PASSIVE SMOKE AND EXHALED NITRIC OXIDE

To the Editor :

We read with great interest the article by Yates and colleagues (1) on the effect of environmental tobacco smoke (ETS) on exhaled nitric oxide (eNO) in nonsmoking normal subjects. The authors found a rapid (15 minutes) fall in eNO, remaining low for 60 minutes during ETS exposure, which was slightly lower than the eNO decrease observed during active smoking in the same subjects. The authors have proposed several mechanisms for the eNO decrease, including possible downregulation of airway nitric oxide synthase (NOS) by oxides of nitrogen-rich cigarette smoke, accelerated uptake of NO, inactivation of NO by oxidants in cigarette smoke, increased breakdown of NO, or damage to NO-producing epithelial cells by toxins. We recently observed in normal non-atopic subjects a significant eNO decrease soon after 30 minutes of acute cigarette smoke exposure (causing a median increase of NO ambient air in the smoking room from 3 ppb to 830 ppb) (2). Exhaled NO remained significantly decreased under the baseline level recorded during 1 hour before the smoke exposure, but reverted within 30 minutes after the end of exposure to the passive smoke. We think this time course of eNO response may be not consistent with an effect of cigarette smoke on NOS expression or activity. Actually, in vitro regulation of airway epithelium NOS by smoke extracts takes a long time, and is usually irreversible (3). Moreover, the effect of inhaled heated smoke itself could not be excluded, as a local increase in aqueous vapor pressure in the airway might be expected with a consequent quenching effect on NO chemiluminescence measurement, especially using wide bore teflon tubing in the exhalation apparatus (4). Nevertheless, also preventing the quenching effect using dryers membrane in the tubing, small volumes of aqueous hypotonic inhaled solution could decrease airway NO concentration in the absence of significant changes in airway NO diffusion when NO airway output is measured at different expiratory flow rates (5).

In conclusion, we agree that the mechanism for the decrease in eNO with smoking is uncertain, and that measurement of eNO after passive smoke exposure may provide a novel and sensitive tool to investigate the mechanisms of cigarette-induced lung damage. However, the role of factors influencing the pattern and the time course of the response to acute exposure to ETS in humans requires further studies.

AO Monaldi, University "Federico II", Naples, Italy

1. Yates DH, Breen H, Thomas PS. Passive smoke inhalation decreases exhaled nitric oxide in normal subjects. Am J Respir Crit Care Med 2001; 164: 1043-1046 [Abstract/Free Full Text].

2. Maniscalco M, Stanziola A, Di Mauro V, Grieco L, Ferrara G, Sofia M. Acute exposure to passive smoke decreases exhaled nitric oxide in healthy non-smoking subjects. Eur Respir J 2001; 18: 284s .

3. Assreuy J, Cunha FQ, Liew FY, Moncada S. Feedback inhibition of nitric oxide synthase activity by nitric oxide. Br J Pharmacol 1993; 108: 833-837 [Medline].

4. American Thoracic Society. Recommendations for standardized procedures for the online and offline measurement of exhaled lower respiratory nitric oxide and nasal nitric oxide in adults and children. Am J Respir Crit Care Med 1999;160:2104-2117.

5. Maniscalco M, Vatrella A, Cremona G, Carratù L, Sofia M. Exhaled nitric oxide after inhalation of isotonic and hypotonic solutions in healthy subjects. Clin Sci 2001; 101: 645-650 [Medline].

From the Authors:

We thank Dr. Maniscalco and colleagues for their helpful comments on our paper (1). They raise important points regarding the mechanism underlying the fall in exhaled nitric oxide (eNO) observed with passive smoke exposure.

We agree that the time course of the effect is rapid for cigarette exposure on inducible nitric oxide synthase (iNOS) expression when based on in vitro data. However, in humans, inhalation of NOS inhibitors produces a rapid decrease in eNO (2). This also occurs with more specific iNOS inhibitors (e.g., aminoguanidine) (3), and is probably related to inhibition of enzyme activity, rather than to protein expression. The time course of this effect is similar to that with passive smoke exposure. We acknowledge that hypotonic inhaled solution decreases eNO, as does repeated exhalation. The mechanism of this effect is uncertain but the magnitude is less than that observed with passive smoke, so could only account for part of the effect, if any. We cannot speculate on the effect of heated smoke itself, but suspect that changes due to inhaled vapor pressure in the airway are not the primary factor. The reason for this is that active smoke inhalation, which would be expected to be at a higher temperature and vapor pressure than passive smoke, produced a similar decrement in eNO in our study.

We are curently further investigating the mechanism of the effect of smoke inhalation by using NOS substrate supplementation and iNOS inhibitors. Preliminary data suggest that the effects of smoking on eNO can be partially reversed, both in vitro and in vivo (unpublished data). In addition to smoke, several other agents such as alcohol (4) and caffeine (5), drugs, and exercise may alter eNO and need to be considered in clinical studies (6). Elucidation of the mechanisms underlying such effects may yield useful insights into the biology of NO in humans, which could have useful therapeutic implications.

St. Vincent's Hospital, Darlinghurst, Sydney, Australia

Paul S. Thomas

UNSW and Prince of Wales Hospital, Randwick, Australia

1. Yates DH, Breen H, Thomas PS. Passive smoke inhalation decreases exhaled nitric oxide in normal subjects. Am J Respir Crit Care Med 2001; 164: 1043-1046 .

2. Yates DH, Kharitonov SA, Robbins RA, Thomas PS, Barnes PJ. Effect of a nitric oxide synthase inhibitor and a glucocorticosteroid on exhaled nitric oxide. Am J Respir Crit Care Med 1995; 152: 892-896 [Abstract].

3. Yates DH, Kharitonov SA, Thomas PS, Barnes PJ. Endogenous nitric oxide is decreased in asthmatic patients by an inhibitor of inducible nitric oxide synthase. Am J Respir Crit Care Med 1996; 154: 247-250 [Abstract].

4. Yates DH, Kharitonov SA, Robbins RA, Thomas PS, Barnes PJ. Effect of alcohol ingestion on exhaled nitric oxide. Eur Respir J 1996; 9: 1130-1133 [Abstract].

5. Bruce C, Yates DH, Thomas PS. Caffeine reduces exhaled nitric oxide. Thorax 2002 (in press).

6. Yates DH. Role of exhaled nitric oxide in asthma. Immunol Cell Biol 2001; 79: 178-190 [Medline].