Tiitto Leena H, Peltoniemi Mirva J, Kaarteenaho-Wiik Riitta L, Soini Ylermi M, Pääkkö Paavo K, Sormunen Raija T, Kinnula Vuokko L
Department of Internal Medicine, Biocenter Oulu, University of Oulu, Oulu University Hospital, Oulu, Finland.
Hum Pathol. 2004 Jul;35(7):832-9. doi: 10.1016/j.humpath.2004.03.010.
The pathogenesis of interstitial lung diseases (ILDs) is known to be associated with reactive oxygen and nitrogen metabolites and increased oxidant stress. One of the major antioxidants in human lung is glutathione (GSH) and enzymes linked to its synthesis. The rate-limiting enzyme of GSH synthesis is gamma-glutamylcysteine synthetase (gamma-GCS) containing catalytically active heavy (gamma-GCSh) and regulatory light (gamma-GCSl) subunits. It can be hypothesized that gamma-GCS is the major determinant in explaining reduced GSH levels in fibrotic lung disorders. We investigated the regulation of gamma-GCS by transforming growth factor beta(1) (TGF-beta(1)) and tumor necrosis factor alpha (TNF-alpha) in human lung cells and its expression and distribution in fibrotic (biopsy-proven idiopathic pulmonary fibrosis, for instance, usual interstitial pneumonia, UIP, n = 15), inflammatory, and granulomatous diseases of human lung parenchyma (desquamative interstitial pneumonia, n = 10; ILD associated with collagen diseases, n = 10; sarcoidosis, n = 19 and allergic alveolitis, n = 8). In human lung alveolar epithelial cells, gamma-GCSh was decreased by TGF-beta(1), whereas TNF-alpha caused a transient enzyme induction. In normal lung, gamma-GCS was mainly localized to the bronchiolar epithelium. In UIP, the highest immunoreactivities were observed in the airway epithelium and metaplastic alveolar epithelium, but fibroblastic foci were negative. In sarcoidosis, the highest reactivities were detected in the epithelium, alveolar macrophages and pulmonary granulomas. gamma-GCS was ultrastructurally localized to the cytoplasm of regenerating type II pneumocytes and macrophages. In conclusion, gamma-GCS is widely expressed in sarcoidosis and regenerating epithelium but is low in the fibrotic areas of usual interstitial pneumonia, probably because of enzyme down-regulation.
已知间质性肺疾病（ILDs）的发病机制与活性氧和氮代谢产物以及氧化应激增加有关。人肺中的主要抗氧化剂之一是谷胱甘肽（GSH）及其合成相关酶。GSH合成的限速酶是γ-谷氨酰半胱氨酸合成酶（γ-GCS），它含有具有催化活性的重链（γ-GCSh）和调节性轻链（γ-GCSl）亚基。可以推测，γ-GCS是解释纤维化肺部疾病中GSH水平降低的主要决定因素。我们研究了转化生长因子β(1)（TGF-β(1)）和肿瘤坏死因子α（TNF-α）对人肺细胞中γ-GCS的调节作用，以及其在人肺实质纤维化（例如经活检证实的特发性肺纤维化，常见间质性肺炎，UIP，n = 15）、炎症性和肉芽肿性疾病（脱屑性间质性肺炎，n = 10；与胶原疾病相关的ILD，n = 10；结节病，n = 19和过敏性肺泡炎，n = 8）中的表达和分布。在人肺泡上皮细胞中，TGF-β(1)可降低γ-GCSh水平，而TNF-α可引起该酶的短暂诱导。在正常肺组织中，γ-GCS主要定位于细支气管上皮。在UIP中，气道上皮和化生的肺泡上皮中观察到最高的免疫反应性，但成纤维细胞灶为阴性。在结节病中，上皮、肺泡巨噬细胞和肺肉芽肿中检测到最高的反应性。γ-GCS在超微结构上定位于再生II型肺细胞和巨噬细胞的细胞质中。总之，γ-GCS在结节病和再生上皮中广泛表达，但在常见间质性肺炎的纤维化区域中较低，可能是由于酶的下调所致。
