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)

Alcohol abuse markedly increases the risk of sepsis-mediated acute lung injury. In a rat model, ethanol ingestion alone (in the absence of any other stress) causes pulmonary glutathione depletion, increased expression of transforming growth factor-beta1 (TGF-beta1), and alveolar epithelial barrier dysfunction, even though the lung appears grossly normal. However, during endotoxemia, ethanol-fed rats release more activated TGF-beta1 into the alveolar space where it can exacerbate epithelial barrier dysfunction and lung edema. Ethanol ingestion activates the renin-angiotensin system, and angiotensin II is capable of inducing oxidative stress and TGF-beta1 expression. We determined that lisinopril, an angiotensin-converting enzyme inhibitor that decreases angiotensin II formation, limited lung glutathione depletion, and treatment with either lisinopril or losartan, a selective angiotensin II type 1 receptor blocker, normalized TGF-beta1 expression. The glutathione precursor procysteine also prevented TGF-beta1 expression, suggesting that TGF-beta1 may be induced indirectly by angiotensin II-mediated oxidative stress and glutathione depletion. Importantly, lisinopril treatment normalized barrier function in alveolar epithelial cell monolayers from ethanol-fed rats, and treatment with either lisinopril or losartan normalized alveolar epithelial barrier function in ethanol-fed rats in vivo, as reflected by lung liquid clearance of an intratracheal saline challenge, even during endotoxemia. In parallel, lisinopril treatment limited TGF-beta1 protein release into the alveolar space during endotoxemia. Together, these results suggest that angiotensin II mediates oxidative stress and the consequent TGF-beta1 expression and alveolar epithelial barrier dysfunction that characterize the alcoholic lung.
Am J Physiol Lung Cell Mol Physiol 2005 Sep
PMID:Angiotensin II mediates glutathione depletion, transforming growth factor-beta1 expression, and epithelial barrier dysfunction in the alcoholic rat lung. 1590 76

Reexpansion of a collapsed lung increases the microvascular permeability and causes reexpansion pulmonary edema. Neutrophils and their products have been implicated in the development of this phenomenon. The small GTP-binding proteins Rho and its target Rho-kinase (ROCK) regulate endothelial permeability, although their roles in reexpansion pulmonary edema remain unclear. We studied the contribution of ROCK to pulmonary endothelial and epithelial permeability in a rabbit model of this disorder. Endothelial and epithelial permeability was assessed by measuring the tissue-to-plasma (T/P) and bronchoalveolar lavage (BAL) fluid-to-plasma (B/P) ratios with (125)I-labeled albumin. After intratracheal instillation of (125)I-albumin, epithelial permeability was also assessed from the plasma leak (PL) index, the ratio of (125)I-albumin in plasma/total amount of instilled (125)I-albumin. T/P, B/P, and PL index were significantly increased in the reexpanded lung. These increases were attenuated by pretreatment with Y-27632, a specific ROCK inhibitor. However, neutrophil influx, neutrophil elastase activity, and malondialdehyde concentrations in BAL fluid collected from the reexpanded lung were not changed by Y-27632. In endothelial monolayers, Y-27632 significantly attenuated the H(2)O(2)-induced increase in permeability and mitigated the morphological changes in the actin microfilament cytoskeleton of endothelial cells. These in vivo and in vitro observations suggest that the Rho/ROCK pathway contributes to the increase in alveolar barrier permeability associated with reexpansion pulmonary edema.
Am J Physiol Lung Cell Mol Physiol 2005 Dec
PMID:Role of Rho-kinase in reexpansion pulmonary edema in rabbits. 1600 83

Clinical and laboratory data indicate that the liver plays an important role in the incidence, pathogenesis, and outcome of acute lung injury/acute respiratory distress syndrome. To distinguish direct effects of endotoxin on the lungs from liver-dependent effects during the early phase of the response to endotoxemia, we used an in situ perfused piglet preparation in which only the ventilated lung or both the lung and liver could be included in a blood perfused circuit. We monitored pulmonary vascular resistance, oxygenation, neutrophil count, lung edema as reflected by wet-dry weights of lung tissue, perfusate concentrations of TNF-alpha, IL-6, and 8-isoprostane (a marker of oxidative stress), and activation of the transcription factor (NF-kappaB) in lung tissue before and for 2 h after endotoxin. When only the lung was perfused, endotoxin caused pulmonary hypertension and neutropenia; but oxygenation was maintained; TNF-alpha, IL-6, and 8-isoprostane levels were minimally elevated; and there was no lung edema. When both the liver and lung were perfused, endotoxin caused marked hypoxemia, large increases in perfusate TNF-alpha, IL-6, and 8-isoprostane concentrations, and severe lung edema. NF-kappaB activation in the lung was greatest when the liver was in the perfusion circuit. We conclude that the direct effects of endotoxemia on the lungs include vasoconstriction and leukocyte sequestration, but not lung injury. Intense activation of the inflammatory response and oxidative injury that results in pulmonary edema and hypoxemia (acute lung injury) requires interaction of the lungs with the liver.
Am J Physiol Lung Cell Mol Physiol 2005 Nov
PMID:Endotoxin-induced acute lung injury requires interaction with the liver. 1600 84

Vascular endothelial growth factor (VEGF)-mediated physiological angiogenesis results from the concerted action of three major VEGF isoforms (VEGF121, 165, 189), which arise from alternate splicing. We have previously shown that expression of a mixture of VEGF isoforms via gene transfer is considerably more potent than expression of a single VEGF isoform. To test the hypothesis that different mixtures of VEGF isoforms may offer the same therapeutic benefit with a better safety profile, we compared the efficacy and safety of an adenovirus gene transfer vector expressing the three major VEGF isoforms (AdVEGF-All) in the normal ratio to those of AdVEGF-All6A+, in which the splicing sequences for exon 6A were altered to promote expression of VEGF189 at the expense of VEGF121. Both vectors were equally potent in mediating recovery of hind-limb blood flow following experimental ischemia. By contrast, intravenous administration of AdVEGF-All6A+ yielded enhanced survival and a lower capacity to support tumor growth compared to AdVEGF-All, and intratracheal administration of AdVEGF-All6A+ resulted in less pulmonary edema than that of AdVEGF-All. We conclude that AdVEGF-All and AdVEGF-All6A+ are similar in potency but that AdVEGF-All6A+ is safer. This suggests that AdVEGF-All6A+ may be the preferred candidate for clinical development.
Mol Ther 2005 Oct
PMID:Alteration of splicing signals in a genomic/cDNA hybrid VEGF gene to modify the ratio of expressed VEGF isoforms enhances safety of angiogenic gene therapy. 1603 63

Viral respiratory infections increase the susceptibility of young animals to hypoxia-induced pulmonary edema formation. Previous work has shown that increased lung levels of endothelin (ET) contribute to this effect, though the mechanisms by which ET promotes vascular leak remain uncertain. Both in vitro and in vivo evidence suggests that ET can upregulate the production of VEGF, which is known to increase vascular permeability. We hypothesized that increases in lung ET promote increases in lung VEGF, which in turn increases vascular leak in the lung. Weanling rats were exposed to moderate hypoxia for 24 h while recovering from a mild viral respiratory infection, to hypoxia alone, or to viral infection alone. Lung VEGF mRNA and protein content were measured by RT-PCR and Western blotting, respectively. Animals exposed to hypoxia + virus demonstrated significant increases in lung VEGF mRNA and protein content. Immunohistochemical studies showed increased VEGF expression in alveolar septa and small pulmonary vessels in those animals. ET receptor blockade with bosentan prevented this increase in lung VEGF content, suggesting that ET promotes VEGF accumulation in the lung in this setting. Animals exposed to hypoxia + virus also demonstrated substantial increases in lung albumin extravasation, and those increases were blocked by both ET receptor blockade and VEGF antagonism. These findings suggest that ET-driven increases in lung VEGF content can contribute to the formation of pulmonary edema.
Am J Physiol Lung Cell Mol Physiol 2005 Dec
PMID:Endothelin-mediated increases in lung VEGF content promote vascular leak in young rats exposed to viral infection and hypoxia. 1604 Jun 26

The mechanisms of pulmonary edema resolution are different from those regulating edema formation. Absorption of excess alveolar fluid is an active process that involves vectorial transport of Na+ out of alveolar air spaces with water following the Na+ osmotic gradient. Active Na+ transport across the alveolar epithelium is regulated via apical Na+ and chloride channels and basolateral Na-K-ATPase in normal and injured lungs. During lung injury, mechanisms regulating alveolar fluid reabsorption are inhibited by yet unclear pathways and can be upregulated by pharmacological means. Better understanding of the mechanisms that regulate edema clearance may lead to therapeutic interventions to improve the ability of lungs to clear fluid, which is of clinical significance.
Am J Physiol Lung Cell Mol Physiol 2005 Nov
PMID:Mechanisms of pulmonary edema clearance. 1621 19

Stimulation of dopamine receptors in the lung or kidney epithelia has distinct and opposite effects on the function of Na,K-ATPase, which results in increased Na(+) absorption across the alveolar epithelium and increased sodium excretion via the kidney epithelium. In the lung, dopamine increases Na,K-ATPase by increasing cell basolateral surface expression of Na(+),K(+)-ATPase molecules, whereas in the kidney epithelia it decreases Na(+),K(+)-ATPase activity by removing active units from the plasma membrane by endocytosis. The opposite effects of dopamine over the same target (the Na(+),K(+)-ATPase) involve the activation of a distinct signaling network that it is target specific, and has a different spatial resolution. Understanding the specific signaling pathways involved in these actions of dopamine and their hierarchical organization may facilitate the drug discovery process that could lead to the design of new therapeutic approaches to clear lung edema in patients with acute lung injury and to decrease fluid overload during congestive heart failure and hypertension.
Am J Respir Cell Mol Biol 2005 Nov
PMID:The dopamine paradox in lung and kidney epithelia: sharing the same target but operating different signaling networks. 1623 32

Fumonisin B(1) is a mycotoxin produced by Fusarium verticillioides, frequently associated with corn. It produces species-specific and organ-specific toxicity, including equine leukoencephalomalacia, porcine pulmonary edema, and hepatic or renal damage in most animal species. Fumonisin B(1) perturbs sphingolipid metabolism by inhibiting ceramide synthase. Our previous studies indicated that fumonisin B(1) caused localized activation of cytokines in liver produced by macrophages and other cell types that modulate fumonisin B(1) induced hepatic apoptosis in mice. The role of tumor necrosis factor alpha (TNFalpha) in fumonisin B(1) mediated hepatocyte apoptosis has been established; not much is known about the downstream events leading to apoptosis. In the current study, fumonisin B(1) induced apoptosis in primary culture of liver cells. In consistence with previous reports, fumonisin B(1) caused accumulation of sphingoid bases and led to increase in TNFalpha expression. Phosphorylated and total c-Jun NH(2)-terminal kinase (JNK) activities were increased after 24 h fumonisin B(1) treatment. JNK inhibitor (SP600125) and anti-TNFalpha reduced the apoptosis induced by fumonisin B(1). The role of JNK signaling in fumonisin B(1) induced apoptosis is downstream of TNFalpha production, as fumonisin B(1)-mediated activation of JNK was reduced by the presence of anti-TNFalpha in the medium, whereas the presence of JNK inhibitor did not change the fumonisin B(1) induced TNFalpha expression. Results of this study imply that generation of fumonisin B(1) induced TNFalpha results in modulation of mitogen activated protein kinases, particularly of JNK, and provides a possible mechanism for apoptosis in murine hepatocytes.
J Biochem Mol Toxicol 2005
PMID:Tumor necrosis factor alpha-mediated activation of c-Jun NH(2)-terminal kinase as a mechanism for fumonisin B(1) induced apoptosis in murine primary hepatocytes. 1642 93

Enterovirus 71 (EV71) is one of the main causative agents of hand, foot and mouth disease (HFMD) in young children. Infections caused by EV71 could lead to many complications, ranging from brainstem encephalitis to pulmonary oedema, resulting in high mortality. Thus, rapid detection of the virus is required to enable measures to be implemented in preventing widespread transmission. Based on primers and probes targeting at the VP1 region, a real-time reverse-transcriptase polymerase chain reaction (RT-PCR) hybridization probe assay was developed for specific detection of EV71 from clinical specimens. Quantitative analysis showed that the assay was able to detect as low as 5 EV71 viral copies and EV71 was detected from 46 of the 55 clinical specimens obtained from pediatric patients suffering from HFMD during the period from 2000 to 2003 in Singapore. This study showed that the single tube real-time RT-PCR assay developed in this study can be applied as a rapid and sensitive method for specific detection of EV71 directly from clinical specimens.
Mol Cell Probes 2006 Apr
PMID:Specific detection of enterovirus 71 directly from clinical specimens using real-time RT-PCR hybridization probe assay. 1646 Sep 10

Subacute exposure to moderate hypoxia can promote pulmonary edema formation. The tachykinins, a family of proinflammatory neuropeptides, have been implicated in the pathogenesis of pulmonary edema in some settings, including the pulmonary vascular leak associated with exposure to hypoxia. The effects of hypoxia on tachykinin receptor and peptide expression in the lung, however, remain poorly understood. We hypothesized that subacute exposure to moderate hypoxia increases lung neurokinin-1 (NK-1) receptor expression as well as lung substance P levels. We tested this hypothesis by exposing weanling Sprague-Dawley rats to hypobaric hypoxia (barometric pressure 0.5 atm) for 0, 24, 48, or 72 h. Hypoxia led to time-dependent increases in lung NK-1 receptor mRNA expression and lung NK-1 receptor protein levels at 48 and 72 h of exposure (P < 0.05). Immunohistochemistry and in situ NK-1 receptor labeling with substance P-conjugated fluorescent nanocrystals demonstrated that hypoxia increased NK-1 expression primarily in the pulmonary microvasculature and in alveolar macrophages. Hypoxia also led to increases in lung substance P levels by 48 and 72 h (P < 0.05) but led to a decrease in preprotachykinin mRNA levels (P < 0.05). We conclude that subacute exposure to moderate hypoxia upregulates lung NK-1 receptor expression and lung substance P peptide levels primarily in the lung microvasculature. We speculate that this effect may contribute to the formation of pulmonary edema in the setting of regional or environmental hypoxia.
Am J Physiol Lung Cell Mol Physiol 2006 Jul
PMID:Hypoxia upregulates lung microvascular neurokinin-1 receptor expression. 1646 32


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