Mukherjee Shyamali, Stone William L, Yang Hongsong, Smith Milton G, Das Salil K
Department of Cancer Biology, Meharry Medical College, Nashville, TN 37208, USA.
J Biochem Mol Toxicol. 2009 Mar-Apr;23(2):143-53. doi: 10.1002/jbt.20279.
The purpose of this study was to develop antioxidant liposomes as an antidote for mustard gas-induced lung injury in a guinea pig model. Five liposomes (LIP-1, LIP-2, LIP-3, LIP-4, and LIP-5) were tested with differing levels of phospholipid, cholesterol, phosphatidic acid, tocopherol (alpha, gamma, delta), N-acetylcysteine (NAC), and glutathione (GSH). A single dose (200 microL) of liposome was administered intratracheally 5 min or 1 h after exposure to 2-chloroethyl ethyl sulfide (CEES). The animals were sacrificed either 2 h after exposure (for lung injury study) or 30 days after exposure (for histology study). The liposomes offered 9%-76% protection against lung injury. The maximum protection was with LIP-2 (71.5% protection) and LIP-4 (75.4%) when administered 5 min after CEES exposure. Delaying the liposome administration 1 h after CEES exposure decreased the efficacy. Both liposomes contained 11 mM alpha-tocopherol, 11 mM gamma-tocopherol, and 75 mM NAC. However, LIP-2 contained additionally 5 mM delta-tocopherol. Overall, LIP-2 and LIP-4 offered significant protection by controlling the recruitment of neutrophils, eosinophils, and the accumulation of septal and perivascular fibrin and collagen. However, LIP-2 showed better protection than LIP-4 against the accumulation of red blood cells in the bronchi, alveolar space, arterioles and veins, and fibrin and collagen deposition in the alveolar space. The antifibrotic effect of the liposomes, particularly LIP-2, was further evident by a decreased level of lipid peroxidation and hydroxyproline in the lung. Thus, antioxidant liposomes containing both NAC and vitamin E are an effective antidote against CEES-induced lung injury.
本研究的目的是开发抗氧化脂质体，作为豚鼠模型中芥子气诱导的肺损伤的解毒剂。测试了五种脂质体（LIP-1、LIP-2、LIP-3、LIP-4和LIP-5），它们含有不同水平的磷脂、胆固醇、磷脂酸、生育酚（α、γ、δ）、N-乙酰半胱氨酸（NAC）和谷胱甘肽（GSH）。在暴露于2-氯乙基乙硫醚（CEES）后5分钟或1小时，经气管内给予单剂量（200微升）的脂质体。在暴露后2小时（用于肺损伤研究）或暴露后30天（用于组织学研究）处死动物。脂质体对肺损伤提供了9%-76%的保护。在CEES暴露后5分钟给予脂质体时，LIP-2（保护率71.5%）和LIP-4（保护率75.4%）提供的保护作用最大。在CEES暴露后1小时延迟给予脂质体降低了疗效。两种脂质体均含有11 mM的α-生育酚、11 mM的γ-生育酚和75 mM的NAC。然而，LIP-2还额外含有5 mM的δ-生育酚。总体而言，LIP-2和LIP-4通过控制中性粒细胞、嗜酸性粒细胞的募集以及间隔和血管周围纤维蛋白和胶原蛋白的积累提供了显著的保护作用。然而，在支气管、肺泡腔、小动脉和静脉中红细胞的积累以及肺泡腔中纤维蛋白和胶原蛋白的沉积方面，LIP-2比LIP-4表现出更好的保护作用。脂质体，特别是LIP-2的抗纤维化作用，通过肺中脂质过氧化和羟脯氨酸水平的降低进一步显现出来。因此，含有NAC和维生素E的抗氧化脂质体是对抗CEES诱导的肺损伤的有效解毒剂。
