Role of Endogenous Nitric Oxide in Airflow Obstruction in Smokers (Discussion)

16 Dec

Role of Endogenous Nitric Oxide in Airflow Obstruction in Smokers (Discussion)In this study, we examined healthy male volunteers who were relatively young and had normal pulmonary function to evaluate the effect of smoking alone. We used the difference in NO concentration (ANO) as a parameter to determine the degree of airflow obstruction because it is a sensitive indicator of NO synthesis in the respiratory tract. In nonsmokers, the increase in NO in exhaled air after breath-holding was probably due to accumulation of basally excreted NO, since the amount of NO in exhaled air after breath-holding differed from that produced during normal breathing. The level of exhaled NO was higher in nonsmokers than in smokers, in agreement with findings of other recent studies. The amount of synthesis of NO was reduced in smokers. Our findings suggest that since NO acts as an endogenous bronchodilator, it appears likely that the reduced synthesis of NO may be a contributing factor to airflow obstruction in smokers.

Airflow obstruction in smokers has a well-defined component, that is, an increased airway resistance, which is found predominantly in small airways. Morphomet-ric studies of the peripheral airways of young cigarette smokers have shown that smokers have increased epithelial abnormalities, cellular inflammatory infiltrates in the walls of small airways, and increased muscle and fibrosis compared with nonsmokers. Recent studies have shown that bronchial hyperresponsiveness precedes the decline of lung function in smokers, and that airways of smokers constrict when exposed to nonspecific stimuli more than those of ex-smokers and non-smokers. Regardless of the presence or absence of bronchial hyperresponsiveness, airway smooth muscle constriction is probably an important component of airflow obstruction in smokers. Respiratory epithelium appears to directly modulate the responsiveness of bronchial smooth muscle by releasing inhibitory factors, one of which is endogenous NO. Previous studies suggested that reduced NO synthesis in airway epithelial cells might be related to the development of airway hyperresponsiveness, and endogenous NO has an inhibitory effect on bronchial obstruction. Per-sson et al’ demonstrated that the NO detected in exhaled air is formed primarily in the terminal and respiratory bronchioles. Most recent reports have indicated that constitutive NO synthase is expressed in epithelial cells of small airways, where it may have autocrine effects via activation of guanyl cyclase. The pathologic change found in smokers that could be responsible for active muscle constriction and airway narrowing is small airway damage, which should result in decreased synthesis of NO. The low concentration of NO in exhaled air of smokers might be related to toxic damage of NO-producing bronchiolar epithelial cells caused by smoking. These considerations suggest that endogenous NO in exhaled air may play an important role in the maintenance of basal bronchial tone.

Cigarette smoke can impair the function of terminal and respiratory bronchioles early in life, and this abnormality can be detected by tests of small airway function. However, these early physiologic and pathologic abnormalities do not progress in all smokers, and tests specifically designed to detect early physiologic abnormalities in the small airways of smokers are required. Measurement of exhaled NO is noninvasive, and our new parameter (ANO) is a good indicator of the synthesis of endogenous NO within the respiratory tract. If endogenous NO is formed primarily in small airways, measurement of ANO may enable detection of smoking-related epithelial dysfunction in its early stages. However, it could not be completely discriminated whether it is epithelial dysfunction or the current smoking that is causing the NO levels in exhaled air to be lower. It will be useful in future studies to compare exhaled NO levels in smokers with those in the same individuals after a period of abstinence from smoking.