Xu Heping, Chen Mei, Forrester John V
Immunology and Infection, Division of Applied Medicine, University of Aberdeen School of Medicine, Foresterhill, UK.
Prog Retin Eye Res. 2009 Sep;28(5):348-68. doi: 10.1016/j.preteyeres.2009.06.001. Epub 2009 Jun 26.
Para-inflammation is a tissue adaptive response to noxious stress or malfunction and has characteristics that are intermediate between basal and inflammatory states (Medzhitov, 2008). The physiological purpose of para-inflammation is to restore tissue functionality and homeostasis. Para-inflammation may become chronic or turn into inflammation if tissue stress or malfunction persists for a sustained period. Chronic para-inflammation contributes to the initiation and progression of many human diseases including obesity, type 2 diabetes, atherosclerosis, and age-related neurodegenerative diseases. Evidence from our studies and the studies of some others suggests that para-inflammation also exists in the aging retina in physiological conditions and might contribute to age-related retinal pathologies. The purpose of this review is to introduce the notion of "para-inflammation" as a state between frank, overt destructive inflammation and the non-inflammatory removal of dead or dying cells by apoptosis, to the retinal community. In diabetes and atherosclerosis, leukocytes particularly monocytes and vascular endothelial cells are constantly under noxious stress due to glycaemic and/or lipidaemic dysregulation. These blood-borne stresses trigger para-inflammatory responses in leukocytes and endothelial cells by up-regulating the expression of adhesion molecules or releasing cytokines/chemokines, which in turn cause abnormal leukocyte-endothelial interactions and ultimately vascular damage. In the aging retina, on the other hand, oxidized lipoproteins and free radicals are considered to be major causes of tissue stress and serve as local triggers for retinal para-inflammation. Microarray analysis has revealed the up-regulation of a large number of inflammatory genes, including genes involved in complement activation and inflammatory cytokine/chemokine production, in the aging retina. Para-inflammatory responses in the neuroretina of aged mice are characterized by microglial activation and subretinal migration, and breakdown of blood-retinal barrier. At the retinal/choroidal interface para-inflammation is manifested by complement activation in Bruch's membrane and RPE cells, and microglia accumulation in subretinal space. With age, para-inflammatory changes have also been observed in the choroidal tissue, evidenced by 1) increased thickness of choroid; 2) increased number of CD45(+)CRIg(+) macrophages; 3) morphological abnormalities in choroidal melanocytes; and 4) fibrosis in choroidal tissue. An increased knowledge of contribution of retinal para-inflammation to various pathological conditions is essential for the better understanding of the pathogenesis of various age-related retinal diseases including diabetic retinopathy, glaucoma and age-related macular degeneration.
类炎症是组织对有害应激或功能障碍的一种适应性反应，具有介于基础状态和炎症状态之间的特征（梅德齐托夫，2008年）。类炎症的生理目的是恢复组织功能和内环境稳定。如果组织应激或功能障碍持续一段时间，类炎症可能会发展为慢性或转变为炎症。慢性类炎症会促进包括肥胖、2型糖尿病、动脉粥样硬化和年龄相关性神经退行性疾病在内的多种人类疾病的发生和发展。我们的研究以及其他一些研究的证据表明，在生理条件下，类炎症也存在于衰老的视网膜中，并且可能与年龄相关性视网膜病变有关。这篇综述的目的是向视网膜领域介绍“类炎症”这一概念，它是一种介于明显的、具有破坏性的炎症与通过凋亡对死亡或濒死细胞进行非炎症性清除之间的状态。在糖尿病和动脉粥样硬化中，白细胞尤其是单核细胞和血管内皮细胞由于血糖和/或血脂失调而持续处于有害应激状态。这些血源性应激通过上调黏附分子的表达或释放细胞因子/趋化因子，触发白细胞和内皮细胞中的类炎症反应，进而导致异常的白细胞 - 内皮细胞相互作用并最终造成血管损伤。另一方面，在衰老的视网膜中，氧化脂蛋白和自由基被认为是组织应激的主要原因，并作为视网膜类炎症的局部触发因素。微阵列分析显示，衰老视网膜中大量炎症基因上调，包括参与补体激活和炎症细胞因子/趋化因子产生的基因。老年小鼠神经视网膜中的类炎症反应以小胶质细胞激活和视网膜下迁移以及血视网膜屏障破坏为特征。在视网膜/脉络膜界面，类炎症表现为布鲁赫膜和视网膜色素上皮（RPE）细胞中的补体激活以及视网膜下间隙中的小胶质细胞积聚。随着年龄增长，脉络膜组织中也观察到类炎症变化，表现为：1）脉络膜厚度增加；2）CD45(+)CRIg(+)巨噬细胞数量增加；3）脉络膜黑素细胞形态异常；4）脉络膜组织纤维化。深入了解视网膜类炎症对各种病理状况的作用，对于更好地理解包括糖尿病视网膜病变、青光眼和年龄相关性黄斑变性在内的各种年龄相关性视网膜疾病的发病机制至关重要。
