Lowered platelet glutathione peroxidase activity in patients with intrinsic asthma

Platelet glutathione peroxidase (GSH-Px) activity and serum selenium (Se) levels were determined in 20 patients with intrinsic asthma. Nine of the patients had NSAID-intolerance. The mean value of GSH-Px activity in the patients was 47.0±7.1 U/10¹¹ platelets, which is significantly lower than that of 56.4±12 U/10¹¹ platelets in the controls ( P < 0.01). There was also a tendency towards lowered Se levels in the patients compared with controls. The results are discussed in view of the protective role of GSH-Px against oxidative stress and the tentative regulatory function of GSH-Px in arachidonic acid metabolism.     

Erythrocyte glutathione peroxidase activity in asthmatic children

Erythrocyte glutathione peroxidase (GPX) levels were determined in 56 asthmatic children. Lowest levels were found during acute asthmatic attack (13.53 +/- 2.94 IU) which were significantly less than controls (20.4 +/- 5.44 IU) (P less than .001). Post-attack levels 1 week later rose significantly (16.77 +/- 2.63 IU), but were still less than normal values (P = .001). GPX levels (16.96 +/- 3.28 IU) were less than controls (P less than .03) even in patients with mild symptomatology. Asymptomatic patients receiving theophylline had normal levels. Low GPX activity in asthmatic patients may play a role in the pathogenesis of the disease.     

Salsalate cross-sensitivity in aspirin-sensitive patients with asthma

Ten aspirin (ASA)-sensitive patients with asthma underwent double-blind, placebo-controlled oral challenges with salsalate followed by ASA-sensitive confirmatory challenges. All 10 patients sustained asthmatic reactions to ASA, but only two developed respiratory reactions to 2 gm of salsalate. In these two patients, repeat confirmatory challenges with 2 gm of salsalate reproduced the same asthmatic reactions. Both patients were desensitized to ASA, and cross-desensitization with 2 gm of salsalate was then achieved. We conclude that salsalate, a weak inhibitor of cyclooxygenase in vitro, is less likely than ASA to induce asthma in known ASA-sensitive patients with asthma but may occasionally cross-react in these patients. Such reactions were mild and easily treated with beta 2-agonists.     

Red blood cell glutathione peroxidase activity in multiple sclerosis

Summary Glutathione peroxidase (GSH-Px) activity of red blood cells of 23 multiple sclerosis (MS) patients (10 men and 13 women, aged 22–64 years) was examined and compared to the enzyme activity of 26 healthy persons (15 men and 11 women, aged 19–50 years). It was found that the mean GSH-Px activity was significantly higher (P<0.001) in red blood cells of MS patients (39.1±8.1 IU/g Hb) as compared to the group of healthy persons (25.9±5.2 IU/g Hb). There was no difference according to sexes in both the MS patients and the control group. The results are discussed based on the hypothesis that organic peroxides play a role in the etiology of multiple sclerosis.     

The activity of erythrocyte glutathione peroxidase in chronic renal failure

Summary In 18 patients with terminal chronic renal failure on twice weekly maintenance hemodialysis, the predialysis activity of glutathione peroxidase was not impaired but rather slightly but significantly elevated when compared with healthy controls (2.7 versus 2.1 units/p<0.01). This was attributed to the reduced mean cell age.     

Catalase and glutathione peroxidase activity in cells with trisomy 21

CuZnSOD is produced in overdose in cells with trisomy 21. This has been considered to be a cause of increased oxidative stress. In the present work we have studied the catalase and glutathione peroxidase activity in fibroblasts from 6, and blood cells from 30, subjects affected by Down syndrome. In the fibroblasts, catalase and glutathione peroxidase activities did not differ significantly from control cells. In platelets, lymphocytes, polymorphs and erythrocytes, no significant increase of catalase activity was found while glutathione peroxidase activity appeared significantly increased in platelets, polymorphs and erythrocytes but not in lymphocytes. These data seem to indicate that the increase of CuZnSOD in trisomy 21 cells does not affect the production of catalase. An increase, instead, of glutathione peroxidase has been detected in all blood cells, except in lymphocytes; this is a sign of a greater need for protection against the risk of lipoperoxidation. The fact that the enhancement of glutathione peroxidase activity could be assessed only in some types of cells examined suggests that the observed increase in those cells is probably a result of an additive effect of the overproduction of CuZnSOD due to gene dosage and the ordinarily higher content of oxygen radicals and peroxides.     

Effect of sarcolysin on glutathione peroxidase and glutathione reductase activity in sarcoma C-45

A decrease in glutathione peroxidase and glutathione reductase activity in sarcoma C-45 was discovered during the period of its most rapid growth. Repeated injections of sarcolysin (1.2 mg/kg, intraperitoneally) caused a sharp decrease in the activity of both enzymes and a simultaneous decrease in the ratio between glutathione reductase and glutathione peroxidase activities. It is suggested that the glutathione redox enzyme system plays an important role in the mechanisms of the antitumor action of chemotherapeutic agents.Laboratory of Biochemistry, Rostov-on-Don Oncologic Research Institute. Department of Biochemistry, Medico-Biological Faculty, N. I. Pirogov Second Moscow Medical Institute. (Presented by Academician of the Academy of Medical Sciences of the USSR V. N. Orekhovich.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 84, No. 11, pp. 597–600, November, 1977.     

Cross sensitivity with acetaminophen in aspirin-sensitive subjects with asthma

Drugs inhibiting cyclooxygenase regularly cross-react with aspirin (ASA). Although some experiments suggest that acetaminophen (ACETM) is a weak inhibitor of cyclooxygenase in certain tissues, it has not been studied in human lung tissue, and controversy exists whether or not true cross-reactivity occurs between ASA and ACETM. Three ASA-sensitive subjects with asthma, who gave a history of reactions to ACETM, underwent double-blind, placebo-controlled challenges and reacted to 1000 mg of ACETM with a greater than 20% fall in FEV1. Two patients were desensitized to ASA and then were rechallenged with 1000 mg of ACETM without reaction. Two patients were desensitized to increasing doses of ACETM, achieving refractoriness to 1500 mg, but not 2000 mg. Thus, cross sensitivity between ASA and ACETM was documented when large challenge doses (1000 mg) of ACETM were used. Furthermore, cross desensitization suggests that in ASA-sensitive subjects with asthma, similar mechanisms are likely to be responsible for reactions to ASA, nonsteroidal anti-inflammatory drugs, and ACETM.     

Possible role of glutathione peroxidase in the regulation of collagenase activity

Glutathione peroxidase (Se-GPx) is a selenoenzyme which catalyzes the reduction of hydroperoxides by glutathione (GSH), in most mammalian cells. Several Slow-acting drugs that are used in the treatment of rheumatoid arthritis, including D-Penicillamine, alpha-mercaptopropionylglycine and gold salts, are specific inhibitors of Se-GPx. In situation of oxidant stress, Se-GPx activity is a major source of glutathione disulfide (GSSG), an essential activator of leucocyte collagenase. Hence the possibility that the enzymatic reduction of hydroperoxides produced during chronic inflammation would play an important role in the destruction of joint tissue of arthritic patients. Inhibition of a protective system such as Se-GPx may therefore be involved in the mechanism of action of D-Penicillamine and gold salts, but it could also explain some of their undesirable or toxic effects. Confirmation of this hypothesis would open the way to new pharmacological strategies.     

Urinary eosinophil protein X in relation to disease activity in childhood asthma

Lugosi E, Halmerbauer G, Frischer T, Koller DY. Urinary eosinophil protein X in relation to disease activity in childhood asthma.
The clinical use of urinary eosinophil protein X 'U-EPX' measurements in monitoring inflammation in childhood asthma was investigated. U-EPX and pulmonary function were assessed in 80 children with bronchial asthma and 24 healthy, age-matched controls. In addition, 14 patients with asthma were re-examined after 1–2 months. U-EPX levels were increased in children with asthma compared with controls 'median 68.4 vs 35.3 μg/mmol creatinine; P < 0·0001'. In addition, U-EPX levels were higher in symptomatic than in asymptomatic patients 'median 123.5 vs 48·9 μg/mmol creatinine; P < 0·0001' independent of treatment modalities 'i.e., inhaled steroids or disodium cromoglycate' or atopy 'median 65.1 vs 86·0 μg/mmol creatinine'. Furthermore, U-EPX levels were significantly correlated with pulmonary function. During the follow-up period, changes in U-EPX values were significantly related to changes in pulmonary function. In conclusion, our findings demonstrate that eosinophil activation can be measured in urine in childhood asthma. Concentrations of U-EPX are related to disease activity and pulmonary function, as shown in both cross-sectional and longitudinal analyses, but are independent of atopy and treatment modalities. Measurement of U-EPX may be useful in assessing the inflammatory process and therefore in the management of childhood asthma.     

Reduced platelet glutathione peroxidase activity and serum selenium concentration in atopic asthmatic patients

Background Asthmatic inflammation results in increased oxygen free radical generation and assessment of the activity of the selenitim (Se) dependent anti-oxidant enzyme, glutathione peroxidase (GSH-Px) in asthma may therefore be important. Objective To test the hypothesis that reduced GSH-Px activity and Se intake contribute to asthmatic infiammation, platelet and whole blood GSH-Px activities and serum and whole blood Se concentrations were measured and compared in atopic and non-atopic asthmatic patients and non-asthmatic control subjects. Methods GSH-Px activities of whole blood and isolated platelets were assessed in 41 asthmatic patients (33 atopic) and 41 age- and sex-matched non-asthmatic sttbjects (15 atopic) by spectrophotometric assay based oti the oxidation of NADPH. Se concentrations were determined by semi-automated fluorimetric assay. Results Mean (± sd) platelet GSH-Px activity was lower in asthmatic (89.5 ± 45.7 μmol NADPH oxidized min^?1 g^?1 of protein) than in non-asthmatic subjects (109,9 ± 41.9; P= 0.038) and in atopic (89.7 ± 45.1, n = 48) compared with non-atopie subiects (113.7 ± 40.9, n= 34: P= 0.016). Mean whole blood GSH-Px activity was also lower in atopic (12.2 ± 5.2 μmol NADPH oxidized min^?1 g^?1 of Hb) than in non-atopic subjects (14.5 ± 4.2; P= 0.038). In non-asthmatic subjects, the mean whole blood GSH-Px activity was lower in men (9.9 ± 3.5) than in women (14.5 ± 3.7; P = 0.0004) and was positively correlated with age (r= 0.51; P = 0.0006). Mean serum Se was lower in asthmatic (1.07 ± 0.12 μmol/L) than in non-asthmatic subjects (1.16 ± 0.31; P = 0.036), Using multiple linear regression, asthma was an independent predictor of decreased platelet GSH-Px after gender, age and serum Se were taken into account (P = 0.048) while atopy was a significant predictor of low whole blood GSH-Px independent of asthma, gender, age and whole blood Se (P = 0.033). Conclusions In addition to Se status, atopy, gender and uge all appear to influence GSH-Px activity, although the relative importance of these factors may difler in asthmatic and non-asthmatic populations. It seems likely that the reduced activity of this enzyme in platelets und hiood may reflect mechanisms associated with the pathogenesis and severity of asthma.     

Lack of cross-reactivity between rofecoxib and aspirin in aspirin-sensitive patients with asthma.

BACKGROUND: Patients with aspirin-sensitive respiratory disease experience cross-reactions to all nonsteroidal anti-inflammatory drugs, which inhibit cyclooxygenase enzymes. With the introduction of antiarthritis drugs, which selectively inhibit cyclooxygenase-2, questions are raised as to whether cross-reactivity occurs between aspirin and these new cyclooxygenase-2 inhibitors. OBJECTIVE: The goal of this study was to determine whether rofecoxib cross-reacts in aspirin-sensitive patients with asthma. METHODS: Sixty patients with asthma underwent doubleblinded, placebo-controlled oral challenges with rofecoxib (12.5 mg, 25 mg, and 2 placebos) over 48 hours in our General Clinical Research Center. The next day, aspirin sensitivity was proven in each of the 60 patients through use of single-blinded oral aspirin challenges. RESULTS: None of the 60 patients experienced any symptoms, changes in nasal examination findings, or declines in FEV(1) values during their challenges with rofecoxib. All 60 patients experienced typical naso-ocular and asthmatic reactions to aspirin with a mean provoking dose of 61 mg. The exact 1-sided CI for the probability of rofecoxib inducing crossreactions in aspirin-sensitive patients with asthma is calculated to be between 0% and 0.05%. CONCLUSION: Given that none of the 60 patients reacted to rofecoxib and given the statistical power of this large sample size, we conclude that cross-reactivity between aspirin and rofecoxib does not occur in patients with aspirin-sensitive respiratory disease. This does not exclude rofecoxib from participating in other types of reactions, including immune recognition after prior treatment with the drug. From the standpoint of the mechanisms involved in aspirin-induced respiratory reactions, this study strongly supports inhibition of cyclooxygenase-1 as the essential initiator of these types of reactions.     

Protection against exercise-induced bronchoconstriction by montelukast in aspirin-sensitive and aspirin-tolerant patients with asthma

BACKGROUND: Montelukast, a cysteinyl-leukotriene receptor antagonist, was reported to have a protective effect against exercise-induced bronchoconstriction (EIB). Aspirin-induced asthma (AIA) is characterized by overproduction of cysteinyl-leukotrienes. OBJECTIVE: The aim of the study was to compare the response to exercise and the effect of montelukast on EIB in AIA as compared to aspirin-tolerant asthma (ATA). METHODS: A placebo-controlled, double blind, cross-over randomized study was performed in 19 AIA and 21 ATA patients with stable asthma. A single dose of montelukast (10 mg) or placebo (PL), was given orally one hour prior to exercise challenge. FEV1 was measured before and 5, 10, 15 min after exercise and then at 15-minute intervals for 4 h. Urinary LTE4 excretion and blood eosinophil count were measured at baseline, 2 h and 4 h following exercise challenge. RESULTS: Positive bronchial response to exercise was observed in 47.5% of all patients studied. Exercise led to almost identical maximal fall in FEV1 in AIA and ATA patients (23.5% +/- 6.8% vs. 21.8% +/- 12.0%, respectively; P = 0.7). Montelukast, as compared to PL, significantly attenuated EIB in 63.2% of 19 patients with positive exercise test preceded by PL. The mean of maximum fall in FEV1 from the pre-exercise value was 10.2% +/- 13.8 after montelukast as compared to 22.5% +/- 10.2 after placebo (P < 0.001). No significant differences between protective effect of montelukast was observed in AIA as compared to ATA patients (P = 0.63, anova). Urinary LTE4 excretion showed no change following exercise, irrespective of the result of the test in all subjects. CONCLUSION: Patients with AIA and ATA react similarly to exercise challenge and obtain similar protection against EIB by montelukast.     

Contribution of glutathione peroxidase to the virulence of Streptococcus pyogenes

Glutathione peroxidases are widespread among eukaryotic organisms and function as a major defense against hydrogen peroxide and organic peroxides. However, glutathione peroxidases are not well studied among prokaryotic organisms and have not previously been shown to promote bacterial virulence. Recently, a gene with homology to glutathione peroxidase was shown to contribute to the antioxidant defenses of Streptococcus pyogenes (group A streptococcus). Since this bacterium causes numerous suppurative diseases that require it to thrive in highly inflamed tissue, it was of interest to determine if glutathione peroxidase is important for virulence. In this study, we report that GpoA glutathione peroxidase is the major glutathione peroxidase in S. pyogenes and is essential for S. pyogenes pathogenesis in several murine models that mimic different aspects of streptococcal suppurative disease. In contrast, glutathione peroxidase is not essential for virulence in a zebrafish model of streptococcal myositis, a disease characterized by the absence of an inflammatory cell infiltrate. Taken together, these data suggest that S. pyogenes requires glutathione peroxidase to adapt to oxidative stress that accompanies an inflammatory response, and the data provide the first demonstration of a role for glutathione peroxidase in bacterial virulence. The fact that genes encoding putative glutathione peroxidases are found in the genomes of many pathogenic bacterial species suggests that glutathione peroxidase may have a general role in bacterial pathogenesis.