Bench To Bedside: New Findings in Primary Ciliary Dyskinesia

By Joseph H. Sisson, MD; and Johnny L. Carson, PhD

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Exhaled Nitric Oxide: An Emerging Diagnostic Tool?

The mucociliary escalator is elegantly evolved to efficiently limit and clear irritant gases and particulates from the respiratory airways. This is accomplished by regulation of both the volume and composition of the surface liquids bathing the mucosal surface as well as control mechanisms for the regulation of ciliary beat. While the coordinated interaction of secretion and ciliary activity is obvious, recent studies have begun to suggest that other constitutive and signaling cell functions may come into play to optimize mucociliary activity in periods of stress. To this end, there is considerable evidence for the influence of nitric oxide (NO) as a signaling molecule in a variety of cell functions,⁵³ including the regulation of ciliary beat.⁵⁴ Studies of exhaled NO levels from upper and lower airways in patients with PCD have consistently demonstrated reduced levels relative to those in normal control subjects and patients with cystic fibrosis.⁵⁵ Intermediate levels of exhaled NO have been documented in healthy PCD heterozygotes, suggesting a possible link between PCD and NO generation.⁵⁶ NO is produced through the activity of three isoforms of nitric oxide synthase on the substrate L-arginine. Two of these synthases, inducible (type II or iNOS) and endothelial (type III or eNOS), are present in normal airway epithelium.^57,58 In an effort to evaluate the potential for augmentation of low NO levels among patients with PCD, exogenous L-arginine, the substrate for nitric oxide synthase, was instilled into the upper and lower airways of groups of patients with cystic fibrosis and PCD.⁵⁹ These studies found that while NO concentrations increased significantly in both groups when they were given supplemental L-arginine, pulmonary function remained unchanged, suggesting that achievement of normal NO concentrations and therefore long-term therapeutic efficacy was not proven. Unfortunately, in this study, the pulmonary function was measured by spirometry and not mucociliary clearance. At this juncture, the findings of a very low nasal NO level may be helpful in identifying patients with possible PCD,⁶⁰ although the role NO plays in the course of the disease or NO’s possible role as a therapeutic agent remain undefined.

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