Lansoprazole Worsens Asthma Control in Poor Metabolizers: Is Nitric Oxide Involved?

To the Editor: We enjoyed the article of Lang and colleagues (1). This well-designed longitudinal study demonstrates that the proton pump inhibitor lansoprazole worsens asthma control in a cohort of children characterized as poor metabolizers of proton pump inhibitors as a result of cytochrome P450 polymorphism. The authors speculated that prolonged proton pump inhibitor treatment in poor metabolizers could result in oversuppression of gastric acid that could favor development of upper respiratory infections, as suppressed acidity is associated with prolonged retention of upper respiratory infection pathogens in gastric epithelium. However, as pointed out by the authors, they did not observe differences between the lansoprazole and placebo groups in asthma control after recent upper respiratory infections. There is an alternative explanation for the findings of Lang and colleagues: The negative effect of proton pump inhibition on asthma control might be mediated by asymmetrical dimethylarginine. As a result of the degradation of some methylated proteins, asymmetrical dimethylarginine is generated by lung vascular and parenchymal cells. This molecule is an endogenous inhibitor of nitric oxide synthase (NOS) and may also induce oxidative stress by causing NOS to generate reactive oxygen species (2). Asymmetrical dimethylarginine is thought to exacerbate airway inflammation, increase airway hyperactivity, and promote lung collagen formation and deposition (3). Increased asymmetrical dimethylarginine levels were found in a preclinical model and in patients with asthma, including children (3, 4). Our group discovered that the entire class of proton pump inhibitors inhibits dimethylarginine dimethylaminohydrolase, an enzyme responsible for asymmetrical dimethylarginine degradation in cells. We have demonstrated that proton pump inhibitors increase plasma asymmetrical dimethylarginine level in animals and reduce NO production in human endothelial cells and saphenous veins (5). Because endothelial NO is an antiatherogenic molecule (6), and because asymmetrical dimethylarginine is associated with increased cardiovascular risk (7), the inhibition of dimethylarginine dimethylaminohydrolase by proton pump inhibitors might be expected to increase the risk for major adverse cardiovascular events. Indeed, we have recently reported that the use of proton pump inhibitors is associated with increased cardiovascular mortality (8). As asymmetrical dimethylarginine is a nonselective NOS inhibitor, it is also possible that proton pump inhibitor–mediated accumulation of asymmetrical dimethylarginine may reduce activity of inducible NOS. Because inducible NOS participates in immune defense, its inhibition by proton pump inhibitors may reduce the clearance of pathogens. As Lang and colleagues pointed out, impaired defense against pathogens could be particularly problematic in poor metabolizers of lansoprazole. The study by Lang and colleagues, as well as our work and that of others, raises concerns about the routine availability of proton pump inhibitors for purchase without a prescription. There are strong indications for the use of proton pump inhibitors, but these drugs may have serious adverse effects. We feel that they should be prescribed as necessary and used under the guidance of a medical professional.