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首页> 外文期刊>Thorax: The Journal of the British Thoracic Society >Inter-relationship between tumour necrosis factor-alpha (TNF-alpha) and TNF soluble receptors in pulmonary sarcoidosis.
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Inter-relationship between tumour necrosis factor-alpha (TNF-alpha) and TNF soluble receptors in pulmonary sarcoidosis.

机译：肺结节病中肿瘤坏死因子-α（TNF-alpha）和TNF可溶性受体之间的相互关系。

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BACKGROUND: The importance of tumour necrosis factor-alpha (TNF-alpha) in the pathogenesis of pulmonary sarcoidosis has remained uncertain because of the paucity of clinical features associated with excessive levels of this cytokine. Increased levels of soluble TNF receptors (TNF-R), which are known to inhibit TNF-alpha activity, were recently described in the lungs of subjects with sarcoidosis. We hypothesised that TNF-alpha bioactivity may be inhibited in sarcoidosis by the presence of TNF-R. A study was therefore undertaken to investigate for the first time the relationship between soluble receptors and TNF-alpha bioactivity in the lungs of subjects with sarcoidosis. METHODS: Alveolar macrophages (AMs) from 16 subjects with histologically proven sarcoidosis and 13 healthy controls were cultured in the presence and absence of lipopolysaccharide (LPS). The subjects with sarcoidosis were grouped by radiological assessment into stage I (n = 6) and stage II/III (n = 10). The cell culture supernatants and bronchoalveolar lavage (BAL) fluid were assayed for TNF bioactivity using the WEHI 164 clone 13 assay. Immunoreactive (bound and free) TNF-alpha and free TNF-Rs (p55 and p75) were determined by ELISA. RESULTS: Bioactive TNF-alpha was undetectable in the BAL fluid of all the subjects with sarcoidosis and most of the healthy controls. However, there was significantly more immunoreactive TNF-alpha in the BAL fluid from subjects with sarcoidosis than from the controls (median values 0.304 ng/ml and 0.004 ng/ml, respectively, 95% CI 0. 076 to 0.455, p<0.001). The levels of both p55 and p75 in the BAL fluid were higher in both sarcoidosis groups than in the controls (p<0.0005 and p<0.001, respectively). In LPS stimulated AM supernatants reduced TNF-alpha bioactivity was seen in subjects with stage I sarcoidosis compared with those with stage II/III disease and healthy controls (median 0.333 ng/ml vs 1.362 ng/ml and 2.385 ng/ml, respectively, p<0.01). This contrasted with increased p55 levels in the AM supernatants derived from subjects with stage I sarcoidosis compared with those with stage II/III disease and healthy controls (median 0.449 ng/ml vs 0.058 ng/ml and 0.078 ng/ml, respectively, p<0.01). The levels of p75 were increased in unstimulated AM cultures in subjects with stage II/III disease compared with those with stage I disease and healthy controls (median 0.326 ng/ml vs 0.064 ng/ml and 0.102 ng/ml, p<0.05). CONCLUSIONS: These results indicate that TNF-alpha bioactivity may be inhibited by increased soluble TNF-R in the lungs of subjects with sarcoidosis, and this inhibition may be greater in patients with stage I sarcoidosis than in those with stage II/III disease. This may represent a homeostatic mechanism which protects the lung from excessive TNF production characteristic of chronic inflammation.
机译：背景：肿瘤坏死因子-α（TNF-alpha）在肺结节病发病机理中的重要性仍然不确定，因为这种细胞因子水平过高与临床特征缺乏相关。最近，在结节病患者的肺部中发现已知水平的可溶性TNF受体（TNF-R）水平升高，可抑制TNF-α活性。我们假设TNF-R的存在可能会在结节病中抑制TNF-α的生物活性。因此，进行了一项研究以首次调查结节病患者的肺中可溶性受体与TNF-α生物活性之间的关系。方法：在存在和不存在脂多糖（LPS）的情况下，培养16名经组织学证实为结节病的受试者和13名健康对照的肺泡巨噬细胞（AM）。通过放射学评估将结节病患者分为I期（n = 6）和II / III期（n = 10）。细胞培养上清液和支气管肺泡灌洗液（BAL）使用WEHI 164克隆13试验检测TNF的生物活性。通过ELISA确定免疫反应性（结合的和游离的）TNF-α和游离的TNF-R（p55和p75）。结果：在所有结节病患者和大多数健康对照者的BAL液中均未检测到生物活性TNF-α。但是，结节病患者的BAL液中的免疫反应性TNF-α明显高于对照组（中位数分别为0.304 ng / ml和0.004 ng / ml，95％CI0。076至0.455，p <0.001） 。在两个结节病组中，BAL液中p55和p75的水平均高于对照组（分别为p <0.0005和p <0.001）。在LPS刺激的AM上清液中，与I / III期疾病和健康对照组相比，I期结节病患者的TNF-α生物活性降低（中位数分别为0.333 ng / ml与1.362 ng / ml和2.385 ng / ml，p <0.01）。与之相反，与患有II / III期疾病和健康对照组的I期结节病患者相比，AM上清液中p55水平升高（中位数分别为0.449 ng / ml与0.058 ng / ml和0.078 ng / ml，p < 0.01）。与I期疾病和健康对照组相比，II / III期疾病的受试者在未刺激的AM培养物中p75的水平升高（中位数0.326 ng / ml对0.064 ng / ml和0.102 ng / ml，p <0.05）。结论：这些结果表明，结节病患者的肺中可溶性TNF-R的增加可能会抑制TNF-α的生物活性，与I / III期疾病相比，I期结节病患者的这种抑制作用可能更大。这可能代表了一种稳态机制，可以保护肺部免受慢性炎症导致的过多的TNF产生。

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