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)

Ingestion or injection of the herbicide paraquat (1,1'-dimethyl-4,4'-dipyridylium dichloride) has caused more than 120 deaths in humans. Most have been due to respiratory failure caused by pulmonary edema, hemorrhage, and atelectasis, or subsequent pulmonary fibrosis. Paraquat is concentrated in lung tissue and is believed to cause superoxide radical formation in the presence of oxygen and suitable electron donors. Exposure to increased concentrations of oxygen has been reported to accelerate the toxicity of paraquat. The therapeutic efficacy of a reduced oxygen environment was investigated by exposing paraquat-poisoned mice to 10% oxygen after stepwise drops from 14% oxygen. Sixty-one mice were given intraperitoneal injections of 27 mg. per kg. of paraquat. The 25 mice in hypoxia for 7 days had a 32% mortality rate versus a 78% mortality rate for the remainder of the mice in room air, p less than 0.01. After a dose of 20 mg. per kg. of paraquat administered intraperitoneally, 24 mice in hypoxia had a 25% mortality rate versus 51% for 35 animals in room air. Brief exposures of the hypoxic group to "normoxia" (room air) led to pulmonary edema and death. The continuous exposure of paraquat-poisoned animals to hypoxic environments was protective. This approach may be useful in other oxidant lung injuries.
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PMID:Hypoxic protection in paraquat poisoning. 99 61

Paraquat (1,1'-dimethyl-4,4'-bipyridylium dichloride) has in the last decade gained popularity as an effective weedicide. It is marketed for commercial use as a liquid concentrate Gramoxone ICI (20% paraquat). Accidental or intentional ingestion of Gramoxone has caused 232 human deaths between 1964 and 1973 (Anon 1974). Most human patients suffer transient renal and hepatic insufficiency and pulmonary oedema followed after a latent period by progressive pulmonary fibrosis leading to death from respiratory failure (Harrison 1972). The clinical features of non-fatal paraquet poisoning in a cat and the clinical and pathological findings in fatal poisoning in a dog are reported.
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PMID:Paraquat poisoning in a dog and cat. 125 80

Paraquat is a herbicide known to cause pulmonary edema in its acute toxic phase. Many investigators showed that paraquat induces morphological changes of alveolar epithelial cells even in its early phase. Controversy still exists, however, as to whether pulmonary vascular endothelial cells are also morphologically vulnerable to paraquat. To test the direct toxicity and metabolic changes of pulmonary vascular endothelial cells after paraquat addition, porcine pulmonary artery endothelial cells (PPAEC) were cultured. Thrombin- or bradykinin-stimulated PGI2 production was enhanced significantly, and the angiotensin converting enzyme (ACE) activity of cell lysate of PPAEC was significantly suppressed after a 24-hour incubation with 10(-4) M of paraquat. No further thrombin-induced enhancement of PGI2 production was noted after a 48-hour incubation. The alterations in arachidonic acid metabolism and ACE activity mentioned above did not result from cytotoxicity of paraquat because LDH release into culture medium was not increased during 72 hours of incubation with paraquat. Longer incubation more than 48 hours, in turn, induces obvious toxic effects on PPAEC.
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PMID:[Arachidonic acid metabolism and angiotensin converting enzyme activity by cultured porcine pulmonary artery endothelial cells are affected with paraquat]. 166 45

Paraquat (PQ; 1,1'-dimethyl-4,4'-bipyridylium dichloride), a widely used herbicide, causes pulmonary edema by a cyclic oxidation and reduction reaction with oxygen molecules with the production of oxygen free radicals. Because fructose 1,6-diphosphate (FDP) has recently been shown to inhibit the generation of oxygen free radicals by activated neutrophils, we determined the effects of FDP on PQ-induced increase in microvascular permeability in isolated blood-perfused dog lungs. Vascular permeability was assessed using the capillary filtration coefficient (Kf,c) and isogravimetric capillary pressure (Pc,i). There was no change in these variables over 5 h in the control lungs treated with saline (n = 5). A significant increase in Kf,c and a decrease in Pc,i, both of which indicated increased vascular permeability, were observed at 5 h of perfusion with 4 x 10(-3) M PQ (n = 5). Unexpectedly, an increase in microvascular permeability occurred within 4 h after administration of PQ in the lungs that were pretreated with FDP (2.7-14.2 mM, n = 6). Moreover the increases of Kf,c in the FDP-pretreated lungs were significantly greater than those in the lungs treated with PQ alone. Also, the final-to-initial lung weight ratio of the FDP-pretreated group was greater than those of the other groups. Thus the FDP dose used in the present study accentuated rather than prevented the PQ lung injury.
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PMID:Fructose 1,6-diphosphate augments paraquat injury in isolated dog lungs. 176 80

Paraquat is known to cause severe lung damage through pulmonary edema as its initial feature of toxicity. The purpose of this study was to investigate the toxicity of paraquat in rabbits intraperitoneally injected with 2 or 4 mg/kg/day of the herbicide for a period of 7 days. In the lung, prostaglandin levels of the intoxicated rabbits showed a significant increase in PGF2 alpha. This increase was dose dependent. However, a nonsignificant change in the 6-keto-PGF1 alpha was also observed. Plasma and serum levels of thromboxane-B2 were also significantly elevated but the levels of 6-keto-PGF1 alpha were affected nonsignificantly. The pathology of elevated levels of PGF2 alpha and TXB2 in the lung and blood, in response to paraquat toxicity, is discussed.
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PMID:Involvement of prostaglandins in paraquat intoxication. 233 51

The effect of radiotherapy on the pulmonary damage caused by paraquat (24% solution of 1,1'-dimethyl-4,4'-bipyridylium dichloride) was investigated in a preliminary series of nine patients. Paraquat intoxication was diagnosed by quantitative analysis of urine and plasma using colorimetry after extraction of a cation exchange column. The irradiation was given as a planned procedure from day 2 in cases 1 to 7, and after changes in chest X-ray were recognized in cases 8 and 9. A cobalt-60 unit with opposed anterior and posterior portals was used to give a total dose of 12.50 Gy (uncorrected) over 10 fractions, sparing the pericardium and mediastinum as much as possible. Each fraction consisted of 1.25 Gy (125 rad) given once a day, alternating between the left and right lungs. Radiological diagnosis consisted of clear chest X-rays (cases 2 to 4), pulmonary oedema (cases 7 and 9) and interstitial infiltrates (cases 1, 5, 6 and 8). Cases 1, 5 and 8 survived. Case 8 had residual interstitial infiltrates three months after ingestion but these had cleared one month later, suggesting that the diagnosis of irreversible fibrosis should only be made after a follow-up period of at least one year. The results have failed to show a definite benefit, but do support the fact that radiotherapy should be assessed carefully in a randomized trial which is now in progress.
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PMID:Radiotherapy for the treatment of pulmonary complications of paraquat poisoning. 304 80

Paraquat, a widely used herbicide, causes severe lung damage in humans and laboratory animals. Pulmonary edema is a common initial feature of paraquat toxicity, but its pathophysiology is not well understood. The purpose of this investigation was to determine the acute toxic effect of paraquat (30 mg/kg) on pulmonary transvascular protein and fluid fluxes, histologic features, and prostanoid production, using awake sheep with chronic lung lymph fistulas (n = 6). Lung lymph flow increased significantly 3.5 h after intravenous infusion of paraquat and rose to 2.6 times baseline within 8 h (from 4.4 +/- 0.4 to 11.4 +/- 1.5 ml/h, p less than 0.05). Lymph-plasma protein concentration ratio increased during the same time period (from 0.64 +/- 0.05 to 0.75 +/- 0.04, p less than 0.05). Lung lymph protein clearance also increased at 3.5 h and remained elevated throughout the duration of the experiment. Pulmonary arterial and left atrial pressure were only slightly altered. Plasma and lung lymph thromboxane A2 (as TXB2) concentrations were significantly increased at 30 min and continued so thereafter. Plasma and lung lymph prostacyclin (6-keto-PGF1 alpha) concentrations increased significantly at 3 h and were more than 5 times baseline by 7 h. The time course of the increase in 6-keto-PGF1 alpha concentrations seemed similar to that of lung lymph flow. The high flow of protein-rich lymph strongly suggested an increase in pulmonary vascular permeability, which may indicate pulmonary endothelial damage. Histologic studies of the lungs revealed only minor changes in perivascular cuffing, minimal alveolar hemorrhage, and slight neutrophilic alveolar wall infiltration.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Acute effect of paraquat on lung fluid balance and prostanoid production in awake sheep. 378 25

Paraquat poisoning and hyperbaric oxygen exposure are well established models of oxidative stress in lung. The aim of this study was focused on the contribution of oxygen free radicals and other cytotoxic species, such as lipid hydroperoxides, to the overall toxicity. Adult Wistar rats were injected with paraquat (30 or 60 mg/kg b.w.) or exposed to hyperbaric oxygen (0.2 MPa), and several parameters of lung damage were measured. Both treatments resulted in increased spontaneous lung chemiluminescence, number of lung PMN, malondialdehyde content, lung edema, and pleural liquid. Of note, spontaneous lung chemiluminescence, used to monitor the steady-state concentration of oxygen free radicals in vivo, did not increase significantly after either treatment. The increase in spontaneous lung chemiluminescence started after PMN migration, being both maxima separated by a delay time of 4-6 h. After PMN migrated and became activated in the lung, the survival of the animals started to decline. Thus, PMN can be considered as additional sources of oxygen free radicals supported by the subsequent increase in chemiluminescence. Their role in lung damage was evidenced by the increase in lung edema, augmented pleural liquid, and decreased survival after PMN migration. Lipid hydroperoxide concentration in lung membranes was also increased after either treatment. This increased concentration may be a consequence of an increased rate of lipid peroxidation, initiated by oxidative stress on lipid membranes, or by an inhibition of their catabolism. Ester lipid hydroperoxides normally produced in membranes cannot be catabolized directly by the glutathione peroxidase-reductase system unless phospholipase A2 catalyses the release of free lipid hydroperoxides. In both experimental models, phospholipase A2 activity was decreased to almost negligible values. Betamethasone (1 mg/ml; IV) administered to the rats 3 h before paraquat injection accelerated the decrease in survival and phospholipase A2 inactivation. Inactivation of phospholipase A2, detected in paraquat or oxygen exposed rats, could be attributed to a O2(.-)-driven Fenton reaction. However, phospholipase A2 inactivation by betamethasone pretreatment may be attributed to the presence of lipocortin, a corticosteroid-inducible factor and inhibitor of phospholipase A2. Besides the mechanism underlying the inactivation of phospholipase A2, the increase in lipid hydroperoxides may indicate their role as long-lived cytotoxic species that contribute to the damage already initiated by oxidative stress. Indeed, lipid hydroperoxides are very well known modifiers of membrane physical properties.
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PMID:Lung damage in paraquat poisoning and hyperbaric oxygen exposure: superoxide-mediated inhibition of phospholipase A2. 774 3

The rodenticide alpha-naphthylthiourea (ANTU) causes pulmonary edema and pleural effusion that leads to death via pulmonary insufficiency. Rats become resistant to the lethal effect of ANTU if they are first exposed to a small, nonlethal dose of ANTU. Young rats are also resistant to ANTU. The mechanism by which rats develop resistance by a prior, small dose exposure has yet to be determined. Growth factor induced-pulmonary hyperplasia has been demonstrated to attenuate ANTU-induced lung leak. We hypothesized that a small dose of ANTU protects against a large dose through pulmonary cell hyperplasia induced by the protective dose. Furthermore, we hypothesized that this hyperplasia is associated with altered transcription of growth factors. Male Sprague-Dawley rats (175-225 g) were treated with a low dose of ANTU (5 mg ANTU/kg; ANTU(L)) 24 h before challenge with a 100% lethal dose of ANTU (70 mg ANTU/kg; ANTU(H)) resulting in 100% protection against the lethal effect of ANTU(H). ANTU(L) protection against ANTU(H) lasted for 5 days, slowly phased out, all being lost by day 20. Injury was assessed by estimating pulmonary vascular permeability and through histopathological examination. ANTU(H) alone resulted in an increase in pulmonary edema leading to animal death. However, injury was prevented if the rats were first treated with ANTU(L). There was a stimulation of pulmonary cell hyperplasia in the lungs of ANTU(L) treated rats as measured by [3H]-thymidine and bromodeoxyuridine incorporation. Treatment with the antimitotic agent colchicine abolished ANTU(L)-induced resistance to ANTU(H). ANTU resistant rats were also resistant to the lethal effect of paraquat. Paraquat is not taken up by pneumocytes if they are undergoing hyperplasia. ANTU(L) administration resulted in an up regulation of gene transcription for keratinocyte growth factor, transforming growth factor-beta, keratinocyte growth factor receptor and epidermal growth factor receptor as determined through reverse transcription-polymerase chain reaction. A significant increase in transforming growth factor-alpha was not observed. These findings collectively suggest that ANTU(L)-induced pulmonary cell hyperplasia underlies resistance to ANTU(H). Furthermore, the stimulation of hyperplasia may be due to altered growth factor and growth factor receptor expressions.
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PMID:Stimulated pulmonary cell hyperplasia underlies resistance to alpha-naphthylthiourea. 1075 3

Paraquat (PQ)-induced pulmonary toxicity is characterized by initial development of pulmonary edema, infiltration of inflammatory cells, and damage to the alveolar epithelium, which may progress to severe fibrosis. However, the exact role of PQ in the progression of the pathogenesis has not been clearly established. To understand the mechanism of PQ in pulmonary toxicity, we developed an animal model of PQ-induced lung injury by intranasal instillation of PQ solution using C57Black/6J mice. Twenty microliters of PQ solution (0.01, 0.01, and 0.04 mg/mouse) was applied through the nares, and the same amount of vehicle was applied in control mice. The pathological progression of lung pathology in our mouse model was very similar to that of patients suffering from PQ poisoning. The lungs of some animals exposed to PQ showed acute fulmination, resulting in death from 5 days post-exposure, but others showed a more protracted injury, resulting in typical pulmonary fibrosis at 3 weeks. Using this PQ-poisoned mouse model, we examined the gene expression at the initial destructive phase (within 5 days) that fibrosis has not completely developed. We prepared RNAs after 6h, 24h, and 5 days and examined the changes of the expression levels for 45 selected genes. The genes showing >2-fold increase at 6h or a time-dependent decrease during this experimental period may be the early markers for the destructive phase. These genes are Mt1, Mt2, Hmox1, Gcl, GR, IL-6, IL-13, Txn1, Fas, FasL, Lpin2, Mmp1a, Mmp12, Sfp-B, Sfp-D, CAT, EC-SOD, GST, and Pltp. On the other hand, the genes involved in the development of fibrosis, such as procollagen, Fn1, Eln, SMA, and Mmp9, Timp1 were significantly increased on day 5, not at 6h nor at 24h, after PQ treatment (the late marker). The genes showing a significant increase (Mmp3 and Mmp8) or decrease (VEGFA) at 24h and 5 days and not at 6h may be also the late markers. These changes in gene expression, which are equalled to functional activities of proteins, will be the targets for future studies focused on the development on PQ-induced pulmonary damage.
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PMID:Mouse model of paraquat-poisoned lungs and its gene expression profile. 1721 68


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