In healthy subjects, exhaled NO originates mainly from the upper airways with only a minor contribution from the lower airways and the lungs. A large NO production takes place in the epithelium of the paranasal sinuses and this NO contributes considerably to the levels of NO found in nasally exhaled air. Immunohistochemical and mRNA in situ hybridisation studies suggest that sinus NO synthase is identical or very closely related to the human iNOS. Furthermore, the NOS activity in sinus mucosa is mostly Ca(2+)-independent. However, the regulation of sinus NOS expression seems to differ fundamentally from what has earlier been described for iNOS. Thus, sinus NOS is constitutively expressed and seems resistant to steroids. The high local NO concentrations in the nasal airways and the sinuses may help to protect against airborne infectious agents. Thus, airborne NO may represent the very first line of defence in the airways, possibly acting on pathogens even before they reach the mucosa. 2. Nasal concentrations of NO are markedly reduced in children with Kartagener's syndrome and in patients with CF. A simple chemiluminescence test test could be of help in early non-invasive diagnosis of these chronic airway diseases. 3. Inhaled endogenous NO, derived from the upper airways, may be involved in regulation of pulmonary function in man. NO will reach the lower airways and the lungs with the inspired air and at levels that are especially high during nasal breathing. This NO may act by enhancing blood flow preferentially in well ventilated areas of the lung, thus optimizing ventilation/perfusion matching. The involvement of autogenous NO in regulation of pulmonary function may represent a novel physiological principle, namely that of an enzymatically produced airborne messenger. The term "aerocrine" may be appropriate for this action of NO in the airways. These findings may also help to explain one biological role of the enigmatic human paranasal sinuses, the major sources of NO in the upper airways. 4. A continuous production of NO takes place in the acidic stomach through chemical reduction of nitrite present in swallowed saliva. This is the first evidence of non-enzymatic NO production in humans. Stomach NO may be involved in local defence against swallowed pathogens and in regulation of superficial mucosal blood flow and mucus production. 5. Luminal concentrations of NO are increased in the lower airways of asthmatic children, in the colon of patients with inflammatory bowel disease, and in the urinary bladder of patients with cystitis. Local steroid treatment reduces orally exhaled NO levels in asthmatic children. Nasal NO levels did not differ between controls and asthmatic children with or without concomitant allergic rhinitis. In conclusion, nitric oxide found in exhaled air originates mainly in the upper airways. A large production of NO takes place in the paranasal sinuses from a constitutively-expressed, steroid-resistant "inducible-like" NO synthase in the epithelial cells. Sinus NO contributes substantially to levels of NO found in nasally exhaled air. Sinus NO may have a dual function. First, the very high concentrations in the sinuses may contribute to local host defence. Second, when diluted in the inhaled air, sinus-derived NO may act as an "aerocrine" messenger, with distal effects on pulmonary blood flow and oxygen uptake. Intubated patients are deprived of autogenous NO from the upper airways and might benefit from substitution. Measurements of local NO production in hollow organs may be done easily by analysing the concentrations of NO gas in luminal air. Such noninvasive methods may be useful not only to explore the role of NO in inflammation and host defence, but also in the diagnosis and monitoring of inflammatory mucosal diseases such as asthma, ulcerative colitis and cystitis. Thus, airborne NO may be looked upon as a marker of inflammation and as an aerocrine messenger in humans.
