周青 jun ^(1,2){ }^{1,2} , 杨凌 ling ^(1,2){ }^{1,2} , 王群 ^(1,2){ }^{1,2} , 李 ya ^(1,2){ }^{1,2} , 魏超 ^(1,2){ }^{1,2} 和 谢利 xin ^(1,2**){ }^{1,2 *}^(1){ }^{1} State Key Laboratory Cultivation Base, Eye Institute of Shandong First Medical University, Qingdao, China, ^(2){ }^{2} Shandong Provincial Key Laboratory of Ophthalmology, Eye Institute of Shandong First Medical University, Qingdao, China
Diabetes mellitus (DM) is an endemic disease that occurs all over the world, imposing extensive health burden on society (1, 2). Diabetics with prolonged periods of hyperglycemia suffer from numerous complications affecting almost every organ system, including the ocular tissues (3,4)(3,4). DM-related ocular complications are the leading cause of blindness, especially in developed countries. Although diabetic
retinopathy is the most common and well-known ophthalmic complication, DM also has profound clinically relevant effects on the ocular surface (5,6)(5,6).
The corneal tissue composes five stratified layers: the epithelium, Bowman’s layer, stroma, Descemet’s membrane and the endothelium ( 7,8 ). Corneal epithelium is the cornea’s outermost layer, whose integrity is essential to maintaining healthy vision. Corneal stroma, which is populated by keratocytes, represents almost 90%90 \% of the thickness of the cornea. Corneal endothelium, a single cell layer between the corneal stroma and anterior chamber, exhibits barrier and ‘pump’ functions to maintain corneal dehydration. In addtition, to maintain a healthy ocular surface, the lacrimal gland and meibomian glands produce tears and lipids to prevent excessive evaporation of the tear film. Dysfunctions of these glands will cause dry eye disease (9,10)(9,10).
Several studies have found that corneal epithelium in diabetic patients tends to have increased fragility, lower cell density, thinner thickness and reduced barrier function (20-22). An electron-microscopic examination of corneal epithelium showed an increased epithelial fragility in specimens of diabetic patients (23). Saini and Khandalavla measured the corneal epithelial fragility of healthy people and diabetic patients using an esthesiometer (20). The results revealed that the average corneal epithelial fragility of diabetic patients was significantly higher than that of healthy people, and that the epithelial fragility of diabetic retinopathy patients increased more significantly. Increased corneal epithelial fragility was also found in Goto Kakizaki rats with type 2 DM (24). A few studies reported that there was no statistical significance in the reduction of corneal basal epithelial cell density in diabetic patients (25,26)(25,26). However, more clinical studies have demonstrated that the density of corneal basal epithelial cells was significantly reduced in type 1 and type 2 diabetic patients (21, 27-29), which may be related to the reduction of corneal innervation, impaired of basement membrane and higher turnover rate (21). In the diabetic patients, the mean corneal epithelium thickness was thinner (22,30)(22,30) which is associated with the stage of the disease. Similarly, Cai et al. verified the characteristics of the thinning of corneal epithelium and the decreasing density of basal epithelial cells in the rodent model of type 1 diabetes induced by streptozotocin (31). The changes of corneal epithelial density and thickness reflect the imbalance between cell proliferation, differentiation, migration and death. The corneal epithelium has a strong barrier function, making it the first line of defense for the eyeball to resist the external environment. It has long been found that the barrier function of diabetic corneal epithelium is weakened (32-34) which is related to the increase of glycosylated hemoglobin level (34), and correspondingly, diabetic corneas are more prone to infection than healthy people (35-39). In vitro studies have proven that high glucose exposure leads to the impairment of the human
Corneal nerves, a branch of the ophthalmic division of the trigeminal nerve, enter the peripheral cornea in a radial fashion parallel and then penetrate Bowman’s layer to form the corneal sub-basal nerve plexus, which terminate in free nerve endings in the corneal epithelium and comprises the outermost layer of the cornea and protects cornea from microbial invasion (51,52)(51,52). Diabetic peripheral neuropathy (DPN) is the most common complication of diabetes, affecting up to 50%50 \% of diabetic patients (53). Recent study reported that the density of corneal nerve fiber and branch, and the corneal nerve fiber length are significantly decreased in diabetic patients (12). Moreover, the loss of 6%6 \% or more of corneal nerve fibers per year has been found in 17%17 \% of diabetic patients (54,55)(54,55). Approximately 39%39 \% of diabetic patients experience painful DPN when left untreated (56).
在 1 型和 2 型糖尿病患者及动物模型中，角膜上皮附近的角膜下基质神经丛中的神经纤维长度、分支和密度已被发现
to be reduced, which relates to the severity of diabetic polyneuropathy (24, 31, 57-63). Detailed examination by in vivo confocal microscopy has revealed increased corneal nerve tortuosity and thickness in diabetic patients (60, 64-68). Moreover, reduced corneal sensitivity is observed in diabetic patients and animals, and the degree is correlated with the severity of diabetes ( 60,63,67,69-7160,63,67,69-71 ). Pritchard et al. reported that corneal sensation threshold was significantly higher for patients with neuropathy compared to those without neuropathy and controls (72). Recent studies have identified corneal sensitivity as a potential marker of diabetic neuropathy (73). In addition, the regeneration of corneal subbasal nerves is significantly slower in diabetic animals during corneal epithelial wound healing (24,74)(24,74). Importantly, the reduction of sub-basal nerve plexus density and corneal sensitivity, which precedes other clinical and electrophysiology tests, could be used as markers for DPN assessment (75, 76). In addition, patients with diabetes often have burning, dryness or painful feeling in the eye (77).
病理机制
The pathogenesis is difficult to investigate through human epidemiological studies due to too many confounding factors. Therefore, researchers often use animal diabetes models and in vitro cell models to study pathogenesis (78,79)(78,79). The changes in growth factors, immune cells and signal pathways in diabetic keratopathy have been elaborated in previous reviews ( 4,14,174,14,17, 78, 80). Here, we mainly discuss the following aspects.
慢性炎症
As a significant characteristic of DM, low-grade chronic inflammation is regarded as an important mechanism for the development of DM and its complications, including diabetic nephropathy, diabetic retinopathy, and diabetic cardiomyopathy (81,82)(81,82). These chronic inflammatory scenarios was triggered and sustained by immune cells and structural cells of specific organs/tissues, which activated innate immunity mainly through pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs) and nucleotide-binding oligomerization domain (NOD)like receptors (NLRs) (82,83)(82,83). Therefore, chronic inflammation theoretically also contributes to the development of DK. Several compelling evidence we found consolidated the pathogenic involvement of chronic inflammation in the development of DK (Figure 1).
NOD-like receptor protein 3 (NLRP3) inflammasome, a fully characterized inflammasome, contains NLRP3, adaptor protein ASC, and pro-caspase-1(pro-CASP1), and can be activated by various stimuli, including pathogenic molecules, sterile insults, and metabolic products (84,85)(84,85). NLRP3 inflammasome-mediated inflammation plays key roles in the development and progression of DM and its complications, such as diabetic nephropathy (83),