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)

TNF is a major mediator in the pathogenesis of endotoxic shock, and its inhibition has a protective effect in various animal models of sepsis or endotoxin (lipopolysaccharide, LPS) toxicity. LPS treatment also induces an oxidative damage mediated by increased production of reactive oxygen intermediates. N-Acetylcysteine (NAC) is an antioxidant and a precursor of the synthesis of glutathione (GSH) and was reported to protect against LPS toxicity and LPS-induced pulmonary edema. In this study we investigated the effect of NAC on TNF production and LPS lethality in mice. The results indicated that oral administration of NAC protects against LPS toxicity and inhibits the increase in serum TNF levels in LPS-treated mice. The inhibition was not confined to the released form of TNF, since NAC also inhibited LPS-induced spleen-associated TNF. On the other hand, the inhibitor of GSH synthesis, DL-buthionine-(SR)-sulfoximine (BSO), had the opposite effect of potentiating LPS-induced TNF production, and this was associated with a decrease in liver GSH levels. Repletion of liver GSH with NAC reversed this effect. NAC was also active in inhibiting TNF production and hepatotoxicity in mice treated with LPS in association with a sensitizing dose of Actinomycin D. These data indicate that GSH can be an endogenous modulator of TNF production in vivo. On the other hand, NAC pretreatment did not inhibit other effects of LPS, particularly induction of serum IL-6, spleen IL-1 alpha, and corticosterone, in the same experimental model, suggesting that the observed effect could be specific for TNF.
 ...
PMID:N-acetylcysteine and glutathione as inhibitors of tumor necrosis factor production. 154 68

Perfluoroisobutene (PFIB) is a hydrophobic reactive gas produced by the pyrolysis of polytetrafluoroethane which induces pulmonary oedema similar to that induced by phosgene when inhaled. When a lethal dose is inhaled by Porton strain rats total non-protein thiol (NPSH) and glutathione (GSH) in the lung are reduced by between 30 and 49%, respectively. If the endogenous levels of thiols in the lung are reduced by pretreatment with buthionine sulfoximine (BSO) 16 hr before exposure to PFIB, the rats become more susceptible to the effects of the gas. The effect of BSO pretreatment on toxicity was prevented by pretreatment 30 min before exposure, with 5 mmol/kg N-acetylcysteine (NAc). NAc increased the levels of cysteine (CySH) in the lung by 150% and GSH was unaffected. Similarly pretreatment with 3 mmol/kg CySH also protected against toxicity and raised CySH levels by 100%. A series of cysteine esters and cystine dimethyl ester (CDME) have been synthesised which selectively raise lung levels of CySH in the rat lungs after intraperitoneal (i.p.) injection. The methyl ester and CDME raised lung levels of CySH by 4000 and 2000%, respectively, 10 min after i.p. injection whilst GSH levels remained unchanged. Cysteine isopropyl ester raised lung levels of CySH by 10,600% but liver levels by only 1400%. All esters except the t-butyl ester (CTBE) also raised maximal plasma levels of NPSH by up to 500%; however, when NAc was injected plasma levels increased by over 1500%. Rats treated with these esters at 3 mmol/kg and with NAc at 5 mmol/kg were protected against lethal doses of PFIB in all cases except when CTBE was used. It appears that these cysteine esters may distribute preferentially into the lung, unlike NAc. The selective enhancement of pulmonary CySH levels may provide a method for the protection of lungs against inhaled reactive toxicants by increasing intracellular CySH. Levels of CySH may also be raised in epithelial lining fluid thus reducing access of gaseous toxicants to pulmonary tissue.
 ...
PMID:Protection by cysteine esters against chemically induced pulmonary oedema. 176 85

Clinically, lung injury is characterized by one or more of the following: altered gas exchange, dyspnea, decreased static compliance, and nonhydrostatic pulmonary edema. Although many antioxidants have been investigated in in vitro systems and in animal models, only some are at the developmental stage, or safe for clinical trials. Considerable evidence has recently accumulated supporting the hypothesis that leukocyte activation involves release of large quantities of highly reactive oxygen radicals, and hydrogen peroxide is partially responsible for diffuse microvascular and tissue injury in septic patients. Granulocyte depletion in animal models reduces the degree of fall in dynamic lung compliance and the increase in airflow resistance, lymph flow, and hypoxemia secondary to endotoxin administration. We hypothesized that the partial benefit derived from granulocyte depletion was due to the effective removal of a major source of oxygen radicals. Among the list of free radical scavengers, N-acetylcysteine stands out, because of its established usefulness in at least one human disease thought to be secondary to free radical organ damage (acetaminophen or paracetamol overdose). It is an extremely safe agent with a wide toxic-therapeutic window. An increasing number of animal studies indicate efficacy for this agent in the prevention and therapy of lung injury involving toxic oxygen species. We developed a randomized, double-blind protocol for the study of intravenous N-acetylcysteine in patients with established adult respiratory distress syndrome (ADRS). Results of this trial are preliminary. Nevertheless, they indicate that plasma and red cell glutathione levels are decreased in ADRS patients, and that N-acetylcysteine increases plasma cysteine as well as plasma and red cell glutathione. There are also indications that cardiopulmonary physiology is favorably affected by such therapy including improvements in chest radiograph edema scores, pulmonary vascular resistance, static compliance, oxygen delivery, and oxygen consumption.
 ...
PMID:N-acetylcysteine in experimental and clinical acute lung injury. 192 12

The adult respiratory distress syndrome (ARDS), often referred to as non-cardiac pulmonary oedema, is now regarded as a very complicated inflammatory process with oedema being only one facet. In recognition of this, pharmacologic therapy with anti-inflammatory corticosteroids was used widely until the completion of randomized clinical trials. Unfortunately, corticosteroids have not been proved to be useful in preventing ARDS in septic patients nor in patients with established ARDS and this has led to investigations with pharmacologic agents which are safer and more specifically targeted to certain parts of the inflammatory process. We have examined the role of the glutathione anti-oxidant system in the sheep model of ARDS as well as in patients with established ARDS through use of intravenous N-acetylcysteine (NAC). We have found that the response to endotoxin is markedly blunted in sheep treated with NAC. In our controlled clinical trials with NAC we found that patients with ARDS have depressed plasma and red cell glutathione concentrations, that these levels are substantially increased by therapy with intravenous NAC and there are measurable clinical responses to treatment with regard to increased oxygen delivery, improved lung compliance and resolution of pulmonary oedema.
 ...
PMID:Potential of N-acetylcysteine as treatment for the adult respiratory distress syndrome. 227 10

Amiodarone (ADR), a new antiarrhythmic drug for life-threatening cardiac arrhythmias, causes pneumonitis or lung fibrosis in a sizeable minority of patients. The cause of lung damage is not known. We have shown that infusion of 10 mg amiodarone into the inflow circuit of ventilated and perfused rabbit lungs causes immediate increase in pulmonary artery pressure (mean +/- SEM) (from 13.6 +/- 1.2 to 40.6 +/- 9.5 mm Hg, p less than 0.01) and pulmonary edema with marked increase in the pulmonary generation of thromboxane and leukotrienes C4 and/or D4. Albumin (2 g%) in the perfusate prevents any increase in lung perfusion pressure or edema formation. When lung perfusion pressure increase is blocked with the combined cyclooxygenase and lipoxygenase inhibitor enolicam sodium (CG5391B, 35 microM in perfusate), significant lung edema still occurs after amiodarone, indicating that amiodarone causes increased alveolar-capillary membrane permeability. Addition of catalase (100 U/ml) or superoxide dismutase and catalase (100 U/ml each) to perfusate fails to protect from amiodarone lung injury. Immediate infusion of amiodarone (10 mg) into lungs ventilated with room air (ADR + RA) causes an increase in lung weight gain from baseline (delta W) of 5.7 +/- 1.5 g/min. Compared with ADR + RA, ventilation of lungs with 4% O2 (delta W = 0.7 +/- 0.3 g/min, p less than 0.05), pretreatment of rabbits for 3 days with butylated hydroxyanisole (BHA, 100 mg/kg/day i.p., delta W = 0.05 +/- 0.02 g/min, p less than 0.01), pretreatment of rabbits for 3 days with vitamin E (Vit E, 300 U/day orally, delta W = 0.6 +/- 0.2 g/min, p less than 0.05), or addition of N-acetylcysteine to the lung perfusate (NAC, 5 mM, delta W = 0.1 +/- 0.08 g/min, p less than 0.01) all protect from lung edema formation after amiodarone. Amiodarone (100 mg) also caused a marked increase in luminol-enhanced lung chemiluminescence, lung production of superoxide anion (O2-), and tissue levels of lung glutathione disulfide. These results suggest that amiodarone causes lung injury by an oxidant mechanism.
 ...
PMID:Amiodarone causes acute oxidant lung injury in ventilated and perfused rabbit lungs. 245 31

This paper describes the effects of the thiol compounds glutathione and N-acetylcysteine and the seleno-organic agent Ebselen on the development of Sephadex-induced lung edema and cell infiltration in the rat. Neither thiol had any effect upon the development of the edema when administered in large, repeated doses. In contrast, when Ebselen was co-administered with the thiols, there was a dose-dependent inhibition of the development of the edema, but lung weights could not be returned to normal values. However, when the thiols were omitted and Ebselen was administered alone, the development of the edema was totally blocked. In addition, in Ebselen-only treated animals there was a selective inhibition of the infiltration of lymphocytes, basophils and eosinophils into the lung lumen without affecting the populations of macrophages and neutrophils. Again, the Ebselen-induced effect was reduced by coadministration of either thiol. These findings are discussed in terms of the potential mechanism of action of Ebselen in vivo and of the possibility of Ebselen being of therapeutic potential in cases of diffuse pulmonary inflammation in humans.
 ...
PMID:The anti-inflammatory activity of Ebselen but not thiols in experimental alveolitis and bronchiolitis. 245 36

We have developed a model of reperfusion injury in Krebs buffer-perfused rabbit lungs, characterized by pulmonary vasoconstriction, microvascular injury, and marked lung edema formation. During reperfusion there was a threefold increase in lung superoxide anion (O2-) production, as measured by in vivo reduction of nitroblue tetrazolium, and a twofold increase in the release of O2- into lung perfusate, as measured by reduction of succinylated ferricytochrome c. Injury could be prevented by the xanthine oxidase inhibitor allopurinol, the O2- scavenger SOD, the hydrogen peroxide scavenger catalase, the iron chelator deferoxamine, or the thiols dimethylthiourea or N-acetylcysteine. The protective effect of SOD could be abolished by the anion channel blocker 4,4'-diisothiocyano-2,2'-stilbene disulfonic acid, indicating that SOD consumes O2- in the extracellular medium, thereby creating a concentration gradient favorable for rapid diffusion of O2- out of cells. Our results extend information about the mechanisms of reperfusion lung injury that have been assembled by studies in other organs, and offer potential strategies for improved organ preservation, for treatment of reperfusion injury after pulmonary thromboembolectomy, and for explanation and therapy of many complications of pulmonary embolism.
 ...
PMID:Role of reactive oxygen species in reperfusion injury of the rabbit lung. 246 23

The effect of N-acetylcysteine (NAC), a free radical scavenger, was investigated in a microembolism rat model of adult respiratory distress syndrome (ARDS). Microembolism was induced by an intravenous injection of bovine thrombin and an intraperitoneal injection of a fibrinolysis inhibitor, trans-4-aminomethyl-cyclohexane-carboxylic acid (AMCA). NAC counteracted the experimentally induced increase in lung weight, the development of alveolar oedema, and the amount of fibrin in precapillary vessels. There was also a tendency to a decrease of the experimentally induced interstitial oedema caused by the NAC treatment, although it was not statistically significant. Surprisingly, NAC reduced plasma viscosity in both experimental and control animals. It also seemed to increase PaO2 in animals with pulmonary damage, but had a lowering effect on PaO2 in control animals. The results indicate that NAC has a significant preventive effect in this microembolism rat model of ARDS, and that this effect may be achieved through decreased deposition of fibrin, thus counteracting pulmonary oedema, and a decrease in plasma viscosity.
 ...
PMID:Effect of N-acetylcysteine on pulmonary damage due to microembolism in the rat. 358 17

1. The intraperitoneal administration of cysteine, N-acetylcysteine, the methyl, isopropyl, cyclo pentyl, neo pentyl, cyclo hexyl and tertiary butyl esters of cysteine and of cystine dimethyl ester increased the levels of total non-protein sulphydryls and cysteine in the bronchioalveolar lavage fluid and plasma of rats. In all cases the non-protein sulphydryl levels reflected the increased cysteine levels. 2. Cysteine, N-acetylcysteine, the cysteine esters and cystine dimethyl ester raised the levels of non-protein sulphydryls and hence cysteine in the bronchioalveolar lining fluid as follows: CIPE > CCPE > CME > CDME > CneoPE > CCHE > Nac > CySH > CTBE. 3. Plasma levels of NPSH were increased as follows: Nac > CySH > CCPE > CCHE > CneoPE > CIPE > CME > CDME > CTBE. 4. All except CTBE have been shown to protect against the lethal effects of inhaled perfluoroisobutene, a pyrolysis product of polytetrafluoroethene which induces a fulminating pulmonary oedema. 5. This study showed that by raising the levels of thiols in the bronchioalveolar lavage fluid (BALF), the epithelial cells lining the bronchiolar, alveolar regions of the lung could be protected against inhaled toxicants. 6. It is proposed that increased thiol levels in the BALF may contribute to the overall protection induced by these compounds by reacting with inhaled electrophiles to prevent or reduce damage to tissue in close proximity to the airways.
 ...
PMID:Thiol levels in rat bronchio-alveolar lavage fluid after administration of cysteine esters. 785 97

We examined the effects of treatment with N-acetylcysteine (NAC) on pulmonary edema formation in isolated perfused rabbit lungs following in vivo phosgene exposure. This study focused on posttreatment intratracheal administration of NAC after exposure. Rabbits, 2 to 3 kg, were exposed to a cumulative dose of phosgene to attain a concentration x time exposure effect of 1,500 ppm/min. Lungs were perfused with Krebs-Henseleit buffer at 40 ml/min from 70 to 150 min after exposure. Pulmonary artery pressure (Ppa), tracheal pressure (Pt), and the rate of lung weight gain (LWG) were measured continuously. Perfusate concentration of peptide leukotrienes LTC4, D4, and E4 were measured every 20 min during perfusion. At the conclusion of the experiment, lung tissue was analyzed for reduced and oxidized glutathione (GSH and GSSG) and lipid peroxidation (thiobarbituric acid-reactive substances, TBARS). Exposure to phosgene significantly increased Pt, LWG, LTC4, D4, and E4, TBARS, and GSSG over time compared with controls. Compared with phosgene, intratracheal NAC lowered Ppa, LWG, LTC4, D4, and E4, TBARS, and GSSG. We conclude that NAC protected against phosgene-induced lung injury by acting as an antioxidant by maintaining protective levels of glutathione, reducing both lipid peroxidation and production of arachidonic acid metabolites.
 ...
PMID:Protective effects of N-acetylcysteine treatment after phosgene exposure in rabbits. 788 68


1 2 3 4 Next >>