Patients who suffer from severe burns develop metabolic imbalances and systemic inflammatory response syndrome (SIRS) which can result in multiple organ failure and death. Research aimed at reducing the inflammatory process has yielded new insight into burn injury therapies. In this review, we discuss strategies used to curb inflammation in burn injuries and note that further studies with high quality evidence are necessary.

Age-related macular degeneration (AMD) is the leading cause of blindness in developed countries; with the aging population, the negative health impacts and costs of the disease will increase dramatically over the next decade. Although the exact cause of AMD is unknown, genetic studies have implicated the complement system as well as other immune responses in disease pathogenesis and severity. Furthermore, histologic studies have shown the presence of macrophages, lymphocytes, and mast cells, as well as fibroblasts, in both atrophic lesions and with retinal neovascularization. This review summarizes discussions from the fifth annual conference of the Arnold and Mabel Beckman Initiative for Macular Research by the Inflammation and Immune Response Task Force. These deliberations focused on the role of inflammatory immune responses, including complement, inflammasomes, adaptive immune responses, and para-inflammation, unanswered questions and studies to address these questions, and potential immune-related therapeutic targets for AMD.

The resolution of inflammation is now known to be an active process, armed with a multitude of mediators both lipid and protein in nature. Melanocortins are peptides endowed with considerable promise with their proresolution and anti-inflammatory effects in preclinical models of inflammatory disease, with tissue protective effects. These peptides and their targets are appealing because they can be seen as a natural way of inducing these effects as they harness endogenous pathways of control. Whereas most of the information generated about these mediators derives from several acute models of inflammation (such as zymosan induced peritonitis), there is some indication that these mediators may inhibit chronic inflammation by modulating cytokines, chemokines, and leukocyte apoptosis. In addition, proresolving mediators and their mimics have often been tested alongside therapeutic protocols, hence have been tested in settings more relevant to real life clinical scenarios. We provide here an overview on some of these mediators with a focus on melanocortin peptides and receptors, proposing that they may unveil new opportunities for innovative treatments of inflammatory arthritis.

Cantharidin skin blisters were examined over two days to model the acute and resolving phases of inflammation in human skin. Four blisters were created by topical administration of cantharidin (0.1% v/v) to the forearm of healthy volunteers, with IRB approval. Duplicate skin blisters were aspirated at 16 and 40 hours to model the proinflammatory and resolving phases, respectively. There was a significant increase in leukocyte infiltrate at 40 h with appearance of a "resolving macrophage" phenotype CD14(+)CD163(+) by flow cytometry. Neutrophils acquired apoptotic markers at 40 h and were observed to be phagocytosed by macrophagic "Reiter's" cells. Multiplex cytokine analysis demonstrated that monocyte chemoattractant protein (MCP-1/CCL2), interleukin- (IL-) 6, IL-8/CXCL8, macrophage inflammatory protein (MIP1 α /CCL3), MIP-1 β /CCL4, tumor necrosis factor- (TNF-) α , and eotaxin (CCL11) were all significantly upregulated at 16 h compared with 40 h. In contrast, immunoregulatory transforming growth factor- (TGF-) β , macrophage-derived chemokine (MDC/CCL22), and interferon-inducible protein (IP-10/CXCL10) were significantly elevated at 40 h. Our results demonstrate that the phases of inflammation and resolution can be discriminated in a two-day model of dermal wound healing. This confirms and extends our understanding of wound repair in humans and provides a powerful research tool for use in clinical settings and to track the molecular benefits of therapeutic intervention.

Intraplaque hemorrhage causes adaptive remodelling of macrophages towards a protective phenotype specialized towards handling iron and lipid overload, denoted Mhem. The Mhem phenotype expresses elevated levels of hemoglobin (Hb) scavenger receptor, CD163, capable of endocytosing pro-oxidant free Hb complexed to acute phase protein haptoglobin (Hp). It is notable that individuals homozygous for the Hp 2 allele (a poorer antioxidant) are at increased risk of cardiovascular disease compared to the Hp 1 allele. In this study, we examined whether scavenging of polymorphic Hp:Hb complexes differentially generated downstream anti-inflammatory signals in cultured human macrophages culminating in interleukin (IL)-10 secretion. We describe an anti-inflammatory signalling pathway involving phosphatidylinositol-3-kinase activation upstream of Akt phosphorylation (pSer473Akt) and IL-10 secretion. The pathway is mediated specifically through CD163 and is blocked by anti-CD163 antibody or phagocytosis inhibitor. However, levels of pSer473Akt and IL-10 were significantly diminished when scavenging polymorphic Hp2-2:Hb complexes compared to Hp1-1:Hb complexes (P < 0.05). Impaired anti-inflammatory macrophage signaling through a CD163/pAkt/IL-10 axis may thus represent a possible Hp2-2 disease mechanism in atherosclerosis.

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.