Interdependence of lipoxin A4 and heme-oxygenase in counter-regulating inflammation during corneal wound healing
Interdependence of lipoxin A4 and heme-oxygenase in counter-regulating inflammation during corneal wound healing
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DOI：
10.1096/fj.06-7918com
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发表时间：
2007-07-01
期刊：
影响因子：
4.8
通讯作者：
Gronert, Karsten
中科院分区：
文献类型：
--
作者：
Biteman, Benjamin;Hassan, Iram R.;Gronert, Karsten
在免疫豁免的角膜中，上皮伤口愈合迅速，几乎没有疤痕，并且与大多数其他组织不同，在没有感染的情况下的急性炎症有利于愈合。解释这种惊人特性的分子机制仍有待明确定义，但它们可能包括控制白细胞活化的autacoids。两种主要的酶，12/15-脂氧合酶（LOX），其产生脂质类自体，和血红素加氧酶（HO），其产生抗氧化剂和一氧化碳，在人类和小鼠角膜中高度表达。LXA（4）是一种内源性12/15-LOX产物，被证明是一种有效的炎症抑制剂，可显著增加角膜伤口的上皮再生。在12/15-LOX-/-小鼠中，体内12/15-LOX缺失与炎症加剧和伤口愈合受损相关，这是一种通过LXA治疗挽救的表型（4）。更重要的是，12/15-LOX-/-小鼠在急性和加重炎症中表现出HO-1诱导受损。局部LXA（4）恢复了12/15-LOX-/-小鼠中HO-1的表达，并增强了人角膜上皮细胞中HO-1基因的表达。不能诱导HO-1的HO-2（-/-）小鼠也表现出对损伤的反应，这种表型与内源性LXA（4）形成减少50%显著相关。总的来说，结果证明了LXA（4）在炎症/修复反应中的关键作用，并提供了12/15-LOX和HO系统协同控制炎症的第一个证据。Biteman，B.，哈桑岛R.，步行者，E.，Leedom，A. J.，邓恩，M.，Seta，F.，Laniado-Schwartzman，M.，Gronert，K.角膜伤口愈合过程中脂氧素A（4）和血红素加氧酶在对抗炎症中的相互依赖性
In the immune-privileged cornea, epithelial wounds heal rapidly with almost no scarring and, unlike in most other tissues, acute inflammation in the absence of infection is beneficial to healing. Molecular mechanisms, which account for this striking property, remain to be clearly defined, but they likely include autacoids that control leukocyte activation. Two prominent enzymes, 12/15-lipoxygenase (LOX), which generates antiinflammatory lipid autacoids, and heme-oxygenase (HO), which generates antioxidants and carbon monoxide, are highly expressed in human and mouse corneas. LXA(4), an endogenous 12/15-LOX product, proved to be a potent inhibitor of exacerbated inflammation and significantly increased re-epithelialization in corneal wounds. In vivo deletion of 12/15-LOX correlated with exacerbated inflammation and impaired wound healing in 12/15-LOX-/- mice, a phenotype that was rescued by treatment with LXA(4). More importantly, 12/15-LOX-/- mice demonstrated impaired induction of HO-1 in both acute and exacerbated inflammation. Topical LXA(4) restored HO-1 expression in 12/15-LOX-/- mice and amplified HO-1 gene expression in human corneal epithelial cells. HO-2(-/-) mice, which fail to induce HO-1, also demonstrated exacerbated inflammation in response to injury, a phenotype that, notably, correlated with a 50% reduction in endogenous LXA(4) formation. Collectively, results demonstrate a critical role for LXA(4) in inflammatory/ reparative responses and provide the first evidence that 12/15-LOX and HO systems function in concert to control inflammation.-Biteman, B., Hassan, I. R., Walker, E., Leedom, A. J., Dunn, M., Seta, F., Laniado-Schwartzman, M., Gronert, K. Interdependence of lipoxin A(4) and heme-oxygenase in counterregulating inflammation during corneal wound healing.