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

The primary goal of this study was to determine whether Tx2-5, a sodium channel selective toxin obtained from the venom of the spider Phoneutria nigriventer, produced penile erection by means of nitric oxide mechanism. Toxin identity was analyzed by MALDI-TOF, ES-MS and N-terminal amino acid sequencing. Pretreating mice with the non-selective nitric oxide synthase (NOS) inhibitor N(omega)-Nitro-L-arginine methyl ester hydrochloride (L-NAME) and the selective neuronal-NOS inhibitor 7-Nitroindazole (7-NI) prior to Tx2-5 i.p. (10 microg/25 g mouse) injection challenged the hypothesis above. Controls were injected with the D-isomer or DMSO or saline. Results demonstrated that L-NAME inhibited penile erections in about half the animals treated, while 7-NI completely abolished this effect. Interestingly 7-NI also abolished all the other symptoms of intoxication induced by Tx2-5, including salivation, respiratory distress and death. Tx2-5 killed all the animals of the control group and no one in the 7-NI-treated group. We conclude that (1) intraperitoneal injections of Tx2-5 induce a toxic syndrome that include penile erection, hypersalivation and death by respiratory distress or pulmonary edema; (2) pretreatment with the non-selective NOS inhibitor L-NAME reduces the penile erection and partially protects from the lethal effects of Tx2-5; (3) pretreatment with the nNOS-selective inhibitor 7-NI completely abolishes all the toxic effects of Tx2-5, including penile erection and death suggesting that nNOS is the major player in this intoxication; (4) toxins from other animals that affect sodium channels in the same way as Tx2-5 and induce similar toxic syndromes may have as a major common target, the activation of nitric oxide synthases.
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PMID:Blockade of neuronal nitric oxide synthase abolishes the toxic effects of Tx2-5, a lethal Phoneutria nigriventer spider toxin. 1524 65

During the last decade, major advances in the understanding of the mechanism of high altitude pulmonary edema (HAPE) have supplemented the landmark work done in the previous 30 years. A brief review of the earlier studies will be described, which will then be followed by a more complete treatise on the subsequent research, which has elucidated the role of accentuated pulmonary hypertension in the development of HAPE. Vasoactive mediators, such as nitric oxide (NO) and endothelin-1, have played a major role in this understanding and have led to preventive and therapeutic interventions. Additionally, the role of the alveolar epithelium and the Na-K ATPase pump in alveolar fluid clearance has also more recently been understood. Direction for future work will be given as well.
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PMID:Unraveling the mechanism of high altitude pulmonary edema. 1526 34

The present study was undertaken to evaluate possible roles of L-glutamate ionotropic receptors in neurogenic pulmonary edema. Perfusion of L-glutamate into the fourth ventricles of rats increased nitric oxide (NO) signals in the efflux solution concentration-dependently, significantly reducing both the occurrence and severity of neurogenic pulmonary edema. This effect was completely reversed by prior intracisternal injection of an NO synthase inhibitor, N(omega)-nitro-L-arginine methyl ester (L-NAME), or an N-methyl-D-aspartate (NMDA) receptor antagonist, dizocilpine maleate (MK-801), and partially by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), a 2-amino-3-hydroxy-5-methyl-4-isoxazol propionic acid (AMPA)/kainic acid receptor antagonist. Administration of MK-801 or CNQX alone, without L-glutamate, almost completely prevented neurogenic pulmonary edema development. These results suggest that endogenous L-glutamate may facilitate underlining disease process, whereas L-glutamate exogenously applied into the fourth ventricle may have an inhibitory action via release of NO, through ionotropic receptors.
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PMID:A role for L-glutamate ionotropic receptors in the development of rat neurogenic pulmonary edema. 1538 Oct 47

Chronic hypoxia, viral infections/bacterial toxins, inflammation states, biochemical disorders, and genetic abnormalities are the most likely trigger of sudden infant death syndrome (SIDS). Autopsy studies have shown increased pulmonary density of macrophages and markedly more eosinophils in the lungs accompanied by increased T and B lymphocytes. The elevated levels of immunoglobulins, about 20% more muscle in the pulmonary arteries, increased airway smooth muscle cells, and increased fetal hemoglobin and erythropoietin are evidence of chronic hypoxia before death. Other abnormal findings included mucosal immune stimulation of the tracheal wall, duodenal mucosa, and palatine tonsils, and circulating interferon. Low normal or higher blood levels of cortisol often with petechiae on intrathoracic organs, depleted maternal IgG antibodies to endotoxin core (EndoCAb) and early IgM EndoCAb triggered, partial deletions of the C4 gene, and frequent IL-10-592*A polymorphism in SIDS victims as well as possible hypoxia-induced decreased production of antiinflammatory, antiimmune, and antifibrotic cytokine IL-10, may be responsible for the excessive reactions to otherwise harmless infections. In SIDS infants, during chronic hypoxia and times of infection/inflammation, several proinflammatory cytokines are released in large quantities, sometimes also representing a potential source of tissue damage if their production is not sufficiently well controlled, eg, by pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal polypeptide (VIP). These proinflammatory cytokines down-regulate gene expression of major cytochrome P-450 and/or other enzymes with the specific effects on mRNA levels, protein expression, and enzyme activity, thus affecting metabolism of several endogenous lipophilic substances, such as steroids, lipid-soluble vitamins, prostaglandins, leukotrienes, thromboxanes, and exogenous substances. In SIDS victims, chronic hypoxia, TNF-alpha and other inflammatory cytokines, and arachidonic acid (AA) as well as n-3 polyunsaturated fatty acids (FA), stimulated and/or augmented superoxide generation by polymorphonuclear leukocytes, which contributed to tissue damage. Chronic hypoxia, increased amounts of nonheme iron in the liver and adrenals of these infants, enhanced activity of CYP2C9 regarded as the functional source of reactive oxygen species (ROS) in some endothelial cells, and nicotine accumulation in tissues also intensified production of ROS. These increased quantities of proinflammatory cytokines, ROS, AA, and nitric oxide (NO) also resulted in suppression of many CYP450 and other enzymes, eg, phosphoenolpyruvate carboxykinase (PEPCK), an enzyme important in the metabolism of FA during gluconeogenesis and glyceroneogenesis. PEPCK deficit found in SIDS infants (caused also by vitamin A deficiency) and eventually enhanced by PACAP lipolysis of adipocyte triglycerides resulted in an increased FA level in blood because of their impaired reesterification to triacylglycerol in adipocytes. In turn, the overproduction and release of FA into the blood of SIDS victims could lead to the metabolic syndrome and an early phase of type 2 diabetes. This is probably the reason for the secondary overexpression of the hepatic CYP2C8/9 content and activity reported in SIDS infants, which intensified AA metabolism. Pulmonary edema and petechial hemorrhages often present in SIDS victims may be the result of the vascular leak syndrome caused by IL-2 and IFN-alpha. Chronic hypoxia with the release of proinflammatory mediators IL-1alpha, IL-1beta and IL-6, and overloading of the cardiovascular and respiratory systems due to the narrowing airways and small pulmonary arteries of these children could also contribute to the development of these abnormalities. Moreover, chronic hypoxia of SIDS infants induced also production of hypoxia-inducible factor 1alpha (HIF-1alpha), which stimulated synthesis and release of different growth factors by vascular endothelial cells and intensified subclinical inflammatory reactions in the central nervous system, perhaps potentiated also by PACAP and VIP gene mutations. These processes could lead to the development of brainstem gliosis and disorders in the release of neuromediators important for physiologic sleep regulation. All these changes as well as eventual PACAP abnormalities could result in disturbed homeostatic control of the cardiovascular and respiratory responses of SIDS victims, which, combined with the nicotine effects and metabolic trauma, finally lead to death in these often genetically predisposed children.
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PMID:Possible pathomechanisms of sudden infant death syndrome: key role of chronic hypoxia, infection/inflammation states, cytokine irregularities, and metabolic trauma in genetically predisposed infants. 1554 94

Pulmonary veins have been seen primarily as conduit vessels; however, over the past two decades, a large amount of evidence has accumulated to indicate that pulmonary veins can exhibit substantial vasoactivity. In this review, the role of veins in regulation of the pulmonary circulation, particularly during the perinatal period and under certain pathophysiological conditions, is discussed. In the fetus, pulmonary veins contribute a significant fraction to total pulmonary vascular resistance. At birth, the veins as well as the arteries relax in response to endothelium-derived nitric oxide and dilator prostaglandins, thereby assisting in the fall in pulmonary vascular resistance. These effects are oxygen dependent and modulated by cGMP-dependent protein kinase. Under chronic hypoxic conditions, pulmonary veins undergo remodeling and demonstrate substantial constriction and hypertrophy. In a number of species, including the human, pulmonary veins are also the primary sites of action of certain vasoconstrictors such as endothelin and thromboxane. In various pathological conditions, there is an increased synthesis of these vasoactive agents that may lead to pulmonary venous constriction, increased microvascular pressures for fluid filtration, and formation of pulmonary edema. In conclusion, the significant role of veins in regulation of the pulmonary circulation needs to be appreciated to better prevent, diagnose, and treat lung disease.
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PMID:Role of veins in regulation of pulmonary circulation. 1564 May 20

High-altitude pulmonary edema (HAPE) develops in rapidly ascending nonacclimatized healthy individuals at altitudes above 3,000 m. An excessive rise in pulmonary artery pressure (PAP) preceding edema formation is the crucial pathophysiological factor because drugs that lower PAP prevent HAPE. Measurements of nitric oxide (NO) in exhaled air, of nitrites and nitrates in bronchoalveolar lavage (BAL) fluid, and forearm NO-dependent endothelial function all point to a reduced NO availability in hypoxia as a major cause of the excessive hypoxic PAP rise in HAPE-susceptible individuals. Studies using right heart catheterization or BAL in incipient HAPE have demonstrated that edema is caused by an increased microvascular hydrostatic pressure in the presence of normal left atrial pressure, resulting in leakage of large-molecular-weight proteins and erythrocytes across the alveolarcapillary barrier in the absence of any evidence of inflammation. These studies confirm in humans that high capillary pressure induces a high-permeability-type lung edema in the absence of inflammation, a concept first introduced under the term "stress failure." Recent studies using microspheres in swine and magnetic resonance imaging in humans strongly support the concept and primacy of nonuniform hypoxic arteriolar vasoconstriction to explain how hypoxic pulmonary vasoconstriction occurring predominantly at the arteriolar level can cause leakage. This compelling but as yet unproven mechanism predicts that edema occurs in areas of high blood flow due to lesser vasoconstriction. The combination of high flow at higher pressure results in pressures, which exceed the structural and dynamic capacity of the alveolar capillary barrier to maintain normal alveolar fluid balance.
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PMID:Physiological aspects of high-altitude pulmonary edema. 1570 68

An update is given of the circulating markers and mediators of cardiovascular dysfunction in acute illness. Some of these circulating markers reflect mediator action on the peripheral vasculature, such as endothelium-derived endothelin and nitrite/nitritate, the stable end products of nitric oxide. Other markers mainly reflect actions on the heart, such as the natriuretic peptide family, released from the heart upon dilatation, serving as a marker of congestive heart failure and potentially having negative inotropic effects. Indeed, some factors may be both markers as well as mediators of cardiovascular dysfunction of the acutely ill and bear prognostic significance. Assessing circulating levels may help refine clinical judgment of the cardiovascular derangements encountered at the bedside, together with clinical signs and hemodynamic variables. For instance, assessing natriuretic peptides in patients with pulmonary edema of unclear origin may help to diagnose congestive heart failure and cardiogenic pulmonary edema, when the pulmonary capillary wedge pressure is not measured or inconclusive. Future aligning of hemodynamic abnormalities with patterns of circulating cardiovascular markers/mediators may help to stratify patients for inclusion in studies to assess the causes, response to therapy and prognosis of cardiovascular derangements in the acutely ill.
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PMID:Circulating cardiovascular markers and mediators in acute illness: an update. 1574 96

Inhalation of nitric oxide has been reported to alter pulmonary blood flow in animal and human studies. This effect is related to the relaxant action of nitric oxide on arterial vascular smooth muscle cells. When nitric oxide is administered by inhalation, this effect is limited to the pulmonary vasculature as it is rapidly inactivated by hemoglobin as soon as it enters the blood stream. The effect of inhaled nitric oxide is more pronounced in well ventilated areas of the lung, where it promotes redistribution of pulmonary blood flow to regions with high ventilation-perfusion ratio decreasing pulmonary hypertension and improving oxygenation. Nitric oxide has been used to treat pulmonary hypertension and hypoxemia that occurred in thoracic surgery during one lung ventilation, postpneumonectomy pulmonary edema and lung transplantation. Inhaled nitric oxide may be a useful tool in patients with a low PaO2/FiO2 ratio during one lung ventilation. Further powered studies are still required to define the dose and timing of inhaled nitric oxide in patients who do have ischemia-reperfusion injury after lung transplantation.
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PMID:Nitric oxide in thoracic surgery. 1588 94

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are acute life-threatening forms of hypoxemic respiratory failure. ALI/ARDS patients require intensive care with prolonged mechanical ventilation. Despite advances in our understanding of the pathophysiology of ALI/ARDS, mortality rates remain > 30% and survivors suffer significant decrements in their quality of life. The evolving understanding of ALI/ARDS and the complex interactions involved in ALI/ARDS open the door for many potential targets for treatment. The condition is characterised by an acute inflammatory state that leads to increased capillary permeability and accumulation of proteinaceous pulmonary oedema. The changes that occur as a result of this inflammation clinically manifest themselves as hypoxemia, infiltrates on chest radiograph and reduced lung compliance. Many years have been dedicated to analysing the complexities involved in ALI/ARDS in order to improve current and future possibilities for treatment, with the aim of improving patient outcomes. Although some therapies have demonstrated benefits of improved oxygenation, such as surfactant and nitric oxide, these benefits have not translated into reductions in the duration of mechanical ventilation or mortality. Inflammatory mediator-targeted therapies were promising early on; however, larger trials have found therapies such as cytokine modulation, platelet-activating factor inhibition and neutrophil elastase inhibitors to be ineffective in the treatment of ALI/ARDS. Preclinical studies with beta2-agonists and granulocyte macrophage colony-stimulating factor have shown promise for restoring alveolar capillary barrier integrity or reducing pulmonary oedema, and further studies are being conducted to test for true clinical benefit. Despite previous therapeutic failures, newer surfactant formulations have shown promise, particularly in patients with direct forms of lung injury, and are currently in Phase III trials. Anticoagulant therapy with activated protein C has been shown to improve survival in sepsis, the most common risk factor for the development of ALI/ARDS, and is now being studied in ALI/ARDS. Until new data emerge, the focus must remain on supportive care, including optimised mechanical ventilation, nutritional support, manipulation of fluid balance and prevention of intervening medical complications.
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PMID:Evolution of treatments for patients with acute lung injury. 1592 69

NOS-2-derived NO is involved in hypotension, vasoplegia, metabolic disorders and lung injury in endotoxic shock. On the other hand, NOS-3-derived NO protects against LPS-induced lung injury. We have previously shown that NO limits lung injury in the isolated blood-perfused rat lung. Here we characterize the ultrastructure of microvascular lung injury induced by LPS in the absence of endogenous NO and summarize our data on the mechanisms of immediate lung response to LPS in the presence and absence of endogenous NO. Injection of LPS (from E.Coli, 300 microg/ml) into the isolated blood-perfused rat lung induced an immediate transient constriction of airways and vessels that was not associated with lung edema and pulmonary microcirculation injury. In contrast, in the presence of the NOS inhibitor L-NAME (300 microg/ml), LPS produced an enhanced constriction of airways and vessels, which was accompanied by profound lung edema and capillary-alveolar barrier injury, as evidenced by optic and electron microscopy. Microvascular lung injury was confirmed by the following findings: edema of pulmonary endothelium with low electronic density of endothelial cytoplasm, presence of protein-rich fluid and numerous erythrocytes in alveolar space, concentric figures of damaged tubular myelin of surfactant (myelin-like bodies), edema of epithelium type I cells with low electronic density of their cytoplasm and alterations in ultrastructure of basal membrane of vascular-alveolar barrier. Interestingly, epithelial type II cells did not show signs of injury. It is worth noting that capillary-alveolar barrier injury induced by L-NAME+LPS was associated with sequestration of platelets and neutrophils in pulmonary microcirculation and internalization of LPS by neutrophils. In conclusion, in the absence of endogenous nitric oxide LPS induces injury of microvascular endothelium and vascular-alveolar barrier that leads to fatal pulmonary edema. Mechanisms of immediate lung response to LPS in presence of NO and those leading to acute microvascular lung injury in response to LPS in absence of NO are summarized. In our view, immediate lung response to bacterial endotoxin represents a phylogenetically ancient host defence response involving complement-dependent activation of platelets and neutrophils and subsequent production of lipid mediators. This response is designed for a quick elimination of bacterial endotoxin from the circulation and is safeguarded by endothelial NO.
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PMID:Ultrastructure of immediate microvascular lung injury induced by bacterial endotoxin in the isolated, no-deficient lung perfused with full blood. 1620 76


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