Comparison of airway responsiveness to prostaglandin D2 and histamine, methacholine or exercise in healthy and asthmatic subjects.
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Adult↗
Biomedical subjects
D Nowak
Publications and source records attributed to D Nowak.
Bronchoalveolar lavage (BAL) cell profiles in mild asthmatic and nonasthmatic subjects.
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Adult↗
Effect of ascorbic acid on hydroxyl radical generation by chemical, enzymatic and cellular systems. Importance for antioxidant prevention of pulmonary emphysema.
The ability of ascorbic acid (AA) (25 to 500 microM) to increase OH production by a chemical (Fe(2+)-EDTA-H2O2), an enzymatic (xanthine-xanthine oxidase-Fe(2+)-EDTA) and a cellular system (3.10(6) human polymorphonuclear leukocytes (PMNL) or murine peritoneal macrophages (PM) activated with 7.2 ng PMA/ml) was studied. At all concentrations used AA strongly enhanced OH generation by the chemical and the enzymatic systems. However, the maximal increase of about 14-fold was found for incomplete chemical system (10 microM Fe(2+)-20 microM EDTA) and 500 microM AA. In the case of phorbol-myristate-acetate-activated-PMNL and macrophages, the moderate increase in OH formation was only caused by low AA concentrations. At 50 microM AA, the OH formation was 112 +/- 3 and 117 +/- 4% of control, respectively. Higher AA concentrations had no influence or even decreased OH formation by phagocytes. It is suggested that administration of AA will not significantly enhance OH generation from pulmonary phagocytes and could be useful for prevention of the oxidant-mediated lung injury related to inflammation.
Animals↗
The main serum protease inhibitors; alpha-1-proteinase inhibitor and alpha-2-macroglobulin inhibit H2O2 release from human polymorphonuclear leukocytes stimulated with phorbol myristate acetate.
Since various functions of phagocytes can be affected by protease inhibitors, the ability of alpha-1-proteinase inhibitor (alpha 1PI) and alpha-2-macroglobulin (alpha 2M) to modulate the H2O2 production by human polymorphonuclear leukocytes (PMNL) was studied. The preincubation of PMNL for 30 min with these protease inhibitors at concentrations which may occur in human blood diminished in a dose dependent manner their H2O2 generation induced with phorbol myristate acetate. At alpha 1PI 600 mg/dl and alpha 2M 800 mg/dl the H2O2 response decreased to 61 +/- 2 and 58 + 3% (p less than 0.001, n = 4) of the control value obtained with cells preincubated in phosphate buffered saline with glucose, respectively. Autologous serum alone and with addition of pure alpha 1 PI or alpha 2M also suppressed H2O2 release from PMNL. It is suggested that inhibition of H2O2 generation from PMNL may be another additional way by which these serum protease inhibitors may protect tissues (especially lungs) from acute injury related to inflammation.
Dianisidine↗
Effect of ascorbic acid on killing of lymphocytes and macrophages by hydrogen peroxide.
The ability of ascorbic acid (AA) to modify the H2O2 (0.6 to 9 mM) toxic activity for human lymphocytes (PBMC) and murine peritoneal macrophages (PM) was studied in vitro. 100 microM AA added simultaneously with H2O2 to the cell medium enhanced the killing of PBMC but not of PM independently of the presence of Fe(2+)-EDTA. Similarly, preincubation of PBMC with 500 microM AA that resulted in a 2.5-fold rise in the intracellular level of AA increased their susceptibility to both H2O2 and H2O2-Fe(2+)-EDTA. On the contrary, PM preincubated with AA were more resistant to the toxic action of the H2O2-Fe(2+)-EDTA system and did not reveal any changes of the susceptibility to H2O2 alone. It is suggested that AA under certain conditions may have opposite effects on the H2O2-induced cell damage related to inflammation.
Animals↗
[Pulmonary emphysema and environmental factors].
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Air Pollutants↗
[Standard therapy of tuberculosis and its variants].
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Acquired Immunodeficiency Syndrome↗
[Tuberculosis treatment today].
In West and East Germany the incidence of tuberculosis is declining. However, with an incidence of 22 per 100,000 inhabitants in West Germany and 17 new diseases per 100,000 inhabitants in East Germany it is not a rare disease. In the chemotherapy of pulmonary tuberculosis, isoniazid (INH), rifampicin (RMP), ethambutol (EMB), streptomycin (SM), pyrazinamide (PZA) and prothionamide (PTH) are the most relevant drugs. The chemotherapy of tuberculosis is always carried out as a combination therapy of at least three drugs. A rapid cultural conversion of the sputum as well as low rates of failures and relapses are regarded as parameters of quality. Therefore six-month-regimens with initially four drugs (INH + RMP + PZA + SM or EMB) or nine-(twelve-) month-regimens with initially three medicaments (INH + RMP + PZA, or INH + RMP + EMB or INH + RMP + SM) may be recommended. Peculiarities of the therapy in patients with AIDS, with drug resistance, with relapses.
Antitubercular Agents↗
Increased formation of DNA adducts in cultured fibroblasts of patients with aplastic anemia after in vitro incubation with benzo(a)pyrene.
In inbred mice strain DBA/2, genetically controlled differences in aryl hydrocarbon hydroxylase (AHH) activity have been demonstrated that predispose to aplastic anemia. To test the hypothesis of a similar mechanism in humans, we studied the formation of benzo(a)pyrene DNA adducts and water-soluble metabolites in skin fibroblasts from eight patients with aplastic anemia and eight normal controls. The ratio of water-soluble metabolites and DNA adducts was 46.5 +/- 16.6 in patients and was significantly lower as compared to 82.9 +/- 38.5 in controls (P less than 0.05). We conclude that increased formation of genotoxic intermediates may be a pathogenetic mechanism in some patients with aplastic anemia.
Adult↗
Peripheral neuropathies in patients with chronic obstructive pulmonary disease: a multicenter prevalence study.
To investigate the prevalence and type of peripheral neuropathies (PNP) in patients with chronic obstructive pulmonary disease (COPD), we studied lung function and blood gases, clinical signs of PNP, and neurophysiological function in 151 patients with COPD without known risk factors for PNP. Mean (SD) age was 65 (10) years, mean arterial PO2 was 59 (9) mmHg, mean ratio of forced expiratory volume in the first second to vital capacity (FEV1.0/VC) was 42 (12%). Thirty patients (20%) had clinically detectable and 6 (4%) had subclinical PNP of mild degree. Fourteen (9%) of the patients with clinically detectable PNP had symptoms due to PNP. Prevalence of PNP increased with severity of hypoxemia (p less than 0.05) and was more pronounced in the lower than in the upper limbs. Age and the degree of hypoxemia were predictors to differentiate between COPD patients with and without PNP. Although the cause of PNP in COPD patients remains unknown, our observations suggest that chronic hypoxemia may contribute to PNP.
Adult↗
Nicotine increases human polymorphonuclear leukocytes chemotactic response--a possible additional mechanism of lung injury in cigarette smokers.
Human polymorphonuclear leukocytes (PMNL) which are a potential source of proteolytic enzymes and reactive oxidant species contribute to the development of pulmonary emphysema in cigarette smokers. We found that nicotine at concentrations that occur in smokers' plasma enhances human PMNL chemotactic response to zymosan-activated serum (ZAS) and n-formyl-methionyl-leucyl-phenylalanine (FMLP). Maximal increase in chemotactic migration was at nicotine concentration 1 mumol/l. Higher concentrations, above 0.1 mmol/l inhibited PMNL chemotactic response and spontaneous migration. Nicotine also enhanced PMNL influx to the place of inflammation developed in the mouse pleural cavity after injection of ZAS. The number of PMNL found in the pleural cavity was 1.9-fold higher (p less than 0.001, n = 5) when animals were pretreated with 0.15 mg of nicotine. However, this drug itself (concentrations of 0.1 mumol/l to 10 mmol/l) had weak chemotactic activity for PMNL. It seems that the stimulatory action of nicotine on PMNL chemotaxis may be partly responsible for increased PMNL numbers in the lower airways of cigarette smokers and following formation of the elastase/antielastase imbalance in lung tissue.
Animals↗
Nicotine inhibits alpha-1-proteinase inhibitor inactivation by oxidants derived from human polymorphonuclear leukocytes.
Cigarette smoke can inactivate the alpha-1-proteinase inhibitor (alpha 1PI) by oxidative mechanisms and thus predisposes to the development of pulmonary emphysema. There are differences between the whole smoke and gas phase acting as alpha 1PI inactivators in vitro which suggests that the whole smoke is less oxidizing than the gas phase. Also studies on alpha 1PI oxidative inactivation in the lung of cigarette smokers gave controversial results. The reductive properties of cigarette tar which contains most of smoke nicotine may be some explanation of it. Therefore in this study we have investigated the effect of nicotine (0.4 mumol/l to 4 mmol/l) on the oxidative inactivation of human alpha 1PI by phorbol myristate acetate-activated polymorphonuclear leukocytes (PMNL), chloramine-T (15 mumol/l), hydrogen peroxide (15 mmol/l) and the superoxide radical (O2-.) generating system-xanthine (0.2 mmol/l)-xanthine oxidase (80 U/l). Nicotine at concentrations of greater than 40 mumol/l protected alpha 1PI from stimulated PMNL. The preincubation of PMNL with these concentrations of nicotine did not diminish their ability to inactivate alpha 1PI after stimulation. Nicotine (above 0.4 mumol/l) also protected alpha 1PI from chloramine-T but not from H2O2. The inhibition of O2-.-mediated alpha 1PI inactivation by nicotine was low and was observed only at a concentration of 4 mmol/l. This nicotine concentration did not affect xanthine oxidase activity. It is suggested that cigarettes with low nicotine contents can cause greater oxidative lung injury than their high nicotine counterparts and be a greater risk factor for the development of lung emphysema.
Humans↗
Chemotactic activity of histones for human polymorphonuclear leukocytes.
The chemotactic activity of histones for human polymorphonuclear leukocytes (PMNL) was investigated using the under-agarose method. Total histone and histone fractions H1, H2a, H2b, H3, H4 were prepared from calf thymus and dissolved in phosphate buffered saline (PBS) pH 7.4. At concentrations of 1 and 0.1 mg/ml all histone preparations were chemotactic for PMNL. The PMNL migration (expressed as a chemotactic index) to total histone (1 mg/ml) was 1.5 +/- 0.2 (n = 8) and to histone fractions it ranged from 1.2 to 1.4. The injection of total histone (50 micrograms) to the mouse pleural cavity induced cell influx. The mean PMNL number found in this cavity (0.33 +/- 0.15 X 10(6] was 3.6-fold higher in this group as compared to PBS-treated animals. Human PMNL during 60 min incubation with total histone (10 micrograms/ml) or with total histone and cytochalasin B (CB, 4.8 micrograms/ml) released 12.9 +/- 2.5 (n = 9) and 40.6 +/- 4.9 (n = 4) % of the total myeloperoxidase cell activity. Total histone (1 to 10 micrograms/ml) did not stimulate hydrogen peroxide generation independently of the presence of CB and had no influence on its production induced by phorbol myristate acetate. Our results suggest that histones released from cell debris in the place of inflammation could secondarily modulate to some extent its course by enhancing PMNL influx and their activation. These findings may be important for the course of inflammatory response in lungs especially in the light of their susceptibility to proteolytic injury.
Chemotaxis, Leukocyte↗
DNA activates human polymorphonuclear leukocytes--a new importance of DNA presented in the inflammatory tracheobronchial secretion.
DNA from calf thymus (1 to 10 micrograms/ml) was shown to stimulate the release of myeloperoxidase (MPO) and low amounts of H2O2 (about 1.5 nmoles/10(6) cells) from human polymorphonuclear leukocytes (PMNL). PMNL during 60 min incubation with DNA (10 micrograms/ml) and with DNA and cytochalasin B (4.8 micrograms/ml) released 14.4 +/- 3.4 and 25.5 +/- 4.8% (n = 7) of the total MPO cell activity, respectively. Higher DNA concentrations (0.25 to 1mg/ml) were chemotactic for PMNL as assayed under agarose method. At DNA concentration 1mg/ml the chemotactic index reached 1.5 +/- 0.2 and was approximate to value 1.7 +/- 0.2 (n = 7) obtained with zymosan-activated serum. However, the introduction of DNA to the mouse pleural cavity caused insignificant increase in the number of PMNL and lymphocytes recovered from the cavity at 3 h after injection, comparing it to material obtained from buffer-treated animals. The yield of DNA preparation from purulent sputum (about 10 micrograms/ml) indicates that DNA concentrations which activate PMNL in vitro occur in the inflammatory tracheobronchial secretion. The DNA from sputum electrophoresed on the 0.6% agarose gel reveal pattern which could be the result of nucleosomal DNA degradation. These results suggest that DNA released from nuclear debris in the place of inflammation, especially in the lower respiratory tract could secondarily modulate its course by PMNL activation. This novel role of DNA may be important for pulmonary pathology since lungs are susceptible to proteolytic and oxidant mediated injury.
Animals↗
[In 76% of patients with active tuberculosis treated with triple therapy (isoniazid-rifampicin-pyrazinamide) cultural conversion precedes microscopic conversion].
The time course of smear and culture conversion was studied in 50 previously untreated patients with cavitary pulmonary tuberculosis. Treatment consisted of isoniazid, rifampicin and pyrazinamide for three months, followed by isoniazid and rifampicin. After eight weeks of treatment, negative smears and cultures were obtained in 46 and 84% of the patients, respectively. In 76% of patients, cultural conversion preceded smear conversion, and in 24% of the patients, cultural conversion occurred up to 6 weeks after smear conversion. Thus, the time course of smear conversion provides reliable information on the loss of infectivity in patients with pulmonary tuberculosis receiving chemotherapy.
Adolescent↗
Hydrogen peroxide release from human polymorphonuclear leukocytes measured with horseradish peroxidase and o-dianisidine. Effect of various stimulators and cytochalasin B.
A simple, rapid and inexpensive method (o-DD method) is described for the measurement of hydrogen peroxide released by human polymorphonuclear leukocytes (PMNL) stimulated with phorbol myristate acetate (PMA), n-formyl-methionyl-leucyl-phenylalanine (FMLP) and concanavalin A (Con A). The method is based on the horseradish peroxidase-catalysed oxidation of o-dianisidine by H2O2 which results in the formation of a compound exhibiting an increased absorbance at 470 nm. A linear relationship between the absorbance at 470 nm and the concentration of H2O2 was found in the 1-150 microM range. Using this assay the time course of H2O2 release by PMNL, the dependence of H2O2 release on cell number, the agonist concentration and the presence of cytochalasin B (4.8 micrograms/ml) were studied. The maximal PMNL H2O2 response was found for PMA at 10 ng/ml. Con A at 200 micrograms/ml, FMLP at 300 ng/ml and reached 39 +/- 1.5, 14 +/- 1.2, 2.2 +/- 0.7 nmol for 10(6) cells incubated for 60 min at 37 degrees C. respectively. FMLP under these conditions was a most potent stimulator of myeloperoxidase release (MPO). Cytochalasin B having a weak influence on FMLP- and Con A-mediated H2O2 production enhanced strongly their stimulatory effect on MPO release. It is suggested that measurement of the H2O2 release with the o-DD method could be useful for monitoring PMNL respiratory burst especially in the cases of low MPO release.
Concanavalin A↗
[Patients with sarcoidosis frequently have bronchial hyperreactivity].
Histamine provocation challenges were performed in 60 patients with pulmonary sarcoidosis. Bronchial hyperreactivity was present in 14 (23%) of them, have an increased prevalence of 8 (13%) patients with hyperreactive airways had an additional history of bronchial asthma. Our findings thus suggest an increased prevalence of bronchial hyperreactivity in patients with sarcoidosis, which may be due to bronchial asthma in some of them.
Adult↗
Reduced O6-methylguanine repair in fibroblast cultures from patients with lung cancer.
The activity of O6-methylguanine-DNA methyltransferase was determined in fibroblast cultures from 45 patients with lung cancer, 39 patients with cutaneous malignant melanoma, and 29 healthy controls. This enzyme is a critical parameter for the capacity to repair O6-methylguanine (O6-mGua) adducts in DNA, and a decreased activity might therefore be responsible for an enhanced susceptibility to cancer. The assay was performed with 8 x 10(6) fibroblasts which were homogenized and incubated with a known amount of O6-mGua containing DNA. The remaining substrate was determined fluorimetrically after high performance liquid chromatographic separation. O6-mGua repair was significantly reduced in lung cancer patients [6.64 +/- 4.32 (SD) pmol O6-methylguanine repaired/8 x 10(6) cells] as compared to healthy controls [10.35 +/- 5.42, P less than 0.0022] or patients with cutaneous malignant melanoma [10.83 +/- 6.66]. The lowest mean values were detected in a subgroup of 16 lung cancer patients with a tumor manifestation below 46 years of age (5.06 +/- 3.89). Fibroblasts from 4 patients with lung cancer had no detectable repair. We conclude that a reduced capacity to remove O6-mGua adducts may represent a further mechanism of individually enhanced lung cancer risk.
Adult↗