Insulin-like growth factor-1 binding protein 3 (IGFBP-3) promotes recovery from trauma-induced expression of inflammatory and apoptotic factors in retina
Insulin-like growth factor-1 binding protein 3 (IGFBP-3) promotes recovery from trauma-induced expression of inflammatory and apoptotic factors in retina
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DOI：
10.1016/j.cyto.2014.07.004
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发表时间：
2014-12-01
期刊：
影响因子：
3.8
通讯作者：
Steinle, Jena J.
中科院分区：
文献类型：
--
作者：
Jiang, Youde;Pagadala, Jayaprakash;Steinle, Jena J.
眼部创伤影响了20%的美国人，并可能导致永久性的视觉系统损伤。我们使用眼外伤小鼠模型（暴露于彩弹枪的空气爆炸）来检查引发视网膜损伤的途径，并制定可能改善创伤对视网膜组织有害影响的治疗策略。我们之前的研究表明，眼母细胞引起炎症介质和凋亡因子的蛋白水平升高，包括肿瘤坏死因子α (TNF α)和白细胞介素-1- β (IL-1 β)，以及凋亡标志物Bax、细胞色素C和cleaved caspase 3。此外，通过滴眼液局部应用β -肾上腺素能受体激动剂化合物49b，可以减少这些炎症/凋亡标志物，从而改善爆炸创伤的影响。我们假设化合物49b的保护作用可能与其已证实的激活β -肾上腺素能受体的能力有关，进而触发胰岛素样生长因子结合蛋白3 （IGFBP-3）的产生。在目前的研究中，我们用IGFBP-3活性最低的小鼠（IGFBP-3敲低小鼠）和野生型小鼠验证了这一假设。我们发现，单独眼爆炸并不影响野生型或敲除小鼠视网膜中的IGFBP-3水平，令人惊讶的是，敲除动物中较低水平的IGFBP-3并没有加剧爆炸诱导的炎症/凋亡标志物蛋白水平的增加。然而，创伤后24小时用化合物49b治疗后，IGFBP-3水平在敲低的小鼠视网膜中显著增加，正如预期的那样，IGFBP-3水平的增加与炎症/凋亡标志物的减少有关。我们得出结论，虽然IGFBP-3的降低可能不会使视网膜更容易受到爆炸损伤，但创伤后IGFBP-3的增加可能在限制创伤诱导的炎症和凋亡途径中发挥重要作用，从而导致视网膜损伤。滴眼液应用p-肾上腺素能受体激动剂化合物49b，增加IGFBP-3水平，促进眼母细胞后视网膜炎症和细胞凋亡的恢复，提供了一种很有前景的治疗策略。(C) 2014 Elsevier Ltd.版权所有。
Ocular trauma affects 20% of Americans in their lifetime and can cause permanent visual system damage. We have used a mouse model of ocular trauma (exposure to an air blast from a paintball gun) to examine pathways that trigger the resulting retinal damage and to develop treatment strategies that might ameliorate the deleterious effects of trauma on retinal tissue. Our previous studies have shown that ocular blast causes an increase in protein levels of inflammatory mediators and apoptotic factors, including tumor necrosis factor alpha (TNF alpha) and interleukin-1-beta (IL-1 beta), as well as the apoptotic markers, Bax, cytochrome C, and cleaved caspase 3. Furthermore, topical treatment by eye drop application of a beta-adrenergic receptor agonist, Compound 49b, was shown to decrease these inflammation/apoptosis markers and thus ameliorate the effects of blast trauma. We postulate that the protective effect of Compound 49b may be linked to its demonstrated ability to activate the beta-adrenergic receptor and in turn trigger production of insulin-like growth factor binding protein 3 (IGFBP-3). In the current study, we tested this hypothesis using mice with minimal IGFBP-3 activity (IGFBP-3 knockdown mouse) vs. wildtype mice. We found that ocular blast alone did not affect IGFBP-3 levels in retinas of wild type or knockdown mice and surprisingly, the lower levels of IGFBP-3 in knockdown animals did not exacerbate the blast-induced increase in protein levels of inflammation/apoptosis markers. Nevertheless, the levels of IGFBP-3 were significantly increased in knockdown mouse retina by treatment with Compound 49b 24 h post-trauma and as expected, the increase in IGFBP-3 was linked to a decrease in inflammation/apoptosis markers. We conclude that while lowered IGFBP-3 may not make the retina more vulnerable to blast injury, an increase in IGFBP-3 post-trauma may play an important role in limiting trauma-induced inflammatory and apoptotic pathways leading to retinal damage. Eye drop application of the p-adrenergic receptor agonist, Compound 49b, provides a promising treatment strategy for increasing IGFBP-3 levels to promote recovery from retinal inflammation and apoptosis after ocular blast. (C) 2014 Elsevier Ltd. All rights reserved.