INCREASED EXHALED NITRIC-OXIDE IN ACTIVE PULMONARY TUBERCULOSIS DUE TO INDUCIBLE NO SYNTHASE UP-REGULATION IN ALVEOLAR MACROPHAGES

Nitric oxide (NO) plays an important role in resistance to Mycobacteri um tuberculosis infection, Our aim was to determine whether inducible NO synthase (iNOS) expression and generation of reactive nitrogen inte rmediates (RNI) by alveolar macrophages (AM) are increased in patients infected with M. tuberculosis. NO levels in the exhaled air of 19 act ive pulmonary tuberculosis (TB) and 14 control subjects were measured using a chemiluminescence NO analyser. The expression of iNOS on AM wa s studied by labelling AM with anti-mac iNOS polyclonal antibody analy sed with a flow cytometer. The spontaneous generation of RNI by cultur ed AM was also measured, Data are presented as mean+/-SEM. The level o f NO in exhaled air was higher in patients with active TB (16.2+/-1.2 parts per billion (ppb)) compared to control subjects (6.5+/-0.9 ppb), p<0.0001. Exhaled NO decreased with anti-TB treatment. Compared to co ntrol subjects (29.0+/-4.5 fluorescence intensity (FI)), iNOS expressi on on AM was upregulated in TB patients (86.3+/-12.5 FI) p<0.001 and t he capacity for spontaneous generation of nitrite was enhanced. Nitrit e production was inhibited by N-G-monomethyl-L-arginine (L-NMMA), a co mpetitive inhibitor of iNOS, The expression of iNOS on AM was related to the concentration of exhaled NO (r=0.66, p<0.001) and the nitrite g eneration capacity of AM (r(s)=0.77, p<0.001). We conclude that the in crease in exhaled nitric oxide observed in patients with active pulmon ary tuberculosis is due to an upregulation of inhaled NO synthase expr ession in alveolar macrophages which have an enhanced capacity for nit ric oxide production.