Lung vascular permeability following progressive pulmonary embolization

SUMMARY. We examined the role of thromboxane in mediating the alterations in pulmonary hemodynamics and in lung fluid and protein exchange after thrombin. Studies were made in control sheep and in sheep pretreated with the thromboxane synthetase inhibitor, Dazoxiben (injection of 10 mg/kg followed by infusion of 4 mg/kg per hr). Thrombin infusion caused an increase in mixed venous and aortic concentrations of thromboxane B2, a stable degradation product of thromboxane A2, whereas the concentrations of 6-keto-PGFi a , a degradation product of prostacyclin, did not change significantly. In sheep pretreated with Dazoxiben, thromboxane B 2 concentrations did not increase, indicating effectiveness of the thromboxane synthetase inhibitor. The blood concentrations of 6-keto-PGFi a after thrombin increased in the thromboxane synthetase-inhibited group, indicating shunting towards prostacyclin synthesis. Thrombin in untreated sheep increased pulmonary lymph flow (Qiym) and the lymph protein clearance (Qiym * lymph-to-plasma protein concentration ratio). The increases in lymph parameters were due to an increase in pulmonary vascular permeability to proteins because raising left atrial pressure further increased Qiym but did not change lymph-to-plasma ratio. Dazoxiben prevented the thrombininduced increase in pulmonary vascular permeability because the increase in left atrial pressure resulted in an increase in Qiym and a decrease in lymph-to-plasma ratio, as was the case after left atrial hypertension in normal animals. Therefore, thrombin results in selective release of thromboxane A 2 which precedes the increase in pulmonary vascular permeability. Thromboxane A 2 may contribute to the increased permeability after thrombin, since inhibition of thromboxane synthesis prevents the permeability change. (Circ Res 53: 214-222, 1983)

Section: Discussionsupporting

confidence: 72%

“…The caudal mediastinal node and its efferent duct were isolated through a right thoracotomy for collection of pulmonary lymph (Staub et al, 1975;Malik and van der Zee, 1978). The node was resected just caudal to the distal margin of the pulmonary ligament to minimize systemic contamination.…”

mentioning

confidence: 99%

Thromboxane generation after thrombin. Protective effect of thromboxane synthetase inhibition on lung fluid balance.

Garcia-Szabo

Peterson

Watkins

et al. 1983

“…Chromatographic analysis showed that the active components (which resolved into two peaks by reversed-phase high-performance liquid chromatography) were T hrombin-induced pulmonary intravascular coagulation increases pulmonary capillary permeability to protein. [1][2][3] This response is characterized by formation of interendothelial junctional gaps and endothelial injury.1 '4 The intravenous infusion of a-thrombin in animal models causes the uptake of neutrophils in the pulmonary vascular bed, which precedes the increase in capillary permeability.5-8 Neutrophil-derived oxidants and proteases have been implicated in mediating the thrombininduced pulmonary microvascular injury. 9 The basis of pulmonary vascular neutrophil uptake after pulmonary intravascular coagulation remains un-Pharmaceuticals.…”

Section: Thrombin-mediated Release Of Lipids Frommentioning

confidence: 99%

Thrombin-mediated release of lipids from pulmonary artery endothelial cells promotes neutrophil adherence.

Fisher

Vecchio

Palace

et al. 1991

We previously have described the ability of a-thrombin (the native procoagulant enzyme) to stimulate adherence of neutrophils to pulmonary artery endothelial cells. In the present study, we observed that conditioned medium factors released by a-thrombin (10-8 M) treatment of cultured ovine pulmonary artery endothelial cells increased neutrophil adherence to naive pulmonary artery endothelial monolayers. This effect was independent of any residual aothrombin present in the medium. In contrast to thrombin-induced neutrophil adherence, adherence of neutrophils mediated by the conditioned medium was not inhibited by the anti-CD18 monoclonal antibody 60.3, indicating a CD18-independent mechanism. The factors generated by the action of a-thrombin on endothelial cells also resulted in concentrationdependent neutrophil migration. The neutrophil adherence-and migration-promoting activities were isolated in the ether portion after extraction of the conditioned medium. Chromatographic analysis showed that the active components (which resolved into two peaks by reversed-phase high-performance liquid chromatography) were relatively hydrophilic low molecular weight lipids without phosphorus or amino acids. Reconstitution of these peaks indicated that they mediated neutrophil adhesion and migration responses. The results indicate that lipid factors promoting neutrophil adhesion and migration are generated by the action of thrombin on pulmonary artery endothelial cells. The generation of these factors may contribute to the amplification of the lung inflammatory response after pulmonary intravascular coagulation induced by thrombin. (Circulation Research 1991;68:930-939) T hrombin-induced pulmonary intravascular coagulation increases pulmonary capillary permeability to protein.1-3 This response is characterized by formation of interendothelial junctional gaps and endothelial injury.1'4 The intravenous infusion of a-thrombin in animal models causes the uptake of neutrophils in the pulmonary vascular bed, which precedes the increase in capillary permeability.5-8 Neutrophil-derived oxidants and proteases have been implicated in mediating the thrombininduced pulmonary microvascular injury.9The basis of pulmonary vascular neutrophil uptake after pulmonary intravascular coagulation remains unFrom the

“…The caudal mediastinal node and its efferent duct were identified through a right thoracotomy; the duct was isolated for collection of pulmonary lymph (Erdmann et al, 1975;Malik and van der Zee, 1978). The node was resected just caudal to the distal margin of the pulmonary ligament to eliminate most systemic contamination (Erdmann et al, 1975;Malik and van der Zee, 1978).…”

mentioning

confidence: 99%

Role of intravascular coagulation and granulocytes in lung vascular injury after bone marrow embolism.

Barie¹,

Malik²

1982

SUMMARY. We examined the role of intravascular coagulation and granulocytes in mediating the alterations in pulmonary transvascular fluid and protein exchange after an intravenous injection of bone marrow. The injection of 0.2 ml/kg of bone marrow suspension (BMS) increased pulmonary arterial pressure (Ppi) and pulmonary vascular resistance (PVR) indicating the embolization of pulmonary vessels. BMS also produced steady state increases in pulmonary lymph flow (Qlym), lymph-to-plasma concentration (L/P) ratio, and lymph protein clearance (Qlym X L/P ratio). An increase in pulmonary microvascular pressure (Pmv) produced by inflating a left atrial balloon catheter after injection of BMS produced further increases in Qlym and protein clearance without a decrease in L/P ratio, indicating that the small quantities of marrow increased lung endothelial permeability to proteins. Defibrinogenation induced by treating sheep with Ancrod prevented the increases in Qlym, L/P ratio, protein clearance, Ppi, and PVR after the injection of BMS. To test whether defibrinogenation prevented the increase in endothelial permeability, Pmv was increased after injection of BMS in Ancrod-treated sheep. In contrast to the control animals, in the defibrinogenated sheep, Qlym increased but L/P ratio decreased. In another group, the role of granulocytes in mediating the marrow-induced increase in lung vascular permeability was examined by granulocyte depletion produced with hydroxyurea. Injection of BMS resulted in an increase in Qlym and decreased in L/P ratio, changes which could be explained by increased Pmv. Therefore, granulocyte depletion, like fibrinogen depletion, also inhibited the increase in permeability. However, in contrast to defibrinogenation, granulocytopenia did not inhibit the increases in P^j and PVR after the marrow injection. The results indicate that fibrinogen depletion prevents pulmonary vascular obstruction after injection of BMS and the associated increase in pulmonary endothelial permeability, whereas granulocyte depletion prevents only the increase in permeability. Therefore, both intravascular coagulation and granulocytes are required for the development of lung vascular injury after bone marrow pulmonary embolism. (Circ Res 50: 830-838, 1982)