Sonett Jarrod, Goldklang Monica, Sklepkiewicz Piotr, Gerber Adam, Trischler Jordis, Zelonina Tina, Westerterp Marit, Lemaître Vincent, Okada Yasunori, D'Armiento Jeanine
Department of Anesthesiology, Center for Molecular Pulmonary Disease, College of Physicians and Surgeons, Columbia University, New York, New York, USA.
Division of Molecular Medicine, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York, USA.
FASEB J. 2018 Jun 15;32(12):fj201701381. doi: 10.1096/fj.201701381.
Macrophage infiltration is common to both emphysema and atherosclerosis, and cigarette smoke down-regulates the macrophage cholesterol efflux transporter ATP binding cassette (ABC)A1. This decreased cholesterol efflux results in lipid-laden macrophages. We hypothesize that cigarette smoke adversely affects cholesterol transport via an ABCA1-dependent mechanism in macrophages, enhancing TLR4/myeloid differentiation primary response gene 88 (Myd88) signaling and resulting in matrix metalloproteinase (MMP) up-regulation and exacerbation of pulmonary inflammation. ABCA1 is significantly down-regulated in the lung upon smoke exposure conditions. Macrophages exposed to cigarette smoke in vivo and in vitro exhibit impaired cholesterol efflux correlating with significantly decreased ABCA1 expression, up-regulation of the TLR4/Myd88 pathway, and downstream MMP-9 and MMP-13 expression. Treatment with liver X receptor (LXR) agonist restores ABCA1 expression after short-term smoke exposure and attenuates the inflammatory response; after long-term smoke exposure, there is also attenuated physiologic and morphologic changes of emphysema. In vitro, treatment with LXR agonist decreases macrophage inflammatory activation in wild-type but not ABCA1 knockout mice, suggesting an ABCA1-dependent mechanism of action. These studies demonstrate an important association between cigarette smoke exposure and cholesterol-mediated pathways in the macrophage inflammatory response. Modulation of these pathways through manipulation of ABCA1 activity effectively blocks cigarette smoke-induced inflammation and provides a potential novel therapeutic approach for the treatment of chronic obstructive pulmonary disease.-Sonett, J., Goldklang, M., Sklepkiewicz, P., Gerber, A., Trischler, J., Zelonina, T., Westerterp, M., Lemaître, V., Okada, V., D'Armiento, J. A critical role for ABC transporters in persistent lung inflammation in the development of emphysema after smoke exposure.
巨噬细胞浸润在肺气肿和动脉粥样硬化中都很常见，并且香烟烟雾会下调巨噬细胞胆固醇流出转运蛋白ATP结合盒（ABC）A1。这种胆固醇流出减少会导致巨噬细胞充满脂质。我们推测，香烟烟雾通过巨噬细胞中依赖ABCA1的机制对胆固醇转运产生不利影响，增强Toll样受体4（TLR4）/髓样分化初级反应基因88（Myd88）信号传导，导致基质金属蛋白酶（MMP）上调并加剧肺部炎症。在烟雾暴露条件下，肺中的ABCA1会显著下调。体内和体外暴露于香烟烟雾的巨噬细胞表现出胆固醇流出受损，这与ABCA1表达显著降低、TLR4/Myd88途径上调以及下游MMP-9和MMP-13表达相关。用肝X受体（LXR）激动剂治疗可在短期烟雾暴露后恢复ABCA1表达并减轻炎症反应；长期烟雾暴露后，肺气肿的生理和形态学变化也会减轻。在体外，用LXR激动剂治疗可降低野生型小鼠而非ABCA1基因敲除小鼠的巨噬细胞炎症激活，提示存在依赖ABCA1的作用机制。这些研究表明，香烟烟雾暴露与巨噬细胞炎症反应中胆固醇介导的途径之间存在重要关联。通过操纵ABCA1活性来调节这些途径可有效阻断香烟烟雾诱导的炎症，并为慢性阻塞性肺疾病的治疗提供一种潜在的新治疗方法。-索内特，J.；戈德克兰，M.；斯克莱皮维茨，P.；格伯，A.；特里施勒，J.；泽洛尼娜，T.；韦斯特特普，M.；勒迈特，V.；冈田，V.；达米恩托，J. ABC转运蛋白在烟雾暴露后肺气肿发展过程中持续性肺部炎症中的关键作用。
