Persson H L, Vainikka L K
Division of Pulmonary Medicine, Faculty of Health Sciences, University of Linköping, Linköping, Sweden.
Eur Respir J. 2009 Mar;33(3):673-9. doi: 10.1183/09031936.00044108.
Pulmonary alveolar proteinosis is characterised by accumulation of surfactant-like material in the distal air spaces. Since lysosomes play a crucial role for degradation of large biomolecules taken up from the cell's environment, it was hypothesised that oxidant-induced lysosomal disruption and ensuing cell death might play a role in disease development. In the present study, alveolar macrophages, harvested by whole-lung lavage from a patient diagnosed with pulmonary alveolar proteinosis, are shown to contain large amounts of undigested material within lysosomes, and the same organelle exhibits increased amounts of haemosiderin-bound iron. Compared with murine macrophage-like J774 cells (iron exposed or not), the status of human macrophages was pro-oxidative, i.e. macrophages exhibited a low level of the antioxidant glutathione and large amounts of iron available for Fenton-type chemistry. As a consequence, macrophageal lysosomes were particularly fragile when exposed to physiological concentrations of hydrogen peroxide (generated by glucose oxidase in culture medium). Such lysosomal disruption resulted in extensive cell death by both necrosis and apoptosis independent of caspase-3 activation. Considering the potential role of iron-catalysed oxidant-induced lysosomal rupture and ensuing cell killing for pulmonary alveolar proteinosis pathology and disease progression, whole-lung lavage might be considered early in those cases in which cytochemical staining reveals great numbers of haemosiderin-laden alveolar macrophages.
肺泡蛋白沉积症的特征是远端气腔内存在类似表面活性剂的物质积聚。由于溶酶体在降解从细胞外环境摄取的大分子中起关键作用，因此有人推测，氧化剂诱导的溶酶体破坏及随后的细胞死亡可能在疾病发展中起作用。在本研究中，从一名诊断为肺泡蛋白沉积症的患者全肺灌洗获取的肺泡巨噬细胞显示，溶酶体内含有大量未消化的物质，且同一细胞器内结合铁血黄素的铁含量增加。与鼠类巨噬细胞样J774细胞（无论是否暴露于铁）相比，人类巨噬细胞的状态呈促氧化状态，即巨噬细胞的抗氧化剂谷胱甘肽水平较低，且有大量铁可用于芬顿型化学反应。因此，当暴露于生理浓度的过氧化氢（由培养基中的葡萄糖氧化酶产生）时，巨噬细胞的溶酶体特别脆弱。这种溶酶体破坏导致广泛的细胞死亡，包括坏死和凋亡，且与半胱天冬酶-3激活无关。考虑到铁催化的氧化剂诱导的溶酶体破裂及随后的细胞杀伤对肺泡蛋白沉积症病理和疾病进展的潜在作用，对于那些细胞化学染色显示有大量含铁血黄素的肺泡巨噬细胞的病例，可在早期考虑进行全肺灌洗。
