Increased level of exhaled nitric oxide and up-regulation of inducible nitric oxide synthase in patients with primary lung cancer

Abstract

Summary 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 28 patients with primary lung cancer and 20 control subjects, we measured the concentration of exhaled NO and nitrite in epithelial lining fluid (ELF) using a chemiluminescence NO analyser, and studied NOS expression in alveolar macrophages (AM) and lung tissues by flow cytometry; immunohistochemical analysis was also undertaken. The mean fluorescence intensity (Fl) of iNOS expression in AM was significantly increased in patients with lung cancer (tumour side 263.5 ± 15.2 Fl, normal side 232.4 ± 18.6 Fl; n = 28) compared with that in control subjects (27.3 ± 3.2 Fl; n = 20, P< 0.001). The level of exhaled NO from cancer patients (16.9 ± 0.9 p.p.b.; n = 28) was significantly higher than 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 (rS = 0.73, n = 76, P < 0.001) and the nitrite released in ELF (r, = 0.56, n = 76, P < 0.001). The nitrite generation of cultured AM from patients 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 gM per 106 cells vs control group 38.3 + 3.6 nm per 106 cells; P< 0.001). The distribution of iNOS was identified in AM, tumour-associated macrophages, endothelium, chondrocytes, airway epithelium of both lungs and malignant cells (adenocarcinoma and alveolar cell carcinoma) of cancer patients. cNOS was labelled 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 as a result of the up-regulation of iNOS activity. The increased NO production was not specific to the tumour side and might be attributed to the tumour-associated non-specific immunological and inflammatory processes of the host.Keywords: lung cancer; alveolar macrophage; nitric oxide; nitric oxide synthase; nitrite; cytotoxicity The host defence mechanism is important in the development and growth of tumours. The incidence of malignancy is reported to be increased in subjects with compromised immunity (Penn, 1986). The complex defence and immunological mechanisms against cancer contain several types of cells, including macrophages (Fidler et al, 1988) and mediators, such as nitric oxide (NO) (Farias-Eisner et al, 1996).Macrophages have a role in host surveillance against cancer (Hibbs et al, 1978). Macrophages can be activated both in vivo and in vitro to kill tumour cells. The oncolytic activity of macrophag...

Part I. Molecular and cellular characterization of high nitric oxide-adapted human breast adenocarcinoma cell lines

“…As indicated in our prior works, a number of tumor cell lines have been adapted to HNO concentration levels including those from lung [11,[46][47][48], head and neck [3,[49][50][51][52], and breast [7], suggesting that NO adaptation is also a universal property. In an attempt to further elucidate the impact of extended exposure from NO on underlying biological systems, we herein characterize the four newly The ten most up-regulated appear first and the ten most down-regulated appear below within each cell line type NA not available a Gene symbols used vary according to the supplier of the gene chip created breast adenocarcinoma HNO cell lines [7], along with each respective parent cell line.…”

Transfection of K-rasAsp12 cDNA markedly elevates IL-1β- and lipopolysaccharide-mediated inducible nitric oxide synthase expression in rat intestinal epithelial cells

“…There is a possibility that NO production by iNOS may be one of the mechanisms underlying the tumor-promoting effects of activated K-ras. Indeed, increased iNOS expression has been observed in human colorectal (Ambs et al, 1998), non-small-cell lung (Liu et al, 1998), and pancreatic tumors (Vickers et al, 1999), in which K-ras mutations are frequent (Adjei, 2001). …”

Effect of Enalapril on Exhaled Nitric Oxide in Normotensive and Hypertensive Subjects

“…pathophysiological conditions: It is increased in patients with asthma, 11 primary lung cancer, 12 and systemic lupus erythematosus. 13 Exhaled NO levels have also been found to increase with exercise 14 and in response to orally administered L-arginine 15 and intravenously infused nitroglycerin.…”