Nitric oxide and S-nitrosoglutathione exchange dynamics in healthy and diseased human airways

Nitric oxide (NO) performs many regulatory functions including smooth muscle relaxation, host defense, inhibition of platelet aggregation and neurotransmission, and appears in the exhaled breath. The fact that exhaled NO concentration increases in inflammatory airway diseases such as asthma has generated interest in using exhaled NO as a non-invasive marker of inflammation. However, due to its relatively short in vivo half-life (0.1–15 sec), S-nitrosoglutathione (GSNO), which demonstrates NO-like bioactivity, has been proposed as a possible carrier molecule for NO. Recent reports have demonstrated that GSNO concentrations in human airway fluids are significantly lower in both asthmatics and patients with cystic fibrosis, whereas expired NO concentration is higher for asthma and lower or similar in cystic fibrosis. At the present time, the actual mechanisms of NO and GSNO metabolism are not fully developed, and have created difficulty interpreting the NO and GSNO levels even in healthy airways.; To improve our understanding of NO and GSNO exchange dynamics in both healthy and diseased human airways, we have developed the following experimental and modeling studies: (1) a steady state mathematical model of the bronchial mucosa for small and large airways to understand NO and GSNO kinetics and transport in healthy lung, (2) estimation of NO parameters (maximum flux of NO from the airways: J_NO,max, pl·s −1, diffusing capacity of NO in the airways: D_NO,air, pl·s−1·ppb −1, and steady state alveolar concentration: C_alv,ss, ppb) which are flow-independent and characterize endogenous NO exchange by utilizing a pre-expiratory breathhold followed by a decreasing flow rate maneuver in both healthy and diseased lungs, and (3) an in vitro experiment to examine the role of GSH and pH to release NO from non-enzymatic catabolism of GSNO. Based on the above studies, we conclude that (1) for healthy human airways, the majority of free NO in the mucus, and thus exhaled NO, is due to diffusion of free NO from the epithelial cell, and the heterogeneous airway contribution to exhaled NO is due to heterogeneous airway geometry such as epithelium and mucus thickness, (2) flow-independent NO exchange parameters can distinguish airway and alveoli contributions and provide specific information for healthy and diseased airways, and (3) an increase in GSH, at physiologic concentrations, increases the NO concentration due to non-enzymatic degradation of GSNO, and may explain, in part, the rise in exhaled NO observed in asthma.