Lipoxin A4 inhibits platelet-activating factor inflammatory response and stimulates corneal wound healing of injuries that compromise the stroma
Lipoxin A4 inhibits platelet-activating factor inflammatory response and stimulates corneal wound healing of injuries that compromise the stroma
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DOI：
10.1016/j.exer.2012.07.008
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发表时间：
2012-10-01
影响因子：
3.4
通讯作者：
Bazan, Haydee E. P.
中科院分区：
文献类型：
--
作者：
Kakazu, Azucena;He, Jiucheng;Bazan, Haydee E. P.
血小板激活因子（PAF）是一种具有强炎症特性的生物活性脂质介质。 PAF 诱导角膜上皮细胞和肌成纤维细胞中金属蛋白酶 9 (MMP-9) 的表达和激活，并延迟器官培养系统中的上皮伤口愈合。 Lipoxin A(4) (LXA(4)) 是一种脂质介质，参与炎症消退和角膜上皮伤口愈合。我们开发了一种由 PAF 维持的前基质损伤的体内小鼠模型，并评估了 LXA(4) 的作用。在该模型中，小鼠接受媒介物、单独的PAF以及与PAF受体拮抗剂LAU-0901或LXA(4)的组合治疗。损伤后 1、2 和 7 天对小鼠实施安乐死，并用 MMP-9、α-平滑肌肌动蛋白 (α-SMA)、纤连蛋白 (FN) 和中性粒细胞的抗体对角膜进行组织学检查（H&E 染色）和免疫荧光检查。通过 ELISA 测定白细胞介素 1-α (IL-1 α) 和角质细胞衍生趋化因子 (KC/CXCL1)。在角膜匀浆中进行髓过氧化物酶（MPO）活性。在该体内模型中，PAF 抑制上皮伤口愈合，而这种愈合被 PAF 受体拮抗剂 LAU-0901 阻断。与 PAF 相比，LXA4 治疗在治疗 1 天和 2 天时显着减少了受伤面积。 LXA(4) 处理也降低了 PAF 刺激的强基质细胞浸润和 MPO 活性。与载体治疗相比，PAF 增加了 MMP-9 并减少了 FN 表达，并且迁移到受伤区域的 α-SMA 阳性细胞更少。 LXA4 治疗可恢复 PAF 作用。结果表明，LXA4 通过减少炎症和促进伤口愈合，在保护基质受损的角膜方面具有强大的作用。 (c) 2012 Elsevier Ltd. 保留所有权利。
Platelet-activating factor (PAF) is a bioactive lipid mediator with strong inflammatory properties. PAF induces the expression and activation of metalloproteinase-9 (MMP-9) in corneal epithelial cells and myofibroblasts, and delays epithelial wound healing in an organ culture system. Lipoxin A(4) (LXA(4)) is a lipid mediator involved in resolution of inflammation and cornea epithelial wound healing. We developed an in vivo mouse model of injury to the anterior stroma that is sustained by PAF and evaluated the action of LXA(4). In this model mice were treated with vehicle, PAF alone and in combination with PAF receptor antagonist LAU-0901 or LXA(4). Mice were euthanized 1, 2 and 7 days after injury and corneas were processed for histology (H&E staining) and immunofluorescence with antibodies for MMP-9, alpha-smooth muscle actin (alpha-SMA), fibronectin (FN) and neutrophil. Interleukin 1-alpha (IL-1 alpha) and keratinocyte-derived chemokine (KC/CXCL1) were assayed by ELISA. Myeloperoxidase (MPO) activity was performed in corneal homogenates. In this in vivo model PAF inhibited epithelial wound healing that was blocked by the PAF receptor antagonist LAU-0901. Treatment with LXA4 significantly reduced the injured area compared to PAF at 1 and 2 days of treatment. The strong stromal cell infiltration and MPO activity stimulated by PAF was also decreased with LXA(4) treatment. PAF increased MMP-9 and decreased FN expression compared to vehicle treatment and less alpha-SMA positive cells migrated to the wounded area. The PAF actions were reverted by LXA4 treatment. The results demonstrated a powerful action of LXA4 in protecting corneas with injuries that compromise the stroma by decreasing inflammation and increasing wound healing. (c) 2012 Elsevier Ltd. All rights reserved.