炎症和氧化应激在干眼发病中的作用及干眼的抗炎治疗

干眼在全球的患病率日益增高,其发病机制尚不明确。研究表明炎症和氧化应激是其主要的致病机制。体内和体外的多种刺激因素都会激活氧化应激反应,活性氧水平与抗氧化酶作用的失衡会激活炎症反应,造成眼表组织损伤,最终导致干眼。本文综述炎症和氧化应激在干眼发病中的重要作用及抗炎治疗。     

Mitochondrial function and redox control in the aging eye: role of MsrA and other repair systems in cataract and macular degenerations

Oxidative stress occurs when the level of prooxidants exceeds the level of antioxidants in cells resulting in oxidation of cellular components and consequent loss of cellular function. Oxidative stress is implicated in wide range of age-related disorders including Alzheimer's disease, Parkinson's disease amyotrophic lateral sclerosis (ALS), Huntington's disease and the aging process itself. In the anterior segment of the eye, oxidative stress has been linked to lens cataract and glaucoma while in the posterior segment of the eye oxidative stress has been associated with macular degeneration. Key to many oxidative stress conditions are alterations in the efficiency of mitochondrial respiration resulting in superoxide (O₂⁻) production. Superoxide production precedes subsequent reactions that form potentially more dangerous reactive oxygen species (ROS) species such as the hydroxyl radical (OH), hydrogen peroxide (H₂O₂) and peroxynitrite (OONO⁻). The major source of ROS in the mitochondria, and in the cell overall, is leakage of electrons from complexes I and III of the electron transport chain. It is estimated that 0.2-2% of oxygen taken up by cells is converted to ROS, through mitochondrial superoxide generation, by the mitochondria. Generation of superoxide at complexes I and III has been shown to occur at both the matrix side of the inner mitochondrial membrane and the cytosolic side of the membrane. While exogenous sources of ROS such as UV light, visible light, ionizing radiation, chemotherapeutics, and environmental toxins may contribute to the oxidative milieu, mitochondria are perhaps the most significant contribution to ROS production affecting the aging process. In addition to producing ROS, mitochondria are also a target for ROS which in turn reduces mitochondrial efficiency and leads to the generation of more ROS in a vicious self-destructive cycle. Consequently, the mitochondria have evolved a number of antioxidant and key repair systems to limit the damaging potential of free oxygen radicals and to repair damaged proteins (Fig. 1). The aging eye appears to be at considerable risk from oxidative stress. This review will outline the potential role of mitochondrial function and redox balance in age-related eye diseases, and detail how the methionine sulfoxide reductase (Msr) protein repair system and other redox systems play key roles in the function and maintenance of the aging eye.     

干燥环境相关性干眼的发病机制研究进展

干燥环境相关性干眼是指由长期处于低湿度环境中引起的干眼,与生活环境密切相关。目前干燥环境相关性干眼的发病机制尚不完全明确。炎症是干眼发病机制的关键一环,暴露于干燥环境在干眼的炎症进程中起着重要的作用,主要表现为干燥应激对眼表各方面产生不利影响,促进炎症,进而引起干眼。本文将从干燥环境出发,从眼表免疫稳态失衡、泪膜稳定性下降、氧化应激、神经调控异常几个方面对干燥环境因素在眼表炎症中的作用进行综述,以期全面认识干燥环境对干眼发病的影响,重视干燥环境因素在干眼诊疗中的作用。     

Role of growth factors and the wound healing response in age-related macular degeneration

Growth factors (GF) are important in several stages of the pathogenesis of age-related macular disease (AMD). In choroidal neovascularization (CNV) in exudative AMD, the GF involved are similar to those involved in wound healing of the skin. Like granulation tissue of skin, CNV is characterized by clotting, inflammation, angiogenesis and fibrosis, and like in skin wounds, members of the VEGF, angiopoietin, PDGF and TGF- families of GF are expressed. However, several of these GF may also serve physiological functions in the normal eye, where the retinal pigment epithelium (RPE) employs them to provide trophic support to the neuroretina and choriocapillaris, in addition to maintaining an anti-angiogenic state. Derangement of these physiological functions may underlie the initiation of CNV in AMD. Basolateral secretion of VEGF-A by the RPE maintains the choriocapillaris, and is enhanced by hypoxia. Age-related changes in Bruchs membrane lead to impairment of this trophic function and choriocapillaris atrophy, as well as to decreased diffusion of oxygen towards the neuroretina. The resulting outer retina hypoxia may be an important driving force of CNV formation, by stimulating VEGF overexpression by the RPE, in addition to the effects of increased oxidative stress and low-grade inflammation. RPE senescence and hypoxia may also decrease expression of angiogenesis inhibitors such as PEDF, further shifting the balance to a pro-angiogenic state in the aging eye.     

Herbal molecules in eye diseases

The eyes are exposed to oxidative stress due to light absorption and the high metabolism rate of their tissue cells. Oxidative stress plays an important role in the pathogenesis of many major eye diseases, including ocular inflammation, neovascularization, age-related macular degeneration, glaucoma, and cataracts. Herbal molecules, such as lutein, zeaxanthin, omega-3 fatty acids, vitamin C, and vitamin E, have been tried as ocular aliments. Although there are many positive outcomes for preventive or even therapeutic uses for ocular diseases, the efficacy remains controversial. Nevertheless, traditional Chinese medicine remains the best choice of herbal molecules mining for ocular remedies.     

The role of oxidative stress in the pathogenesis of age-related macular degeneration

Age-related macular degeneration (AMD) is the leading cause of blind registration in the developed world, and yet its pathogenesis remains poorly understood. Oxidative stress, which refers to cellular damage caused by reactive oxygen intermediates (ROI), has been implicated in many disease processes, especially age-related disorders. ROIs include free radicals, hydrogen peroxide, and singlet oxygen, and they are often the byproducts of oxygen metabolism. The retina is particularly susceptible to oxidative stress because of its high consumption of oxygen, its high proportion of polyunsaturated fatty acids, and its exposure to visible light. In vitro studies have consistently shown that photochemical retinal injury is attributable to oxidative stress and that the antioxidant vitamins A, C, and E protect against this type of injury. Furthermore, there is strong evidence suggesting that lipofuscin is derived, at least in part, from oxidatively damaged photoreceptor outer segments and that it is itself a photoreactive substance. However, the relationships between dietary and serum levels of the antioxidant vitamins and age-related macular disease are less clear, although a protective effect of high plasma concentrations of alpha-tocopherol has been convincingly demonstrated. Macular pigment is also believed to limit retinal oxidative damage by absorbing incoming blue light and/or quenching ROIs. Many putative risk-factors for AMD have been linked to a lack of macular pigment, including female gender, lens density, tobacco use, light iris color, and reduced visual sensitivity. Moreover, the Eye Disease Case-Control Study found that high plasma levels of lutein and zeaxanthin were associated with reduced risk of neovascular AMD. The concept that AMD can be attributed to cumulative oxidative stress is enticing, but remains unproven. With a view to reducing oxidative damage, the effect of nutritional antioxidant supplements on the onset and natural course of age-related macular disease is currently being evaluated.     

Growth-related effects of oxidant-induced stress on cultured RPE and choroidal endothelial cells

Mounting evidence suggests that oxidative stress caused by reactive oxygen intermediates is a significant mechanism in the pathogenesis of age-related macular degeneration (AMD). Although vascular endothelial growth factor (VEGF) and other cytokines are involved in choroidal neovascularization (CNV) it is largely unknown whether oxidative stress may predispose the eye to increased levels of proangiogenic factors. In an in vitro study we have determined viability and proliferation of both human retinal pigment epithelial (RPE) cells and bovine choroidal endothelial cells (CECs) and assessed the release of basic fibroblast growth factor (bFGF) and VEGF from RPE cells after exposing them to oxidative stress. Permanent presence of tert-butyl-hydroperoxide (tBH), a pro-oxidative stressor, in the cell cultures resulted in decreasing viability and proliferation of RPE cells and CECs. Loss of RPE cell viability was associated with activation of apoptosis by tBH in a dose-dependent manner. The antioxidant, N-acetyl-l-cysteine (NAC), and secreted soluble mediators of RPE cells were appropriate to attenuate the effects of tBH-mediated oxidative stress. RPE cells exposed to tBH were found to release increasing amounts of bFGF but not VEGF after 24 h of culture, thereby supporting proliferation of CECs. These findings suggest that oxidative stress compromises the viability of RPE cells and CECs. However, increased bFGF levels concomitantly released from RPE cells may attenuate the CEC-directed effect, protect CECs from oxidative insults, and are likely to promote CNV.     

年龄相关性白内障患者氧化损伤修复基因表观遗传学研究进展

氧化损伤是目前较为公认的年龄相关性白内障(ARC)发病机制.晶状体上皮细胞的氧化损伤会引起DNA损伤,而DNA氧化损伤修复能力不足或不及时均会引起ARC的发生.近年来发现,许多眼睛疾患的发病机制受表观遗传、环境及遗传等因素的影响,并且表观遗传学通过调控DNA氧化损伤修复基因的表达在ARC发生机制中起重要作用.本文系统阐...     

Molecular mechanism for choroidal neovascularization in age-related macular degeneration

Choroidal neovascularization (CNV) in age-related macular degeneration (AMD) is the most common cause of severe visual loss in patients over age 60 years in developed countries. While much is unknown about the underlying pathogenesis of CNV, the increased production of vascular endothelial growth factor(VEGF) by retinal pigment epithelium (RPE) is thought to play a central role in the development of this condition. However, recent studies using gene-manipulated mice question the importance of VEGF alone in promoting CNV. Angiogenesis is thought to result from the balance between angiogenesis stimulation and inhibition. A potent antiangiogenic factor recently has been identified in the retina and shown to be secreted by RPE cells. The inhibitor, pigment epithelium-derived factor(PEDF) is considered the key factor associated with avascularity of the cornea, vitreous, and outer retinal layer of the eye. We recently demonstrated that an imbalance between PEDF and VEGF in RPE cells caused by aging and oxidative stress may contribute to the disregulation of endothelial cell proliferation in CNV. In this review, we also discuss the angiogenic role of inflammatory cells in CNV, age-related changes in Bruch's membrane, and the possibility of the development of animal models reflecting CNV in AMD.     

慢性移植物抗宿主病相关干眼纤维化发病机制研究进展

慢性移植物抗宿主病(cGVHD)是异基因造血干细胞移植(allo-HSCT)后的一个主要并发症,类似于自身免疫性疾病,累及全身多个器官。干眼是cGVHD眼部的主要表现,严重影响患者的生活质量。研究发现,慢性炎症和纤维化是cGVHD相关干眼患者眼部多个组织的主要病理生理表现。目前关于cGVHD相关干眼纤维化的发病机制尚不清楚,因此本文从成纤维细胞、免疫细胞、促纤维化细胞因子、肾素-血管紧张素系统和内质网应激方面对cGVHD相关干眼纤维化机制进行综述,以期能针对纤维化研发出新的诊断、治疗和预防策略。     

Antiinflammatory therapy for dry eye

PURPOSE: To present evidence establishing the relationship between inflammation and dry eye and supporting the use of antiinflammatory therapy for dry eye. DESIGN: Analysis of literature. METHODS: Research studies that evaluated inflammation in dry eye pathogenesis and clinical trials of antiinflammatory therapies for dry eye were reviewed. RESULTS: There is increasing evidence that decreased tear secretion, decreased tear turnover, and desiccation promote inflammation on the ocular surface. An increase in soluble mediators (cytokines and proteases) in the tear fluid, adhesion molecule expression by the conjunctival epithelium, and T-cell infiltration of the conjunctiva have been observed in dry eye patients. This inflammation appears to have a role in the pathogenesis of the ocular surface epithelial disease, termed keratoconjunctivitis sicca (KCS), that develops in dry eye. Clinical improvement of KCS has been observed after therapy with antiinflammatory agents including corticosteroids, cyclosporin and doxycycline. Cyclosporin A emulsion was approved by the Food and Drug Administration as therapy for dry eye. Randomized placebo-controlled FDA clinical trials showed that cyclosporine A was superior to vehicle in stimulating aqueous tear production, decreasing corneal punctuate fluorescein staining, reducing symptoms of blurred vision, and decreasing artificial tear use in patients with KCS. No ocular or systemic toxicity was observed from this medication. CONCLUSIONS: Ocular surface and lacrimal gland inflammation has been identified in dry eye that plays a role in the pathogenesis of KCS. Antiinflammatory therapy has efficacy for treating KCS. Cyclosporin A is the first FDA approved therapy for this indication. It improved signs and symptoms of KCS, and it is safe for long-term use.     

干眼的免疫机制研究进展

干眼是一种由多因素所致,发病机制众多的常见眼表疾病。随着我国干眼发病率逐年升高,干眼逐渐引起人们的重视。干眼的发病机制较为复杂,其中炎症、角结膜上皮细胞改变、泪膜成分改变、角膜神经改变、睑板腺功能异常改变等均为重要因素。泪膜高渗导致眼表上皮细胞高渗,刺激炎症发生级联反应,眼表炎症反应为干眼发病机制中最为关键的环节。该过程中有多种炎症介质和免疫细胞参与,越来越多的人认为干眼是一种抗原特异性自身免疫性炎症疾病且二者存在联系。临床治疗中,各类抗炎药物及促进泪液分泌药物在一定程度上标志着干眼药物治疗的快速发展,但干眼治疗并非仅仅为了改善症状,而要根据具体病因展开治疗。近年关于干眼免疫机制的研究日益增多,据此本文就干眼的免疫机制研究进展进行综述,希望系统性了解免疫在干眼发生发展过程中的作用及临床意义。     

干性年龄相关性黄斑变性患者视网膜色素上皮细胞损伤机制

年龄相关性黄斑变性(age-related macular degeneration,AMD)是中老年人视力障碍的重要原因之一。AMD分为2型:萎缩型(干性)和渗出型(湿性)。本文从光照损伤、脂褐素积累、氧化损伤、内质网应激4个方面,综述了干性AMD研究中基于视网膜色素上皮细胞损伤的相关研究进展,为进一步探索其发病机制提供依据和方向。     

氧化应激因素在干眼中的临床研究

干眼是由于泪液的量或质的异常引起的泪膜不稳定和眼表面的损害,从而导致眼不适症状的一类疾病。干眼与多种因素相关。本文主要探讨氧化应激因素对干眼的影响及临床治疗。针对氧化应激因素,干眼周期概念、干眼的眼表炎症和蛋白质组学相关研究证明了两者的相关性,有利于进行针对性临床治疗。针对氧化应激因素的治疗是干眼的潜在治疗方式,无防腐剂眼药水的使用、碘离子电渗疗法及其他蛋白质组学方法的临床试验证明了其合理性与有效性。随着近年来对抗老化药物、预防性整体健康以及环境科学作用的重视,对眼表氧化应激的研究可能会在未来几年产生越来越大的影响。     

The impact of oxidative stress and inflammation on RPE degeneration in non-neovascular AMD

The retinal pigment epithelium (RPE) is a highly specialized, unique epithelial cell that interacts with photoreceptors on its apical side and with Bruch's membrane and the choriocapillaris on its basal side. Due to vital functions that keep photoreceptors healthy, the RPE is essential for maintaining vision. With aging and the accumulated effects of environmental stresses, the RPE can become dysfunctional and die. This degeneration plays a central role in age-related macular degeneration (AMD) pathobiology, the leading cause of blindness among the elderly in western societies. Oxidative stress and inflammation have both physiological and potentially pathological roles in RPE degeneration. Given the central role of the RPE, this review will focus on the impact of oxidative stress and inflammation on the RPE with AMD pathobiology. Physiological sources of oxidative stress as well as unique sources from photo-oxidative stress, the phagocytosis of photoreceptor outer segments, and modifiable factors such as cigarette smoking and high fat diet ingestion that can convert oxidative stress into a pathological role, and the negative impact of impairing the cytoprotective roles of mitochondrial dynamics and the Nrf2 signaling system on RPE health in AMD will be discussed. Likewise, the response by the innate immune system to an inciting trigger, and the potential role of local RPE production of inflammation, as well as a potential role for damage by inflammation with chronicity if the inciting trigger is not neutralized, will be debated.     

Inflammation and oxidative stress induced by lipid peroxidation metabolite 4-hydroxynonenal in human corneal epithelial cells

Graefe's Archive for Clinical and Experimental Ophthalmology - Oxidative stress is widely known to be a major contributor in the pathogenesis of dry eye disease (DED). 4-Hydroxynonenal (4-HNE),...     

T细胞介导的炎症反应机制在干眼病中的研究现状

干眼病是眼科常见的眼表疾病,其发病机制复杂,目前尚无一种理想的动物模型能较好地模拟出干眼病发病缓慢、反复发生、逐渐恶化的特点。研究认为,炎症是干眼病发的主要因素。本文主要对Th1细胞和Th17细胞及其相关细胞因子在干眼病发病中作用做简要概述。     

Functional MRI of brain activation by eye blinking.

Functional magnetic resonance imaging (fMRI) was used to map cortical areas that control eye blinking. T2*-weighted asymmetric spin-echo MRI (or BOLD-blood oxygen level dependent-MRI) was used to detect changes caused by focal variations in blood oxygenation. Six normal volunteers and two cases of dry eye (less than 5-mm Schirmer's test) entered the study. The experimental scheme consisted of three cycles of a two-step sequence: (eyes closed)-(blink or blink inhibition). And to minimize contamination from photic activation, the experiments were carried out in a dark environment and the volunteers reported no light perception during the MR scans.In all eight cases, normal blinking (about one blink every 4 sec) activated areas in the orbitofrontal cortex and in some cases, the visual cortex including the anterior portion of the visual cortex and the primary visual cortex. In severe dry eye, blink-inhibition strongly activated the visual cortex even after irritation due to corneal desiccation was removed by topical anesthesia.The blinking process, especially the rate, appears to be controlled in the orbitofrontal cortex. The significance of visual cortex activation in the dark and in the case of severe dry eye still remains unclear; although it may be associated with attention and arousal.     

Involvement of oxidative stress on corneal epithelial alterations in a blink-suppressed dry eye

PURPOSE: To investigate whether oxidative stress is involved in the etiology of the corneal disorder in blink-suppressed dry eye in a clinically relevant in vivo rat model. METHODS: A series of treatments were performed under continuous exposure to low-humidity airflow. Rats were placed on a jogging board (JB) made of a plastic pipe for 7.5 h/d, and for 16.5 hours, they were placed in individual cages without a JB. This protocol was repeated for up to 30 days. Corneal surface alteration was evaluated by the score of punctate fluorescein staining. To assess oxidative stress status, the levels of damaged DNA, and the protein modification by reactive aldehydes in corneal epithelia were detected by immunohistochemistry, using 8-hydroxy-2-deoxyguanosine, 4-hydroxynonenal- and malondialdehyde-specific antibodies. RESULTS: Significant increases in the fluorescein staining score were observed from days 1 to 30 compared with the initial value. The average score for the dry eye group was significantly increased compared with that for the nontreatment group at all time points throughout the experiment. Immunoreactivity of all oxidative stress markers increased in the dry eye treatment. Quantitative analysis of the positive-stained cells showed a significant increase in the number of positive cells after 10 and 30 days in the dry eye treatment group compared with the nontreatment group. CONCLUSIONS: These results suggest a relationship between the accumulation of oxidative stress and the etiology of corneal epithelial alterations in blink-suppressed dry eye.