Neutrophil mediated inflammatory lung damage following single Sub lethal inhalation exposure to plant protein toxin abrin in mice.

Abrin, a highly toxic plant protein found in the seeds of Abrus precatorius plant. To date, there is no antidote against abrin intoxication. Abrin is toxic by all routes of exposure, but inhalation exposure is the most toxic of all routes. Present study was conducted to evaluate the acute inhalation toxicity of aerosolized abrin in BALB/c mice. Animals were exposed to 0.2 and 0.8LC50 doses of aerosolized abrin and evaluated at 1 and 3 day post toxin exposure. Bronchoalveolar fluid from lungs was used for evaluation of markers for lung injury. Abrin inhalation exposure caused rise in LDH activity, protein content, increase in ß-glucuronidase and myeloperoxidase activity. Increase in CRP activity, MMP-9 expression and recruitment of CD11b + inflammatory cells in lungs was also observed which was associated with severe inflammation and lung damage. Histopathological findings support the lung damage after abrin exposure. Our results indicate lung injury after single aerosol inhalation exposure, associated with excessive inflammation, oxidative stress, pulmonary edema followed by lung damage. These results could supplement treatment strategies and planning for therapeutic approaches against aerosolized abrin inhalation exposure.

Effect of diallyl sulfide on in vitro and in vivo Nrf2-mediated pulmonic antioxidant enzyme expression via activation ERK/p38 signaling pathway.

Increasing oxidative stress is intimately involved in the pathogenesis of lung failure. Nuclear factor-erythroid 2 related factor 2 (Nrf2) is a key element in redox homeostasis. Nrf2 regulates antioxidant-associated genes that are often the target of phytochemicals in chemoprevention. This study evaluated the effect of diallyl sulfide (DAS), which is present in garlic, on the expression of antioxidant enzymes in the rat lung and the Nrf2 modulation in MRC-5 lung cells. DAS increased the activities of glutathione S-transferase, glutathione reductase, and catalase as well as the GSH/GSSG ratio compared with the lung of untreated control rats (p < 0.05). The pulmonic superoxide dismutase, glutathione peroxidase, NAD(P)H:quinone oxidoreductase 1, and catalase mRNA levels were also significantly increased (p < 0.05) after DAS treatment. Following DAS treatment, DAS level was measured in the plasma after 7 days of oral administration, and the C(max) value was 15 ± 4.2 µM. The total amount of pulmonic Nrf2 and the nuclear translocation of Nrf2 were elevated in DAS-treated rats, clarifying the effect of DAS on the modulation of antioxidant enzymes. Furthermore, DAS could induce nuclear translocation of Nrf2 via ERK/p38 signaling pathway in lung MRC-5 cells. This study demonstrates that DAS administration can significantly induce the activity of antioxidant enzymes in rat lungs and suggests a possible use for DAS as a dietary preventive agent against oxidative stress-induced lung injury.

Establishing the use of melatonin as an adjuvant therapeutic against paraquat-induced lung toxicity in rats.

It is well known that the intake of paraquat (PQ) causes severe tissue injury leading to numerous fatalities. Considering that the main target for PQ toxicity is the lung and involves the production of reactive oxygen and nitrogen species, transcription factors and inflammatory cytokines, it may be hypothesized that the combination of a potent antiinflammatory and antioxidant agent may counteract more of PQ's effects than an antiinflammatory agent alone. For this purpose, combination of dexamethasone (Dex) and melatonin (Mel) was compared with Dex alone. A total of 40 male Wistar albino rats were divided into four groups as control, PQ, Dex only, and Dex plus Mel. The animals were given intraperitoneally a toxic dose of 19 mg/kg PQ dissolved in 1 ml saline. Control animals were injected with the same amount of saline only. A dose of 1 mg/kg Dex was administered 2 hrs after PQ administration. In the combination treatment group, 20 mg/kg Mel was given with Dex. All drugs were given every 12 hrs for a total of six doses. Five animals in PQ group and three animals in Dex only group died by the end of the study. No deaths occurred in the Dex+Mel group. Dex exerted improvements in several oxidative and antioxidative parameters. However, combination treatment provided beneficial effects against PQ toxicity far greater than Dex alone. This difference was also apparent when tissues were histologically compared. In conclusion, Mel exhibited strong additive beneficial effects with Dex and can be considered as a safe treatment modality against PQ toxicity.

Study on effect and mechanism of sodium ferulate in preventing and treating ozone induced lung injury in mice.

OBJECTIVE: To study the effect and mechanism of sodium ferulate (SF) in preventing and treating ozone (O3) induced lung oxidative injury in mice. METHODS: Lung oxidative injury model mice were established by making them inhale O3. The activity of anti-oxidase and membranous microviscosity in epithelial cells in the lung of mice were determined, and the ultrastructural change of lung tissues was observed with electromicroscopy. RESULTS: Activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) were reduced, while membranous lipo-microviscosity significantly increased in the pulmonary epithelial cells of model mice, revealing ultrastructural change. These abnormal changes were reversed by SF treatment, which was manifested as the significantly raised activities of SOD and GSH-Px after treatment with high and moderate doses of SF, showing a significant difference compared with those in the model group (P<0.01). Membranous lipo-microviscosity basically approached that in the control group (P>0.05); electron microscopic examination showed a basically normal morphological structure of pulmonary epithelial cells, with the change in lung injury significantly milder than that in the model group. CONCLUSION: O3 could induce oxidative injury of lungs in mice, and SF could enhance the anti-oxidation capacity of mice and scavenge the oxygen free radicals so as to alleviate the injury.

Therapeutic treatment with poly(ADP-ribose) polymerase inhibitors attenuates the severity of acute pancreatitis and associated liver and lung injury.

BACKGROUND AND PURPOSE: The mortality associated with acute pancreatitis (AP) is largely attributable to abnormalities that occur in distant organs and supportive care remains the only treatment for patients with these complications. Recently, prophylactic pharmacological blockade of poly(ADP-ribose) polymerase (PARP) enzymes has been shown to attenuate the severity of the disease. However, the clinical relevance of PARP inhibitors administered after the onset of AP remains uncertain. The aim of the present study was to investigate the therapeutic effects of PARP inhibitors in established AP. EXPERIMENTAL APPROACH: Mice were fed a choline/methionine-deficient/ethionine-supplemented (CMDE) diet to induce AP. PARP inhibitors were given at 36 h after the onset of CMDE diet. Severity of pancreatitis was assessed by measurements of serum amylase, lipase, IL-1beta and IL-6, and histological grading. Serum hepatic enzymes, myeloperoxidase (MPO) activity and morphological changes were measured as indicators of hepatic insult. Lung injury was evaluated by MPO activity and morphological changes. Survival rates of mice were monitored for 7 days. KEY RESULTS: CMDE diet administration resulted in a significant increase in serum amylase, lipase, IL-1beta, IL-6, alanine aminotransferase and aspartate aminotranferase levels, indicating AP and associated liver injury. Analysis of the histopathological changes in pancreas, liver and lung revealed extensive tissue damage. Treatment of mice with PARP-inhibitors after the onset of AP was associated with a reduction in the severity of AP and, accordingly, with a reduced mortality rate. CONCLUSIONS AND IMPLICATIONS: Our results support the therapeutic application of PARP inhibitors in the treatment of established AP.

Altered regulation of retinoic acid synthesis in nitrofen-induced hypoplastic lung.

Retinoids are a group of molecules derived from vitamin A, which play an important role in lung development. Within the cell, retinol can either be oxidized to retinal or esterified to retinyl esters by lecithin : retinol acyltransferase (LRAT) for storage. Retinal is then oxidized to an active metabolite of vitamin A, retinoic acid (RA) by retinal dehydrogenase (RALDH). RA is the active metabolite of vitamin A. Cyp26 (a1,b1, and c1), which is a member of the cytochrome P450 family, acts by reducing the activity of RA. Cyp26 type b1 is the predominant subtype expressed in the murine lung. Several studies have suggested that nitrofen may interfere with the retinoid pathway resulting in congenital diaphragmatic hernia (CDH) and pulmonary hypoplasia. Recently, it was reported that nitrofen may act by inhibiting RALDH2. The aim of this study was to examine the pulmonary expression of Cyp26b1, LRAT, and RALDH2, the key enzymes involved in the synthesis of RA, in order to understand the mechanisms underlying pulmonary hypoplasia in the nitrofen CDH model. Pregnant rats were exposed to either olive oil or 100 mg of nitrofen on day 9 of gestation (D9). Fetal lungs were harvested at D15, D17, D19, and D21. D17, D19, and D21 lungs were divided into three groups: control, nitrofen without CDH and nitrofen with CDH, whereas D15 lungs were divided into only two groups; control and nitrofen as the diaphragm is not fully formed yet at this stage. Real- time PCR was performed to evaluate the relative level of Cyp26b1, LRAT, and RALDH2 expression in the lung. Relative levels of Cyp26b1 mRNA were significantly decreased in the lungs of nitrofen with CDH (D17;0.19 +/- 0.09, D19;0.70 +/- 0.20, D21;0.40 +/- 0.36) and nitrofen without CDH (D17;0.14 +/- 0.06, D19;0.54 +/- 0.42, D21;0.51 +/- 0.56) compared to controls (D17;0.35 +/- 0.16, D19;1.15 +/- 0.48, D21;1.28 +/- 0.78) (P < 0.05). LRAT expression was also significantly decreased in nitrofen with CDH (D17; 19.3 +/- 7.8, D19; 4.3 +/- 1.1, D21; 3.3 +/- 1.6) and nitrofen without CDH (D17; 21.2 +/- 11.1, D19; 4.5 +/- 3.6, D21; 4.1 +/- 1.6) compared to controls (D17; 153.7 +/- 29.8, D19; 26.8 +/- 16.8 D21; 10.1 +/- 3.8) (P < 0.05). There was no significant difference in the relative levels of Cyp26b1 and LRAT between nitrofen with CDH and nitrofen without CDH. There were no significant differences in RALDH2 expression among the groups at any stages. Down-regulation of Cryp26b1 and LRAT demonstrates that RA content is decreased in nitrofen induced hypoplastic lungs compared to controls. The finding that RALDH2 expression in the hypoplastic lung is not altered suggests that nitrofen may act by interfering with the retinoid metabolism during the early stage of the retinoid signaling pathway.

Effect of Radix Paeoniae Rubra on the expression of HO-1 and iNOS in rats with endotoxin-induced acute lung injury.

OBJECTIVE: To investigate the effect of Radix Paeoniae Rubra (RPR) on the expression of heme oxygenase (HO-1) and induced nitric oxide synthase (iNOS) in endotoxin-induced acute lung injury in rats and its protective mechanism. METHODS: Forty Wistar rats were divided randomly into 5 groups with 8 rats in each group: saline control group (NS group), lipopolysaccharide group (LPS group), RPR-treatment group, RPR-prevention group and Hemin group. The effect of RPR on protein content, the ratio of neutrophiles in bronchoalveolar lavage fluid, malondialdehyde (MDA) content in the lung and the activity of serum NO were observed. Arterial blood was drawn for blood-gas analysis. The expression of HO-1 and iNOS in lung tissues was detected by immunohistochemistry and morphometry computer image analysis. The histological changes of the lung were observed under light microscope. RESULTS: Compared with that in NS group, the expression of HO-1 and iNOS was markedly increased in LPS group (P<0.01). In RPR-treatment, RPR-prevention, and Hemin groups, the expression of iNOS was significantly lower, while the expression of HO-1 was higher than that in LPS group (P<0.05). The protein content, the ratio of neutrophiles in bronchoalveolar lavage fluid, the content of MDA and the activity of serum NO in LPS group were significantly higher than those in NS group (P<0.01). There was a significant decrease in the level of arterial bicarbonate and partial pressure of oxygen in the LPS group (P<0.01); these parameters of lung injury however, were significantly lower in RPR-treatment, RPR-prevention, and Hemin groups than LPS group (P<0.05 or P<0.01). The pathologic changes of lung tissues were substantially attenuated in RPR-treatment, RPR-prevention, and Hemin groups than LPS group. CONCLUSIONS: The high expression of HO-1 reflects an important protective function of the body during lipopolysaccharide-induced acute lung injury. The protective effect of RPR on lipopolysaccharide-induced acute lung injury is related to the inhibition of iNOS expression and the induction of HO-1 expression.

[Expression of NF-kappaB and COX-2 mRNA in rats with phlegm obstruction due to lung-deficiency].

OBJECTIVE: To study the role of nuclear factor-kappa B (NF-kappaB) and cycloxygenase-2 (COX-2) in the onset of phlegm obstruction due to lung-deficiency in rats and the therapeutic mechanism of Huatan Recipe. METHODS: Twenty-four SD rats were randomly divided into normal group, model group and treatment group, with 8 rats in each group. The rats in the model group and treatment group were exposed to sulfur dioxide and cold wind to establish the rat model of phlegm obstruction due to lung-deficiency, and the rats in the treatment group were also treated with Huatan Recipe, a compound traditional Chinese medicine. The expression of NF-kappaB in the bronchial epithelial cells of the rats was tested with the method of immunohistochemistry, and the COX-2 mRNA in the lung tissues of the rats was measured by using reverse transcription-polymerase chain reaction. RESULTS: The expressions of NF-kappaB and COX-2 mRNA in rats of the model group were higher than those of the normal group (P<0.01), and the expressions of NF-kappaB and COX-2 mRNA in rats of the treatment group were obviously lower than those of the model group (P<0.01). CONCLUSION: The NF-kappaB and COX-2 play an important role in the onset of phlegm obstruction in rats. Huatan Recipe may prevent the development of phlegm obstruction by down-regulating the expressions of NF-kappaB and COX-2 mRNA.

Superoxide dismutases in the lung and human lung diseases.

The lungs are directly exposed to higher oxygen concentrations than most other tissues. Increased oxidative stress is a significant part of the pathogenesis of obstructive lung diseases such as asthma and chronic obstructive pulmonary disease, parenchymal lung diseases (e.g., idiopathic pulmonary fibrosis and lung granulomatous diseases), and lung malignancies. Lung tissue is protected against these oxidants by a variety of antioxidant mechanisms among which the superoxide dismutases (SODs) are the only ones converting superoxide radicals to hydrogen peroxide. There are three SODs: cytosolic copper-zinc, mitochondrial manganese, and extracellular SODs. These enzymes have specific distributions and functions. Their importance in protecting lung tissue has been confirmed in transgenic and knockout animal studies. Relatively few studies have been conducted on these enzymes in the normal human lung or in human lung diseases. Most human studies suggest that there is induction of manganese SOD and, possibly, extracellular SOD during inflammatory, but not fibrotic, phases of parenchymal lung diseases and that both copper-zinc SOD and manganese SOD may be downregulated in asthmatic airways. Many previous antioxidant therapies have been disappointing, but newly characterized SOD mimetics are being shown to protect against oxidant-related lung disorders in animal models.

Garlic attenuates chrysotile-mediated pulmonary toxicity in rats by altering the phase I and phase II drug metabolizing enzyme system.

Asbestos and its carcinogenic properties have been extensively documented. Asbestos exposure induces diverse cellular events associated with lung injury. Previously, we have shown that treatment with chrysotile shows significant alteration in phase I and phase II drug metabolizing enzyme system. In this study we have examined some potential mechanisms by which garlic treatment attenuates chrysotile-mediated pulmonary toxicity in rat. Female Wistar rats received an intratracheal instillation of 5 mg chrysotile (0.5 mL saline) as well as intragastric garlic treatment (1% body weight (v/w); 6 days per week). Effect of garlic treatment was evaluated after 1, 15, 30, 90, and 180 days by assaying aryl hydrocarbon hydroxylase (AHH), glutathione (GSH), glutathione S-transferase (GST), and production of thiobarbituric acid reactive substances (TBARS) in rat lung microsome. The results showed that AHH and TBARS formation were significantly reduced at day 90 and day 180 in chrysotile treated garlic cofed rats; GSH recovered 15 days later to the near normal level and GST elevated significantly after treatment of garlic as compared to chrysotile alone treated rat lung microsome. The data obtained shows that inhibition of AHH activity and induction of GST activity could be contributing factor in chrysotile-mediated pulmonary toxicity in garlic cofed rats. However, recovery of GSH and inhibition of TBARS formation by garlic and its constituent(s) showed that garlic may give protection by altering the drug metabolizing enzyme system.

The effects of neutrophil depletion on a completely noninvasive model of acute pancreatitis-associated lung injury.

CONCLUSION: A completely noninvasive animal model of acute pancreatitis-associated lung injury was used to show that neutrophils, activated by pancreatitis, play a key role in mediating pancreatitis-associated lung injury. BACKGROUND: Significant pulmonary complications have been known to occur in over 50% of patients with severe acute pancreatitis. Recent studies using a variety of animal models of pancreatitis have suggested that neutrophil activation may play an important role in mediating lung injury. However, in these models, the interpretation of the results is complicated because surgical manipulations alone could have resulted in the activation of neutrophils. METHODS: Young female mice were fed a choline deficient ethionine (CDE) supplemented diet. The severity of pancreatitis was evaluated by measuring hyperamylasemia, acinar cell necrosis, and pancreatic myeloperoxidase activity. Lung injury was quantified by measuring lung microvascular permeability and lung myeloperoxidase activity. To evaluate the role of neutrophils in CDE diet-induced pancreatitis-associated lung injury, animals were pretreated with antineutrophil serum. RESULTS: Mice fed the CDE diet develop pancreatitis-associated lung injury. Pretreatment of mice with antineutrophil serum results in marked depletion of circulating neutrophils. Under these conditions, the severity of pancreatitis is reduced and lung injury is completely prevented.

Neutral endopeptidase (NEP) and its role in pathological pulmonary change with inhalation exposure to JP-8 jet fuel.

Through a simulated flightline exposure protocol, Fischer 344 rats (F344) were subjected to an aerosol/vapor mix of the military jet fuel, JP-8. Previous studies with this model of lung injury have revealed significant increases in pulmonary resistance, increased alveolar clearance of 99mTcDTPA, and a decrease in bronchoalveolar lavage fluid (BALF) concentration of the neuropeptide substance P (SP). Exposures to JP-8 were nose-only and for one hour daily. Six groups of Fischer 344 rats were exposed for 7, 28, or 56 days at two JP-8 concentrations (low dose = 469-520 mg/m3/hr, high dose = 814-1263 mg/m3/hr). Exposed groups were matched with longitudinal controls. In response to JP-8 inhalation, exposure animals demonstrated a dose-dependent as well as duration-determined reduction in BALF SP concentration. Both JP-8 concentrations caused significant pathological changes in lower pulmonary structures.

Carboxypeptidase M activity is increased in bronchoalveolar lavage in human lung disease.

Carboxypeptidase M (CPM) cleaves the C-terminal arginine and lysine of peptides; it is expressed in the lung, especially on the plasma membrane of alveolar type I cells. Here, we report on CPM in human bronchoalveolar lavage (BAL) collected from 69 patients and analyzed for activity, cell number and type, and protein level. Seventy-six percent of CPM activity, measured at pH 7.5 with 5-dimethylamino-naphthalene-1-sulfonyl-alanyl-arginine (Dansyl-Ala-Arg) substrate, was immunoprecipitated with polyclonal antibody to purified human enzyme. In patients without active lung disease, CPM activity in BAL was 7.69 (+/- 2.12) nmol/h/mg protein, but in patients with acute pneumonia, it was 29.25 (+/- 4.06) (p < 0.01). In patients with Pneumocystis carinii pneumonia, CPM activity was elevated to 26.00 (+/- 4.85) (p < 0.01) and in patients with lung cancer, to 30.95 (+/- 4.12) (p < 0.01). The activity was not associated with the cellular elements of BAL. The highest specific activity was in the large aggregate fraction of surfactant, which also contained the highest concentration of phosphorus. Transmission electron microscopy of this fraction revealed the presence of typical lamellar bodies and tubular myelin structures. The high CPM activity may stem from its induction and release in acute lung disease. In addition, CPM may be a marker of infection with certain pathogens and an indicator of type I cell injury in parenchymal lung diseases.

The role of prostaglandin H synthase in 3-methylindole-induced pneumotoxicity in goat.

1. Aspirin and indomethacin were used to investigate the role of prostaglandin H synthase (PHS) system in 3-methylindole (3MI)-induced pneumotoxicity. 2. A functional test was developed to detect the inhibitory effect of oral doses of aspirin and indomethacin on PHS activity based on thromboxane B2 (TXB2) production from thrombin-stimulated platelets in whole blood. 3. Goats which received oral doses of aspirin or indomethacin before administration of 3MI (0.1 g 3MI/kg body wt) showed a reduced severity in clinical signs and pathological lesions in the lung than those that received 3MI alone. 4. There was no difference in the severity of the disease between the control and the aspirin-treated animals if aspirin was given after 3MI administration. 5. The protective effect of inhibitors when administered before, but not after, 3MI dosing suggests it is the inhibition of PHS activity in activation of 3MI, not in production of prostanoids which prevented the disease process.

Protection against chemical-induced lung injury by inhibition of pulmonary cytochrome P-450.

Protection afforded by trialkyl phosphorothionates against the lung injury caused by trialkyl phosphorothiolates probably results from the inhibition by the P = S moiety of the thionates, of one or more pulmonary cytochrome P-450 isozymes. The aromatic hydrocarbons p-xylene and pseudocumene also protect against this injury and inhibit some P-450 isozymes, but by a different mechanism. OOS-Trimethylphosphorothionate and p-xylene were compared as protective agents against the effect of OOS-trimethylphosphorothiolate and two other lung toxins ipomeanol and 1-nitronaphthalene that are known to be activated by cytochrome P-450. The effects of these protective compounds, in vivo, on pulmonary cytochrome P-450 activity were also determined. Both compounds inhibited pentoxyresorufin O-deethylase activity, but not ethoxyresorufin O-deethylase. The phosphorothionate was most effective against lung injury caused by the phosphorothiolates and 1-nitronaphthalene, whereas p-xylene was much more effective against ipomeanol. beta-Naphthoflavone, which induces pulmonary ethoxyresorufin O-deethylase activity, did not protect against phosphorothiolate or 1-nitronaphthalene injury, and it was only marginally effective in decreasing the toxicity of ipomeanol.

Cathepsin B and D activity in alveolar macrophages from rats with pulmonary granulomatous inflammation or acute lung injury.

Cathepsin B and D activity was determined using specific synthetic substrates in alveolar macrophages (AMs) obtained from Sprague-Dawley rats with experimentally induced pulmonary granulomatous inflammation. Increased cathepsin B activity was found 4 days after intravenous injection of complete Freund's adjuvant (CFA), but not after injection of live bacillus Calmette-Guérin organisms (BCG), indicating that the enzyme response was unrelated to the subsequent development of granulomatous inflammation. Findings of comparable increases in enzyme activity following injection of mineral oil (MO) indicate that the response to CFA was due to the oil component. Significantly, oleic acid (OA), a natural fatty acid, did not stimulate enzyme activity although the agent, like MO, caused acute lung injury as assessed by 125I albumin uptake. At 7 and 28 days following injection of CFA, cathepsin B levels in AMs were the same as those in animals given normal saline (NS), although bronchoalveolar lavage (BAL) samples still contained increased numbers of AMs, and cells obtained at 28 days phagocytosed more polystyrene microspheres. Cathepsin D activity did not increase 4 days after injection of CFA or BCG + CFA; at 28 days following injection of BCG + CFA activity was significantly decreased as compared to animals given NS. The data reveal a differential response of two lysosomal enzymes during the early phases of granulomatous inflammation.

Amylase inhibitor from wheat: its action and clinical application.

The electrophoretic and column chromatographic characteristics of an amylase inhibitor of wheat origin were investigated. Further, the clinical usefulness of this inhibitor for determining the ratio of pancreatic to salivary isoamylase activity in serum was evaluated. Amylase inhibitor inhibits the action of salivary alpha-amylase by making an amylase-inhibitor complex, which is easily separated into its individual component during electrophoresis with full recovery of amylase activity. Using the specific inhibitory effect of this inhibitor on salivary alpha-amylase activity, the ratio of pancreatic to salivary isoamylase activity (P/S) in serum was determined. There was a good correlation in P/S ratio in serum between the results obtained with the inhibitor method and those with electrophoretic method. The P/S ratio in sera from patients with acute pancreatitis was over 8.0, whereas that in sera from patients with salivary-type hyperamylasemia such as mumps, pulmonary diseases and following surgery was less than 0.1. However, hyperamylasemia due to macroamylase or renal failure could not be identified by the inhibitor method.

Enhanced lung toxicity of O2 in selenium-deficient rats.

To test the hypothesis that glutathione (GSH) peroxidase is an important component of the lung's anti-oxidant defense systemes, O2 toxicity was studied in selenium (Se)-deficient rats. Chronic respiratory disease free rats fed a Se-deficient diet or a diet supplemented with Se for 40 days after weaning were exposed to 80% O2 at atmospheric pressures for 3 days. Activities of GSH peroxidase in lungs of Se-deficient rats were markedly lower than corresponding activities in rats supplemented with 0.5 or 2.0 ppm Se. With O2 exposure, 35% of the rats fed the Se-deficient regimen died, whereas all rats fed Se-supplemented diets survived. Lungs from surviving Se-deficient rats exposed to O2 were edematous. The data suggest that the toxic effects of O2 are enhanced in Se-deficient rats and that nutritional factors contribute to lung susceptibility to oxidant-induced damage.