Cell-specific regulation of gamma-glutamylcysteine synthetase in human interstitial lung diseases
| Autor: | Leena H, Tiitto, Mirva J, Peltoniemi, Riitta L, Kaarteenaho-Wiik, Ylermi M, Soini, Paavo K, Pääkkö, Raija T, Sormunen, Vuokko L, Kinnula |
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| Rok vydání: | 2004 |
| Předmět: |
Adult
Male Tumor Necrosis Factor-alpha Glutamate-Cysteine Ligase Blotting Western Respiratory Mucosa Middle Aged Immunohistochemistry Cell Line Respiratory Function Tests Pulmonary Alveoli Transforming Growth Factor beta1 Transforming Growth Factor beta Humans Female Lung Diseases Interstitial Microscopy Immunoelectron Aged |
| Zdroj: | Human pathology. 35(7) |
| ISSN: | 0046-8177 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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