Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: HUMANGGP:009336 (ATPase)
 59,826 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fetuses of streptozotocin-induced diabetic rats exhibited delayed lung maturation and a 40% reduction in the steady-state level of lung Na+,K(+)-ATPase alpha 1 subunit mRNA and Na+,K(+)-ATPase activity at 21 d of gestation. In in situ hybridization experiments the signal specific for Na(+)-pump alpha 1 subunit message was strongest above columnar epithelial cells of air-conducting structures. Strong labeling was also present above cuboidal cells lining the forming alveoli, but not above mesenchymal cells. Immunocytochemical localization of the protein paralleled the distribution of the mRNA. Mesenchymal cells were more abundant in fetal lungs of diabetic mothers, and thus the decreased overall levels of Na+,K(+)-ATPase may result from the observed morphological pulmonary immaturity. One day after birth there was no apparent difference in lung morphology at the light microscopic level, in the localization or the steady-state level of Na+,K(+)-ATPase alpha 1 isoform mRNA, or in enzyme activity. Na+,K(+)-ATPase has a likely role in the active phase of fluid absorption in the airways of newborns before the onset of breathing. Decreased fluid clearance and lack of thinning of the lung's connective tissue may contribute to the increased risk for respiratory distress in infants of diabetic mothers.
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PMID:Effects of maternal diabetes on fetal rat lung ion transport. Contribution of alveolar and bronchiolar epithelial cells to Na+,K(+)-ATPase expression. 184 38

Active ion transport plays a critical role in the liquid movement across the fetal and perinatal lung epithelium. The fetal lung liquid production is coupled with active secretion of Cl- into the luminal space. The potential for fluid absorbing mechanisms related to active Na+ transport from the apical to the basolateral side of the epithelium appears near the end of gestation. At birth there is a dramatic change of environment with commencement of air-breathing, sudden increase in oxygen partial pressure (PO2) and profound changes in the pulmonary circulation. A concurrent switch from fluid secretion to maintenance of low amounts of alveolar fluid is another major physiological adjustment taking place in the perinatal distal lung epithelium. The fluid-absorbing mechanism is a result of a well-synchronized co-operation between the basolateral membrane Na-K-ATPase and the apical membrane Na+ channels and it promotes salt and water movement from the airspace. Inability of the fetal lung epithelium to switch from fluid secretion to Na+ transport-dependent absorption seems to be an important factor adversely contributing to the respiratory distress of the newborn premature infant.
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PMID:Significance of ion transport during lung development and in respiratory disease of the newborn. 966 91

Several studies have established that transport of sodium from the air spaces to the lung interstitium is a primary mechanism driving alveolar fluid clearance, although further work is needed to determine the role of chloride in vectorial fluid transport across the alveolar epithelium. Although there are significant differences among species in the basal rates of sodium and fluid transport, the basic mechanism seems to depend on sodium uptake by channels on the apical membrane of alveolar type II cells, followed by extrusion of sodium on the basolateral surface by Na,K-ATPase. This process can be upregulated by several catecholamine-dependent and independent mechanisms. The identification of water channels expressed in lung, together with the high water permeabilities, suggest a potential role for channel-mediated water movement between the air space and capillary compartments, although definitive evidence will depend on the results of transgenic mouse knock-out studies. The application of this new knowledge regarding salt and water transport in alveolar epithelium in relation to pathologic conditions has been successful in clinically relevant experimental studies, as well as in a few clinical studies. The studies of exogenous and endogenous catecholamine regulation of alveolar fluid clearance are a good example of how new insights into the basic mechanisms of alveolar sodium and fluid transport can be translated to clinically relevant experimental studies. Exogenous catecholamines can increase the rate of alveolar fluid clearance in several species, including the human lung, and it is also apparent that release of endogenous catecholamines can upregulate alveolar fluid clearance in animals with septic or hypovolemic shock. It is possible that therapy with beta-adrenergic agonists might be useful to accelerate the resolution of alveolar edema in some patients. In some patients, the extent of injury to the alveolar epithelial barrier may be too severe for beta-adrenergic agonists to enhance the resolution of alveolar edema, although some experimental studies indicate that alveolar fluid clearance can be augmented in the presence of moderately severe lung injury. A longer-term upregulation of alveolar epithelial fluid transport might be achieved by strategies that accelerate the proliferation of alveolar type II cells repopulating the injured epithelium in clinical lung injury. More clinical research is needed to evaluate the strategies that can upregulate alveolar epithelial fluid transport with both short-term therapy (i.e., beta-agonists) and more sustained, longer-term effects of epithelial mitogens such as keratinocyte growth factor. These approaches may be useful in reducing mortality in the acute respiratory distress syndrome.
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PMID:Alveolar epithelial barrier. Role in lung fluid balance in clinical lung injury. 1101 21

Lung epithelial ion transport promotes salt and water movement across the fetal and neonatal lung epithelium. The mechanism is dependent on basolateral membrane Na-K-ATPase and the apical membrane Cl(-) and Na(+) channels. During fetal life active secretion of Cl(-) and parallel movement of Na(+) across the epithelium into the developing lung lumen induce accumulation of liquid into the future airspaces. Postnatally, however, absorption of fluid from the airspaces must start. Present evidence suggests that activation of Na(+) transport from the lumen into the basolateral direction drives fluid absorption and results in an essentially dry air-filled alveolus. In laboratory animals amiloride, a Na(+) channel blocker, induces respiratory distress and impedes lung fluid clearance. One of the epithelial amiloride-sensitive Na(+) channels, ENaC, is composed of three homologous subunits that differentially respond to glucocorticoid hormone. In newborn infants an increase in pulmonary fluid and a defective Na(+) transport associate with respiratory distress. The ontogeny, subunit composition and function of ENaC along the respiratory tract are currently under investigation. It will be interesting to find out whether the subunit composition and function of lung ENaC respond to the therapy of the critically ill newborn infant.
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PMID:Lung epithelial ion transport in neonatal lung disease. 1135 39

Acute respiratory distress syndrome (ARDS) is a life threatening condition associated with great morbidity and mortality. it is characterized initially by accumulation of fluid in the alveolar space that impairs alveolar oxygen exchange. Eventually, this syndrome leads to multiorgan failure. Therefore, rapid edema clearance has generally been associated with better outcome in patients with acute respiratory distress syndrome. Clearance of alveolar fluid is driven predominantly by active Na+ transport out of the alveolar space, mediated by increased apical Na(+)-channel and Na-K-ATPase activity. It has been demonstrated that increases in Na-K-ATPase in response to catecholamines in the alveolar epithelium are associated with increased lung edema clearance. The cellular mechanisms involve the recruitment of new Na-K-ATPase molecules to the plasma membrane from intracellular organelles. It also appears that adenovirus-mediated Na-K-ATPase gene transfer and increased Na-K-ATPase expression may provide an alternative and efficient pathway for transient increase in alveolar fluid reabsorption and resolution of pulmonary edema.
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PMID:[Respiratory distress. New Perspectives to lung edema treatment]. 1203 43

Pulmonary edema is the hallmark of acute respiratory distress syndrome. It occurs when the permeability of the alveolar-capillary barrier is increased, causing alveolar flooding and impaired gas exchange. The mechanisms of alveolar fluid resorption are different from those of alveolar edema formation. Alveolar fluid resorption into the vessels is brought about mainly by active transport of sodium ions (Na+) out of the alveolar spaces with water following the osmotic gradient. Na+ transport across the alveolar epithelium, and thus alveolar fluid resorption, is regulated by apical Na+ channels, the basolateral sodium potassium-adenosine triphosphatase (Na,K-ATPase), and possibly chloride channels. The Na,K-ATPase has been localized to the alveolar epithelium and the importance of its role in contributing to lung edema clearance has been demonstrated. In models of lung injury, several reports have shown that catecholamines such as isoproterenol and dopamine up-regulate Na+ channels and the Na,K-ATPase giving rise to increased alveolar fluid resorption. Although recombinant gene technology is not yet a therapeutic option for the treatment of pulmonary edema, several experimental studies have reported that overexpression of Na,K-ATPase genes causes increased fluid resorption during hyperoxic lung injury. There is significant evidence that fluid clearance is impaired in patients with lung injury. Therapeutic strategies aimed at increasing the ability of alveolar epithelium to resorb the edema should lead to benefits for patients with acute respiratory distress syndrome.
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PMID:Mechanisms of pulmonary edema clearance during acute hypoxemic respiratory failure: role of the Na,K-ATPase. 1268 48

Cysteinyl leukotrienes are increased during acute lung injury in animals and humans. In this study, we determined the effect of leukotriene D4 (LTD4) on the function of Na,K-ATPase in alveolar epithelial cells and on alveolar fluid clearance in rat lungs. LTD4 (1 x 10(-7) M) increased Na,K-ATPase activity at 1 and 5 minutes by 14% (p < 0.05) and 31% (p < 0.001), respectively, in A549 alveolar epithelial cells. This was accompanied by recruitment of Na,K-ATPase alpha1 subunits from intracellular compartment(s) to the basolateral plasma membrane. LTD4-induced alpha1 Na,K-ATPase membrane translocation was blocked by the dual cysteinyl LT1 (cysLT1)/ cysteinyl LT3 (cysLT3) receptor antagonist BAY-u9773, but not by the cysLT1 antagonist MK571, implicating the cysLT3 receptor. Expression of mRNA for cysLT2, but not cysLT1, was confirmed in A549 cells and rat alveolar type 2 cells by reverse transcriptase-polymerase chain reaction. Finally, compared with control, LTD4 (1 x 10(-11) M) increased alveolar fluid clearance by 41% (p < 0.001) in isolated, perfused rat lungs; this was also blocked by BAY-u9773 but not MK571. By activating alveolar epithelial Na,K-ATPase and increasing alveolar fluid reabsorption, cysteinyl leukotrienes may, in part, have a beneficial role in the acute respiratory distress syndrome.
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PMID:Leukotriene D4 activates alveolar epithelial Na,K-ATPase and increases alveolar fluid clearance. 1473 32

We tested the hypothesis that interleukin (IL)-1beta-induced cortisol synthesis stimulates alveolar fluid clearance in preterm fetuses. IL-1beta was administered subcutaneously daily to timed-pregnant guinea pigs for 3 days with and without simultaneous cortisol synthesis inhibition by metyrapone. Fetuses were obtained by abdominal hysterotomy at 61 and 68 days gestation and instilled with isosmolar 5% albumin in the lungs, and alveolar fluid movement was measured over 1 h from the change in alveolar protein concentration. Alveolar fluid clearance was induced at 61 days gestation and stimulated at 68 days gestation by IL-1beta, which both were attenuated by cortisol synthesis inhibition. Plasma ACTH and cortisol concentrations were increased by IL-1beta at both gestational ages, and metyrapone reduced cortisol concentrations. IL-1beta was mostly low or undetectable in both fetal and maternal blood. Prenatal alveolar fluid clearance, when present as well as IL-1beta induced, was always propranolol and amiloride sensitive, suggesting that beta-adrenoceptor stimulation and amiloride-sensitive Na+ channels were critical for fluid absorption. IL-1beta increased lung beta-adrenoceptor density at gestation day 61, and cortisol synthesis inhibition attenuated the increased beta-adrenoceptor density. Epithelial Na+ channel and Na+-K+-ATPase subunit expressions were both increased by IL-1beta and attenuated by cortisol synthesis inhibition. These results may explain why babies delivered preterm after intrauterine inflammation have a reduced risk of developing severe respiratory distress.
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PMID:IL-1beta stimulates alveolar fluid absorption in fetal guinea pig lungs via the hypothalamus-pituitary-adrenal gland axis. 1464 57

The antioxidant and anti-inflammatory properties of N-acetylcysteine has been documented in many experimental lung injury models. Because intravenous injection of oleic acid induces histopathologic changes similar to those seen in human acute lung injury or acute respiratory distress syndrome, the authors evaluated the effects of N-acetylcysteine (NAC) on oxidative stress and lung damage in an oleic acid (OA)-induced lung injury model. Thirty-five rats were divided into 5 groups as sham, NAC, OA, pre-OA-NAC, and post-OA-NAC. Lung damage was induced by intravenous administration of oleic acid. Pre-OA-NACgroup received intravenous (IV) N-acetylcysteine 15 minutes before oleic acid infusion and post-OA-NAC group received IV N-acetylcysteine 2 hours after oleic acid infusion. In both of the N-acetylcysteine treatment groups, blood and tissue samples were collected 4 hours after oleic acid infusion, independent from the time of N-acetylcysteine infusion. In other groups, blood and tissue samples were collected 4 hours after ethanol, NAC, or OA infusions. Serum myeloperoxidase activity, total antioxidant capacity, malondialdehyde levels, and lung tissue Na+ - K+ ATPase activity were measured and light microscopic analyses of lung specimens were performed. The administration of N-acetylcysteine significantly restored Na+ - K+ ATPase activity and total antioxidant capacity levels and ameliorated lung architecture. N-acetylcysteine has been shown to have some attenuating effects in experimental animal studies. However, further investigations are necessary to suggest N-acetylcysteine as a treatment agent in critically ill patients with lung injury.
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PMID:Effects of N-acetylcysteine on oxidant-antioxidant balance in oleic acid-induced lung injury. 1552 3

Levels of oleic acid (OA) are elevated in plasma and bronchoalveolar lavage fluids of patients with acute respiratory distress syndrome (ARDS). OA is also widely used to provoke edema, by unknown mechanisms, in experimental models of ARDS. We investigated the impact of intravascularly applied OA on epithelial lining fluid balance. OA (25 microM) dramatically blocked active transepithelial (22)Na(+) transport (by 92%) in an isolated, ventilated, and perfused rabbit lung model, provoking alveolar edema, assessed by increases in lung weight and epithelial lining fluid volume. OA did not alter epithelial permeability, measured by [(3)H]mannitol and fluorescently labeled albumin flux, but did increase endothelial permeability, assessed by capillary filtration coefficient. In A549 cells, OA completely blocked amiloride-sensitive sodium currents measured by patch clamp, and also largely abrogated ouabain-sensitive Na(+),K(+)-ATPase-mediated (86)Rb(+) uptake. Although OA did not alter epithelial sodium channel or Na(+),K(+)-ATPase surface expression, it covalently associated with both molecules and directly, dramatically, and dose-dependently inhibited the catalytic activity of purified Na(+),K(+)-ATPase. Therefore, OA impaired the two essential transepithelial active sodium transport mechanisms of the lung, and could thus promote alveolar edema formation and prevent edema resolution, thereby contributing to the development of ARDS.
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PMID:Oleic acid inhibits alveolar fluid reabsorption: a role in acute respiratory distress syndrome? 1572 19


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