Lovastatin enhances clearance of apoptotic cells (efferocytosis) with implications for chronic obstructive pulmonary disease
Lovastatin enhances clearance of apoptotic cells (efferocytosis) with implications for chronic obstructive pulmonary disease
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DOI：
10.4049/jimmunol.176.12.7657
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发表时间：
2006-06-15
影响因子：
4.4
通讯作者：
Vandivier, R. William
中科院分区：
文献类型：
--
作者：
Morimoto, Konosuke;Janssen, William J.;Vandivier, R. William
他汀类药物是一种有效的降胆固醇药物，具有新发现的广泛抗炎特性，主要基于其阻断Rho GTP酶（包括RhoA）异戊烯化的能力。由于凋亡细胞的吞噬作用（吞噬作用）是炎症的关键调节因子，它被RhoA抑制，我们试图确定他汀类药物是否增强吞噬作用。在原代人巨噬细胞、鼠肺和取自慢性阻塞性肺疾病患者的人肺泡巨噬细胞中研究了洛伐他汀对巨噬细胞增多症的影响。在这项研究中，我们表明，洛伐他汀增加红细胞在体外的3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶依赖性的方式。洛伐他汀通过抑制香叶基香叶基化和法尼基化，而不是通过改变关键摄取受体的表达或通过增加凋亡细胞与吞噬细胞的结合。洛伐他汀似乎通过抑制RhoA对红细胞增多症发挥其积极作用，因为它1）比Rac-1更大程度地减少RhoA的膜定位，2）防止溶血磷脂酸（RhoA的有效诱导剂）导致的红细胞增多症受损。最后，洛伐他汀以HMG-CoA还原酶依赖性方式增加了幼稚小鼠肺和离体慢性阻塞性肺疾病肺泡巨噬细胞中的巨噬细胞增多。这些发现表明，他汀类药物在体外和体内增强红细胞增多，并表明它们可能在红细胞增多受损和炎症失调的疾病中发挥重要的治疗作用。
Statins are potent, cholesterol-lowering agents with newly appreciated, broad anti-inflammatory properties, largely based upon their ability to block the prenylation of Rho GTPases, including RhoA. Because phagocytosis of apoptotic cells (efferocytosis) is a pivotal regulator of inflammation, which is inhibited by RhoA, we sought to determine whether statins enhanced efferocytosis. The effect of lovastatin on efferocytosis was investigated in primary human macrophages, in the murine lung, and in human alveolar macrophages taken from patients with chronic obstructive pulmonary disease. In this study, we show that lovastatin increased efferocytosis in vitro in an 3-hydroxyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase-dependent manner. Lovastatin acted by inhibiting both geranylgeranylation and farnesylation, and not by altering expression of key uptake receptors or by increasing binding of apoptotic cells to phagocytes. Lovastatin appeared to exert its positive effect on efferocytosis by inhibiting RhoA, because it 1) decreased membrane localization of RhoA, to a greater extent than Rac-1, and 2) prevented impaired efferocytosis by lysophosphatidic acid, a potent inducer of RhoA. Finally, lovastatin increased efferocytosis in the naive murine lung and ex vivo in chronic obstructive pulmonary disease alveolar macrophages in an HMG-CoA reductase-dependent manner. These findings indicate that statins enhance efferocytosis in vitro and in vivo, and suggest that they may play an important therapeutic role in diseases where efferocytosis is impaired and inflammation is dysregulated.