Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0034063 (pulmonary edema)
 10,665 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of a selective leukotriene receptor antagonist, the peptide ICI 198,615, on thrombin-induced pulmonary edema was studied in rats. Administration of thrombin produced a significant increase in lung weight (p < 0.05), wet weight to dry weight ratio (WW/DW; p < 0.05), and relative lung water content (p < 0.05). These increases were all significantly reduced (p < 0.05) by ICI 198,615 (bolus 15 mg/kg, infusion 15 mg/kg/h). Thrombin infusion caused a significant increase in myeloperoxidase activity in the lung tissue (p < 0.05). This increase was further accentuated by ICI 198,615, indicating that the effect of this antagonist is not due to reduction of leukocyte infiltration in the lungs. The results thus show that a leukotriene receptor antagonist effectively counteracts the increase in lung vascular permeability to protein caused by thrombin, and indicate that leukotrienes are important mediators of thrombin-induced pulmonary edema in the rat.
 ...
PMID:Beneficial effects of a leukotriene receptor antagonist on thrombin-induced pulmonary edema in the rat. 882 Nov 25

The regulation of endothelial permeability is poorly understood. An increase in endothelial permeability in the pulmonary microvasculature, however, is critical in noncardiogenic pulmonary edema and other diffuse inflammatory reactions. In the present study thrombin and Escherichia coli hemolysin (HlyA), a membrane-perturbing bacterial exotoxin, were used to alter hydraulic permeability of porcine pulmonary artery and human endothelial cell monolayers. We also investigated the pharmacological approach of adenylyl cyclase activation/phosphodiesterase (PDE) inhibition to block endothelial hyperpermeability. Thrombin (1-5 units/ml) and HlyA (0.5-3 hemolytic units/ml) dose and time dependently (> 15 min) increased endothelial permeability. Forskolin, cholera toxin, and prostaglandin E1, which all stimulate adenylyl cyclase activity, abrogated this effect. One mM dibutyryl cAMP, a cell membrane-permeable cAMP analogue, was similarly active. Endothelial hyperpermeability was also reduced dose dependently by inhibitors of different PDE isoenzymes (motapizone, rolipram, and zardaverine, which block PDE3 and/or PDE4). The effectiveness of PDE inhibitors was increased in the presence of adenylyl cyclase activators. Analysis of cyclic nucleotide hydrolyzing PDE activity in lysates of human umbilical vein endothelial cells showed high activities of PDE isoenzymes 2, 3, and 4. Consistent with the functional data PDE3 and PDE4 were the major cAMP hydrolysis enzymes in intact endothelial cells. We conclude that the hyperpermeability of pulmonary endothelial monolayers, evoked by thrombin or HlyA, can be blocked by the simultaneous activation of adenylyl cyclase and inhibition of PDEs, especially of PDE3 and PDE4. The demonstration of PDE isoenzymes 2-4 in human endothelial cells will help optimize this therapeutic approach.
 ...
PMID:Hyperpermeability of pulmonary endothelial monolayer: protective role of phosphodiesterase isoenzymes 3 and 4. 883 Jan 94

The effect of a selective leukocyte elastase inhibitor, ICI 200,355, on thrombin-induced pulmonary oedema was studied in rats. Thrombin administration produced an increase in lung weight (P < 0.05), wet weight/ dry weight ratio (P < 0.05), and relative lung water content (P < 0.05). The lung weight increase was reduced by the elastase inhibitor in doses of 2000, 200 and 20 micrograms/kg per h (P < 0.05), but not by 2 micrograms/kg per h. A dose of 20 micrograms/ kg per h seems to be optimal, since 10-fold and 100-fold increases in dose did not further improve the effect. Free elastase activity in lung tissue was higher after thrombin infusion than in controls, but was not depleted by the elastase inhibitor in vivo (P < 0.05). This elastase activity in the lung was, however, inhibited by the elastase inhibitor in vitro, indicating that the inhibitor can block extracellular, but not intracellular elastase activity. Thrombin infusion resulted in a significant decrease in plasma elastase inhibitory capacity (P < 0.05), which was depleted by the elastase inhibitor (20 micrograms/kg per h) (P < 0.05). Myeloperoxidase activity was significantly increased in lung tissue after thrombin infusion (P < 0.05). Lung myeloperoxidase activity 5 min after thrombin infusion was not affected by the elastase inhibitor, but the inhibitor induced a further increase in myeloperoxidase as seen 90 min after thrombin infusion, indicating that the effect of this inhibitor on pulmonary oedema is not due to reduction of leukocyte infiltration in the lungs, but may partly be exerted by prevention of neutrophil destruction.
 ...
PMID:A leukocyte elastase inhibitor reduces thrombin-induced pulmonary oedema in the rat: mechanisms of action. 1010 47

The present study was undertaken to determine the contribution of neuropeptide Y to edema occurrence in neurogenic and hydrostatic pulmonary edema. To induce neurogenic pulmonary edema, fibrinogen and thrombin were injected into the cisterna magna; and to evoke hydrostatic pulmonary edema, saline was infused intravenously. Concentrations of neuropeptide Y in serum and edema fluid were measured using enzyme-linked immunosorbent assay (ELISA), which showed a mean value of 158 nM (95% confidence limit 124-202 nM) in the neurogenic edema fluid, significantly higher than that in the hydrostatic one. Using immunohistochemistry, fluorescent signals reactive to neuropeptide Y were found in the alveolar macrophages and edema fluid in case of fibrin-induced pulmonary edema, but were almost absent in hydrostatic edema and absent in normal lungs. Mean ratio of protein concentrations in edema fluid to that in serum was 74.9 +/- 0.9% in fibrin-induced pulmonary edema, being higher than that in hydrostatic one. From these results, we conclude that neuropeptide Y has a relationship to the high protein concentration ratio, i.e., to increased pulmonary vascular permeability, and consequently may contribute to the development of neurogenic pulmonary edema in rats.
 ...
PMID:Presence and quantification of neuropeptide Y in pulmonary edema fluids in rats. 1081 87

The effects of carbazochrome sodium sulfonate (AC-17), a capillary stabilizer, on pulmonary edema and dysfunction induced by ioxaglate, an ionic radiographic contrast medium, were evaluated in rats. The pulmonary edema was evaluated by the extravasation of intravenously injected Evans blue into lung tissues, while pulmonary dysfunction was determined by monitoring blood gasses including pO(2). Ioxaglate (4 g I/kg, i.v.) caused a marked increase in vascular permeability and a decrease in arterial pO(2). AC-17 reversed the ioxaglate-induced vascular hyperpermeability in a dose-dependent manner. In addition, AC-17 (10 mg/kg) significantly inhibited the decrease in arterial pO(2). In isolated rat pulmonary mast cells, ioxaglate markedly enhanced the histamine release, which was not affected by AC-17. On the other hand, AC-17 did significantly blocked the hyperpermeability induced in cultured bovine endothelial cells by tryptase, thrombin and proteinase-activated receptor-2 agonist peptide (SLIGKV-NH(2)). These findings suggest that AC-17 blocks radiographic contrast medium-induced pulmonary dysfunction by maintaining the endothelial barrier function. Thus, the compound is potentially useful for the prophylaxis of contrast media-induced acute pulmonary adverse events during angiography.
 ...
PMID:Carbazochrome attenuates pulmonary dysfunction induced by a radiographic contrast medium in rats. 1220 59

In the course of investigations on mechanisms underlying development of neurogenic pulmonary edema (NPE), we have evaluated effects of nitric oxide (NO) in the central nervous system on incidence and severity in the fibrin-induced pulmonary edema model. Rats left-unilaterally vagotomized 1, 2 and 4 weeks before injections of fibrinogen and thrombin into the cisterna magna, after cutting the right vagus nerve, grouped as LVIW, LV2W or LV4W, respectively. The brain NO synthase (NOS) mRNA level in the left medulla oblongata was elevated in the LV2W group, compared to the control, but decreased in the LV4W rats. Incidences of pulmonary edema were 100% in the control group, decreasing to 78% in LV1W group, 17% in LV2W group, and back to 72% in LV4W group. The lung water ratio, a parameter of severity, demonstrated a similar pattern of change as the incidence. The lowered incidence and severity obtained in the LV2W group were reversed by intracisternal injection of N-nitro-L-arginine methyl ester (L-NAME). From these results, we propose that an increase in nitric oxide, possibly in the nucleus tractus solitarius 2 weeks after left vagotomy, may have an inhibitory action on the development of neurogenic pulmonary edema in rats.
 ...
PMID:Inhibition of fibrin-induced neurogenic pulmonary edema by previous unilateral left-vagotomy correlates with increased levels of brain nitric oxide synthase in the nucleus tractus solitarii of rats. 1249 29

An 81-year-old man with previous syncopal episodes, progressive shortness of breath, pulmonary edema, severe calcific aortic stenosis, and a history of heparin-induced thrombocytopenia required aortic valve replacement. Bivalirudin, a thrombin-specific anticoagulant, was used in place of heparin. The patient received a 50 mg bivalirudin bolus followed by an infusion between 1.5 mg x kg(-1) x h(-1) and 1.75 mg x kg(-1) x h(-1). Adequate anticoagulation was readily obtained resulting in an uneventful cardiopulmonary bypass. Activated clotting time (ACT) values steadily declined after discontinuation of the bivalirudin infusion. Bivalirudin is a practical alternative to heparin during cardiac surgical procedures.
 ...
PMID:Favorable outcome with bivalirudin anticoagulation during cardiopulmonary bypass. 1253 26

The intracellular serine/threonine kinase protein kinase C (PKC) has an important role in the genesis of pulmonary edema. This review discusses the PKC-mediated mechanisms that participate in the pulmonary endothelial response to agents involved in lung injury characteristic of the respiratory distress syndrome. Thus the paradigms of PKC-induced lung injury are discussed within the context of pulmonary transvascular fluid exchange. We focus on the signal transduction pathways that are modulated by PKC and their effect on lung endothelial permeability. Specifically, alpha-thrombin, tumor necrosis factor (TNF)-alpha, and reactive oxygen species are discussed because of their well-established roles in both human and experimental lung injury. We conclude that PKC, most likely PKC-alpha, is a primary supporter for lung endothelial injury in response to alpha-thrombin, TNF-alpha, and reactive oxygen species.
 ...
PMID:Protein kinase C modulates pulmonary endothelial permeability: a paradigm for acute lung injury. 1257 83

Thrombin-induced barrier dysfunction of pulmonary endothelial monolayer is associated with dramatic cytoskeletal reorganization, activation of actomyosin contraction, and gap formation. Phosphorylation of regulatory myosin light chains (MLC) is a key mechanism of endothelial cell (EC) contraction and barrier dysfunction, which is triggered by Ca(2+)/calmodulin-dependent MLC kinase (MLCK) and Rho-associated kinase (Rho-kinase). The role of MLCK in EC barrier regulation has been previously described; however, Rho-mediated pathway in thrombin-induced pulmonary EC dysfunction is not yet precisely characterized. Here, we demonstrate that thrombin-induced decreases in transendothelial electrical resistance (TER) indicating EC barrier dysfunction are universal for human and bovine pulmonary endothelium, and involve membrane translocation and direct activation of small GTPase Rho and its downstream target Rho-kinase. Transient Rho membrane translocation coincided with translocation of upstream Rho activator, guanosine nucleotide exchange factor p115-RhoGEF. Rho mediated activation of downstream target, Rho-kinase induced phosphorylation of the EC MLC phosphatase (MYPT1) at Thr(686) and Thr(850), resulting in MYPT1 inactivation, accumulation of diphospho-MLC, actin remodeling, and cell contraction. The specific Rho-kinase inhibitor, Y27632, abolished MYPT1 phosphorylation, MLC phosphorylation, significantly attenuated stress fiber formation and thrombin-induced TER decrease. Furthermore, expression of dominant-negative Rho and Rho-kinase abolished thrombin-induced stress fiber formation and MLC phosphorylation. Our data, which provide comprehensive analysis of Rho-mediated signal transduction in pulmonary EC, demonstrate involvement of guanosine nucleotide exchange factor, p115-RhoGEF, in thrombin-mediated Rho regulation, and suggest Rho, Rho-kinase, and MYPT1 as potential pharmacological and gene therapy targets critical for prevention of thrombin-induced EC barrier disruption and pulmonary edema associated with acute lung injury.
 ...
PMID:Role of Rho GTPases in thrombin-induced lung vascular endothelial cells barrier dysfunction. 1470 4

RhoA GTPases modulate endothelial permeability. We have previously shown that adenosine and homocysteine enhance basal barrier function in pulmonary artery endothelial cells by a mechanism involving diminution of RhoA carboxyl methylation and activity. In the current study, we investigated the effects of adenosine and homocysteine on endothelial monolayer permeability in cultured monolayers. Adenosine and homocysteine significantly attenuated thrombin-induced endothelial barrier dysfunction and intercellular gap formation. We found significantly diminished RhoA associated with the membrane subcellular fraction in endothelial cells pretreated with adenosine and homocysteine, compared with vehicle-treated endothelial cells. Additionally, adenosine and homocysteine significantly blunted RhoA activation following thrombin exposure. Incubation with adenosine and homocysteine also enhanced in vitro interactions between RhoA and RhoGDI, as well as subcellular translocation of p190RhoGAP to the cytosol. These data demonstrate that elevated intracellular concentrations of homocysteine and adenosine enhance endothelial barrier function in cultured endothelial cells isolated from the main pulmonary artery and lung microvasculature, suggesting a potentially protective effect against pulmonary edema in response to lung injury. We speculate that homocysteine and adenosine modulate the level of endothelial barrier dysfunction through modulation of RhoA posttranslational processing resulting in diminished GTPase activity through altered interactions with modulators of RhoA activation.
 ...
PMID:Barrier dysfunction and RhoA activation are blunted by homocysteine and adenosine in pulmonary endothelium. 1528 3


<< Previous 1 2 3 4 5 6 Next >>