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 identification of plasma markers of the course of the acute respiratory distress syndrome (ARDS) is needed to improve its treatment and to further advance the development of new therapeutic agents. The status of markers of lung injury in ARDS is reviewed and some new potential markers are proposed. This study focused on plasma amino acids, related amino compounds, and catecholamine levels during the acute phase of endotoxin-induced lung injury in 8 sheep characterized by the onset of pulmonary edema caused by increased microvascular permeability. A number of significant changes from baseline values were found. During the sixth hour of a 12-hour period of endotoxin infusion, norepinephrine, epinephrine, and alanine levels increased whereas the isoleucine level decreased. During the sixth hour of the immediate postendotoxin period, the taurine level increased while the levels of arginine, citrulline, glycine, isoleucine, methionine, ornithine, serine, threonine, and tryptophan decreased. These findings are compared with prior studies in human subjects detailing the amino acid profile characteristic of advanced sepsis. We conclude that the present profile of catecholamine and amino acid changes during endotoxemia in sheep deserves further study in human subjects to determine its significance as a marker of the early stage of ARDS.
 ...
PMID:A profile of amino acid and catecholamine levels during endotoxin-induced acute lung injury in sheep: searching for potential markers of the acute respiratory distress syndrome. 896 Jun 37

Stimulation of dopaminergic type 1 (D(1)) receptors increases lung edema clearance by regulating Na,K-ATPase function in the alveolar epithelium. We studied the role of serine/threonine protein phosphatases in the Na,K-ATPase regulation by D(1) agonists in A549 cells. We found that low doses of the type 1/2A protein phosphatase inhibitor okadaic acid as well as SV40 small t antigen transiently transfected into A549 cells prevented the D(1) agonist-induced increase in Na,K-ATPase activity and translocation from intracellular pools to the plasma membrane. This was associated with a rapid and transient increase in protein phosphatase 2A activity. We conclude that D(1) stimulation regulates Na,K-ATPase activity by promoting recruitment of Na,K-ATPases from intracellular pools into the basolateral membranes of A549 cells via a type 2A protein phosphatase.
 ...
PMID:A novel role for protein phosphatase 2A in the dopaminergic regulation of Na,K-ATPase. 1100 67

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

Barrier dysfunction of pulmonary endothelial monolayer is associated with dramatic cytoskeletal reorganization, activation of actomyosin contractility, and gap formation. The linkage between the microtubule (MT) network and the contractile cytoskeleton has not been fully explored, however, clinical observations suggest that intravenous administration of anti-cancer drugs and MT inhibitors (such as the vinca alkaloids) can lead to the sudden development of pulmonary edema in breast cancer patients. In this study, we investigated the crosstalk between MT and actomyosin cytoskeleton and characterized specific molecular mechanisms of endothelial cells (EC) barrier dysfunction induced by MT inhibitor nocodazole (ND). Our results demonstrate that MT disassembly by ND induced rapid decreases in transendothelial electrical resistance (TER) and actin cytoskeletal remodeling, indicating EC barrier dysfunction. These effects involved ND-induced activation of Rho GTPase. Rho-mediated activation of its downstream target, Rho-kinase, induced phosphorylation of Rho-kinase effector EC MLC phosphatase (MYPT1) at Thr(696) and Thr(850) resulting in MYPT1 inactivation. Phosphatase inhibition leaded to accumulation of diphospho-MLC, which induced acto-myosin polymerization, stress fiber formation and gap formation. Inhibition of Rho-kinase by Y27632 abolished ND-induced MYPT1 phosphorylation, MLC phosphorylation, and stress fiber formation. In addition, MT preservation via the MT stabilizer paclitaxel, Rho inhibition (via C3 exotoxin, or dominant negative (DN)-Rho, or DN-Rho-kinase) attenuated ND-induced TER decreases, stress fiber formation and MLC phosphorylation. Collectively, our results demonstrate a leading role for Rho-dependent mechanisms in crosstalk between the MT and actomyosin cytoskeleton, and suggest Rho-kinase and MYPT1 as major Rho effectors mediating pulmonary EC barrier disruption in response to ND-induced MT disassembly.
 ...
PMID:Microtubule disassembly induces cytoskeletal remodeling and lung vascular barrier dysfunction: role of Rho-dependent mechanisms. 1528 Oct 89

Ceramide is a lipid second messenger that was recently identified as mediator of pulmonary edema in vivo. Here, we investigated the effect of ceramide on the permeability of confluent endothelial cell monolayers. In monolayers of bovine pulmonary artery and human microvascular pulmonary endothelial cells, incubation with C6-ceramide for 3 h elevated permeability in a concentration-dependent manner, whereas dihydroceramide was without effect. After 3 h of incubation with ceramide, we found no signs of necrosis (release of lactate dehydrogenase, loss of thiazylyl blue reduction) or apoptosis (ssDNA, caspase-8 activity). The increased endothelial permeability in response to ceramide was attenuated by the Ser/Thr protein kinase inhibitors K252a, K252b and H-7, as well as by the phosphatidylinositol-specific phospholipase C inhibitor L108. Since in some systems sphingosine-1-phosphate (S1P) acts antagonistic to ceramide, the effect of S1P was studied. S1P transiently increased endothelial cell resistance, whether it was given together with ceramide or 90 min thereafter. These data provide a novel example of the antagonism between S1P and ceramide. Our findings further suggest that ceramide alters vascular permeability by activation of pathways dependent on unidentified phospholipase C and Ser/Thr kinase isoenzymes.
 ...
PMID:Ceramide alters endothelial cell permeability by a nonapoptotic mechanism. 1573 57

Multiple endocrine neoplasia (MEN) type 2B is a rare hereditary disorder characterized by medullary thyroid carcinoma, pheochromocytoma, and neuroma. Early signs of MEN 2B are usually neuroma, gastrointestinal problems, and medullary thyroid carcinoma. Noncardiogenic pulmonary edema is rare as a presenting symptom. We report a 31-year-old male who was admitted to our hospital because of noncardiogenic pulmonary edema. He was 168 cm in height, weighed 55 kg, and had an arm span of 166 cm. No marfanoid habitus was evident, but thickened lips and tongue neuroma were present. Chronic constipation had been present since childhood, and the patient had a two-year history of untreated hypertension. Noncardiogenic pulmonary edema and toxic megacolon were noted, and abdominal computed tomography revealed bilateral adrenal tumors. Ultrasonography of the thyroid showed two mass lesions. Intubation and mechanical ventilation were performed because of severe hypoxemia. Endocrinological examinations showed high levels of serum and urinary fractionated catecholamines, serum calcitonin, serum carcinoembryonic antigen, and serum intact parathyroid hormone. It was suggested that the high level of catecholamine from pheochromocytoma had caused the pulmonary edema. RET gene analysis showed a codon 918 mutation in exon 16 resulting in an ATG (methionine) to ACG (threonine) substitution, but analysis of the patient's parents showed the wild type. Therefore, the patient was diagnosed as having de novo MEN 2B. He underwent laparoscopic bilateral adrenectomy and total thyroidectomy. However, the values of serum calcitonin and CEA did not decrease to the normal ranges. Patients with early-stage MEN 2B have distinct characteristics that can aid early detection of the disease, thus possibly allowing them to be saved.
 ...
PMID:De novo multiple endocrine neoplasia type 2B with noncardiogenic pulmonary edema as the presenting symptom. 1682 4

Reversible phosphorylation of cytoskeletal and cytoskeleton-associated proteins is a significant element of endothelial barrier function regulation. Therefore, understanding the mechanisms of phosphorylation/dephosphorylation of endothelial cell cytoskeletal proteins is vital to the treatment of severe lung disorders such as high permeability pulmonary edema. In vivo, there is a controlled balance between the activities of protein kinases and phosphatases. Due to various external or internal signals, this balance may be shifted. The actual balances at a given time alter the phosphorylation level of certain proteins with appropriate physiological consequences. The latest information about the structure and regulation of different types of Ser/Thr protein phosphatases participating in the regulation of endothelial cytoskeletal organization and barrier function will be reviewed here.
 ...
PMID:Regulation of vascular endothelial cell barrier function and cytoskeleton structure by protein phosphatases of the PPP family. 1769 86

Exercise training (ET) is a coadjuvant therapy in preventive cardiology. It delays cardiac dysfunction and exercise intolerance in heart failure (HF); however, the molecular mechanisms underlying its cardioprotection are poorly understood. We tested the hypothesis that ET would prevent Ca(2+) handling abnormalities and ventricular dysfunction in sympathetic hyperactivity-induced HF mice. A cohort of male wild-type (WT) and congenic alpha(2A)/alpha(2C)-adrenoceptor knockout (alpha(2A)/alpha(2C)ARKO) mice with C57BL6/J genetic background (3-5 mo of age) were randomly assigned into untrained and exercise-trained groups. ET consisted of 8-wk swimming session, 60 min, 5 days/wk. Fractional shortening (FS) was assessed by two-dimensional guided M-mode echocardiography. The protein expression of ryanodine receptor (RyR), phospho-Ser(2809)-RyR, sarcoplasmic reticulum Ca(2+) ATPase (SERCA2), Na(+)/Ca(2+) exchanger (NCX), phospholamban (PLN), phospho-Ser(16)-PLN, and phospho-Thr(17)-PLN were analyzed by Western blotting. At 3 mo of age, no significant difference in FS and exercise tolerance was observed between WT and alpha(2A)/alpha(2C)ARKO mice. At 5 mo, when cardiac dysfunction is associated with lung edema and increased plasma norepinephrine levels, alpha(2A)/alpha(2C)ARKO mice presented reduced FS paralleled by decreased SERCA2 (26%) and NCX (34%). Conversely, alpha(2A)/alpha(2C)ARKO mice displayed increased phospho-Ser(16)-PLN (76%) and phospho-Ser(2809)-RyR (49%). ET in alpha(2A)/alpha(2C)ARKO mice prevented exercise intolerance, ventricular dysfunction, and decreased plasma norepinephrine. ET significantly increased the expression of SERCA2 (58%) and phospho-Ser(16)-PLN (30%) while it restored the expression of phospho-Ser(2809)-RyR to WT levels. Collectively, we provide evidence that improved net balance of Ca(2+) handling proteins paralleled by a decreased sympathetic activity on ET are, at least in part, compensatory mechanisms against deteriorating ventricular function in HF.
 ...
PMID:Exercise training delays cardiac dysfunction and prevents calcium handling abnormalities in sympathetic hyperactivity-induced heart failure mice. 1797 26

Endothelial cell (EC) barrier disruption induced by inflammatory agonists such as thrombin leads to potentially lethal physiological dysfunction such as alveolar flooding, hypoxemia, and pulmonary edema. Thrombin stimulates paracellular gap and F-actin stress fiber formation, triggers actomyosin contraction, and alters EC permeability through multiple mechanisms that include protein kinase C (PKC) activation. We previously have shown that the ezrin, radixin, and moesin (ERM) actin-binding proteins differentially participate in sphingosine-1 phosphate-induced EC barrier enhancement. Phosphorylation of a conserved threonine residue in the COOH-terminus of ERM proteins causes conformational changes in ERM to unmask binding sites and is considered a hallmark of ERM activation. In the present study we test the hypothesis that ERM proteins are phosphorylated on this critical threonine residue by thrombin-induced signaling events and explore the role of the ERM family in modulating thrombin-induced cytoskeletal rearrangement and EC barrier function. Thrombin promotes ERM phosphorylation at this threonine residue (ezrin Thr567, radixin Thr564, moesin Thr558) in a PKC-dependent fashion and induces translocation of phosphorylated ERM to the EC periphery. Thrombin-induced ERM threonine phosphorylation is likely synergistically mediated by protease-activated receptors PAR1 and PAR2. Using the siRNA approach, depletion of either moesin alone or of all three ERM proteins significantly attenuates thrombin-induced increase in EC barrier permeability (transendothelial electrical resistance), cytoskeletal rearrangements, paracellular gap formation, and accumulation of phospho-myosin light chain. In contrast, radixin depletion exerts opposing effects on these indexes. These data suggest that ERM proteins play important differential roles in the thrombin-induced modulation of EC permeability, with moesin promoting barrier dysfunction and radixin opposing it.
...
PMID:Ezrin/radixin/moesin proteins differentially regulate endothelial hyperpermeability after thrombin. 2372 86