In the present study, we reported AH cytokine profiles in eyes with Coats disease in a relatively large sample size. We found that the concentrations of 8 out of 22 cytokines (VEGF, IL-6, IL-8, MCP-1, MIP-1α, IP-10, VACM-1 and ICAM-1) were significantly increased in the AH of eyes with Coats disease. Among which, the concentrations of VEGF, IL-8, MCP-1, MIP-1α were significantly associated with the extent of retinal exudation and ERD. The above elevated cytokines are involved in angiogenesis, increased vascular permeability and inflammatory response in the retina. The present study broadens the understanding of the pathogenesis of Coats disease, which may be valuable for further clinical treatment.
Consistent with previous studies [6-8], we found significantly increased VEGF concentration in the AH of eyes with Coats disease; furthermore, the VEGF concentration was positively associated with the increasing severity of the retinal exudation and ERD. VEGF is an important proangiogenic cytokine and is also associated with vascular leakage in the retina . An immunohistopathological study reported that VEGF was highly expressed by infiltrated macrophage in enucleated eyes with Coats disease, which contained typical retinal vascular abnormalities . Clinically, mounting studies confirmed the effect of intravitreal anti-VEGF therapy by reducing vascular leakage and retinal exudation in Coats disease [5, 9-11]. Therefore, VEGF may act an important role in the general pathogenesis of Coats disease and may be one of driving force in stimulating vascular leakage and neovascularization. Additionally, the present study showed a significant increase of VEGF concentration from stage 2 to stage 3, which implies that anti-VEGF therapy in the early stage of Coats disease appears to be effective in preventing disease progression.
Previous studies suggested that inflammation might be involved in the pathogenesis of Coats disease [7, 8], and intravitreal anti-inflammation therapy was reported to have a certain treatment effect on Coats disease [17-19]. However, the molecular mechanisms are still poor understood. Coats disease may be not a classic inflammatory disease, which is supported by AH cytokine profiles revealed in this study. Despite the increase of IL-6, IL-8, MCP-1 and MIP-1α, we found no comparable increase of IL-1β or TNF-α, which were hallmarks of inflammatory activation of macrophage . In addition, we also found no increase of typical cytokines associated with T- or B-lymphocyte activation, such as IL-2, IL-4, IL-5, IL-10, IL-12 and IFN-γ [21-24]. Thus, inflammatory activation of macrophage, and T- and B-lymphocyte mediated inflammatory responses may be limited in Coats disease.
Although inflammation may be not a prominent feature in Coats disease, inflammatory cells such as macrophage and T-lymphocyte were identified in enucleated eyes with Coats disease [16, 25]. The pathological change of retinal vascular structure causes the destruction of blood-retinal barrier, which makes it possible to collect inflammatory cells at the perivascular spaces and leads to higher concentrations of intraocular inflammatory cytokines. Correspondingly, changes in inflammatory cytokines suggested a possible association between the aggravation of the disease and the intensification of inflammation. In our study, the concentrations of inflammatory cytokines, including IL-6, IL-8, MCP-1 and MIP-1α, were significantly increased, and showed a progressive increase in parallel with the disease stage; moreover, the concentrations of IL-8, MCP-1 and MIP-1α showed moderate to strong associations with the severity of retinal exudation and ERD. The above elevated inflammatory cytokines are important proinflammatory factors, and also involve the regulation of angiogenesis and the increase of vascular permeability [26-28]. These inflammatory cytokines may participate the progression of Coats disease; however, their sources and true roles in Coats disease remain to be investigated. Based on the cytokine profiles in eyes with Coats disease, further studies designing to probe the identity of different cellular components and their state of activation may provide important information to unveil the mechanisms driving disease progression.
Other significantly elevated cytokines in our study should be noted. VCAM-1 and ICAM-1 play important roles in traversing leukocytes across endothelial cells, which also exacerbate the destruction of blood-retinal barrier [29, 30]. In the present study, significantly elevated VCAM-1 and ICAM-1 provide a possible molecular evidence for increased vascular permeability and accumulation of inflammatory cells in Coats disease. However, the above two cytokines showed no increase from stage 2 to stage 3, suggesting that vascular permeability may not change during the disease progression. IP-10, a potent T-lymphocyte chemoattractant , was also found significantly elevated, which may contribute to T-lymphocyte attraction in Coats disease.
The present study has several limitations. Firstly, compared with AH samples used in our study, the cytokine profiles of vitreous and/or subretinal fluid samples may better reflect fundus condition, however, which is limited by the need for more invasive approaches. Secondly, retinal fibrosis, one of the common clinical manifestations in Coats disease, and its association with AH cytokine concentrations should be taken into account. However, retinal fibrosis is usually late-onset in Coats disease ; in our study, none of the patients showed retinal fibrosis at presentation. Further studies investigating the association of AH cytokines with retinal fibrosis in Coats disease are needed. Last but not least, there may be some cytokines associated with Coats disease that the present study has not fully covered. In further studies, using a protein array chip to detect abundant proteins in the AH may be more helpful for a comprehensive understanding of the pathogenesis of Coats disease.