidification for detection. Samples of lung lymph from hypertensive sheep showed a transient and early two- to threefold increase in concentrations of latent TGF-beta. This activity could be partially blocked by TGF-beta antibodies. These studies indicate that sheep lung lymph contains TGF-beta and that the level of TGF-beta increases early during the development of pulmonary hypertension. Thus, TGF-beta may contribute to the development of the structural changes in the pulmonary arteries that occur during the onset of chronic pulmonary hypertension.

Animals↗
PubMed1990

Acute endotoxin-induced lymphocyte subset sequestration in sheep lungs.

Endotoxemia is associated with an early phase of pulmonary hypertension and a later increase in microvascular permeability. These physiologic changes are attended by peripheral blood and lung lymph leukopenia and a rapid accumulation of both granulocytes and lymphocytes in the peripheral lung. In the present study, the numbers of lymphocytes in blood, lung lymph, and lung tissue after infusion of endotoxin were determined by fluorescent labeling of lymphocyte populations with monoclonal antibodies to sheep T1, T4, T8, or leukocyte common antigen and with rabbit anti-sheep immunoglobulins (B cells). Peripheral blood, lung lymph, and lung tissue samples were collected at baseline and 15, 30, 60, 120, 180, and 240 minutes after the start of intravenous infusion of E. coli endotoxin (1.25 micrograms/kg, N = 6) or saline (N = 4) from open-chest anesthetized sheep. Pulmonary artery pressure and lung lymph flow were also monitored at these times. Endotoxin caused marked reductions in the number of T and B lymphocytes in blood and lung lymph. As compared with baseline, total blood leukocytes and granulocytes were significantly reduced below control levels from 30 minutes of endotoxin, and lymphocyte numbers were reduced from 60 minutes. T1, T4, T8 and B lymphocyte subsets contributed to the fall in blood lymphocytes. Endotoxin caused a significant fall in number of lung lymph leukocytes (T1, T4 and T8 cells) from 120 minutes; numbers of B lymphocytes were also reduced. Counts of the number of lymphocytes in the biopsy tissue revealed a significant rise in T lymphocytes sequestered in the lung. We conclude endotoxemia in sheep causes a reduction in lymphocytes in blood and lung lymph and an increase in these cell types in peripheral lung tissue. These findings suggest that lymphocyte subpopulations accumulate in the lungs during periods of pulmonary hypertension and increased permeability and may participate in endotoxin-induced lung injury.

Animals↗
PubMed1989

In vitro effects of endotoxin on bovine and sheep lung microvascular and pulmonary artery endothelial cells.

A single infusion of Escherichia coli endotoxin into sheep results in structural evidence of pulmonary endothelial injury, increases in both prostacyclin and prostaglandin E2 (PGE2) in lung lymph, and an increase in pulmonary microvascular permeability. Endotoxin-induced lung endothelial damage can also be induced in vitro, but to date these studies have utilized endothelium from large pulmonary vessels. In the present study, we have grown endothelial cells from peripheral lung vessels of cows and sheep and exposed these microvascular endothelial cells to endotoxin. Controls included lung microvascular endothelium without endotoxin and endothelial cells from bovine and sheep main pulmonary artery with and without addition of endotoxin. We found that endotoxin caused significant increases in release of prostacyclin and PGE2 from both bovine and sheep lung microvascular and pulmonary artery endothelium. Normal bovine and sheep pulmonary artery and bovine lung microvascular endothelium released greater levels of prostacyclin than PGE2 (ng/ng); release of PGE2 from the microvascular cells was greater than from the pulmonary artery endothelium in both species. Exposure of endothelial cells from cow and sheep main pulmonary artery to endotoxin results in endothelial cell retraction and pyknosis, a loss of barrier function, increased release of prostacyclin and PGE2 and eventual cell lysis. In lung microvascular cells, the increases in prostanoids were accompanied by changes in cell shape but occurred in the absence of either detectable alterations in barrier function or cytolysis. Thus, while endotoxin causes alterations to endothelial cells from both large and small pulmonary vessels, the effects are not identical suggesting site specific phenotypic expression of endothelial cells even within a single vessel. To determine whether the response of either the large or small pulmonary vessel endothelial cells in culture mimics most closely the in vivo response of the lung to endotoxin requires further study.

Animals↗
PubMed1989

In vivo transfection of murine lungs with a functioning prokaryotic gene using a liposome vehicle.

The authors report successful in vivo transfection of lungs of mice with a functioning prokaryotic gene encoding the intracellular enzyme, chloramphenicol acetyltransferase (CAT). Transfection was accomplished by injecting a plasmid containing the coding region for CAT driven by the SV40 early promoter (pSV2CAT) complexed to specially synthesized cationic liposomes. Intravenous or intratracheal injection of DNA-liposomes resulted in expression of the CAT gene in the lungs, persisting for at least a week, with little enzyme activity detectable in systemic organs. This method should permit either transient or stable in vivo transfection of the lungs with a gene encoding any protein of interest, providing a powerful experimental tool and potentially a novel and broadly applicable clinical therapeutic technique.

Acetylation↗
PubMed1989

Human recombinant tumor necrosis factor alpha infusion mimics endotoxemia in awake sheep.

The macrophage-derived cytokine tumor necrosis factor alpha (TNF alpha) has been proposed as the major mediator of endotoxin-induced injury. To examine whether a single infusion of human recombinant TNF alpha (rTNF alpha) reproduces the pulmonary effects of endotoxemia, we infused rTNF alpha (0.01 mg/kg) over 30 min into six chronically instrumented awake sheep and assessed the ensuing changes in hemodynamics, lung lymph flow and protein concentration, and number of peripheral blood and lung lymph leukocytes. In addition, levels of thromboxane B2, 6-ketoprostaglandin F1 alpha, prostaglandin E2, and leukotriene B4 were measured in lung lymph. Pulmonary arterial pressure (Ppa) peaked within 15 min of the start of rTNF alpha infusion [base-line Ppa = 22.0 +/- 1.5 (SE) cmH2O; after 15 min of rTNF alpha infusion, Ppa = 54.2 +/- 5.4] and then fell toward base line. The pulmonary hypertension was accompanied by hypoxemia and peripheral blood and lung lymph leukopenia, both of which persisted throughout the 4 h of study. These changes were followed by an increase in protein-rich lung lymph flow (base-line lymph protein clearance = 1.8 +/- 0.4 cmH2O; 3 h after rTNF alpha infusion, clearance = 5.6 +/- 1.2), consistent with an increase in pulmonary microvascular permeability. Cardiac output and left atrial pressure did not change significantly throughout the experiment. Light-microscopic examination of lung tissue at autopsy revealed congestion, neutrophil sequestration, and patchy interstitial edema. We conclude that rTNF alpha induces a response in awake sheep remarkable similar to that of endotoxemia. Because endotoxin is a known stimulant of TNF alpha production, TNF alpha may mediate endotoxin-induced lung injury.

Animals↗
PubMed1989

Expression of a prokaryotic gene in cultured lung endothelial cells after lipofection with a plasmid vector.

Transfection of cultured cells with functioning foreign genes can be a powerful tool for delineating mechanisms controlling gene expression and for manipulating cellular synthetic machinery. We transfected cultured bovine pulmonary artery endothelial cells with a plasmid (pRSVCAT) containing the prokaryotic gene, chloramphenicol acetyltransferase (CAT), driven by a Rous sarcoma virus (RSV) promoter. Transfection was accomplished by binding the plasmid DNA to specially synthesized cationic liposomes and incubating cell monolayers with the liposome-DNA complex (a process called lipofection). We found marked CAT expression in endothelial cells by 24 h after lipofection (complete chloramphenicol acetylation in a 4-h assay incubation with less than 0.1 mg cell protein). Marked CAT expression persisted after splitting the cells 1:2 at 6 days after lipofection. Detectable CAT activity was present 14 days after lipofection following two 1:2 splits of the cells. CAT expression was related to the quantity of plasmid DNA used for lipofection; 1.0 micrograms DNA per 60-mm dish of cells resulted in less CAT activity at 48 h than did 5 or 10 micrograms DNA per dish. Ten micrograms of DNA-liposome complex per dish caused substantial numbers of endothelial cells to detach from the dish, but little cytotoxic effect was seen with 5 or 1 micrograms DNA-liposome complex per dish. This simple, highly efficient method for introducing functioning foreign genes into cultured endothelial cells will permit a broad range of studies of molecular mechanisms of endothelial cell function and studies of the consequences of highly specific modifications in protein synthesis on endothelial responses.

Animals↗
PubMed1988

Phagocytic and motile properties of endothelial cells measured magnetometrically: effects of endotoxin.

Endothelial cells lining the vasculature share some properties with macrophages and neutrophils in that they can take up material from the blood and are known to migrate, particularly during wound healing. We observed that endothelial cells isolated from bovine pulmonary arteries ingested magnetic iron oxide particles during culture in vitro. Using a non-optical, magnetometric method, we examined motions of magnetic-particle containing intracellular vacuoles. We demonstrated that these organelles move within endothelial cells, but at a slower rate than phagosomes within macrophages. Magnetometry was used to show that incubation with endotoxin (10 micrograms/ml) for 4 hr resulted in a decrease in cytoplasmic movement; yet the fluidity of the cytoplasm was increased, as measured by intracellular particle response to forced motion. We conclude that intracellular magnetic probe particles can detect vesicular motion in endothelial cells, and that endotoxin exposure can affect endothelial cells directly, altering their physical properties; these alterations precede ultrastructural evidence of cell death.

Animals↗
PubMed1988

Prostaglandin E2 attenuation of sheep lung responses to endotoxin.

Prostaglandin (PG) E2 can inhibit inflammatory responses of neutrophils and lymphocytes, including eicosanoid release. Diffuse lung injury after endotoxemia in sheep is accompanied by sequestration of neutrophils and lymphocytes in the lungs, and eicosanoids mediate some of the pathophysiology of the response. To determine whether exogenous PGE2 could prevent the endotoxin response, we measured pulmonary hemodynamics, gas exchange, and lung lymph responses to infusion of Escherichia coli endotoxin (0.5 micrograms/kg iv over 30 min) in unanesthetized sheep in the presence and absence of PGE2 (0.5 micrograms.kg-1.min-1) infused intravenously for 4 h beginning 0.5 h before endotoxin infusion. We also measured lung lymph concentrations of thromboxane B2 (TxB2) and prostacyclin metabolite, 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha), by radioimmunoassay and leukotriene B4 (LTB4) by gas chromatography-mass spectrometry. PGE2 decreased endotoxin-induced pulmonary hypertension and hypoxemia and markedly attenuated the lymph flow and lymph protein clearance responses. PGE2 also attenuated endotoxin-induced increases in lung lymph TxB2 and 6-keto-PGF1 alpha and decreased lymph LTB4 flow after endotoxin without decreasing lymph LTB4 concentrations. We conclude that PGE2 infusion attenuates lung dysfunction caused by endotoxemia, possibly by preventing endogenous release of other eicosanoids.

6-Ketoprostaglandin F1 alpha↗