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Biomedical subjects

D Langleben

Publications and source records attributed to D Langleben.

At least 37 records · Page 2Linked to original sources
PubMed1993

Expression of endothelin-1 in the lungs of patients with pulmonary hypertension.

BACKGROUND: Pulmonary hypertension is characterized by an increase in vascular tone or an abnormal proliferation of muscle cells in the walls of small pulmonary arteries. Endothelin-1 is a potent endothelium-derived vasoconstrictor peptide with important mitogenic properties. It has therefore been suggested that endothelin-1 may contribute to increases in pulmonary arterial tone or smooth-muscle proliferation in patients with pulmonary hypertension. We studied the sites and magnitude of endothelin-1 production in the lungs of patients with various causes of pulmonary hypertension. METHODS: We studied the distribution of endothelin-1-like immunoreactivity (by immunocytochemical analysis) and endothelin-1 messenger RNA (by in situ hybridization) in lung specimens from 15 control subjects, 11 patients with plexogenic pulmonary arteriopathy (grades 4 through 6), and 17 patients with secondary pulmonary hypertension and pulmonary arteriopathy of grades 1 through 3. RESULTS: In the controls, endothelin-1-like immunoreactivity was rarely seen in vascular endothelial cells. In the patients with pulmonary hypertension, endothelin-1-like immunoreactivity was abundant, predominantly in endothelial cells of pulmonary arteries with medial thickening and intimal fibrosis. Likewise, endothelin-1 messenger RNA was increased in the patients with pulmonary hypertension and was expressed primarily at sites of endothelin-1-like immunoreactivity. There was a strong correlation between the intensity of endothelin-1-like immunoreactivity and pulmonary vascular resistance in the patients with plexogenic pulmonary arteriopathy, but not in those with secondary pulmonary hypertension. CONCLUSIONS: Pulmonary hypertension is associated with the increased expression of endothelin-1 in vascular endothelial cells, suggesting that the local production of endothelin-1 may contribute to the vascular abnormalities associated with this disorder.

Adult↗
PubMed1993

Endothelin-1 in acute lung injury and the adult respiratory distress syndrome.

Endothelial damage is a hallmark of acute lung injury. Endothelial mediators may increase pulmonary vascular tone and induce pulmonary arterial muscularization, thereby contributing to the pulmonary hypertension seen with acute lung injury. We measured plasma levels and net pulmonary clearance of endothelin-1, a potent endothelium-derived vasoconstrictor peptide and smooth muscle mitogen, in 26 patients with early acute lung injury, the adult respiratory distress syndrome, and pulmonary hypertension. Nineteen had another data collection at clinical improvement or worsening. Control subjects (n = 25) had no pulmonary hypertension or lung injury. Initial mixed venous and systemic arterial plasma endothelin-1 levels were elevated (4.6 +/- 0.6 SEM and 4.9 +/- 0.6 pg/ml, respectively) as compared with control subjects (0.9 +/- 0.1 and 0.6 +/- 0.1 pg/ml). The systemic arterial/venous endothelin-1 ratio was 1.1 +/- 0.1 (0.7 +/- 0.1 in control subjects), indicating a reduction in normal net pulmonary endothelin-1 clearance. With clinical improvement, as compared with clinical worsening, mean plasma endothelin-1 levels, arterial/venous ratio, and pulmonary arterial pressure fell significantly towards normal. Thus, patients with acute lung injury have marked early increases in circulating plasma endothelin-1 levels, associated with abnormal pulmonary endothelin-1 metabolism. These abnormalities reverse in patients who recover. Through its actions, endothelin-1 could contribute to the pulmonary hypertension seen in acute lung injury.

Blood Pressure↗
PubMed1992

Hemodynamic differences between continual positive and two types of negative pressure ventilation.

In seven anesthetized dogs, ventilated with matching lung volumes, tidal volumes, and respiratory rates, we compared the effects on cardiac output (CO), arterial venous oxygen saturation difference (SaO2 - SVO2), and femoral and inferior vena cava pressure (1) intermittent positive pressure ventilation with positive end-expiratory pressure (CPPV); (2) iron-lung ventilation with negative end-expiratory pressure (ILV-NEEP); (3) grid and wrap ventilation with NEEP applied to the thorax and upper abdomen (G&W-NEEP). The values of CO and SaO2 - SVO2 with ILV-NEEP were similar to those with CPPV. However, with G&W-NEEP as compared with ILV-NEEP, mean CO was greater (2.9 versus 2.6 L/min, p = 0.02) and mean (SaO2 - SVO2) was lower (26.6% versus 28.3%, p = NS). Mean PFEM-IVC was higher with G&W-NEEP than with the other types of ventilation. We conclude that (1) ILV-NEEP is hemodynamically equivalent to CPPV and (2) G&W-NEEP has less adverse hemodynamic consequences. has less adverse hemodynamic consequences.

Animals↗
PubMed1991

Increased plasma endothelin-1 in pulmonary hypertension: marker or mediator of disease?

OBJECTIVE: To explore the role of endothelin-1, a potent endothelial-derived vasoconstrictor peptide, in pulmonary hypertension, by measuring its concentration in arterial and venous plasma. DESIGN: A survey, case series study. SETTING: University-affiliated hospitals and outpatient clinics. PATIENTS: Twenty-seven patients with pulmonary hypertension: 7 with primary, and 20 with secondary pulmonary hypertension of various causes. The control groups (n = 16) comprised 8 healthy volunteers and 8 patients with coronary artery disease but without evidence of pulmonary hypertension. MEASUREMENTS AND MAIN RESULTS: Pulmonary artery pressure was markedly increased (94/43 +/- 23/13 mm Hg) in the patients with pulmonary hypertension. Venous plasma immunoreactive endothelin-1, measured by a specific radioimmunoassay, was significantly higher in patients with pulmonary hypertension (3.5 +/- 2.5 pg/mL, P less than 0.001) than in normal subjects (1.45 +/- 0.45 pg/mL), or patients with coronary disease (0.75 +/- 0.64 pg/mL). The arterial-to-venous ratio of immunoreactive endothelin-1 was significantly greater than unity in primary pulmonary hypertension (2.21 +/- 0.72, P = 0.01), whereas the patients with secondary pulmonary hypertension had a mean ratio not different from 1 (0.97 +/- 0.42). In contrast, the mean arterial-to-venous ratios were significantly less than unity in both control groups (0.59 +/- 0.35, and 0.54 +/- 0.64; P less than 0.02, for normal subjects and coronary disease patients, respectively), indicating a possible clearance of endothelin-1 across the healthy lung. CONCLUSIONS: Patient with pulmonary hypertension have substantial alterations in plasma immunoreactive endothelin-1, which may reflect changes in net release or clearance of endothelin-1 by the lung. In patients with primary pulmonary hypertension, the high levels in arterial compared with venous plasma suggest pulmonary production of endothelin-1, which may contribute to elevated pulmonary vascular resistance.

Adult↗
PubMed1991

Lung scintigraphy in pulmonary capillary hemangiomatosis. A rare disorder causing primary pulmonary hypertension.

The authors report the results of lung scintigraphy in two patients with primary pulmonary hypertension caused by pulmonary capillary hemangiomatosis, a rare disorder resulting from the proliferation of histologically normal capillaries in the lung. Perfusion studies revealed a nonhomogeneous pattern with some focal defects, similar to that seen with some other histologic types of primary pulmonary hypertension. The mechanisms underlying this perfusion pattern are unknown.

Adult↗
PubMed1991

Interspecies variation in the cellular phase of blood fibrinolytic activity.

In normal humans, whole blood fibrinolytic activity is three to six times greater than that of companion plasma. This additional activity derives from neutrophil enzymes, with possible contributions from other cell types. Rats and dogs are frequently used to study fibrinolysis in animal models of human disease. Compared with humans, rats are relatively neutropenic, whereas dogs have a relative neutrophilic leukocytosis. Interspecies variation in cellular phase fibrinolytic activity has not been examined. We therefore determined whole blood, plasma, and cellular phase fibrinolytic activity in 27 rats and 6 dogs, using a 125I-fibrin solid phase assay. Whole blood and plasma activities were similar in rats, consistent with very low cellular activity. Dogs, however, had high cellular phase activity, making up an average 91% of whole blood activity. These results suggest that blood fibrinolytic mechanisms in rats differ from those in humans and dogs, and that this difference should be considered when studying fibrinolysis in models of human disease.

Animals↗
PubMed1990

Cellular-phase fibrinolysis and coronary reperfusion during acute myocardial infarction: a study in patients receiving intravenous streptokinase-methylprednisolone therapy.

Activation of plasma plasminogen to plasmin is the objective of current strategies for thrombolytic therapy. Although thrombolytic activity in blood involves a large cellular component as well as that in plasma, the contribution of this cellular phase to clinical thrombolysis has not been examined. Using a 125I-fibrin test tube assay, we determined blood, plasma and calculated cellular phase fibrinolytic activities in 39 patients with acute myocardial infarction before, immediately after, and at 2 hours after therapy with an intravenous streptokinase-methylprednisolone regimen. By coronary angiography and time to peak creatine phosphokinase levels, 32 patients had coronary reperfusion and 7 did not. Before streptokinase therapy, cellular phase activity of patients who reperfused was more than 2-fold greater than that of patients who did not reperfuse (p less than 0.001), while plasma activities were identical, suggesting that intrinsic cellular phase activity may be a determinant of the success of subsequent thrombolytic therapy. In both groups, in addition to the expected (and similar) increases in plasma activity, cellular phase activity increased when compared with pre-treatment values (+96% to +248%; p less than 0.001), with accompanying increase in blood granulocyte count (+23% to +65%), indicating that blood cells, as well as plasma, are major contributors to streptokinase-mediated fibrinolysis. Cellular phase stimulation was reproduced in a patient receiving streptokinase without methylprednisolone, and by addition of streptokinase to normal blood in vitro, indicating that streptokinase alone could account for these effects. Increased cellular phase activity in patients who reperfused after streptokinase was similar to that in those who did not reperfuse, when pre-treatment values were considered. These findings indicate that initial cellular phase activity in blood may determine subsequent fibrinolytic response, and that there is a significant cellular phase component to the fibrinolytic response to streptokinase, probably mediated by increased numbers of blood neutrophils, with a possible contribution from increased activity of individual neutrophils.

Blood Cell Count↗
PubMed1990

Endothelin release is inhibited by coculture of endothelial cells with cells of vascular media.

Endothelin is a potent vasoconstrictor peptide and a smooth muscle mitogen produced in large amounts by endothelial cells in culture. To determine whether other cellular elements of the vessel wall modify the release or clearance of endothelin, we studied the effect of coculture of endothelial cells with vascular smooth muscle cells or fibroblasts on endothelin release. Endothelial cells were grown to confluence on microcarrier beads and transferred to dishes containing confluent cultures of smooth muscle cells or fibroblasts or control media only. In parallel experiments, endothelial cells on microcarrier beads were incubated in media conditioned by 48-h exposure to smooth muscle cells or fibroblasts. Endothelin concentration was determined by radioimmunoassay (rabbit anti-endothelin-1 serum). Endothelial cells alone released large amounts of endothelin: 169 +/- 60 and 982 +/- 237 pg/10(6) endothelial cells at 4 and 24 h, respectively. Endothelin accumulation was markedly reduced in coculture with smooth muscle cells or fibroblasts by 81 +/- 10 and 49 +/- 5% (P less than 0.05), respectively, at 24 h. This difference could not be explained by smooth muscle cell binding or degradation of endothelin. Furthermore, smooth muscle cell- or fibroblast-conditioned media significantly reduced endothelin release, and twofold concentration of smooth muscle cell-conditioned media fully reproduced the inhibition of endothelin release found in coculture, confirming the presence of a transferable inhibitor. Therefore, we propose that endothelin secretion from endothelial cells may be regulated by an inhibitory factor produced by the vascular media. This mechanism might limit the production of endothelin in intact vessels and thereby protect against excessive vasoconstriction or proliferation of vascular target cells.

Animals↗
PubMed1989

Regional pulmonary perfusion following human heart-lung transplantation.

Ventilation and perfusion scans were obtained in six subjects who had undergone heart-lung transplantation with consequent denervation of the cardiopulmonary axis. Two of the subjects had developed obliterative bronchiolitis, which is believed to be a form of chronic rejection. Their pulmonary function tests demonstrated airflow obstruction and their scintigraphic studies were abnormal. In the remaining four subjects without obstructive airways disease, ventilation and planar perfusion scans were normal. Single photon emission computed tomography imaging of pulmonary perfusion in these patients revealed a layered distribution of blood flow indistinguishable from that of normal individuals. It is concluded that neurogenic mechanisms have little influence on the pattern of local pulmonary blood flow at rest.

Adult↗
PubMed1989

Effects of dimethylthiourea on chronic hypoxia-induced pulmonary arterial remodelling and ventricular hypertrophy in rats.

Ischemia, followed by reperfusion and restoration of oxygen to tissues, generates hydrogen peroxide which in turn generates injurious free radicals, particularly hydroxyl. Chronic hypoxia may also result in liberation of free radicals. In rats, chronic hypoxia causes pulmonary hypertension, associated with structural remodelling of pulmonary arteries, polycythemia, and vasoconstriction. We studied in rats the effects of dimethylthiourea (DMTU), a hydroxyl and hydrogen peroxide scavenger, on acute hypoxic vasoconstriction, and on the arterial structure and development of polycythemia after chronic hypoxia (FIO2 0.10 for 10 days, daily DMTU). DMTU did not affect acute vasoconstriction nor polycythemia. It significantly reduced muscularization of alveolar wall and alveolar duct arteries, medial thickening of alveolar wall and preacinar arteries, and right ventricular hypertrophy, suggesting reduction of pulmonary hypertension. However, DMTU caused marked growth retardation in both control and hypoxic rats, an effect not previously described. In other rats a similar degree of growth retardation due to reduced food intake failed to prevent the effects of hypoxia, suggesting that DMTU's effect is not through this mechanism. The results of this study support but do not confirm the hypothesis that free radicals may have a role in the pathogenesis of the arterial structural changes in the microcirculation contributing to chronic hypoxic pulmonary hypertension. However, in view of DMTU's effects on growth, definitive testing of the hypothesis will not be possible until other, less toxic, chronic hydroxyl scavengers become available.

Animals↗
PubMed1988

Familial pulmonary capillary hemangiomatosis resulting in primary pulmonary hypertension.

We describe the first cases of familial pulmonary capillary hemangiomatosis, a disorder in which capillaries in the lungs proliferate. Three siblings died from primary pulmonary hypertension. One developed pulmonary congestion preterminally after vasodilator treatment. The inheritance pattern seems autosomal recessive. Lung specimens obtained in two siblings showed extensive pulmonary capillary hemangiomatosis, with normal capillaries proliferating into veins and alveoli. Including our patients, four of the nine patients with pulmonary capillary hemangiomatosis have presented with the clinical picture of primary pulmonary hypertension. Thus, pulmonary capillary hemangiomatosis should be considered as a histologic pattern of primary pulmonary hypertension. Most other cases of pulmonary capillary hemangiomatosis have been similar to pulmonary veno-occlusive disease. Recently, disorders involving the proliferation of cytologically normal capillaries have been termed angiogenic diseases. Pulmonary capillary hemangiomatosis may be an angiogenic disease.

Adult↗
PubMed1988

Altered artery mechanics and structure in monocrotaline pulmonary hypertension.

Pulmonary hypertension in rats, induced by an injection of monocrotaline, is associated with changes in the wall structure of the pulmonary arterial bed. We have studied the effects of this remodeling on mechanical properties of cylindrical pulmonary artery segments from rats 21 days after monocrotaline (MCT) injection. Resting and active (KCl induced) circumference-tension relationships were established for segments of extrapulmonary and intrapulmonary arteries isolated from the hilum and the fifth lateral branch from the axial pathway (all preacinar). The thicknesses of the vessel wall, the media, and adventitia were measured at several positions around the circumference of the artery by computerized analysis of histological cross sections of the segments fixed at a standard circumference. Resting and active stress were also calculated. The study shows that active circumferential tension and active stress are reduced in vessels from MCT-treated rats. Based on our findings, it is unlikely that altered contractile function of preacinar arteries contributes significantly to the increased vascular resistance seen in this model.

Animals↗
PubMed1987

Characteristics of lung pericytes in culture including their growth inhibition by endothelial substrate.

Pericytes and endothelial cells from the same sample of adult rat lung have been separately established in culture by use of selective growth media. The endothelial cells are positive and the pericytes negative for angiotensin-converting enzyme activity and tissue plasminogen activator. Morphologically in culture, the pericytes are similar to pericytes from bovine retina and other sites and show positive immunofluorescence to both human platelet (non-muscle) myosin and smooth muscle myosin. In this respect they resemble smooth muscle cells grown from the rat main pulmonary artery, but lack the myofilaments and dense bodies characteristic of muscle cells. Lung endothelial cells and fibroblasts are positive only for platelet myosin. Pericytes in culture demonstrate an unusual growth response to endothelial substrate, obtained by removing confluent endothelial monolayers with nonionic detergent or alkali. When plated onto this material at low density, pericyte growth is inhibited. By contrast, the substrate stimulates the growth of endothelial cells and has no effect on smooth muscle cells. Initial attachment of endothelial cells and pericytes to the substrate is similar.

Animals↗
PubMed1987

Pulmonary artery structural changes in two colonies of rats with different sensitivity to chronic hypoxia.

Chronic hypoxia causes more severe pulmonary hypertension in the Hilltop colony of Sprague-Dawley rats than in the Madison colony and also greater polycythemia and vasoconstriction. This study examines the structural features of the pulmonary artery bed, another contributing factor to hypoxic hypertension. After 14 days of hypobaric hypoxia, in Hilltop rats, more of the intraacinar arteries became muscular, and the medial thickness of intraacinar and preacinar arteries was greater. In Hilltop control rats, muscle was found in more intraacinar arteries, but, paradoxically, acute hypoxic vasoconstriction was less. Thus, while in chronic hypoxia increased muscle correlates with pulmonary hypertension, in control rats the reserve seems to be true. The increased muscle in control Hilltop rats could, however, predispose to the greater muscularization seen after chronic hypoxia.

Animals↗
PubMed1986

Abnormalities in the cellular phase of blood fibrinolytic activity in systemic lupus erythematosus and in venous thromboembolism.

Fibrinolytic activities of whole blood and plasma were determined by 125I-fibrin radiometric assay in 16 normal subjects, and in 11 patients with systemic lupus erythematosus (SLE), 14 with progressive systemic sclerosis (PSS), 23 with venous thromboembolic disease, and 20 patients awaiting elective surgery. Mean whole blood and plasma activities for patients with PSS, and for those awaiting elective surgery, were similar to normal values, as was the mean plasma activity in patients with SLE. However, mean whole blood activity in SLE was significantly decreased compared with normals (p less than 0.05), with mean plasma activity accounting for 44% of mean whole blood activity (compared with 17% in normal subjects), representing a 67% decrease in mean calculated cellular phase activity in SLE, when compared with normals. Since the numbers of cells (neutrophils, monocytes) possibly involved in cellular activity were not decreased, the findings suggest a functional defect in fibrinolytic activity of one or more blood cell types in SLE. An additional finding was the participation of the cellular phase as well as the well-known plasma phase of blood in the fibrinolytic response to thromboembolism.

Female↗