Biomedical subjects

Y C Huang

Publications and source records attributed to Y C Huang.

At least 19 recordsLinked to original sources

PubMed1998

Identification of the subunit and important target peptides of pig heart NAD-dependent isocitrate dehydrogenase modified by the affinity label adenosine 5'-O-[S-(4-bromo-2, 3-dioxobutyl)thiophosphate].

Pig heart NAD-dependent isocitrate dehydrogenase is inactivated by adenosine 5'-O-[S-(4-bromo-2,3-dioxobutyl)thiophosphate] (AMPS-BDB) with incorporation of 1.78 mol of reagent/mol of average subunit. Complete protection against the inactivation is provided by 20 mM isocitrate + 1 mM Mn2+, and the incorporation is decreased to about 1.3 mol of reagent/mol of average subunit. The addition of NAD, NADH, or Mn2+ alone has little effect on the functional changes produced by AMPS-BDB, while ADP gives only partial protection against the inactivation. The ability of ADP to decrease the Km for isocitrate is not affected by the AMPS-BDB modification of the enzyme. These results indicate that the isocitrate substrate site is the target of AMPS-BDB. The enzyme has three types of subunits with a tetramer having the composition alpha2 beta gamma. Here, [2-3H]AMPS-BDB-modified subunits are separated by HPLC on a C4 reverse-phase column, after the treatment of the modified enzyme with 4 M urea. The predominant radioactivity is distributed in alpha and gamma subunits. However, evidence based on recombination of subunits from modified and unmodified enzymes indicates that only labeling of the alpha subunit is responsible for inactivation by AMPS-BDB. Subsequently, the separated modified subunits were chemically cleaved by CNBr and then purified by HPLC using a C18 column. The labeled peptides were further digested by pepsin, purified by HPLC, and sequenced. These results indicate that R88 and R98 from the alpha subunit are the major targets of AMPS-BDB which cause inactivation and that these are at or near the isocitrate site of the enzyme.

Adenosine Diphosphate↗

PubMed1998

Cardiokymograph system with a capacitance transducer and its preliminary application in the measurement of heart wall movement.

A novel cardiokymograph system is introduced. The new system features a capacitance transducer with increased sensitivity and can be used in multichannel measurements. The novelty of this technique is the injection of a current into the patient coupled with the use of a capacitive displacement transducer and the possibility of multichannel monitoring. It provides for the possibility of removing breath noise when some signal processing technique, such as adaptive filtering, is used. Further investigation is needed to demonstrate clinical significance and pathologies.

Adult↗

PubMed1998

Yeast carriage on hands of hospital personnel working in intensive care units.

The frequency and distribution of yeast carriage on the hands of hospital personnel working in intensive care unit (ICUs), was investigated. Hand carriage of yeast and Candida species was 46 and 29%, respectively. Rhodotorula sp. and Candida parapsilosis were most frequently recovered. There was no significant difference in frequency or distribution of yeasts and Candida sp. recovered among the three ICUs. Seventeen C. parapsilosis isolates and three Candida albicans isolates were genotyped by electrophoretic karyotyping using contour-clamped homogenous electric-field gel electrophoresis. Eleven separate types of C. parapsilosis and two types of C. albicans were identified. There was no common genotype among these isolates, even within the same unit. We conclude that yeast carriage on the hands of personnel working in ICU is common, but these yeasts are usually not acquired from a common source in the ICU.

Candida↗

PubMed1998

Vitamin B-6 requirement and status assessment of young women fed a high-protein diet with various levels of vitamin B-6.

The vitamin B-6 requirement of young women consuming a constant high-protein diet (1.55 g/kg body wt) and the effect of various ratios of vitamin B-6 to protein on this requirement were studied. Eight women were fed a lactoovovegetarian basal diet containing 0.45 mg vitamin B-6 (2.66 micromol as pyridoxine) and 30 micromol carnitine for 92 d. The protocol consisted of successive baseline adjustment (9 d), depletion (27 d), and repletion (two 21-d and then one 14-d) periods. Vitamin B-6 intakes were 1.60, 0.45, 1.26, 1.66, and 2.06 mg, resulting in ratios of vitamin B-6 (in mg) to protein (in g) for the five periods of 0.016, 0.005, 0.013, 0.017, and 0.021, respectively. Direct and indirect as well as short- and long-term vitamin B-6 status measures were assessed weekly. Regression analysis revealed that the amount of dietary vitamin B-6 required to normalize urinary 4-pyridoxic acid, plasma pyridoxal-P, erythrocyte pyridoxal-P and pyridoxal, and erythrocyte alanine and aspartate aminotransferase activity coefficients to predepletion baseline values was 1.94 mg vitamin B-6/d (0.019 mg vitamin B-6/g protein). This study suggests that the current vitamin B-6 recommended dietary allowance of 1.6 mg/d based on 0.016 mg/g protein is not an adequate intake and may require reevaluation.

Adult↗

PubMed1998

Urinary, plasma, and erythrocyte carnitine concentrations during transition to a lactoovovegetarian diet with vitamin B-6 depletion and repletion in young adult women.

The purpose of the present study was to determine whether vitamin B-6 depletion and repletion influence carnitine concentrations in the plasma, erythrocytes, and urine of young adult women consuming a low-carnitine (30 micromol/d), lactoovovegetarian diet. Doses of vitamin B-6 were administered sequentially as follows: 1.60 mg/d during adjustment for 9 d, 0.46 mg/d during depletion for 27 d, 1.26 mg/d during the first repletion for 21 d, 1.66 mg/d during the second repletion for 21 d, and 2.06 mg/d during the third repletion for 14 d. Urinary carnitine tended to decline but was not significantly different throughout the 92-d study period. Plasma short-chain acylcarnitine and total carnitine decreased during vitamin B-6 depletion; however, the ratio of plasma acylcarnitine to total carnitine was not significantly different during changes in vitamin B-6 intake. Erythrocyte long-chain acylcarnitine increased during vitamin B-6 depletion, but the ratio of erythrocyte acylcarnitine to total carnitine did not respond to changes in vitamin B-6 intake. Plasma free and total carnitine concentrations were only weakly correlated with plasma pyridoxal-P concentration (r = 0.28 and r = 0.29, respectively; P < 0.01). No significant correlations were observed between urinary carnitine excretion or erythrocyte carnitine concentrations and plasma or erythrocyte pyridoxal-P concentrations. Thus, a vitamin B-6 intake of 0.5 mg/d does not affect carnitine concentrations in biological fluids and therefore is unlikely to affect endogenous carnitine synthesis over 27 d. The changes in carnitine indexes that we observed were probably due to adaptation to a vegetarian pattern of exogenous carnitine consumption.

Adult↗

PubMed1998

A highly selective beta1-adrenergic blocker with partial beta2-agonist activity derived from ferulic acid, an active component of Ligusticum wallichii Franch.

Short-term injection of ferulinolol (0.1, 0.5, and 1.0 mg/kg, i.v.) produced dose-dependent bradycardia responses in pentobarbital-anesthetized Wistar rats, whereas it had no significant effects on the blood pressure. Ferulinolol markedly inhibited the tachycardia effects induced by (-)isoproterenol but did not show any blocking effect on the arterial pressor responses induced by (-)phenylephrine. These findings clearly suggested that ferulinolol had a beta-adrenergic blocking activity; nevertheless, it did not involve an alpha-adrenergic blocking action. In isolated guinea pig tissues, ferulinolol competitively antagonized (-)isoproterenol-induced positive inotropic and chronotropic effects of the atria and tracheal relaxation responses. The parallel shift to the right of the concentration-response curve of (-)isoproterenol suggested that ferulinolol was a beta-adrenoceptor-competitive antagonist. The apparent pA2 values for ferulinolol on right atria, left atria, and trachea were 7.62 +/- 0.05, 7.54 +/- 0.01, and 6.28 +/- 0.11, respectively. Ferulinolol was more potent on the atria than on tracheal tissues, demonstrating that it possessed beta1-adrenoceptor selectivity. The intrinsic sympathomimetic activity (ISA) of ferulinolol and propranolol were determined on isolated atria and trachea from reserpine-treated guinea pig. Propranolol caused significantly negative inotropic and chronotropic effects at > or =1 microM, whereas ferulinolol possessed fewer cardiodepressant activities than propranolol. In reserpine-treated tracheal strips, ferulinolol produced dose-dependent relaxant responses, but propranolol was without effectiveness. Preincubating the preparations with ICI 118,551 (0.1, 1.0, and 10 nM), a beta2-adrenoceptor antagonist, significantly shifted the concentration-relaxation curves of ferulinolol to a region of higher concentrations. These results implied that ferulinolol had a partial beta2-agonist activity. Further, binding characteristics of ferulinolol and various beta-adrenoceptor antagonists were evaluated in [3H]CGP-12177 binding to rat ventricular or lung membranes. The Ki values of ferulinolol, atenolol, metoprolol, and (-)propranolol were 103, 262, 123, and 0.23 nM, respectively, in ventricular membranes, and 2,412, 7,539, 2,186, and 0.72 nM, respectively, in lung membranes. In conclusion, ferulinolol was found to be a highly selective beta1-adrenoceptor antagonist with partial beta2-agonist activity but was devoid of alpha-adrenoceptor blocking action.

Adrenergic beta-1 Receptor Antagonists↗

PubMed1998

Anti-intercellular adhesion molecule-1 antibody and intercellular adhesion molecule-1 gene deficiency do not prevent pulmonary neutrophil recruitment in polymicrobial sepsis.

The intercellular adhesion molecule (ICAM)-1 is expressed constitutively in normal lungs and increased in pulmonary inflammation. Whether increased ICAM-1 expression in the lung contributes to neutrophil sequestration during lung inflammation in sepsis is unclear. We tested this hypothesis in mice after systemic sepsis from cecal ligation and puncture (CLP). ICAM-1 expression in mouse CLP lung tissue was found to increase with time. The time course of lung ICAM-1 up-regulation correlated with increases in lung myeloperoxidase (MPO) activity and neutrophil sequestration by light microscopy. The monoclonal IgG2b rat anti-mouse antibody, an anti-ICAM-1 antibody (YN1/1.7), administered intravenously at doses of 3, 10, or 30 mg/kg, however, did not decrease the lung MPO levels compared with nonimmune rat IgG. In support of these findings, lung MPO content in ICAM-1-deficient mice that underwent CLP was significantly higher than similarly treated ICAM-1-sufficient mice. Our results suggest that neutrophil sequestration in the mouse lung after CLP is not dependent on ICAM-1.

Animals↗

PubMed1998

Antibody to E- and L-selectin does not prevent lung injury or mortality in septic baboons.

Recruitment of polymorphonuclear leukocytes (PMN) through upregulation of cellular adhesion molecules is a proposed mechanism of injury in sepsis and acute respiratory distress syndrome (ARDS). We hypothesized that pretreatment of baboons with a monoclonal antibody to human E- and L-selectin (EL-246) during sepsis would decrease PMN influx into tissues and result in less organ injury during gram-negative sepsis. We studied 14 anesthetized, ventilated adult baboons; six animals received 1 mg/kg of EL-246 before infusion of an LD100 of live Escherichia coli and six received the E. coli infusion without antibody therapy. Two other animals received 1 mg/kg of EL-246 intravenously without an infusion of bacteria. Intermittent measurements were made of circulatory pressures, cardiac output, urine output, arterial blood gases, ventilation:perfusion ratio (VA/Q), and hematologic status. The experiments were ended at 48 h or at the time of death. Tissues were harvested for pathology and biochemical measurements. The E. coli infusions were associated with a hyperdynamic state, pulmonary hypertension, systemic hypotension, decreased urine output (UOP), and metabolic acidosis. The antibody partly blocked PMN migration, but there were few significant physiologic or biochemical differences between the EL-246-treated and untreated animals. In the antibody-treated animals, UOP was decreased, metabolic acidosis was worsened, and median survival time was decreased significantly. We conclude that treatment with an antibody to E- and L-selectin in gram-negative sepsis does not improve gas exchange or protect against lung injury, and is associated with decreased survival time in primates.

Acidosis↗

PubMed1997

Identification of the subunits and target peptides of pig heart NAD-specific isocitrate dehydrogenase modified by the affinity label 8-(4-bromo-2,3-dioxobutylthio)NAD.

Pig heart NAD-dependent isocitrate dehydrogenase reacts with 8-(4-bromo-2,3-dioxobutylthio)-NAD (8-BDB-TNAD) with incorporation of 1.21 mol of reagent/mol of average subunit when the enzyme reaches the limit of 25% residual activity (Kumar, A., and Colman, R. F., Arch. Biochem. Biophys. 308, 357-366, 1994). Inclusion of NADPH decreases both the extent of inactivation and the reagent incorporation to 0.55 mol/mol of average subunit. We have now isolated the peptides labeled by radioactive 8-(4-bromo-2,3-dioxobutylthio)-[2-3H]NAD and have located them within the sequence of pig heart NAD-dependent isocitrate dehydrogenase. The enzyme is composed of three types of subunits, present as alpha 2 beta gamma. We have separated the subunits from unmodified and 8-BDBT[2-3H]NAD-modified enzymes by HPLC on a C4 reverse-phase column, after pretreatment of the enzymes with sodium dodecyl sulfate or urea, and compared the subunit sequences of the porcine enzyme with those of the corresponding subunits from other mammalian NAD-dependent isocitrate dehydrogenases. The predominant radioactivity of 8-BDBT[2-3H]NAD is observed in the alpha and gamma peaks, and the NADPH-protected enzyme exhibits marked reduction in incorporation into these peaks. However, evidence based on recombination of subunits from modified and unmodified enzymes indicates that only labeling of the alpha-subunit is responsible for inactivation by 8-BDB-TNAD. Cyanogen bromide was used to cleave the modified enzyme, and we purified one labeled peptide from the alpha-subunit (amino acids 84-177) as well as one from the gamma-subunit (amino acids 67-186). In the alpha-subunit, decreased modification by [7-14C]-phenylglyoxal of Arg88 and Arg98 after prior labeling of the enzyme by 8-BDB-TNAD indicates that these residues are the critical target sites of the reactive nucleotide analogue. We conclude that alpha subunit's Arg88 and Arg98 are both at or near the allosteric NADPH sites of the pig heart isocitrate dehydrogenase.

Affinity Labels↗

PubMed1997

Small neuraminidase gene of Clostridium perfringens ATCC 10543: cloning, nucleotide sequence, and production.

The small nanH gene encoding a neuraminidase from Clostridium perfringens ATCC 10543 was cloned in JM109 using pUC19 as a vector. Sequence analysis revealed an ORF, nt 310-1455, encoding 382 amino acids that was proceeded by a typical Shine-Dalgarno sequence, GGACGAGA. The nt sequence in the 15-402 region had in vivo promoter activity in an Escherichia coli promoter probe plasmid pKK232-8, which suggested that the small nanH promoter is functional in E. coli. Four regions of amino acids demonstrated great similarity to the "Asp boxes" (-Ser-X-Asp-X-Gly-X-Thr-Trp-) of other bacterial nanH proteins. The small nanH expressing clone, pCPN-1, which was cultured under aerobic conditions resulted in NanH activity which was 203-fold in culture and 211-fold in intracellular fraction compared to that of C. perfringens which has to be cultured under anaerobic conditions. Production of small NanH was also induced by adding sialyllactose to the culture medium of JM109 [pCPN-1]. The enzyme activity could be detected in the periplasmic fraction and the culture medium of JM109 [pCPN-1] after culturing to the stationary phase. The molecular weight, K(m), and optimum pH and pI of the cloned enzyme are identical to those of the parent strain. The cloned, small nanH could be used to study the structure-functional relationship of nanH, while the pCPN-1 clone could be used in the aerobic production of neuraminidase.

Amino Acid Sequence↗

PubMed1997

Changes in the lung after prolonged positive pressure ventilation in normal baboons.

PURPOSE: The effects of prolonged positive pressure ventilation on lung ultrastructure are not well defined in primates. This study was designed to measure cardiopulmonary and morphological responses to 4 days of positive pressure ventilation in normal baboons. MATERIALS AND METHODS: Six adult male baboons were mechanically ventilated on air for 96 hours with 2.5 cm positive end-expiratory ventilation and a tidal volume of 12 to 15 mL/kg. Physiological measurements were obtained every 12 hours and serial measurements of ventilation-perfusion (VA/Q) were performed using the multiple inert gas elimination technique. Quantitative morphotometry, lung dry-to-wet ratio, and surfactant analysis were performed at the end of the experiment. RESULTS: Cardiovascular variables, except for a small increase in mean pulmonary artery pressure at 84 and 96 hours, were not significantly affected by positive pressure ventilation. Arterial Po2 decreased, and shunt fraction increased from 0.7% of cardiac output to 5.4% (P < .01). Dispersion of perfusion increased threefold (P < .01), and dispersion of ventilation doubled (P < .01) indicating increased VA/Q mismatch mismatch. Respiratory system compliance decreased by 30% (P < .01). There was no lung edema or change in surfactant composition. Lung morphometry showed increases in polymorphonuclear cells and type II cell volume. Vacuolated endothelial cells and bare basement membrane were observed consistently. CONCLUSION: Four days of positive pressure ventilation decreases lung compliance and worsens gas exchange by increasing shunt and VA/Q mismatch in healthy baboons. These effects are accompanied by only minor ultrastructural changes and mild inflammatory responses in the lung.

Animals↗

PubMed1997

Prospective and retrospective longitudinal studies of the growth, maturation, and fitness of Polish youth active in sport.

Results of three longitudinal studies of the growth, maturation and fitness of youth active in sport are summarized. Data include size attained and growth rates for height and body mass, secondary sex characteristics, skeletal age, age at peak height velocity, and two indicators of fitness, peak O2 uptake and power output at a heart rate of 170 bpm (PWC 170). The data for active youth are compared to local reference data and where appropriate to data from other European longitudinal studies. Allowing for variation in methodology and sampling, regular training in sport during puberty and the adolescent spurt does not influence size attained, growth rate, and the timing and progression of somatic, sexual and skeletal maturation in boys and girls. Active and nonactive boys and girls, respectively, do not differ significantly in the mean age at maximum growth in power output at a heart rate of 170 bpm. Boys active in sport, however, have a greater maximal gain in submaximal power output than nonactive boys. Analysis of ontogenetic allometry of peak oxygen uptake and stature and body mass indicate variation between individuals, and between boys of contrasting maturity status.

Adolescent↗

PubMed1997

Oral acyclovir prophylaxis of varicella after intimate contact.

OBJECTIVES: Whether oral acyclovir (ACV) given in late incubation can prevent clinical varicella or not. MATERIALS AND METHODS: Twenty-seven healthy infants and children susceptible to varicella received oral ACV (40 mg/kg daily in four divided doses) for 5 days, starting 9 or 11 days after exposure from the index case in the family (2 in the classroom). The clinical features were compared with 13 control children who did not receive ACV. Enzyme-linked immunoassay was used to detect varicella-zoster virus (VZV) antibody and, in follow-up immunologic studies, lymphocyte proliferative response was added. In some cases, blood culture and polymerase chain reaction with Southern hybridization were used for detection of viremia. RESULTS: Among the 27 children in the treatment group, two (7.4%) developed the disease and seroconversion was observed in 17 subjects (63%). Follow-up immunologic studies in 12 of these 17 seroconverted subjects 30 months later showed persistent cellular and/or humoral immunity to VZV. Only one subject, bled 11 days after exposure, had positive VZV DNA and blood culture for VZV. On the other hand 10 of 13 (77%) control subjects developed clinical varicella. CONCLUSIONS: Oral ACV administration to healthy susceptible subjects at the beginning of secondary viremia in the late incubation period (9 days after exposure) can effectively prevent or modify clinical varicella.

Acyclovir↗

PubMed1997

Hypoxia inhibits nitric oxide synthesis in isolated rabbit lung.

Nitric oxide (NO.) has been proposed to modulate hypoxic vasoconstriction in the lung. The activity of nitric oxide synthase (NOS) can be inhibited by hypoxia because molecular oxygen is a necessary substrate for the enzyme. On the basis of this mechanism, we hypothesized that NOS activity has a key role in regulation of pulmonary vascular tone during hypoxia. We measured oxidation products of NO. released into the vasculature of isolated buffer-perfused rabbit lung ventilated with normoxic (21% O2), moderately hypoxic (5% O2), or anoxic (0% O2) gas using two methods. Mean PO2 in perfusate exiting the lung was 25 Torr during anoxic ventilation and 47 Torr during moderately hypoxic ventilation. We found that the amount of the NO. oxidation product nitrite released into the perfusate was suppressed significantly during ventilation with anoxic but not moderately hypoxic gas. During normoxic ventilation, nitrite release was inhibited by pretreatment with NG-monomethyl-L-arginine, a competitive inhibitor of NOS. To confirm that changes in nitrite concentration reflected changes in NO. release into the perfusate, major oxidation products of NO. (NOx) were assayed using a method for reduction of these products to NO. by vanadium(III) Cl. Release of NOx into the perfusate was suppressed by severe hypoxia (anoxic ventilation), and this effect was reversed by normoxia. Pulmonary vasoconstriction was observed during severe but not moderate hypoxia and was related inversely to the rate of nitrite release. These observations provide evidence that decreased NO. production contributes to the pulmonary vasoconstrictor response during severe hypoxia.

Animals↗

PubMed1997

Protection of perfused lung from oxidant injury by inhibitors of anion exchange.

Hyperoxic lung injury is enhanced in isolated perfused lungs (IPL) in the presence of L-arginine. Reactive O2 species such as superoxide anion (O2-.) produced during hyperoxia are known to react with nitric oxide to form the strong oxidant species peroxynitrite. The appearance of O2-. in red blood cell membranes in vitro and in buffer-perfused lung preparations can be inhibited by the stilbene compound 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS) DIDS also inhibits anion exchange across the cell membrane regulated by a family of anion exchange proteins (AE). In this study, we hypothesized that anion exchange inhibitors would prevent lung injury from hyperoxia and L-arginine (O2 + L-Arg) by decreasing O2-. flux into the vascular space of the IPL. We found that both DIDS and a structurally distinct anion transport blocker, dipyridamole, protected the rabbit IPL from pulmonary hypertension and edema produced by O2 + L-Arg. The protective effect was associated with increased nitrite concentrations in the perfusate. Protection also was conferred when sodium bicarbonate in the perfusion buffer was replaced with either sodium thiosulfate or N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES). In lungs perfused with thiosulfate or HEPES-containing buffer, protection from O2 and L-arginine was also associated with diminished detection of reducing activity consistent with O2-. in the vascular space. Western blot analysis of lung protein and immunocytochemical staining of lung sections using antibodies against rabbit red blood cell AE1 and mouse gastric AE2 peptide showed that lung contains membrane protein antigenically similar to gastric AE2. These data suggest the possibility that inhibition of AE or other anion transporters may play an important role in mediating oxidative lung injury.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗

PubMed1997

Hypoxia compared with normoxia alters the effects of nitric oxide in ischemia-reperfusion lung injury.

Because both the biosynthesis of nitric oxide (NO.) and its metabolic fate are related to molecular O2, we hypothesized that hypoxia would alter the effects of NO. during ischemia-reperfusion (IR) in the lung. In this study, buffer-perfused lungs from rabbits underwent either normoxic IR (AI), in which lungs were ventilated with 21% O2 during ischemia and reperfusion, or hypoxic IR (NI), in which lungs were ventilated with 95% N2 during ischemia followed by reoxygenation with 21% O2. Lung weight gain (WG) and pulmonary artery pressure (Ppa) were monitored continuously, and microvascular pressure (Pmv) was measured after reperfusion to calculate pulmonary vascular resistance. We found that both AI and NI produced acute lung injury, as shown by increased WG and Ppa during reperfusion. In AI, where perfusate PO2 was > 100 mmHg, the administration of the NO. synthase inhibitor N-nitro-L-arginine methyl ester (L-NAME) before ischemia worsened WG and Ppa. Pmv also increased, suggesting a hydrostatic mechanism involved in edema formation. The effects of L-NAME could be attenuated by giving L-arginine and exogenous NO. donors before ischemia or before reperfusion. Partial protection was also provided by superoxide dismutase. In contrast, lung injury in NI at perfusate PO2 of 25-30 mmHg was attenuated by L-NAME; this effect could be reversed by L-arginine. Exogenous NO. donors given either before ischemia or before reperfusion, however, did not increase lung injury. NO. production was measured by quantifying the total nitrogen oxides (NOx) accumulating in the perfusate. The average rate of NOx accumulation was greater in AI than in NI. We conclude that hypoxia prevented the protective effects of NO on AI lung injury. The effects of hypoxia may be related to lower NO. production relative to oxidant stress during IR and/or altered metabolic fates of NO.-mediated production of peroxynitrite by hypoxic ischemia.

Animals↗

PubMed1997

Aerosolized manganese SOD decreases hyperoxic pulmonary injury in primates. I. Physiology and biochemistry.

Prolonged hyperoxia causes lung injury and respiratory failure secondary to oxidative tissue damage mediated, in part, by the superoxide anion. We hypothesized that aerosol treatment with recombinant human manganese superoxide dismutase (rhMnSOD) would attenuate hyperoxic lung damage in primates. Adult baboons were anesthetized and ventilated with 100% oxygen for 96 h or until death. Six animals were treated with aerosolized rhMnSOD (3 mg . kg-1 . day-1 in divided doses), and six control animals did not receive enzyme therapy. Physiological variables were recorded every 12 h, and ventilation-perfusion ratio relationships were evaluated by using the multiple inert-gas elimination technique. After the experiments, surfactant composition and lung edema were measured. We found that rhMnSOD significantly decreased pulmonary shunt fraction (P < 0.01) and preserved arterial oxygenation (P < 0.01) during hyperoxia. The rhMnSOD increased lung phospholipids, phosphatidylcholine and disaturated phosphatidylcholine, and decreased lung edema in this model. Testing of higher and lower doses of MnSOD (1 and 10 mg . kg-1 . day-1) in two other groups of baboons produced variable physiological protection, suggesting a "window" of effective dosage. We conclude that aerosolized MnSOD (3 mg . kg-1 . day-1) affords significant preservation of pulmonary gas exchange during hyperoxic lung injury.

Aerosols↗

PubMed1997

Aerosolized manganese SOD decreases hyperoxic pulmonary injury in primates. II. Morphometric analysis.

Hyperoxia damages lung parenchyma via increased cellular production of reactive oxygen species that exceeds antioxidant defenses. We hypothesized that aerosolized human recombinant manganese superoxide dismutase (rhMnSOD) would augment extracellular antioxidant defenses and attenuate epithelial injury in the lung during hyperoxia in primates. Twenty-four adult male baboons were anesthetized and mechanically ventilated with 100% oxygen for 96 h. The baboons were divided equally into four groups. Oxygen alone and oxygen plus rhMnSOD given at 3 mg . kg-1 . day-1 were compared to assess efficacy of the drug. Subsequently, aerosolized rhMnSOD was given at 1 or 10 mg . kg-1 . day-1 to study dose effects and toxicity. Quantitative morphometry showed protection of alveolar epithelium from hyperoxia by 3 mg . kg-1 . day-1 rhMnSOD (P < 0.05). In addition, interstitial fibroblast volumes were increased in the treatment group (P = 0.06). This effect appeared greater at the two higher doses of the rhMnSOD. The aerosolized drug was localized to the surface of airways and air spaces and macrophages by immunolabeling studies, suggesting efficacy via physicochemical properties that localize it to cell surfaces or by effects on alveolar macrophage function.

Animals↗