No abstract

Inducible heme oxygenase (HO-1) acts against oxidants that are thought to play a major role in the pathogenesis of chronic obstructive pulmonary disease (COPD), characterised by impaired lung function. A (GT) n repeat polymorphism in the HO-1 gene promoter can modulate the gene transcription in response to oxidative stress. We hypothesised that this polymorphism could be associated with the level of lung function and decline in subjects exposed to oxidative agression (smokers). We genotyped 749 French subjects (20-44 years, 50% men, 40% never smokers) examined in both 1992 and 2000 as part of the ECRHS. Lung function was assessed by forced expiratory volume in 1 second (FEV 1 ) and FEV 1 /forced ventilatory capacity (FVC) ratio. We compared long (L) allele carriers ((GT) n >33 repeats for one or two alleles) to non-carriers. Cross sectionally, in 2000, L allele carriers showed lower FEV 1 / FVC than non-carriers. During the 8 year period, the mean annual FEV 1 and FEV 1 /FVC declines were 230.9 (31.1) ml/ year and 21.8 (6.1) U/year, respectively. FEV 1 /FVC decline was steeper in L allele carriers than in non-carriers (22.6 (5.5) v 21.5 (6.4), p = 0.07). There was a strong interaction between the L allele and smoking. In 2000, the L allele was associated with lower FEV 1 and FEV 1 /FVC in heavy smokers (>20 cigarettes/day) only (p for interaction = 0.07 and 0.002 respectively). Baseline heavy smokers carrying the L allele showed the steepest FEV 1 decline (262.0 (29.5 ml/year) and the steepest FEV 1 /FVC decline (28.8 (5.4 U/year) (p for interaction = 0.009 and 0.0006).These results suggest that a long (L) HO-1 gene promoter in heavy smokers is associated with susceptibility to develop airway obstruction.

No abstract

Background: Oxidative stress is thought to have a major role in the pathogenesis of airway obstruction. A study was undertaken to determine whether subjects with low levels of antioxidants (serum b-carotene, acarotene, vitamins A and E) would be at a higher risk of accelerated decline in forced expiratory volume in 1 second (FEV 1 ) as their lungs would be less protected against oxidative stress. Methods: 1194 French subjects aged 20-44 years were examined in 1992 as part of the European Community Respiratory Health Survey (ECRHS); 864 were followed up in 2000 and 535 (50% men, 40% lifelong non-smokers) had complete data for analysis. Results: During the 8 year study period the mean annual decrease in FEV 1 (adjusted for sex, centre, baseline FEV 1 , age, smoking, body mass index and low density lipoprotein cholesterol) was 29.8 ml/ year. The rate of decrease was lower for the subjects in tertile I of b-carotene at baseline than for those in the two other tertiles (236.5 v 227.6 ml/year; p = 0.004). An increase in b-carotene between the two surveys was associated with a slower decline in FEV 1 . No association was observed between a-carotene, vitamin A, or vitamin E and FEV 1 decline. However, being a heavy smoker (>20 cigarettes/day) in combination with a low level of b-carotene or vitamin E was associated with the steepest decline in FEV 1 (252.5 ml/year, p = 0.0002 and 250.1 ml/year, p = 0.010, respectively). Conclusions: These results strongly suggest that b-carotene protects against the decline in FEV 1 over an 8 year period in the general population, and that b-carotene and vitamin E are protective in heavy smokers.

We investigated the role of heme oxygenase-1 (HO-1), a powerful anti-inflammatory and anti-oxidant enzyme, in modulating cigarette smoke (CS)-induced mucus secretion. In both rats and mice, 5-day CS exposure increased HO-1 expression and activity, mucus secretion, MUCIN 5AC (MUC5AC) gene and protein expression, and local inflammation, along with up-regulation of dual oxidase 1 gene expression and both the activity and phosphorylation of the epidermal growth factor receptor, which is involved in MUC5AC induction. Pharmacological induction of HO-1 prevented these actions and inhibition of HO-1 expression by a specific siRNA potentiated them. In French participants to the European Community Respiratory Health Survey II (n ‫؍‬ 210, 30 to 53 years of age, 50% males) exposed to CS, a significant increase in the percentage of participants with chronic sputum was observed in those harboring at least one allele with a long (GT) n in the HO-1 promoter gene (>33 repeats), which is associated with a low level of HO-1 protein expression, compared with those with a short number of (GT)n repeats (21.7% versus 8.6% , P ‫؍‬ 0.047). No such results were observed in those who had never smoked (n ‫؍‬ 297). We conclude that HO-1 has a significant protective effect against airway mucus hypersecretion in animals and humans exposed to CS.