Retinal vein occlusion is a common, vision-threatening vascular disorder. The role of inflammation in the pathogenesis and clinical consequences of retinal vein occlusion is a topic of growing interest. It has long been recognized that systemic inflammatory disorders, such as autoimmune disease, are a significant risk factor for this condition. A number of more recent laboratory and clinical studies have begun to elucidate the role inflammation may play in the molecular pathways responsible for the vision-impairing consequences of retinal vein occlusion, such as macular edema. This improved understanding of the role of inflammation in retinal vein occlusion has allowed the development of new treatments for the disorder, with additional therapeutic targets and strategies to be identified as our understanding of the topic increases.

Introduction.

Branch retinal vein occlusion (BRVO) is a common retinal vascular condition that results in intraocular inflammatory changes. Ultra wide field fluorescein angiography (UWFFA) is a retinal imaging device that can capture peripheral retinal findings. The purpose of this study was to look for peripheral findings in the fellow eye of patients with BRVO using UWFFA. Methods. Retrospective imaging review of patients diagnosed with BRVO that had both eyes imaged with UWFFA. Images were graded for peripheral findings in other quadrants of the same eye as well as in all quadrants of the fellow eye.

Results.

Of 81 patients, 14 (17%) patients had late vascular leakage in a quadrant other than the BRVO distribution. Five (6%) findings were in the same eye, 8 (10%) findings were in the fellow eye, and 1 (1%) finding was in both the same eye and the fellow eye. Of these 14 patients, 11 (80%) patients had hypertension.

Conclusion.

Late peripheral retinal leakage in the fellow eye of patients with BRVO was detected in this cohort of patients with UWFFA. This novel finding may represent underlying systemic inflammation, hypertension, or bilateral BRVOs.

Age-related macular degeneration (AMD) is a major cause of blindness in the developed world. Oxidative stress and inflammation are implicated in AMD, but precise mechanisms remain poorly defined. Carboxyethylpyrrole (CEP) is an AMD-associated lipid peroxidation product. We previously demonstrated that mice immunized with CEP-modified albumin developed AMD-like degenerative changes in the outer retina. Here, we examined the kinetics of lesion development in immunized mice and the presence of macrophages within the interphotoreceptor matrix (IPM), between the retinal pigment epithelium and photoreceptor outer segments. We observed a significant and time-dependent increase in the number of macrophages in immunized mice relative to young age-matched controls prior to overt pathology. These changes were more pronounced in BALB/c mice than in C57BL/6 mice. Importantly, IPM-infiltrating macrophages were polarized toward the M1 phenotype but only in immunized mice. Moreover, when Ccr2-deficient mice were immunized, macrophages were not present in the IPM and no retinal lesions were observed, suggesting a deleterious role for these cells in our model. This work provides mechanistic evidence linking immune responses against oxidative damage with the presence of proinflammatory macrophages at sites of future AMD and experimentally demonstrates that manipulating immunity may be a target for modulating the development of AMD.

Genetic retinal diseases such as age-related macular degeneration and monogenic diseases such as retinitis pigmentosa account for some of the commonest causes of blindness in the developed world. Diverse genetic abnormalities and environmental causes have been implicated in triggering multiple pathological mechanisms such as oxidative stress, lipofuscin deposits, neovascularisation, and programmed cell death. In recent years, inflammation has also been highlighted although whether inflammatory mediators play a central role in pathogenesis or a more minor secondary role has yet to be established. Despite this, numerous interventional studies, particularly targeting the complement system, are underway with the promise of novel therapeutic strategies for these important blinding conditions.

The docking proteins of the Grb2-associated binder (Gab) family have emerged as crucial signaling compartments in metazoans. In mammals, the Gab proteins, consisting of Gab1, Gab2, and Gab3, are involved in the amplification and integration of signal transduction evoked by a variety of extracellular stimuli, including growth factors, cytokines, antigens, and other molecules. Gab proteins lack the enzymatic activity themselves; however, when phosphorylated on tyrosine residues, they provide binding sites for multiple Src homology-2 (SH2) domain-containing proteins, such as SH2-containing protein tyrosine phosphatase 2 (SHP2), phosphatidylinositol 3-kinase regulatory subunit p85, phospholipase Cγ, Crk, and GC-GAP. Through these interactions, the Gab proteins transduce signals from activated receptors into pathways with distinct biological functions, thereby contributing to signal diversification. They are known to play crucial roles in numerous physiological processes through their associations with SHP2 and p85. In addition, abnormal Gab protein signaling has been linked to human diseases including cancer, cardiovascular disease, and inflammatory disorders. In this paper, we provide an overview of the structure, effector functions, and regulation of the Gab docking proteins, with a special focus on their associations with cardiovascular disease, cancer, and inflammation.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are used extensively in ophthalmology for pain and photophobia after photorefractive surgery and to reduce miosis, inflammation, and cystoid macular edema following cataract surgery. In recent years, the US Food and Drug Administration has approved new topical NSAIDs and previously approved NSAIDs have been reformulated. These changes may allow for greater drug penetration into the retina and thereby offer additional therapeutic advantages. For example, therapeutic effects on diabetic retinopathy and age-related macular degeneration may now be achievable. We provide an updated review on the scientific rationale and clinical use of NSAIDs for retinal disease.

Acute pancreatitis (AP) is a common emergency condition. In the majority of cases, it presents in a mild and self-limited form. However, about 20% of patients develop severe disease with local pancreatic complications (including necrosis, abscess, or pseudocysts), systemic organ dysfunction, or both. A modern classification of AP severity has recently been proposed based on the factors that are causally associated with severity of AP. These factors are both local (peripancreatic necrosis) and systemic (organ failure). In AP, inflammation is initiated by intracellular activation of pancreatic proenzymes and/or nuclear factor-κB. Activated leukocytes infiltrate into and around the pancreas and play a central role in determining AP severity. Inflammatory reaction is first local, but may amplify leading to systemic overwhelming production of inflammatory mediators and early organ failure. Concomitantly, anti-inflammatory cytokines and specific cytokine inhibitors are produced. This anti-inflammatory reaction may overcompensate and inhibit the immune response, rendering the host at risk for systemic infection. Currently, there is no specific treatment for AP. However, there are several early supportive treatments and interventions which are beneficial. Also, increasing the understanding of the pathogenesis of systemic inflammation and the development of organ dysfunction may provide us with future treatment modalities.

Infection with Shiga toxin- (Stx-) producing Escherichia coli can lead to hemolytic uremic syndrome (HUS). Approximately, 30% of patients with HUS suffer from complications in the central nervous system (CNS), which is an important determinant of mortality in such patients. Autopsy shows mostly edema and hypoxic-ischemic changes in the CNS, often with microhemorrhages. It has been suggested that Stx-induced damage to human brain endothelial cells, which are essential constituents of the blood-brain barrier, plays a crucial role in the development of the CNS complications. However, it is unclear whether Stx affects brain neuroglial cells. In the present study, we investigated the direct involvement of Stx in the inflammatory responses of human astrocytes (HASTs) treated with Stx. Immunohistochemistry and real-time PCR revealed that the expression of globotriaosylceramide (Gb3), the receptor for Stx2, and Gb3 synthase (GalT6) in HASTs was increased by interleukin-1β (IL-1β). Expression of both interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1) mRNA in HASTs was significantly upregulated by Stx2. These results suggest that Stx2 induces inflammatory responses, particularly through expression of chemokines, in HASTs expressing Gb3 and may, thus, affect brain glial cells, playing a key role in the pathogenesis of CNS manifestations associated with HUS.