Informative complexity of exhaled nitrogen oxide chemistry

In this issue of Thorax, Ojoo et al¹ conclude their paper with a sentence that is worthy of direct quotation. Their data “draw attention to the complexity of NO [nitric oxide] metabolism, where multiple pathways of NO synthesis and clearance are likely to have variable relevance in different circumstances”. Exhaled NO measurement is now a clinically approved test and, with approximately 1000 articles so far published, there are sufficient data to support its utility as an objectively measurable biomarker relevant to lung disease. However, despite all of the publications, how the multiple intracorporeal biochemical pathways interact and determine NO exhalation remains unclear.

In order to avert confusion, it is necessary to assure that vocabulary is shared. “Exhaled NO” has become the vernacular for the fractional exhalation of NO (FE_NO). This is not the amount of NO produced in the lung. Indeed, only a tiny fraction of NO produced in the lung ends up being exhaled. Increased production of NO in the airway can occur from increased nitric oxide synthase (NOS) activity, from inorganic acidification of nitrite (NO₂⁻),^2–4 and from homolytic cleavage of nitrosothiols.⁵ Increased exhalation of NO can occur from enhanced action of any of these aforementioned processes or, importantly, from decreases in various NO consumptive pathways that also are abundantly active in the airway. Such consumptive pathways include reaction with haemoglobin and various thiols, reduction by bacteria, …