Advances in Pulmonary Laboratory Testing: Exhaled NOGiven the presence of NOS in many of the cell types of the lung’ it should be no surprise that NO can be measured in exhaled air. Since the first description of NO in exhaled air’ much work has been done to characterize the source of NO and to correlate exhaled NO with various disease states. It is important to distinguish exhaled concentration of NO (usually expressed in parts per billion) from NO output (usually expressed in nanograms per minute). Moreover’ mixed expired NO must be distinguished from instantaneous NO measurements. Exhaled NO can thus be documented in at least four ways: the NO output’ the mixed expired NO’ and either peak NO or end-expiratory NO. NO output from the lungs reflects a balance of pulmonary production less the diffusion of NO across the capillaries into the blood. The European Respiratory Society has issued guidelines for measurement of expired NO in an effort to standardize the technique and to optimize detection of pulmonary rather than nasal NO.
Where is the exhaled NO coming from? Exhaled NO was documented in isolated lung perfused with blood-free medium, indicating that the NO was not derived from the circulation. The nose is a significant source of NO that can be admixed in gas sampled at the mouth. The specific cell that produces the measured NO has not been clearly defined, though most investigators assume the source of NO is either the epithelial cell, the endothelial cell, or nonadre-nergic, noncholinergic neurons, although mast cells, macrophages, and eosinophils could also be significant sources. more

There have been numerous studies correlating exhaled NO to various disease states (Table 4). Because the technical details of isolating lower from upper airway contributions have progressed simultaneously with correlations against disease states, much of this work bears repeating with standard methods.
The relatively specific increase in exhaled NO in untreated or steroid-resistant asthma should be evident in Table 4. The role of NO in the pathogenesis of asthma is not fully determined. Although NO is a mild bronchodilator when inhaled from exogenous sources, increasing levels of exhaled NO by using inhaled L-arginine (the precursor for NO) causes acute bronchoconstriction, which is possibly mediated by an increase in vascular permeability that is mediated by high local concentrations of the endogenously released NO. NO also enhances eosinophil survival in vitro,36 which is consistent with the correlation between NO and eosinophil levels and suggests a role for NO in maintaining airway inflammation.
Table 4—Expired NO in Lung Diseases

Disease or Condition Comment Study
Elevated NO Asthma
Untreated Expired NO reduced by NOS inhibitors, indicating NOS as the source. High Dupont et al
correlation with eosinophilia in induced sputum. Kharitonov et al Persson et al
Steroid-resistant Exhaled NO remains elevated Stirling et al
TB NO may be derived from alveolar macrophages, as increased iNOS was demonstrated on macrophages from patients with active TB. Wang et al
Reduced NO
CF Low NO may be explained by reduced expression of iNOS in CF airway epithelial cells, hindering local defense mechanism, particularly in the killing of Pseudomonas aeruginosa Lundberg et al
COPD Maziak et al
ARDS Brett and Evans
Asthma, steroid treated Correlation with methacholine PD20 is poor in treated asthmatics Horvath et al