Department of Medicine, University of Pittsburgh School of Medicine, PA 15213, USA.
Am J Physiol Lung Cell Mol Physiol. 2011 Oct;301(4):L547-56. doi: 10.1152/ajplung.00058.2011. Epub 2011 Aug 5.
Lysophosphatidic acid (LPA), a bioactive phospholipid, plays an important role in lung inflammation by inducing the release of chemokines and lipid mediators. Our previous studies have shown that LPA induces the secretion of interleukin-8 and prostaglandin E(2) in lung epithelial cells. Here, we demonstrate that LPA receptors contribute to lipopolysaccharide (LPS)-induced inflammation. Pretreatment with LPA receptor antagonist Ki16425 or downregulation of LPA receptor 1 (LPA(1)) by small-interfering RNA (siRNA) attenuated LPS-induced phosphorylation of p38 MAPK, I-κB kinase, and I-κB in MLE12 epithelial cells. In addition, the blocking of LPA(1) also suppressed LPS-induced IL-6 production. Furthermore, LPS treatment promoted interaction between LPA(1) and CD14, a LPS coreceptor, in a time- and dose-dependent manner. Disruption of lipid rafts attenuated the interaction between LPA(1) and CD14. Mice challenged with LPS increased plasma LPA levels and enhanced expression of LPA receptors in lung tissues. To further investigate the role of LPA receptors in LPS-induced inflammation, wild-type, or LPA(1)-deficient mice, or wild-type mice pretreated with Ki16425 were intratracheally challenged with LPS for 24 h. Knock down or inhibition of LPA(1) decreased LPS-induced IL-6 release in bronchoalveolar lavage (BAL) fluids and infiltration of cells into alveolar space compared with wild-type mice. However, no significant differences in total protein concentration in BAL fluids were observed. These results showed that knock down or inhibition of LPA(1) offered significant protection against LPS-induced lung inflammation but not against pulmonary leak as observed in the murine model for lung injury.
溶血磷脂酸（LPA）是一种生物活性磷脂，通过诱导趋化因子和脂质介质的释放，在肺部炎症中发挥重要作用。我们之前的研究表明，LPA 可诱导肺上皮细胞分泌白细胞介素-8 和前列腺素 E2。在这里，我们证明 LPA 受体有助于脂多糖（LPS）诱导的炎症。LPA 受体拮抗剂 Ki16425 预处理或通过小干扰 RNA（siRNA）下调 LPA 受体 1（LPA1）可减弱 MLE12 上皮细胞中 LPS 诱导的 p38 MAPK、IκB 激酶和 IκB 的磷酸化。此外，阻断 LPA1 也抑制了 LPS 诱导的 IL-6 产生。此外，LPS 处理以时间和剂量依赖的方式促进了 LPA1 和 LPS 核心受体 CD14 之间的相互作用。破坏脂筏会减弱 LPA1 和 CD14 之间的相互作用。用 LPS 处理的小鼠增加了血浆 LPA 水平，并增强了肺组织中 LPA 受体的表达。为了进一步研究 LPA 受体在 LPS 诱导的炎症中的作用，用 LPS 对野生型、LPA1 缺陷型或 Ki16425 预处理的野生型小鼠进行气管内滴注 24 小时。与野生型小鼠相比，LPA1 敲低或抑制降低了支气管肺泡灌洗液（BAL）中 LPS 诱导的 IL-6 释放和细胞浸润到肺泡空间。然而，BAL 液中总蛋白浓度没有明显差异。这些结果表明，LPA1 敲低或抑制可显著减轻 LPS 诱导的肺部炎症，但对肺部损伤小鼠模型中观察到的肺漏没有显著影响。
