Liu C Y, Wang C H, Chen T C, Lin H C, Yu C T, Kuo H P
Department of Thoracic Medicine II, Chang Gung Memorial Hospital, Taipei, Taiwan.
Br J Cancer. 1998 Aug;78(4):534-41. doi: 10.1038/bjc.1998.528.
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 (FI) of iNOS expression in AM was significantly increased in patients with lung cancer (tumour side 263.5 +/- 15.2 FI, normal side 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 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 (rs = 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 microM 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.
单核细胞-巨噬细胞系列在宿主对癌症的监测中发挥着重要作用。巨噬细胞的细胞毒性/细胞抑制活性在很大程度上归因于诱导型一氧化氮合酶（iNOS）的上调和一氧化氮（NO）的产生。在此，我们使用化学发光NO分析仪测量了28例原发性肺癌患者和20例对照受试者上皮衬液（ELF）中呼出NO和亚硝酸盐的浓度，并通过流式细胞术研究了肺泡巨噬细胞（AM）和肺组织中NOS的表达；还进行了免疫组织化学分析。与对照受试者（27.3±3.2 FI；n = 20，P<0.001）相比，肺癌患者AM中iNOS表达的平均荧光强度（FI）显著增加（肿瘤侧263.5±15.2 FI，正常侧232.4±18.6 FI；n = 28）。癌症患者呼出的NO水平（16.9±0.9 p.p.b.；n = 28）显著高于对照组（6.0±0.5 p.p.b.；n = 20，P<0.001）。癌症患者ELF中的亚硝酸盐水平也显著更高（肿瘤侧271.1±28.9 nM，正常侧257.4±19.6 nM，而对照受试者为32.9±4.1 nM；P<0.001）。AM中iNOS表达的强度与呼出NO水平（rs = 0.73，n = 76，P<0.001）和ELF中释放的亚硝酸盐（rs = 0.56，n = 76，P<0.001）相关。培养24小时后，肺癌患者培养的AM的亚硝酸盐生成与对照受试者相比显著增强（肿瘤侧每106个细胞5.75±0.69和正常侧5.68±0.58微摩尔，而对照组每106个细胞38.3±3.6 nM；P<0.001）。在癌症患者的AM、肿瘤相关巨噬细胞、内皮细胞、软骨细胞、双肺气道上皮和恶性细胞（腺癌和肺泡细胞癌）中鉴定出iNOS的分布。在肺组织的肺泡巨噬细胞、内皮细胞和神经成分中标记了cNOS。我们的结果表明，在原发性肺癌患者中，由于iNOS活性上调，肺泡巨噬细胞产生的NO增加。NO产生的增加并非肿瘤侧特有的，可能归因于宿主的肿瘤相关非特异性免疫和炎症过程。
