Elastase-mediated phosphatidylserine receptor cleavage impairs apoptotic cell clearance in cystic fibrosis and bronchiectasis
Elastase-mediated phosphatidylserine receptor cleavage impairs apoptotic cell clearance in cystic fibrosis and bronchiectasis
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DOI：
10.1172/jci200213572
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发表时间：
2002-03-01
影响因子：
15.9
通讯作者：
Henson, PM
中科院分区：
文献类型：
--
作者：
Vandivier, RW;Fadok, VA;Henson, PM
囊性纤维化的特点是早期和持续的炎症细胞涌入气道，并释放蛋白酶。炎症的消退通常与通过细胞识别受体（如磷脂酰丝氨酸受体、CD36和α - v整合素）有序清除垂死的凋亡炎性细胞有关。因此，在囊性纤维化气道中所见的持续性炎症反应中，凋亡炎性细胞的清除可能受损。囊性纤维化和非囊性纤维化支气管扩张患者的痰液检查显示大量凋亡细胞，超过慢性支气管炎患者。在体外，囊性纤维化和支气管扩张气道液直接抑制肺泡巨噬细胞以中性粒细胞弹性酶依赖的方式清除凋亡细胞，提示弹性酶可能在体内损害凋亡细胞的清除。流式细胞术显示中性粒细胞弹性酶可切割磷脂酰丝氨酸受体，但不能切割CD36或CD32 （FcgammaRII）。中性粒细胞弹性酶对磷脂酰丝氨酸受体的裂解特异性地破坏了凋亡细胞的吞噬作用，这暗示了体内延迟凋亡细胞清除的潜在机制。因此，囊性纤维化和支气管扩张中凋亡细胞的气道清除缺陷可能是由于吞噬细胞上磷脂酰丝氨酸受体的弹性酶介导的裂解，并可能导致持续的气道炎症。
Cystic fibrosis is characterized by an early and sustained influx of inflammatory cells into the airways and by release of proteases. Resolution of inflammation is normally associated with the orderly removal of dying apoptotic inflammatory cells through cell recognition receptors, such as the phosphatidylserine receptor, CD36, and alphav integrins. Accordingly, removal of apoptotic inflammatory cells may be impaired in persistent inflammatory responses such as that seen in cystic fibrosis airways. Examination of sputa from cystic fibrosis and non-cystic fibrosis bronchiectasis patients demonstrated an abundance of apoptotic cells, in excess of that seen in patients with chronic bronchitis. In vitro, cystic fibrosis and bronchiectasis airway fluid directly inhibited apoptotic cell removal by alveolar macrophages in a neutrophil elastase-dependent manner, suggesting that elastase may impair apoptotic cell clearance in vivo. Flow cytometry demonstrated that neutrophil elastase cleaved the phosphatidylserine receptor, but not CD36 or CD32 (FcgammaRII). Cleavage of the phosphatidylserine receptor by neutrophil elastase specifically disrupted phagocytosis of apoptotic cells, implying a potential mechanism for delayed apoptotic cell clearance in vivo. Therefore, defective airway clearance of apoptotic cells in cystic Fibrosis and bronchiectasis maybe due to elastase-mediated cleavage of phosphatidylserine receptor on phagocytes and may contribute to ongoing airway inflammation.