Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0034069 (pulmonary fibrosis)
 7,050 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Paraquat is a potent herbicide, very toxic in the concentrated liquid form as supplied to farmers. Suicidal poisoning represents a serious emergency with a known high mortality rate. Suicidal poisoning following the parenteral route has been rarely reported. A 16-year-old girl was admitted to our emergency unit after subcutaneous injection of gramoxone 20% (about 400 mg of paraquat). Despite immediate surgical excision and revision, and subsequent antioxidant treatment with N-acetylcysteine (400 mg/kg/day during 48 hours), she died 17 days later from refractory hypoxemia following pulmonary fibrosis. From this observation and from the literature, it appears that an effective treatment does not depend on changes in the toxicokinetics of the herbicide (hemoperfusion, antidotes, drugs).
 ...
PMID:[Fatal voluntary poisoning by parenteral paraquat]. 192 59

Paraquat is a bipyridyl compound with no known chronic toxicity or teratogenicity. It is poorly absorbed when inhaled, but causes severe illness when ingested orally, death usually occurring within 2 days of ingestion of 50 mg/kg. At lower doses death may be delayed for several weeks. The toxic compound accumulates in lung tissue where free radicals are formed, lipid peroxidation is induced and nicotinamide adenine dinucleotide phosphate (NADPH) is depleted. This produces diffuse alveolitis followed by extensive pulmonary fibrosis. The most important prognostic indicator is the quantity of paraquat absorbed, as shown by the plasma paraquat concentration. While renal failure will develop in the majority of those patients who eventually die, it may not, if present alone, indicate a fatal outcome. The absence of caustic burns in the upper digestive tract indicates a good prognosis. Treatment of paraquat poisoning remains ineffective, but Fuller's earth, activated charcoal and resins may prevent some absorption of the toxin. When tubular necrosis occurs, renal excretion of the compound decreases rapidly. A 3-compartment pharmacokinetic model has been described following ingestion of tracer doses including a 'deep' compartment for active pulmonary accumulation. Haemodialysis, haemoperfusion and forced dialysis have been attempted, with no clear improvement in survival rates. Superoxide dismutase, glutathione peroxidase, N-acetylcysteine and other 'free radical scavengers' have failed to alter the outcome in poisoned patients. Other theoretical treatments, such as deferoxamine, immunotherapy, NADPH repletion and lung transplantation still require clinical validation.
 ...
PMID:Paraquat poisoning. An overview of the current status. 219 50

Idiopathic pulmonary fibrosis (IPF) is characterized by a huge alveolar oxidant burden and a deficiency of glutathione, a major antioxidant, in the pulmonary epithelial lining fluid (ELF). Therefore, a rational therapeutic strategy is to increase lung glutathione to augment the pulmonary antioxidant protective screen. To evaluate this concept, different doses of N-acetylcysteine (NAC), a glutathione precursor, were administered intravenously to eight patients with pulmonary fibrosis and six control subjects. In patients, bronchoalveolar lavage fluid (BALF) total glutathione increased significantly from 0.99 +/- 0.25 microM to 1.79 +/- 0.37 microM within 3 h following 1.8 g NAC, whereas 4.8 g NAC had no additional effect (1.47 +/- 0.34 microM). In the control subjects, NAC did not significantly alter BALF total glutathione (baseline: 0.79 +/- 0.17 microM, 600 mg NAC: 0.92 +/- 0.33 microM, 1.8 g NAC: 1.39 +/- 0.41 microM, 4.8 g NAC: 1.33 +/- 0.46 microM). The same was true in ELF, 1.8 g NAC significantly raised ELF total glutathione in patients from 186 +/- 47 microM to near normal levels (373 +/- 103 microM), with no further increase following 4.8 g NAC (293 +/- 62 microM). In the control subjects, ELF total glutathione remained unchanged independent of the NAC dose (baseline: 342 +/- 91 microM, 600 mg NAC: 385 +/- 135 microM, 1.8 g NAC: 633 +/- 220 microM, 4.8 g NAC: 646 +/- 263 microM). The increases in total glutathione were almost entirely due to increased levels of reduced glutathione, the form functional as an antioxidant. No adverse effects were noted.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Intravenous N-acetylcysteine and lung glutathione of patients with pulmonary fibrosis and normals. 766 83

Associated with amiodarone (AM) therapy is pneumonitis, which may progress to life-threatening pulmonary fibrosis. Although the etiology of amiodarone-induced pulmonary toxicity (AIPT) is unknown, a role for direct toxicity by oxidative stress has been proposed. We have used a single intratracheal administration of AM (1.8 mg (2.64 mumol)) to male golden Syrian hamsters to investigate the role of oxidative stress in AIPT. The antioxidant capacity of the lung was assessed following AM administration by evaluating glutathione status and antioxidant enzyme activities. The efficacy of treatment with the antioxidant agents butylated hydroxyanisole, diallyl sulfide, and N-acetylcysteine, in attenuation of AM-induced pulmonary fibrosis was also investigated. AM significantly (p < 0.05) increased the ratio of oxidized to total lung glutathione both 30 min (control, 0.93 +/- 0.23%; AM, 2.06 +/- 0.26%) and 120 min (control, 0.90 +/- 0.21%; AM, 3.58 +/- 1.34%) post administration. AM also increased activities of glutathione reductase (by 89%) 3 days post administration, and glutathione peroxidase (by 110 and 45%, respectively) and total superoxide dismutase (by 58 and 35%, respectively) both 3 and 7 days post administration. However, treatment of hamsters with butylated hydroxyanisole (150 mg.kg-1.day-1 s.c.) or diallyl sulfide (200 mg.kg-1.day-1, p.o.) for 3 days prior to AM, or treatment with N-acetylcysteine (10 mg intratracheally) 10 min prior to AM had no effect on pulmonary fibrosis 21 days post treatment, as determined by lung wet weight and hydroxyproline content, and had inconsistent effects on histologically determined disease index.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Investigation of the role of oxidative stress in amiodarone-induced pulmonary toxicity in the hamster. 795 92

Reactive oxygen species (ROS) play an important role in the pathogenesis of pulmonary fibrosis. We previously demonstrated that N-acetylcysteine (NAC), an antioxidant, inhibited adhesion molecule expression and cytokine production in lung cells. When NAC is inhaled into the alveolar space, it is expected to directly interact with inflammatory cells and to elevate glutathione levels in the epithelial lining fluids. We therefore examined whether inhaled NAC inhibits lung fibrosis induced by bleomycin (BLM). Male ICR mice were given a single intravenous injection of BLM (150 mg/ kg). Thirty milliliters of NAC (70 mg/ml) or saline were inhaled twice a day for 28 d using an ultrasonic nebulizer. In the inflammatory phase (Day 7), NAC administration attenuated the cellular infiltration in both bronchoalveolar lavage fluid (BALF) and alveolar tissues. At Day 28, the fibrotic changes estimated by Aschroft's criteria and hydroxyproline content in the NAC inhalation group were significantly decreased compared with the BLM-only group (p < 0.05). CXC chemokines, macrophage inflammatory protein-2 (MIP-2), cytokine-induced neutrophil chemoattractant (KC), and CC chemokines, macrophage inflammatory protein-1alpha (MIP-1alpha), in BALF were mostly elevated on Day 7 in the BLM-only group; however, these elevations were significantly repressed by NAC inhalation (p < 0.05). Lipid hydroperoxide (LPO) was also quantified in BALF. LPO was markedly increased on Day 3 in the BLM-only group, and this increase was significantly decreased by NAC inhalation (p < 0.05). These results revealed that aerosolized NAC ameliorated acute pulmonary inflammation induced by BLM injection via the repression of chemokines and LPO production, resulting in the attenuation of subsequent lung fibrosis. These findings are limited to the BLM-induced lung fibrosis animal model. However, NAC inhalation will be expected to be a potential therapy for patients with other interstitial pneumonias because ROS are involved in the pathogenesis of lung injury in most interstitial pneumonia.
 ...
PMID:Aerosolized administration of N-acetylcysteine attenuates lung fibrosis induced by bleomycin in mice. 1090 46

Chronic inflammation leading to pulmonary fibrosis develops in response to environmental pollutants, radiotherapy, or certain cancer chemotherapeutic agents. We speculated that lung injury might be mediated by p53, a proapoptotic transcription factor widely implicated in the response of cells to DNA damage. Intratracheal administration of bleomycin led to caspase-mediated DNA fragmentation characteristic of apoptosis. The effects of bleomycin were associated with translocation of p53 from the cytosol to the nucleus only in alveolar macrophages that had been exposed to the drug in vivo, suggesting that the lung microenvironment regulated p53 activation. Experiments with a thiol antioxidant (N-acetylcysteine) in vivo and nitric oxide (NO) donors in vitro confirmed that reactive oxygen species were required for p53 activation. A specific role for NO was demonstrated in experiments with inducible nitric oxide synthase (iNOS)(-/)- macrophages, which failed to demonstrate nuclear p53 localization after in vivo bleomycin exposure. Strikingly, rates of bleomycin-induced apoptosis were at least twofold higher in p53(-/)- C57BL/6 mice compared with heterozygous or wild-type littermates. Similarly, levels of apoptosis were also twofold higher in the lungs of iNOS(-/)- mice than were observed in wild-type controls. Consistent with a role for apoptosis in chronic lung injury, levels of bleomycin-induced inflammation were substantially higher in iNOS(-/)- and p53(-/)- mice compared with wild-type controls. Together, our results demonstrate that iNOS and p53 mediate a novel apoptosis-suppressing pathway in the lung.
 ...
PMID:Nitric oxide-dependent activation of p53 suppresses bleomycin-induced apoptosis in the lung. 1099 16

Antioxidant therapy may be useful in diseases with impaired oxidant-antioxidant balance such as pulmonary fibrosis. This study examines the effect of N-acetylcysteine (NAC) on bleomycin-induced lung fibrosis in rats. NAC (3 mmol x kg(-1); oral) was given daily from 1 week prior to a single intratracheal instillation of bleomycin (2.5 U x kg(-1)) or saline, until 14 days postinstillation. NAC partially decreased the augmented collagen deposition in bleomycin-exposed rats (hydroxyproline content was 4,354+/-386 and 3,416+/-326 microg x lung(-1) in vehicle-treated and NAC-treated rats, respectively; p < 0.05). The histological assessment using a semiquantitative score showed less collagen deposition and inflammatory cells in NAC-treated rats compared to those receiving bleomycin alone. NAC failed to inhibit the bleomycin-induced increases in lung wet weight and in cell counts and protein levels of bronchoalveolar lavage fluid, but significantly increased total glutathione and taurine levels in bronchoalveolar lavage fluid. These results indicate that oral N-acetylcysteine improves the pulmonary antioxidant protection and may be useful in reducing lung damage produced by bleomycin.
 ...
PMID:Attenuation by oral N-acetylcysteine of bleomycin-induced lung injury in rats. 1149 Nov 69

The chemotherapeutic agent bleomycin induces pulmonary fibrosis through the generation of reactive oxygen species (ROS), which are thought to contribute to cellular damage and pulmonary injury. We hypothesized that bleomycin activates oxidative stress response pathways and regulates cellular glutathione (GSH). Bovine pulmonary artery endothelial cells exposed to bleomycin exhibit growth arrest and increased cellular GSH content. gamma-Glutamylcysteine synthetase (gamma-GCS) controls the key regulatory step in GSH synthesis, and Northern blots indicate that the gamma-GCS catalytic subunit [gamma-GCS heavy chain (gamma-GCS(h))] is upregulated by bleomycin within 3 h. The promoter for human gamma-GCS(h) contains consensus sites for nuclear factor-kappaB (NF-kappaB) and the antioxidant response element (ARE), both of which are activated in response to oxidative stress. Electrophoretic mobility shift assays show that bleomycin activates the transcription factor NF-kappaB as well as the ARE-binding factors Nrf-1 and -2. Nrf-1 and -2 activation by bleomycin is inhibited by the ROS quenching agent N-acetylcysteine (NAC), but not by U-0126, a MEK1/2 inhibitor that blocks bleomycin-induced MAPK activation. In contrast, NF-kappaB activation by bleomycin is inhibited by U-0126, but not by NAC. NAC and U-0126 both inhibit bleomycin-induced upregulation of gamma-GCS expression. These data suggest that bleomycin can activate oxidative stress response pathways and upregulate cellular GSH.
 ...
PMID:Bleomycin upregulates expression of gamma-glutamylcysteine synthetase in pulmonary artery endothelial cells. 1200 92

1. This study examines the activity of the antioxidant N-acetylcysteine on bleomycin-induced pulmonary fibrosis in rats with emphasis on the early inflammatory phase. 2. Rats receiving N-acetylcysteine (300 mg kg(-1) day(-1), intraperitoneal) had less augmented lung wet weight, and lower levels of proteins, lactate dehydrogenase, neutrophil and macrophage counts in bronchoalveolar lavage fluid and lung myeloperoxidase activity with a betterment of histological score at 3 days postbleomycin. 3. A diminished lung GSH/GSSG ratio and augmented lipid hydroperoxides were observed 3 days postbleomycin. These changes were attenuated by N-acetylcysteine. Alveolar macrophages from bleomycin-exposed rats released augmented amounts of superoxide anion and nitric oxide. N-Acetylcysteine did not modify superoxide anion generation but reduced the increased production of nitric oxide. 4. N-Acetylcysteine suppressed the bleomycin-induced increased activation of lung NF-kappaB (shift assay and immunohistochemistry), and decreased the augmented levels of the early inflammatory cytokines, tumour necrosis factor-alpha, interleukin-beta, interleukin-6 and macrophage inflammatory protein-2 observed in bronchoalveolar lavage fluid at 1 and 3 days postbleomycin exposure. 5. At 15 days postbleomycin, N-acetylcysteine decreased collagen deposition in bleomycin-exposed rats (hydroxyproline content: 6351+/-669 and 4626+/-288 micro g per lung in drug vehicle- and N-acetylcysteine-treated rats, respectively; P<0.05). Semiquantitative histological assessment at this stage showed less collagen deposition in N-acetylcysteine-treated rats compared to those receiving bleomycin alone. 6. These results indicate that N-acetylcysteine reduces the primary inflammatory events, thus preventing cellular damage and the subsequent development of pulmonary fibrosis in the bleomycin rat model.
 ...
PMID:In vivo antioxidant treatment protects against bleomycin-induced lung damage in rats. 1268 59

Oxidative stress is involved in the pathogenesis of pulmonary fibrosis, therefore antioxidants may be of therapeutic value. Clinical work indicates that N-acetylcysteine (NAC) may be beneficial in this disease. The activity of this antioxidant was examined on bleomycin-induced lung damage, mucus secretory cells hyperplasia and mucin Muc5ac gene expression in rats. NAC (3 mmol x kg(-1) x day(-1)) or saline was given orally to Sprague-Dawley rats for 1 week prior to a single intratracheal instillation of bleomycin (2.5 U x kg(-1)) and for 14 days postinstillation. NAC decreased collagen deposition in bleomycin-exposed rats (hydroxyproline content was 4,257+/-323 and 3,200+/-192 microg x lung(-1) in vehicle- and NAC-treated rats, respectively) and lessened the fibrotic area assessed by morphometric analysis. The bleomycin-induced increases in lung tumour necrosis factor-alpha and myeloperoxidase activity were reduced by NAC treatment. The numbers of mucus secretory cells in airway epithelium, and the Muc5ac messenger ribonucleic acid and protein expression, were markedly augmented in rats exposed to bleomycin. These changes were significantly reduced in NAC-treated rats. These results indicate that bleomycin increases the number of airway secretory cells and their mucin production, and that oral N-acetylcysteine improved pulmonary lesions and reduced the mucus hypersecretion in the bleomycin rat model.
 ...
PMID:Oral N-acetylcysteine reduces bleomycin-induced lung damage and mucin Muc5ac expression in rats. 1468 76


1 2 3 4 Next >>