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Bacterial denitrification, nitric oxide and airway pH in CF
  1. D W Reid1
  1. 1Medical School, University of Tasmania, Hobart, Australia 7000; d.e.c.reidutas.edu.au
  1. J C Ojoo2,
  2. S A Mulrennan2,
  3. J A Kastelik2,
  4. A H Morice2,
  5. A E Redington2
  1. 2Division of Academic Medicine, Postgraduate Medical Institute, University of Hull, Hull, UK

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The recent findings of Ojoo et al1 are of considerable interest. However, one confounding factor that appears to have been overlooked in recent studies of airway pH and exhaled breath nitric oxide (eNO) levels in cystic fibrosis (CF) is that of bacterial respiration. Pseudomonas aeruginosa adopts an anaerobic and biofilm mode of existence within the CF lung and, under such environmental conditions, it uses NO rather than oxygen as an electron donor to generate energy via oxidative phosphorylation. This bacterial denitrification results in the stepwise reduction of NO to nitrite (NO2), nitrate (NO3), and ultimately ammonium.2,3 It is surprising that such an important metabolic process has been ignored as the high energy requirements of large bacterial loads in the CF lung imply substantial consumption of NO. This could explain both the low levels of measured eNO and high (NO2)/(NO3) content described in the sputum and exhaled breath condensates of patients with CF. The products of denitrification are likely to alter the chemical milieu substantially, including the pH of the airway. Further research is needed to examine how the metabolic activity of bacteria and the host inflammatory response interact to change the chemical composition of the lung microenvironment in CF.

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Authors’ reply

We thank Dr Reid for his interest in our paper.1 Bacterial denitrification involves the stepwise reduction of oxides of nitrogen to support oxidative phosphorylation.2 Gaston et al3 have previously proposed that consumption of nitric oxide (NO) during this process might be one factor contributing to the low fractional exhaled NO concentration (FeNO) seen in cystic fibrosis (CF). It is clearly not the only mechanism, however, as decreased FeNO levels have been reported in infants with newly diagnosed CF,4 and reduced NO generation is also described in cystic fibrosis transmembrane conductance regulator (CFTR) deficient mice.5 Bacterial denitrification would be expected also to deplete nitrate (NO3) and nitrite (NO2) levels in the local milieu and to increase its pH.

In our study 14 of the 18 subjects with stable CF were chronically colonised with Pseudomonas aeruginosa. Interestingly, FeNO levels were indeed significantly lower in CF subjects with P aeruginosa than in those without (2 (1) v 7 (5) ppb; p = 0.015). The median NO2 and NO2/NO3 levels in exhaled breath condensate (EBC) were also lower in subjects with P aeruginosa, although this difference did not reach statistical significance. Irrespective of the presence of the organism, values for both NO2 and NO2/NO3 were substantially higher in CF subjects than in healthy controls. There was little difference in the median pH of the EBC between CF subjects with and without P aeruginosa.

These further analyses provide support for the suggestion that denitrification by P aeruginosa may modulate the nitrogen redox balance in CF airways. They are consistent with the findings of Gaston et al3 who described NO consumption and ammonium (NH4+) generation by P aeruginosa in vitro and also a reduction in NH4+ levels in the sputum of CF subjects after antipseudomonal treatment. Further comparisons involving larger numbers of CF subjects with and without P aeruginosa, and investigation of the relative impact of antimicrobial therapies in the two groups, may help to define the extent to which this mechanism operates in CF airways in vivo. Its relevance to airway pathophysiology, however, will be more difficult to determine.

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