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/jci13572
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发表时间：
2002-03
期刊：
影响因子：
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通讯作者：
R. Vandivier;V. Fadok;P. Hoffmann;D. Bratton;Churee Penvari;K. Brown;J. Brain;F. Accurso;P. Henson
中科院分区：
文献类型：
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作者：
R. Vandivier;V. Fadok;P. Hoffmann;D. Bratton;Churee Penvari;K. Brown;J. Brain;F. Accurso;P. Henson
囊性纤维化的特征在于炎性细胞早期和持续流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整联蛋白）有序去除死亡的凋亡炎性细胞相关。因此，凋亡炎性细胞的去除可能在持续性炎症反应中受损，例如在囊性纤维化气道中所见。对囊性纤维化和非囊性纤维化支气管扩张患者的肺组织进行检查，发现大量凋亡细胞，超过慢性支气管炎患者的凋亡细胞。在体外，囊性纤维化和支气管扩张症气道液直接抑制凋亡细胞清除肺泡巨噬细胞在中性粒细胞弹性蛋白酶依赖的方式，这表明弹性蛋白酶可能会损害凋亡细胞清除在体内。流式细胞术表明，中性粒细胞弹性蛋白酶切割磷脂酰丝氨酸受体，但不切割CD36或CD32（Fc γ RII）。中性粒细胞弹性蛋白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，这意味着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症中凋亡细胞的气道清除缺陷可能是由于弹性蛋白酶介导的吞噬细胞上磷脂酰丝氨酸受体的裂解，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 alpha v 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 (Fc gamma RII). 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 may be due to elastase-mediated cleavage of phosphatidylserine receptor on phagocytes and may contribute to ongoing airway inflammation.