Department of Pharmacology and Ophthalmology, New York Medical College, Valhalla, New York, United States of America.
PLoS One. 2011;6(6):e21180. doi: 10.1371/journal.pone.0021180. Epub 2011 Jun 17.
Our studies demonstrated that Heme oxygenase (HO), in particular, the constitutive HO-2, is critical for a self-resolving inflammatory and repair response in the cornea. Epithelial injury in HO-2 null mice leads to impaired wound closure and chronic inflammation in the cornea. This study was undertaken to examine the possible relationship between HO-2 and the recruitment of neutrophils following a corneal surface injury in wild type (WT) and HO-2 knockout (HO-2(-/-)) mice treated with Gr-1 monoclonal antibody to deplete peripheral neutrophils. Epithelial injury was performed by removing the entire corneal epithelium. Infiltration of inflammatory cell into the cornea in response to injury was higher in HO-2(-/-) than in WT. However, the rate of corneal wound closure following neutrophil depletion was markedly inhibited in both WT and HO-2(-/-) mice by 60% and 85%, respectively. Neutropenia induced HO-1 expression in WT but not in HO-2(-/-) mice. Moreover, endothelial cells lacking HO-2 expressed higher levels of the Midkine and VE-cadherin and displayed strong adhesion to neutrophils suggesting that perturbation in endothelial cell function caused by HO-2 depletion underlies the increased infiltration of neutrophils into the HO-2(-/-) cornea. Moreover, the fact that neutropenia worsened epithelial healing of the injured cornea in both WT and HO-2(-/-) mice suggest that cells other than neutrophils contribute to the exaggerated inflammation and impaired wound healing seen in the HO-2 null cornea.
我们的研究表明，血红素加氧酶（HO），特别是组成型 HO-2，对于角膜自我修复的炎症和修复反应至关重要。HO-2 基因敲除（HO-2(-/-)）小鼠的角膜上皮损伤导致角膜伤口闭合受损和慢性炎症。本研究旨在探讨 HO-2 与角膜表面损伤后中性粒细胞募集之间的可能关系，采用 Gr-1 单克隆抗体耗竭外周血中性粒细胞，对野生型（WT）和 HO-2 基因敲除（HO-2(-/-)）小鼠进行研究。通过去除整个角膜上皮来进行上皮损伤。与 WT 相比，HO-2(-/-) 小鼠的炎症细胞浸润更高。然而，在用 Gr-1 单克隆抗体耗竭中性粒细胞后，WT 和 HO-2(-/-) 小鼠的角膜伤口闭合率分别显著抑制了 60%和 85%。中性粒细胞耗竭诱导 WT 中 HO-1 的表达，但在 HO-2(-/-) 小鼠中没有。此外，缺乏 HO-2 的内皮细胞表达更高水平的 Midkine 和 VE-钙粘蛋白，并与中性粒细胞表现出强烈的粘附，表明 HO-2 耗竭引起的内皮细胞功能紊乱是导致 HO-2(-/-) 角膜中性粒细胞浸润增加的原因。此外，中性粒细胞耗竭使 WT 和 HO-2(-/-) 小鼠受伤角膜的上皮愈合恶化这一事实表明，除中性粒细胞以外的细胞可能导致 HO-2 基因敲除角膜中炎症反应过度和伤口愈合受损。
