Intravitreal Inflammation: From Benchside to Bedside

The aim of this special issue is to describe the role of inflammation in biological mechanisms of long-known diseases, providing an up-to-date viewpoint for therapeutic approaches. The authors provide a comprehensive overview, with original and review articles, on the implications of inflammation in proliferative vitreous retinopathy, on diabetic retinopathy, and on the potential iatrogenic damage induced by sustained intravitreal anti-VEGF therapy. 
 
Despite the copious literature, the exact mechanism of idiopathic epiretinal membranes formation (iERM) is still unclear. M. Joshi et al. showed the importance of glial cells and hyalocytes in its pathogenesis. Such cellular constituents of iERMs in concert with cytokines, growth factors (TGF and NGF), and anomalous posterior vitreous detachment are responsible for the prognosis and potential growth of epiretinal traction. The proliferative vitreoretinopathy (PVR) is recognized as a common secondary severe inflammatory complication of retinal detachment. C. Azzolini et al. reported two possible pathways (VEGF-A, Otx2, p53, p63, and Otx1 and Otx3) of PVR. These genetic pathways could represent a novel target of therapy of PVR progression. PVR is an even more common complication in patients with open-globe injury. F. Morescalchi et al. describe the role of immune cells into the vitreous gel in penetrating ocular injury. The cells stimulate the production of growth factors and cytokines, in particular PDGFR-α, which seem to be crucial in the development of PVR and, therefore, considered another potential therapeutic target. In a prospective, nonrandomized, observational study, C. Costagliola et al. showed that tear fluid collection is a useful and noninvasive method for the finding of proliferative diabetic retinopathy. The authors reported that TNF-alpha concentrations increase in tears according to the severity of proliferative and nonproliferative diabetic retinopathy. 
 
F. Parmeggiani et al. demonstrated the evidence of a relationship between AMD-risk genotypes, immunoinflammatory endophenotypes, and the networks of acquired or epigenetic factors. 
 
The authors reported that proinflammatory effects secondary to chronic inflammation and heterogeneous types of oxidative stress induce degenerative damage to the photoreceptors and outer retinal-blood barrier. In particular, the carriers of CFH, ARMS2/HRTA1, and C2/CFB genotypes demonstrated high odd ratio values. A score, calculating a risk including genetic findings, could be useful to identify individual risk, in order to provide preventive treatments. 
 
The intraviteral inflammation can be also secondary to iatrogenic treatment as intravitreal anti-VEGF therapy or vitreoretinal surgery. 
 
S. Agrawal et al. compared the sterile inflammation among the different intravitreal anti-VEGF drugs currently used for neovascular diseases. The acute intraocular inflammation is more frequently associated with bevacizumab likely due to the less strict purification procedure of the drug. In most cases, the inflammation solves spontaneously and vision returns to baseline. A history of previous inflammation does not increase the risk with following intravitreal injections. 
 
Previous vitreoretinal surgery can also induce intravitreal inflammation responsible for cytotoxic macular oedema. V. Romano et al. reported that intravitreal inflammation may increase after pars plana vitrectomy due to tractional phenomena at vitreomacular interfaces or due to a vasogenic damage. The oedema is characterized by fluid accumulation in the parenchymatous retinal cells (intracellular oedema) or by extracellular fluid accumulation due to a blood-retinal barrier damage (extracellular oedema). 
 
The treatment of vitreous inflammation is still a challenging issue; however, there are multiple methods of systemic treatment including T-cell inhibitors/calcineurin, antimetabolites, corticosteroids, alkylating agents, inhibitors, and biologic agents. A. Jiang et al. showed that these drugs can be used either alone or together in order to control vitreous inflammation due to variety of etiologies, either infectious or noninfectious. A. Russo et al. demonstrated that the topical nonsteroidal anti-inflammatory drugs (NSAIDs) allow for greater drug penetration into the vitreous. Topical NSAIDs reduce the exudation secondary to age-related macular degeneration or diabetic maculopathy. NSAIDs are also considered a favorable adjunct together with anti-VEGF that could potentially reduce the number of anti-VEGF injections. Finally, the chronicity of certain inflammatory conditions limits the efficacy of locally administered drugs. J. Wang et al. reported the last updates on implantable devices and particulate delivery systems such as nanoparticles, microparticles, and liposomes. These topics are actually considered the research focus of biomedical engineering, pharmacology, and molecular biology. 
 
We wish that this special issue will provide helpful information to recognize the clinical features of vitreous inflammation, to understand the mechanism beyond, and to identify the latest treatments in the disease in which the vitreous is involved. 
 
 
Mario R. Romano 
 
John Christoforidis

In�ammation plays a ma�or role in the formation and in the progression of sight-threatening chorioretinal diseases such as diabetic retinopathy (DR), proliferative vitreoretinopathy (PVR), uveitis, and age-related macular degeneration (AMD). A greater understanding of the underlying pathological mechanisms is necessary for the development of better therapeutic agents and relies on the analysis of clinical specimens as well as on animal models. Contrary to the retina, the vitreous humour (VH) is a transparent gel that �lls the posterior chamber of the eye and can be sampled without causing visual loss. In recent years, advances in the analysis of VH samples have highlighted new biological mechanisms of long-known diseases and have improved the accuracy of diagnostic procedures.
In this special issue, we report how the VH �ndings at the benchside can be translated to the bedside, and how this may help clinical practice. e papers have been contributed by a number of experts in the �eld and include both review articles that provide an overview of the work conducted to date, as well as original articles reporting recent discoveries and innovations. In order to highlight the translational relevance of VH analyses, most of the papers are focused on a speci�c disease entity. We hope that this series of manuscripts will be bene�cial for clinicians in their diagnostic and therapeutic approaches towards intravitreal in�ammatory conditions and for researchers in appreciating some of the recent innovations and their clinical implications in this �eld. Each of the manuscripts in this series is brie�y highlighted as follows.
e paper by M. Angi et al. "Proteomic analyses of the vitreous humour" describes how to correctly collect and handle VH specimens and presents a clear work�ow for proteomic analyses. is is signi�cant since the VH is not a straightforward tissue to analyze due to its viscous consistency. Proteomic technologies have dramatically evolved over the past years, allowing identi�cation of an increasing number of disease-speci�c proteins in the VH. Moreover, recent proteomic studies on the VH from animal models of autoimmune uveitis have highlighted new pathways associated to autoimmune triggers and intravitreal in�ammation that could become the targets for much needed therapies.
Another example of the usefulness of proteomic analyses of the VH in translational research is presented by O. Simó-Servat et al. in "Usefulness of the vitreous �uid analysis in the translational research of diabetic retinopathy" who applied �uorescence-based di�erence gel electrophoresis (DIGE), as well as �ow cytometry, to identify new candidates involved in the in�ammatory process that occurs in DR. e authors provide evidence supporting the role of proin�ammatory mediators such as cytokines (i.e., IL-1 , IL-6, IL-8, and TNF ), chemokines (i.e., MCP-1, SDF-1, and IP-10), and adhesion molecules (i.e., VCAM, ICAM-1, and VAP-1) in the pathogenesis of DR. Such persistent low-grade in�ammation contributes to the damage of the internal blood-retinal barrier and to the development of proliferative diabetic retinopathy (PDR).
A. M. Abu El-Asrar et al. in "Osteopontin and other regulators of angiogenesis and �brogenesis in the vitreous from patients with proliferative vitreoretinal disorders" and "High-mobility group box-1 and endothelial cell angiogenic markers in the vitreous from patients with proliferative diabetic retinopathy" investigate the role of osteopontin and other regulators of angiogenesis and �brogenesis, such as high-mobility group box-1 (HMGB1) and connective tissue growth factor (CTGF) in the pathogenesis of proliferative Mediators of In�ammation vitreoretinal disorders with a concomitant increase of anti�brogenic pigment epithelium-derived factor (PEDF) levels in the VH. Moreover, the authors report that HMGB1, soluble vascular endothelial-cadherin (sVE-cadherin), and soluble endoglin (sEng) regulate the angiogenesis of endothelial cells in PDR.
R. dell'Omo et al. in "Vitreous mediators in retinal hypoxic disease" describe that serum adiponectin (APN) levels correlate with blood in�ammatory marker levels and with DR as response to endothelium dysfunction, indicating the role of APN as endogenous modulator of microvascular function and in�ammation.
S. N. Moysidis et al. in "Mechanisms of in�ammation in proliferative vitreoretinopathy: from bench to bedside" describe the indirect activation of PDGFR by non-PDGFs as trigger that leads to development of PVR. In this pathway, the intracellular reactive oxygen species (ROS) plays a key role, leading to activation of Src family kinases (SFKs) that promote phosphorylation and activation of PDGFR . e ROS could be one of the therapeutic targets of multimodal approach.
D. Gologorsky et al. in "erapeutic interventions against in�ammatory and angiogenic mediators in proliferative diabetic retinopathy" report the latest focus of targeted therapies for proliferative diseases through the block of vascular adhesion molecules such as ICAM-1, VCAM-1, in�ammatory factors including the interleukins, tumor necrosis factor (TNF), insulin-like growth factor (IGF), and angiopoietins (Ang-2).
Analysis of the VH is a valuable adjunct also for the management of patients with uveitis and especially in the diagnosis of neoplastic diseases masquerading as chronic intraocular in�ammation, as reported by E. M. Damato et al. in "Vitreous analysis in the management of uveitis." For example, increased levels of T-cell cytokine, IL-6, in VH is characteristic of uveitis, whereas increased levels of IL-10 and in particular IL-10/IL-6 ratio greater than 1 should prompt cytological analysis for the diagnosis of vitreoretinal lymphoma. e involvement of VH in neoplastic diseases and the pros and cons of performing VH biopsies in the clinical practice are further discussed in the review article by M. Asencio-Duran et al. entitled "Vitreous diagnosis in neoplastic diseases." J. L. Vallejo-Garcia et al. in "Role of in�ammation in endophthalmitis" discuss the role of in�ammation in infective endophthalmitis, reporting that the damage to the retina in this rare but severe diseases is mediated by the host immune reaction through toll-like receptors, cytokines, HMGB1, and aB-crystallin. A better understanding of the host immune reaction and the cellular pathways leading to tissue damage is also essential to improve clinical outcomes. Corticosteroids are frequently administered with antibiotics but oen do not fully control the host immune reaction with consequent visual loss. A novel TLR2 ligand, Pam3Cys, has demonstrated encouraging results when administrated before the onset of endophthalmitis and also when injected in combination with intravitreal antibiotics.
J. B. Christoforidis et al. in "Intravitreal devices for the treatment of vitreous in�ammation" describe the importance of the modulation of pharmacokinetics in the treatment of chronic intraocular in�ammation. Long-term treatments are currently provided by drug-delivery devices, which include nonbiodegradable and biodegradable devices. e therapeutic agents that can be delivered are ganciclovir, �uocinolone acetonide, triamcinolone acetonide, and dexamethasone. e next small-scale biodegradable devices already described are liposomes, microspheres, and nanoparticles from 0.01 to 1,000 m in diameter.
J. B. Christoforidis et al. in "Systemic treatment of vitreous in�ammation" also report that many classes of systemic drugs may be used alone or in combination to control intraocular in�ammation while closely monitoring side effects. Many of these in�ammatory disorders require long-term treatment, and hence steroid-sparing agents, including antimetabolites, alkylating agents, and biological agents, are being used.
e emerging topic of sterile endophthalmitis is presented by J. Marticorena et al. in "Sterile endophthalmitis aer intravitreal injections." It is an infrequent complication of intravitreal injections and seems to develop in the context of the off-label use of drugs that have not been conceived for intravitreous administration. Sterile in�ammation secondary to IVTA and IVB share many characteristics, such as the acute and painless vision loss present in the vast majority of the cases.
In�ammation also plays a major role also in the aging retina, where free radicals and oxidized lipoproteins are considered to be major causes of tissue stress. F. Parmeggiani et al. in "Mechanism of in�ammation in age-related macular degeneration" report that the consequence is a parain�ammation, a chronic status which contributes to initiation and progression of neurodegenerative diseases such as agerelated macular degeneration (AMD). e parain�ammatory deregulation that is already present in the early stage of AMD may notionally support the preventive employment of agents directed against the immune-in�ammatory response in combination with high-dose nutritional supplements.
We sincerely hope that the present special issue may provide useful information to understand the mechanisms, the clinical effects, and the novel treatments of in�ammation in which the vitreous is involved.