1 Department of Pharmacology.
Am J Respir Crit Care Med. 2014 Jun 1;189(11):1402-15. doi: 10.1164/rccm.201310-1917OC.
Lysocardiolipin acyltransferase (LYCAT), a cardiolipin-remodeling enzyme regulating the 18:2 linoleic acid pattern of mammalian mitochondrial cardiolipin, is necessary for maintaining normal mitochondrial function and vascular development. We hypothesized that modulation of LYCAT expression in lung epithelium regulates development of pulmonary fibrosis.
To define a role for LYCAT in human and murine models of pulmonary fibrosis.
We analyzed the correlation of LYCAT expression in peripheral blood mononuclear cells (PBMCs) with the outcomes of pulmonary functions and overall survival, and used the murine models to establish the role of LYCAT in fibrogenesis. We studied the LYCAT action on cardiolipin remodeling, mitochondrial reactive oxygen species generation, and apoptosis of alveolar epithelial cells under bleomycin challenge.
LYCAT expression was significantly altered in PBMCs and lung tissues from patients with idiopathic pulmonary fibrosis (IPF), which was confirmed in two preclinical murine models of IPF, bleomycin- and radiation-induced pulmonary fibrosis. LYCAT mRNA expression in PBMCs directly and significantly correlated with carbon monoxide diffusion capacity, pulmonary function outcomes, and overall survival. In both bleomycin- and radiation-induced pulmonary fibrosis murine models, hLYCAT overexpression reduced several indices of lung fibrosis, whereas down-regulation of native LYCAT expression by siRNA accentuated fibrogenesis. In vitro studies demonstrated that LYCAT modulated bleomycin-induced cardiolipin remodeling, mitochondrial membrane potential, reactive oxygen species generation, and apoptosis of alveolar epithelial cells, potential mechanisms of LYCAT-mediated lung protection.
This study is the first to identify modulation of LYCAT expression in fibrotic lungs and offers a novel therapeutic approach for ameliorating lung inflammation and pulmonary fibrosis.
溶酶心磷脂酰基转移酶（LYCAT）是一种调节哺乳动物线粒体心磷脂 18:2 亚油酸模式的心磷脂重塑酶，对于维持正常的线粒体功能和血管发育是必需的。我们假设肺上皮细胞中 LYCAT 表达的调节可调控肺纤维化的发展。
确定 LYCAT 在人类和小鼠肺纤维化模型中的作用。
我们分析了外周血单个核细胞（PBMCs）中 LYCAT 表达与肺功能和总生存结局的相关性，并利用小鼠模型确定 LYCAT 在纤维化形成中的作用。我们研究了 LYCAT 在博来霉素刺激下对心磷脂重塑、线粒体活性氧生成和肺泡上皮细胞凋亡的作用。
特发性肺纤维化（IPF）患者的 PBMCs 和肺组织中 LYCAT 表达显著改变，这在两种 IPF 的临床前小鼠模型（博来霉素和放射诱导的肺纤维化）中得到了证实。PBMCs 中的 LYCAT mRNA 表达与一氧化碳弥散能力、肺功能结局和总生存直接且显著相关。在博来霉素和放射诱导的肺纤维化小鼠模型中，hLYCAT 过表达减少了几项肺纤维化指标，而 siRNA 下调内源性 LYCAT 表达则加重了纤维化。体外研究表明，LYCAT 调节博来霉素诱导的心磷脂重塑、线粒体膜电位、活性氧生成和肺泡上皮细胞凋亡，这是 LYCAT 介导的肺保护的潜在机制。
本研究首次鉴定了纤维化肺中 LYCAT 表达的调节，并提供了一种改善肺炎症和肺纤维化的新治疗方法。
