Yao Xianglan, Gordon Elizabeth M, Figueroa Debbie M, Barochia Amisha V, Levine Stewart J
Laboratory of Asthma and Lung Inflammation, Cardiovascular and Pulmonary Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland.
Am J Respir Cell Mol Biol. 2016 Aug;55(2):159-69. doi: 10.1165/rcmb.2016-0060TR.
Emerging roles are being recognized increasingly for apolipoproteins in the pathogenesis and treatment of lung diseases on the basis of their ability to suppress inflammation, oxidative stress, and tissue remodeling, and to promote adaptive immunity and host defense. Apolipoproteins, such as apolipoprotein E (apoE) and apolipoprotein A-I (apoA-I), are important components of lipoprotein particles that facilitate the transport of cholesterol, triglycerides, and phospholipids between plasma and cells. ApoE-containing lipoprotein particles are internalized into cells by low-density lipoprotein receptors (LDLRs), whereas apoA-I can interact with the ATP-binding cassette subfamily A member 1 (ABCA1) transporter to efflux cholesterol and phospholipids out of cells. ApoE and apoA-I also mediate receptor-independent effects, such as binding to and neutralizing LPS. Both apoE and apoA-I are expressed by lung cells, which allows apoE/LDLR- and apoA-I/ABCA1-dependent pathways to modulate normal lung health and the pathogenesis of respiratory diseases, including asthma, acute lung injury, cancer, emphysema, pulmonary fibrosis, and pulmonary hypertension. Data from human studies and research using experimental murine model systems have shown that both apoE and apoA-I pathways play primarily protective roles in lung biology and respiratory disease. Furthermore, apolipoprotein mimetic peptides, corresponding to the LDLR-binding domain of apoE or the class A amphipathic α-helical structure of apoA-I, have antiinflammatory and antioxidant effects that attenuate the severity of lung disease in murine models. Thus, the development of inhaled apolipoprotein mimetic peptides as a novel treatment paradigm could represent a significant advance for patients with respiratory disease who do not respond to current therapies.
基于载脂蛋白抑制炎症、氧化应激和组织重塑以及促进适应性免疫和宿主防御的能力，其在肺部疾病的发病机制和治疗中的新作用正越来越受到认可。载脂蛋白，如载脂蛋白E（apoE）和载脂蛋白A-I（apoA-I），是脂蛋白颗粒的重要组成部分，有助于胆固醇、甘油三酯和磷脂在血浆和细胞之间的运输。含apoE的脂蛋白颗粒通过低密度脂蛋白受体（LDLR）内化进入细胞，而apoA-I可以与ATP结合盒亚家族A成员1（ABCA1）转运蛋白相互作用，将胆固醇和磷脂排出细胞。apoE和apoA-I还介导不依赖受体的效应，如结合并中和脂多糖。肺细胞可表达apoE和apoA-I，这使得依赖apoE/LDLR和apoA-I/ABCA1的途径能够调节正常的肺部健康以及包括哮喘、急性肺损伤、癌症、肺气肿、肺纤维化和肺动脉高压在内的呼吸系统疾病的发病机制。来自人体研究和使用实验性小鼠模型系统的研究数据表明，apoE和apoA-I途径在肺生物学和呼吸系统疾病中主要发挥保护作用。此外，与apoE的LDLR结合域或apoA-I的A类两亲性α-螺旋结构相对应的载脂蛋白模拟肽具有抗炎和抗氧化作用，可减轻小鼠模型中肺部疾病的严重程度。因此，开发吸入性载脂蛋白模拟肽作为一种新的治疗模式，对于对当前治疗无反应的呼吸系统疾病患者可能是一项重大进展。
