INCREASED LEVEL OF EXHALED NITRIC-OXIDE AND UP-REGULATION OF INDUCIBLE NITRIC-OXIDE SYNTHASE IN PATIENTS WITH PRIMARY LUNG-CANCER

Monocyte-macrophage series have an important role in host surveillance against cancer, The cytotoxic/cytostatic activity of macrophages is, to a great extent, attributed to the up-regulation of inducible nitric oxide synthase (iNOS) and production of nitric oxide (NO). Here, in 2 8 patients with primary lung cancer and 20 control subjects, we measur ed the concentration of exhaled NO and nitrite in epithelial lining fl uid (ELF) using a chemiluminescence NO analyser. and studied NOS expre ssion in alveolar macrophages (AM) and lung tissues by flow cytometry; immunohistochemical analysis was also undertaken. The mean fluorescen ce intensity (FI) of iNOS expression in AM was significantly increased in patients with lung cancer (tumour side 263.5 +/- 15.2 FI, normal s ide 232.4 +/- 18.6 FI; n = 28) compared with that in control subjects (27.3 +/- 3.2 FI; n = 20, P < 0.001). The level of exhaled NO from can cer patients (16.9 +/- 0.9 p.p.b.; n = 28) was significantly higher th an that in the control group (6.0 +/- 0.5 p.p.b.; n = 20, P < 0.001). The level of nitrite was also significantly higher in ELF from cancer patients (tumour side 271.1 +/- 28.9 nM and normal side 257.4 +/- 19.6 nM vs control subjects 32.9 +/- 4.1 nM; P < 0.001). The intensity of iNOS expression in AM was correlated with the level of exhaled NO (r(s ) = 0.73, n = 76, P < 0.001) and the nitrite released in ELF (r(s) = 0 .56, n = 76, P < 0.001). The nitrite generation of cultured AM from pa tients with lung cancer was significantly enhanced compared with that of control subjects after culture for 24 h (tumour side 5.75 +/- 0.69 and normal side 5.68 +/- 0.58 mu M per 10(6) cells vs control group 38 .3 +/- 3.6 nM per 10(6) cells; P < 0.001). The distribution of iNOS wa s identified in AM, tumour-associated macrophages, endothelium, chondr ocytes, airway epithelium of both lungs and malignant cells (adenocarc inoma and alveolar cell carcinoma) of cancer patients. cNOS was labell ed in alveolar macrophages, endothelial cells and nerve elements from lung tissue. Our results indicate that, in patients with primary lung cancer, the production of NO from alveolar macrophages was increased a s a result of the up-regulation of iNOS activity. The increased NO pro duction was not specific to the tumour side and might be attributed to the tumour-associated non-specific immunological and inflammatory pro cesses of the host.