Catalase, myeloperoxidase and hydrogen peroxide in cystic fibrosis.
Worlitzsch D. Herberth G. Ulrich M. Doring G.
Dept of General and Environmental Hygiene, Hygiene-Institut, University of Tubingen, Federal Republic of Germany.
An oxidant-antioxidant imbalance with damaging consequences for the bronchial epithelium has been hypothesized in the airways of patients with cystic fibrosis (CF). It is based on the assumption that neutrophils entering the lumen of the infected airways undergo activation and release toxic oxygen metabolites and myeloperoxidase (MPO), an enzyme which transforms hydrogen peroxide (H2O2) into highly toxic oxygen metabolites. Our aims were to substantiate this hypothesis. H2O2 levels were measured in breath condensates of 63 CF patients and 51 normal subjects. In CF sputum samples, activities and concentrations of MPO and catalase (CAT) were determined. MPO/H2O2-mediated cytotoxicity of CF sputum was measured in cell culture assays. H2O2 levels were similar in CF patients and normal subjects (mean +/-SD) 0.97 +/- 0.69 versus 1.11+/-0.78 microM; p=0.427). Concentrations and activities of CAT (0.31+/-0.18 microM; 105+/-69 units) and MPO (5.93+/-4.8 microM; 87.8+/-75 units) were detectable in 38 CF sputa. Addition of H2O2 to in vitro cells preincubated with CF sputum did not induce cytotoxicity even when CAT was removed from sputum. Sputum MPO together with H2O2 did not inactivate alpha-proteinase inhibitor. Preincubation of MPO with sulphated glycoconjugates or deoxyribonucleic acid (DNA) totally inhibited its cytotoxic effect. In conclusion, catalase, sulphated glycoconjugates and deoxyribonucleic acid may prevent myeolperoxidase-mediated oxygen radical generation in cystic fibrosis sputum.
Functional upper airway obstruction and chronic irritation of the larynx.
Rothe TB. Karrer W.
Luzemer Hoehenklinik, Montana-Vermala, Switzerland.
Wheezing and dyspnoea are typical symptoms of asthma but can also be found in diseases of the extrathoracic airways. Functional upper airway obstruction may imitate, as well as complicate asthma. Functional upper airway obstruction was first described as a conversion disorder in young females with inspiratory stridor. Subsequently, it was found that functional upper airway obstruction was more often a secondary phenomenon in chronic asthma also involving the expiratory laryngeal airflow. During a period of 15 months, we diagnosed six cases of functional upper airway obstruction. Five patients were female and one male, and four were also asthmatics. Three cases showed chronic sinusitis with postnasal drip (PND) and/or gastro-oesophageal reflux. Both disorders may irritate the larynx. Treatment of sinusitis and gastro-oesophageal reflux led to a significant improvement of dyspnoea in all three of these patients. In asthma refractory to treatment and in the case of an asthmatic exacerbation without obvious cause, functional upper airway obstruction should be excluded to avoid unnecessary treatment with systemic steroids. Some of the possible causative factors of functional upper airway obstruction, such as postnasal drip and gastro-oesophageal reflux, are easily treatable.
Diffuse alveolar damage in a patient treated with gemcitabine.
Marruchella A. Fiorenzano G. Merizzi A. Rossi G. Chiodera PL.
Divisione di Broncopneumologia, Ospedale E. Morelli, Sondalo, Italy.
We present a case of diffuse alveolar damage (DAD) that occurred in a male aged 68 yrs treated with gemcitabine, a novel antineoplastic agent, that was given for hepatic relapse of a previously resected non-small cell lung cancer. The patient developed acute respiratory failure after the sixth drug dose, and died 4 days after admission. Autopsy revealed a pattern of DAD. No evidence of infection or other specific aetiologies could be found. To our knowledge, only three cases of pulmonary toxicity resulting from treatment with gemcitabine have been published; two of them were fatal and postmortem examination revealed a pattern consistent with acute respiratory distress syndrome. A careful survey may determine the incidence of pulmonary toxicity of this new drug in the future.
Alpha1-antitrypsin deficiency alleles and the Taq-I G-->A allele in cystic fibrosis lung disease.
Mahadeva R. Westerbeek RC. Perry DJ. Lovegrove JU. Whitehouse DB. Carroll NR. Ross-Russell RI. Webb AK. Bilton D. Lomas DA.
Dept of Medicine, University of Cambridge, UK.
Cystic fibrosis (CF) is characterized by progressive and ultimately fatal pulmonary disease although there are notable variations in clinical features. This heterogeneity is thought to lie outside the cystic fibrosis transmembrane regulator (CFTR) gene locus and may stem from deficiencies in the antiproteinase screen that protects the lung from proteolytic attack. One hundred and fifty seven patients were recruited from two UK CF centres. The serum concentrations of alpha1-antitrypsin, alpha1-antichymotrypsin and C-reactive protein (CRP) were determined and patients were screened for the common S and Z deficiency alleles of alpha1-antitrypsin and the G-->A mutation in the 3' noncoding region of the alpha1-antitrypsin gene (Taq-I G-->A allele). Alpha1-antitrypsin deficiency phenotypes were detected in 20 (16 MS, 1 S and 3 MZ) out of 147 unrelated tested CF patients and were, surprisingly, associated with significantly better lung function (adjusted mean forced expiratory volume in one second (FEV1) 62.5% of predicted for deficient group and 51.1% pred for normal alleles; p=0.043). The Taq-I G-->A allele was found in 21 out of 150 unrelated patients and had no significant effect on CF lung disease or on levels of alpha1-antitrypsin during the inflammatory response. We show here that, contrary to current thinking, common mutations of alpha1-antitrypsin that are associated with mild to moderate deficiency of the protein predict a subgroup of cystic fibrosis patients with less severe pulmonary disease. Moreover, the Taq-I G-->A allele has no effect on serum levels of alpha1-antitrypsin in the inflammatory response, which suggests that the previously reported association of the Taq-I G-->A allele with chronic obstructive pulmonary disease is not mediated by its effect on the serum level of alpha1-antitrypsin.