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Biomedical subjects

L Frank

Publications and source records attributed to L Frank.

At least 127 records · Page 7Linked to original sources
PubMed1985

Endotoxin-tolerant rats are still protected from oxygen toxicity by low-dose endotoxin treatment.

To determine if we could reduce endotoxin's potential for toxicity, we produced "endotoxin-tolerant" rats by administering progressively increasing daily doses of endotoxin (10 ng, 100 ng, 1 microgram, 10 micrograms/kg). This dosage regimen produced a high degree of tolerance to the toxic actions of endotoxin: whereas only 3/17 (18%) of control rats survived a normally lethal dose of endotoxin (25 mg/kg), survival for the endotoxin-tolerant rats was 16/16. When endotoxin-tolerant rats received a standard protective dose of 500 micrograms/kg endotoxin just before transfer to 96-98% O2, 19/20 survived the 72-h exposure period vs. 20-30% survival for controls. Thus whereas the endotoxin-tolerant state blocked the tested lethal and toxic effects of endotoxin, it did not nullify the O2 protective action of endotoxin. In addition, endotoxin's stimulatory effects on the lung antioxidant enzymes in the 96-98% O2-exposed rats was also not blocked by the endotoxin-tolerant state. Thus the therapeutic ratio (TR) of endotoxin as an experimental pharmacological treatment against O2-induced lung damage has been markedly enhanced (TR = ratio of dose producing beneficial effects to dose producing toxic effects).

Acid Phosphatase↗
PubMed1985

Mitogenic effect of endotoxin on lung and tolerance of rats to hyperoxia.

Treatment of rats with endotoxin, as late as 24 h after beginning exposure to greater than 95 O2 at 1 atm, increases survival at 72 h from 20-30% to greater than 95% (J. Clin. Invest. 65: 1104, 1980), whereas treatment with corticosteroids reduces survival (Toxicol. Appl. Pharmacol. 47: 367, 1979). Since endotoxin is mitogenic to some cells and glucocorticosteroids decrease DNA synthesis by lung cells, we asked 1) is endotoxin mitogenic to the lung, and, if so, 2) is the mitogenic effect required for endotoxin to produce tolerance to hyperoxia? We found endotoxin administered in vivo does have a mitogenic effect on the lung as indicated by an increased rate of DNA synthesis by lung slices; dexamethasone blocked this effect. However, although dexamethasone given alone markedly diminished survival in hyperoxia, dexamethasone did not impair the protection conferred to rats by endotoxin against the edemogenicity and lethality of hyperoxia. Furthermore, dexamethasone did not diminish the rise of antioxidant enzyme activity in the lungs of endotoxin-treated O2-exposed rats. We conclude endotoxin can produce tolerance to hyperoxia even when its mitogenic action on the lung is substantially diminished.

Animals↗
PubMed1985

Oxygen toxicity in rats. Varied effect of dexamethasone treatment depending on duration of hyperoxia.

The low rate of survival in patients with the adult respiratory distress syndrome (ARDS) may in part reflect a failure to consider that the lung's response to applied therapies may not be constant throughout the course of illness. To test this notion, we used hyperoxia to produce progressive lung damage in rats and administered dexamethasone at different times during O2 exposures of various lengths. Dexamethasone improved survival and decreased lung damage if given when exposure to hyperoxia was to be soon terminated; pulmonary inflammation was marked at the time at which the administration of dexamethasone led to increased survival. Dexamethasone worsened lung damage and diminished survival when given early during exposure to hyperoxia; inflammation was minimal early in the course of exposure to hyperoxia. These findings point to the need for a more analytical approach to research on therapy of ARDS; agents that are harmful at one time may be beneficial at another time.

Animals↗
PubMed1985

Intrauterine growth-retarded rat pups show increased susceptibility to pulmonary O2 toxicity.

We used a nutritional deprivation model to produce intrauterine growth-retarded (IGR) rat pups (birth weight = approximately 75% of normal). The IGR newborns evidenced a marked reduction in tolerance to greater than 95% O2 exposure: 10-day survival = 10/47 (21%) versus 18/36 (50%) for control pups, and LT50 = 7.2 days versus 10 days for controls (p less than 0.01). Various lung parameters at birth and during O2 exposure were examined to try to define why prenatal undernutrition should compromise the survival of IGR rats in hyperoxia. We found decreased lung glutathione peroxidase and glucose-6-phosphate dehydrogenase activity (with normal superoxide dismutase and catalase levels) in the IGRs at birth; decreased lung disaturated phosphatidylcholine content (even more markedly decreased in 1-day premature pups); and decreased lung surface area/body weight. These factors and other features of newborn IGRs reported in the literature may help to explain how prenatal undernutrition compromises postnatal tolerance to prolonged high-O2 exposure.

Animals↗
PubMed1985

Dexamethasone stimulation of fetal rat lung antioxidant enzyme activity in parallel with surfactant stimulation.

It has recently been determined that fetal lung antioxidant enzyme activity markedly increases late in gestation. A test was made of whether this normal late-in-gestation change in O2-protective enzymes would be responsive to the maturing effect of hormonal (glucocorticoid) treatment. Pregnant rats received 0.2 mg/kg of dexamethasone (or saline) at 48 and 24 hours prior to delivery of their fetuses on gestational days 19, 20, 21, and 22 (newborn). Lung disaturated phosphatidylcholine showed an expected response to prenatal dexamethasone exposure with significant elevations of surfactant lipid at gestational days 20 and 21. A similar effect of prenatal dexamethasone treatment on the lung antioxidant defensive system was found. Superoxide dismutase, catalase, and glutathione peroxidase--enzymes protective against hyperoxia-induced lung injury--showed an accelerated pattern of maturation with significant increases in the dexamethasone-treated fetal lungs compared with control fetal lung enzyme levels at gestational days 20 and 21. The results suggest that prenatal dexamethasone treatment may have dual benefits when used in impending premature deliveries--that is, it may stimulate maturation of both the surfactant system and also the antioxidant enzyme system, and this maturation can help protect the premature newborn's lungs from the toxic complications of hyperoxic therapy that may be required because of immaturity.

Animals↗
PubMed1985

Effects of oxygen on the newborn.

The free radical theory of O2 toxicity provides a testable explanation of the mechanism of O2's toxic effects on a biochemical and cellular level. In addition, it provides for an understanding of the array of normal antioxidant defenses of the cell and an insight to rational approaches to pharmacologic prophylaxis against clinical O2 toxicity. Neonatal animals of many species are much more resistant to the lethal effects of exposure to high concentrations of O2 than are the adult animals of the species; this increased tolerance is associated with the newborn lungs' ability to increase its normal complement of protective antioxidant enzymes during O2 exposure. Premature infants who require vigorous hyperoxic respiratory support early in life frequently develop acute and chronic lung changes compatible with pulmonary O2 toxicity, so-called bronchopulmonary dysplasia. The lung of the prematurely born may be quite ill-adapted for protecting itself against hyperoxic exposure owing to immaturity of its antioxidant defensive systems. Clinical pharmacologic stratagems designed to augment the intracellular antioxidant defensive capacity of the lung may become available in the near future, which would provide some means to prevent or ameliorate the serious lung damage associated with the clinical use of life-giving O2.

Age Factors↗
PubMed1984

Castration prolongs tolerance of young male rats to pulmonary O2 toxicity.

We tested the hypothesis that the normal loss of tolerance of neonatal rats to prolonged hyperoxic exposure at around 1 mo of age might be related to the marked increase in sex hormones occurring around this period. Male rats castrated at 20 days of age demonstrated significantly increased survival in greater than 95% O2 compared with sham-operated rats when exposed to high O2 at various ages greater than 45 days [castrated, 115 of 166 (69%) vs. sham, 59 of 156 (38%) (P less than 0.001)]. Testosterone replacement led to survival rates comparable with sham-operated rats [30 of 87 (34%)]. No such protective effect was observed in female rats [survival: ovariectomy, 16 of 33 (48%) vs. sham, 14 of 28 (50%)]. The improved survival in the older castrated males was not associated with an increase in lung antioxidant enzymes, which is normally seen in O2-tolerant neonatal rats. Castration did result in marked morphological lung changes, including significantly enlarged lung volumes (4.54 +/- 0.72 vs. 3.76 +/- 0.29 ml/100 g) and terminal air spaces [mean linear intercept (LM) = 51.6 +/- 5.0 vs. 46.3 +/- 4.1 micron (P less than 0.001)]. Testosterone replacement also prevented these morphological changes. The altered lung growth 1) may be related to the influence of other endocrine imbalances after castration and 2) may be an important factor in the relative O2 tolerance of the castrated male rats beyond the neonatal period.

Animals↗
PubMed1984

Endotoxin treatment protects vitamin E-deficient rats from pulmonary O2 toxicity.

Endotoxin treatment in normal rats has a marked protective effect against O2 toxicity (J. Appl. Physiol.: Respirat. Environ. Exercise Physiol. 47: 577-581, 1979 and 51: 577-583, 1981), and endotoxin's protective action is associated with stimulation of the lung's enzymatic antioxidant defense system (superoxide dismutase, catalase, glutathione peroxidase, and glucose-6-phosphate dehydrogenase). Vitamin E-deficient animals are especially sensitive to hyperoxidant stresses, including pulmonary O2 toxicity. In these studies we tested whether endotoxin could reverse the increased susceptibility of vitamin E-deficient rats to hyperoxic challenge. We found that untreated vitamin E-deficient rats do succumb more readily to O2 toxicity [0/11 alive at 72 h in greater than 95% O2, lethal time for 50% of the animals (LT50) = 50 h] than rats fed a regular diet (4/14 alive, LT50 = 69 h). In contrast, 15 of 16 vitamin E-deficient rats treated with endotoxin survived the same O2 exposures (P less than 0.001) and showed significantly reduced pulmonary edema compared with the other groups. The endotoxin-treated vitamin E-deficient group was also the only one to demonstrate significant elevations of all the antioxidant enzymes during O2 exposure, suggesting that the antioxidant enzyme defenses of the lung have a more primary and important role in prevention of O2-induced lung injury than the lipid-associated antioxidant, vitamin E.

Animals↗
PubMed1984

Ozone-induced tolerance to hyperoxia in rats.

Preexposure of adult rats to ozone (0.8 +/- 0.1 ppm for 7 days) has been found to produce a marked degree of tolerance to hyperoxia (greater than 95% O2). The survival of O3-preexposed rats in hyperoxia for 168 h was 28 of 32 (88%) compared with a rate of 2 of 18 (11%) for nonpreexposed rats. Total lung superoxide dismutase (SOD), glutathione peroxidase (GP), glucose 6-phosphate dehydrogenase (G6-PD), and catalase (CAT) activities were all significantly increased after O3 preexposure and after the subsequent hyperoxic challenge. Probable mechanisms accounting for the markedly improved survival in hyperoxia after O3 preexposure include both increased lung antioxidant enzyme and repair of structural damage by proliferation of alveolar lining cells. The demonstration of cross-tolerance between the atmospheric oxidants O3 and O2 suggests that there are similarities in the lung's adaptation to both oxidants.

Animals↗
PubMed1984

Preparation for birth into an O2-rich environment: the antioxidant enzymes in the developing rabbit lung.

To determine if some specific "preparation for birth" occurs in the developing lung to help assure its successful adaptation to a comparatively O2-rich world at birth, we measured the activities of the antioxidant enzymes in the developing lungs of rabbit fetuses from 10 d before parturition to several days after birth. Superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GP) activities showed similar maturational patterns with significant increases in activity, compared with earlier gestational levels, during the last 3-5 d before birth. During the final days in utero, SOD and CAT activities increased by approximately 110% and lung GP activity by approximately 200%. There were no parallel changes in lung O2 consumption demonstrable over this same prenatal period.

Adaptation, Physiological↗
PubMed1982

The effect of bacterial endotoxin on synthesis of (Cu,Zn)superoxide dismutase in lungs of oxygen-exposed rats.

Administration of bacterial endotoxin to rats exposed to greater than 95% O2 results in increased lung superoxide dismutase activity, decreased O2-induced lung damage, and a 3- to 4-fold improvement in survival rate (Frank, L., Yam, J., and Roberts, R. J. (1978) J. Clin. Invest, 61, 269-275). Antibodies to rat liver (Cu,Zn) superoxide dismutase were prepared and utilized to investigate the mechanism by which endotoxin treatment leads to increased lung superoxide dismutase activity. Assay of enzyme activity and of immunodetectable enzyme showed that the increased activity is due to an increase in the number of enzyme molecules rather than activation of existing enzyme. Compared to air controls, lung slices from rats exposed to greater than 95% O2 and treated with endotoxin have elevated rats of synthesis of (Cu,Zn)superoxide dismutase (51%) and of total protein (100%). Lung slices from untreated rats exposed to greater than 95% O2 have no such elevations. Endotoxin treatment thus appears to stimulate lung protein synthesis, leading to greater (Cu,Zn)superoxide dismutase activity due to an increased number of enzyme molecules.

Animals↗
PubMed1982

The activity of pulmonary indoleamine 2,3-dioxygenase in rats and mice is not altered by oxygen exposure.

We tested the hypothesis that pulmonary indoleamine 2,3-dioxygenase (indole:oxygen 2,3-oxidoreductase (decyclizing), EC 1.13.11.17), an enzyme that consumes superoxide anion (O-2), might have an antioxidant role under conditions of hyperoxia. We measured indoleamine 2,3-dioxygenase in three experimental models in which pulmonary superoxide dismutase, catalase and glutathione peroxidase (the known antioxidant enzymes) show increased activity and are associated with greater tolerance to 96-98% O2 exposure: (1) adult rats preexposed to 85% O2 for 5-7 days; (2) neonatal rats exposed directly to greater than 95% O2; and (3) adult rats treated with bacterial endotoxin during O2 exposure. Indoleamine 2,3-dioxygenase did not increase in response to O2 exposure in any of these rat models. Conversely, in adult mice treated with endotoxin, lung indoleamine 2,3-dioxygenase activity did increase, but no protection against O2 toxicity occurred. Thus, a rise in indoleamine 2,3-dioxygenase is neither necessary nor sufficient to confer resistance to O2 toxicity. These data taken together are evidence against its having any important role in the antioxidant defense system of the lung.

Aerobiosis↗
PubMed1982

Protection from O2 toxicity by preexposure to hypoxia: lung antioxidant enzyme role.

Adult rats preexposed to 10% O2 for 3 days had marked tolerance to hyperoxia-induced lung damage and lethality. The survival of preexposed vs. nonpreexposed rats at 72 h of hyperoxic exposure was 62/62 vs. 7/47 (15%), P less than 0.0001; and after 7 days in 96-98% O2, the comparative survival was 31/33 (94%) vs. 1/20 (5%), P less than 0.0005. Hypoxic exposure produced significant elevations in rat lung superoxide dismutase, catalase, glutathione peroxidase, and glucose-6-phosphate dehydrogenase activities. In contrast, in adult mice and hamsters, no increased lung antioxidant enzyme levels were produced by preexposure to hypoxia and no significant tolerance to high O2 was realized. (Lethal time50 values for hypoxia-preexposed and nonpreexposed mice, 5.2 and 4.4 days, respectively; and for hamsters, 6.4 and 6.1 days, respectively.) Thus the protective effect of hypoxic preexposure is correlated with adaptive changes in lung antioxidant enzyme activity. Evidence in the literature suggests that superoxide anion (O-2) and H2O2 production may increase under hypoxic conditions. Increased cellular concentrations of their normal substrates could stimulate antioxidant enzyme rises during the preexposure period in hypoxia.

Animals↗
PubMed1982

Oxygen toxicity in newborn rats: the adverse effects of undernutrition.

Undernutrition was found to compromise the tolerance of newborn rat pups to hyperoxia (greater than 95% O2 for 7 days). Survival rate for the normally nourished pups (11 pups/dam) was 56 of 77 (73%) but only 47 of 108 (44%) for the undernourished (18 pups/dam) group (P less than 0.005). Body growth, lung growth, and lung DNA content were significantly reduced by undernutrition. Hyperoxia inhibited these same parameters in both groups of pups. The growth inhibitory effects of O2 and undernutrition were additive, with an especially marked depression of lung DNA content (decreases 65%). Lung maturation was also markedly inhibited by O2 but to a similar extent in both nutrition groups. Despite the disparity in their O2 tolerance, 18/litter and 11/litter pups in O2 responded with equivalent increases in lung antioxidant enzymes. We suggest that the additive depressive effects of neonatal undernutrition and hyperoxia on lung DNA may compromise repair of ongoing O2-induced lung damage and help account for the compromised O2-tolerance we consistently observed even in the presence of significantly elevated antioxidant enzyme defenses.

Animals↗
PubMed1982

Pulmonary superoxide dismutase activity in the euthyroid and hypothyroid ovine fetus.

Pulmonary superoxide dismutase (SOD) activity was measured in 11 euthyroid and 15 hypothyroid ovine fetuses at 130 days gestation. In the euthyroid fetus, the mean pulmonary SOD activity was similar in saline- and thyroxine-infused groups. Compared to the euthyroid fetus, the mean pulmonary SOD activity was significantly lower in the noninfused or saline-infused athyrotic fetus. Administration of thyroxine to the hypothyroid fetus results in a normalization of pulmonary SOD activity to control values. Thus, thyroxine appears to influence the maturation of pulmonary SOD activity in the ovine fetus during the third trimester.

Animals↗