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Purpose: Previously, we identified increased retinal degeneration and cytokine response in a mouse model of dry age-related macular degeneration (AMD) in the presence of systemic inflammation from rheumatoid arthritis (RA). Histone deacetylases (HDACs) regulate cytokine production by reducing acetylation and are found to be dysregulated in inflammatory diseases, including RA and AMD. Therefore, this current study investigates the effect of HDAC inhibition on AMD progression in the presence of systemic inflammation. Methods: Collagen induced arthritis (CIA) was induced in C57BL6J mice, followed by sodium iodate (NaIO3)-induced retinal degeneration. Mice were treated with a selective HDAC class I inhibitor, MS-275, and retinal structure [optical coherence tomography (OCT)], function (electroretinography), and molecular changes quantitative real-time polymerase chain reaction (RT-qPCR, Western Blot) were assessed. Results: NaIO3 retinal damage was diminished in CIA mice treated with MS-275 (P ≤ 0.05). While no significant difference was observed in retinal pigment epithelium (RPE) function, a trend in increased c-wave amplitude was detected in CIA + NaIO3 mice treated with MS-275. Finally, we identified decreased Hdac1, Hdac3, and Cxcl9 expression in CIA + NaIO3 mouse RPE/choroid when treated with MS-275 (P ≤ 0.05). Conclusions: Our data demonstrate that HDAC inhibition can reduce the additive effect of NaIO3-induced retinal degeneration in the presence of systemic inflammation by CIA as measured by OCT analysis. In addition, HDAC inhibition in CIA + NaIO3 treated mice resulted in reduced cytokine production. These findings are highly innovative and provide additional support to the therapeutic potential of HDAC inhibitors for dry AMD treatment.
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Modelos Animales de Enfermedad , Histona Desacetilasa 1 , Inhibidores de Histona Desacetilasas , Inflamación , Yodatos , Ratones Endogámicos C57BL , Piridinas , Tomografía de Coherencia Óptica , Animales , Ratones , Inhibidores de Histona Desacetilasas/farmacología , Inhibidores de Histona Desacetilasas/administración & dosificación , Inhibidores de Histona Desacetilasas/uso terapéutico , Inflamación/tratamiento farmacológico , Yodatos/administración & dosificación , Yodatos/toxicidad , Piridinas/farmacología , Piridinas/administración & dosificación , Piridinas/uso terapéutico , Histona Desacetilasa 1/antagonistas & inhibidores , Histona Desacetilasa 1/metabolismo , Benzamidas/farmacología , Benzamidas/administración & dosificación , Benzamidas/uso terapéutico , Histona Desacetilasas/metabolismo , Degeneración Retiniana/tratamiento farmacológico , Degeneración Retiniana/patología , Degeneración Macular/tratamiento farmacológico , Degeneración Macular/patología , Masculino , Electrorretinografía , Compuestos de Piridinio/farmacología , Compuestos de Piridinio/administración & dosificación , Atrofia Geográfica/tratamiento farmacológicoRESUMEN
Purpose: The purpose of this study was to check the efficacy and safety of a novel tear substitute containing hyaluronic acid and low-dose hydrocortisone in the treatment of moderate dry eye disease. Methods: In this prospective randomized study, 38 patients with moderate dry eye disease were divided into two treatment groups: Group 1 received one drop of 0.2% sodium hyaluronate and 0.001% hydrocortisone four times daily for 3 months, while Group 2 received 0.15% sodium hyaluronate and 3% trehalose at the same dosage. OSDI and SANDE questionnaires, Non-Invasive Break-Up time (NIBUT), Tear Meniscus Height (TMH), meibography, Lipid Layer Thickness (LLT), Tear Break-Up Time (TBUT), Corneal Staining Score (CFS), and Intraocular Pressure (IOP) were evaluated at baseline and after 1, 2, and 3 months of treatment. Results: During the treatment period, Group 1 showed statistically significant improvement in OSDI score (p = 0.002), SANDE score (p = 0.01), NIBUT (p < 0.0001), LLT (p < 0.0001), TBUT (p = 0.01), and CFS (p = 0.02). In Group 2, significant improvement was observed only in the TBUT score (p < 0.05). Comparison of the two groups showed that NIBUT and LLT were significantly different at the end of treatment (p = 0.001 for both comparisons), with more favorable results for sodium hyaluronate and hydrocortisone than for sodium hyaluronate and trehalose. No significant variations in intraocular pressure were observed in either group during the treatment period (p > 0.05). Conclusions: The study confirms that a 3-months treatment with hyaluronic acid 0.2% in combination with low-dose hydrocortisone 0.001% improves the signs and symptoms of moderate DED and that a low-dosage 0.001% hydrocortisone can be helpful in preventing the progression to chronic stages of DED.
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PURPOSE: A clinical trial was conducted to evaluate the activity of a new artificial tear containing hyaluronic acid (HA) and low-dose hydrocortisone to control dry-eye disease (DED) symptoms. METHODS: a randomized, controlled, double-masked study was carried out at the Ocular Surface and Dry Eye Center, "Luigi Sacco" University Hospital (Milan, Italy), between June 2020 and June 2021. The study involved patients with DED for at least 6 months. After an initial 7-day treatment with corticosteroid, the treatment with the new artificial tear (four-times a day for 6 months) was compared with a control HA solution. RESULTS: A total of 40 patients were considered. We observed a significant improvement in the frequency and intensity of DED symptoms in both groups. After corticosteroid discontinuation, the maintenance of the therapeutic advantage was observed only in the treatment group, which also showed a significant improvement of the tear film break-up time (p ≤ 0.05) and infiltrated macrophages (p < 0.05). A significant reduction in fluorescein and Lissamine staining (p < 0.05) was observed in the treatment group, suggesting damage reduction at both corneal and conjunctival levels. Intraocular pressure did not change at the end of the treatment period and was maintained within the normal range, sustaining the product's safety. CONCLUSIONS: Our findings support the prolonged use of the new eye drop with low-dose hydrocortisone, also in the DED initial stages, to prevent the degenerating towards a chronic condition (http://www.isrctn.com/ISRCTN16288419).
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Síndromes de Ojo Seco , Gotas Lubricantes para Ojos , Humanos , Hidrocortisona , Síndromes de Ojo Seco/tratamiento farmacológico , Síndromes de Ojo Seco/diagnóstico , Ácido Hialurónico , LágrimasRESUMEN
The immune system plays a central role in protecting the ocular surface from exogenous and endogenous insults, maintaining tissue homeostasis thanks to the mechanism of para-inflammation. This physiological adaptive response may induce resident macrophages/monocytes to produce cytokines and growth factors in order to promote epithelial cell recovery. In case of well-controlled para-inflammation, caused by a low amount of stress, cell viability and function are maintained. When stress becomes too intense, there is a response characterized by the activation of autophagic pathways and consequent cell death. Dysregulated homeostasis and chronic sub-clinical inflammation are the starting points for the development of a stable, chronic inflammatory disease, which leads to ocular surface damage, and, in turn, to the onset or progression of chronic dry eye disease (DED). The long-term management of DED should consider all of the pathogenic issues involved in the disease, including the control of persistent external or internal stresses that are capable of activating and maintaining the para-inflammatory adaptive mechanisms, potentially leading to full-blown inflammation. Dysregulated para-inflammation can be corrected by means of the prolonged use of tear substitutes containing minimal doses of safe corticosteroids or other anti-inflammatory molecules (e.g., corticosteroid, cyclosporine) in order to re-equilibrate ocular surface homeostasis.
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Background: Aggressive behaviors are one of the most important negative behaviors that seriously endangers human health. Also, the central para-inflammation of microglia triggered by stress can affect neurological function, plasticity, and behavior. NLRP3 integrates stress-related signals and is a key driver of this neural para-inflammation. However, it is unclear whether the NLRP3 inflammasome is implicated in the development of aggressive behaviors. Methods: First, aggressive behavior model mice were established using the resident intruder paradigm. Then, aggressive behaviors were determined with open-field tests (OFT), elevated plus-maze (EPM), and aggressive behavior tests (AT). Moreover, the expression of P2X7R and NLRP3 inflammasome complexes were assessed by immunofluorescence and Western blot. The levels of NLRP3 and inflammatory cytokines were evaluated using enzyme-linked immunosorbent assay (ELISA) kits. Finally, nerve plasticity damage was observed by immunofluorescence, transmission electron microscope, and BrdU staining. Results: Overall, the resident intruder paradigm induced aggressive behaviors, activated the hippocampal P2X7R and NLRP3 inflammasome, and promoted the release of proinflammatory cytokines IL-1ß in mice. Moreover, NLRP3 knockdown, administration of P2X7R antagonist (A804598), and IL-1ß blocker (IL-1Ra) prevented NLRP3 inflammasome-driven inflammatory responses and ameliorated resident intruder paradigm-induced aggressive behaviors. Also, the resident intruder paradigm promoted the activation of mouse microglia, damaging synapses in the hippocampus, and suppressing hippocampal regeneration in mice. Besides, NLRP3 knockdown, administration of A804598, and IL-1Ra inhibited the activation of microglia, improved synaptic damage, and restored hippocampal regeneration. Conclusion: The NLRP3 inflammasome-driven inflammatory response contributed to resident intruder paradigm-induced aggressive behavior, which might be related to neuroplasticity. Therefore, the NLRP3 inflammasome can be a potential target to treat aggressive behavior-related mental illnesses.
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Age-related macular degeneration (AMD) is a leading cause of irreversible vision loss in the older population. Classical hallmarks of early and intermediate AMD are accumulation of drusen, a waste deposit formed under the retina, and pigmentary abnormalities in the retinal pigment epithelium (RPE). When the disease progresses into late AMD, vision is affected due to death of the RPE and the light-sensitive photoreceptors. The RPE is essential to the health of the retina as it forms the outer blood retinal barrier, which establishes ocular immune regulation, and provides support for the photoreceptors. Due to its unique anatomical position, the RPE can communicate with the retinal environment and the systemic immune environment. In AMD, RPE dysfunction and the accumulation of drusen drive the infiltration of retinal and systemic innate immune cells into the outer retina. While recruited endogenous or systemic mononuclear phagocytes (MPs) contribute to the removal of noxious debris, the accumulation of MPs can also result in chronic inflammation and contribute to AMD progression. In addition, direct communication and indirect molecular signaling between MPs and the RPE may promote RPE cell death, choroidal neovascularization and fibrotic scarring that occur in late AMD. In this review, we explore how the RPE and innate immune cells maintain retinal homeostasis, and detail how RPE dysfunction and aberrant immune cell recruitment contribute to AMD pathogenesis. Evidence from AMD patients will be discussed in conjunction with data from preclinical models, to shed light on future therapeutic targets for the treatment of AMD.
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Corroborating data sustain the pleiotropic effect of nerve growth factor (NGF) in the protection of the visual system from dangerous stimuli, including ultraviolet (UV). Since UV exposure might promote ocular surface changes (conjunctival inflammation and matrix rearrangement), as previously reported from in vivo studies sustaining some protective NGF effects, in vitro cultures of human conjunctival fibroblasts (FBs) were developed and exposed to a single UV exposure over 15 min (0.277 W/m2), either alone or supplemented with NGF (1-10-100 ng/mL). Conditioned media and cell monolayers were collected and analyzed for protein release (ELISA, ELLA microfluidic) and transcript expression (real-time PCR). A specific "inflammatory to remodeling" pattern (IL8, VEGF, IL33, OPN, and CYR61) as well as a few epigenetic transcripts (known as modulator of cell differentiation and matrix-remodeling (DNMT3a, HDAC1, NRF2 and KEAP1)) were investigated in parallel. UV-exposed FBs (i), showed no proliferation or significant cytoskeleton rearrangement; (ii), displayed a trkANGFR/p75NTR phenotype; and (iii), synthesized/released IL8, VEGF-A, IL33, OPN, and CYR61, as compared to unexposed ones. NGF addition counteracted IL8, IL33, OPN, and CYR61 protein release merely at lower NGF concentrations but not VEGF. NGF supplementation did not affect DNMT3a or HDAC1 transcripts, while it significantly upregulated NRF2 at lowest NGF doses and did not change KEAP1 expression. Taken together, a single UV exposure activated conjunctival FBs to release pro-inflammatory/fibrogenic factors in association with epigenetic changes. The effects were selectively counteracted by NGF supplementation in a dose-dependent fashion, most probably accountable to the trkANGFR/p75NTR phenotype. Further in vitro studies are underway to better understand this additional NGF pleiotropic effect. Since UV-shield impairments represent a worldwide alert and UV radiation can slowly affect ocular surface homeostasis (photo-ageing, cataract) or might exacerbate ocular diseases with a preexisting fibrosis (pterygium, VKC), these findings on NGF modulation of UV-exposed FBs might provide additional information for protecting the ocular surface (homeostasis) from low-grade long-lasting UV insults.
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Factor de Crecimiento Nervioso , Receptor trkA , Fibroblastos/metabolismo , Humanos , Interleucina-33/metabolismo , Interleucina-8/metabolismo , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Factor de Crecimiento Nervioso/metabolismo , Receptor de Factor de Crecimiento Nervioso/metabolismo , Receptor trkA/metabolismo , Receptores de Factor de Crecimiento Nervioso/metabolismoRESUMEN
BACKGROUND: To evaluate changes in Toll Like Receptors (TLRs) expression at the ocular surface of healthy volunteers within different age groups. METHODS: Fifty-one healthy volunteers were enrolled in a pilot observational study. Clinical function tests (OSDI questionnaire, Schirmer test type I and Break Up time) were assessed in all subjects. Temporal Conjunctival imprints were performed for molecular and immunohistochemical analysis to measure TLRs expression (TLR2, 4, 3, 5, 7, 8, 9 and MyD88). RESULTS: Immunofluorescence data showed an increased TLR2 and decreased TLR7 and TLR8 immunoreactivity in old conjunctival imprints. Up-regulation of TLR2 and down-regulation of TLR7, TLR8 and MyD88 transcripts expression corroborated the data. A direct correlation was showed between increasing ICAM-1 and increasing TLR2 changes with age. Within the age OSDI score increases, T-BUT values decrease, and goblet cells showed a decreasing trend. CONCLUSION: Changes in TLRs expression are associated with ageing, suggesting physiological role of TLRs in modulating ocular surface immunity. TLRs age related changes may participate to the changes of ocular surface homeostatic mechanisms which lead to inflammAging.
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Receptor Toll-Like 7 , Receptor Toll-Like 8 , Proteínas Adaptadoras Transductoras de Señales , Envejecimiento , Conjuntiva/metabolismo , Humanos , Factor 88 de Diferenciación Mieloide/metabolismo , Receptor Toll-Like 2/metabolismo , Receptor Toll-Like 7/metabolismo , Receptor Toll-Like 8/metabolismo , Receptores Toll-Like/genética , Receptores Toll-Like/metabolismoRESUMEN
BACKGROUND: Nowadays, the continuous increase in air pollution has significantly changed air quality, leading to the onset of the so-called urban syndrome (US), an allergic-like conjunctivitis triggered by pollutants. These patients are characterized by persistent dysregulation of ocular surface para-inflammation, causing chronic low-grade inflammation and ocular discomfort, with significant consequences for occupational health and job productivity prospects. This study aims to investigate the effects of topical glycerophosphoinositol (GPI) eye drops on the signs and symptoms of US. METHODS: A multicenter prospective open interventional study was performed. Patients affected by US, enrolled from occupational medicine clinics, were treated with eye drops containing 0.001% GPI in 0.2% HA vehicle three times a day. Ocular surface disease index (OSDI), tear break-up time (T-BUT), Schirmer test, Oxford score, hyperemia and ocular surface symptoms were recorded at patient enrolment (T0), after 1 week (T1) and after 1 month (T2) of treatment. RESULTS: A total of 113 consecutive patients (226 eyes) were included. OSDI score displayed a significant improvement after one week (T0: 39.9 ± 19, T1: 20.8 ± 17.9, T2: 18.4 ± 15.6, p < 0.0001); T-BUT (T0: 5.2 ± 2, T1: 7.7 ± 2.2, T2: 9.7 ± 1.8, p < 0.0001) and Schirmer Test (T0: 6.6 ± 2.4, T1: 9.7 ± 2.7, T2: 12.6 ± 2.6, p < 0.0001) progressively improved from T0 to T2. CONCLUSIONS: trice-daily topic instillation of 0.001% GPI in 0.02% HA vehicle resulted an effective and well tolerated treatment in US patients.
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In patients with DED, the continuous stimuli induced by excessive or persistent cold fiber sensors and overstimulation of nociceptors, as well as tear hyperosmolarity induced by evaporative stress, induce a transitory protective adaptation response called para-inflammation to restore ocular surface homeostasis. This mild subclinical inflammatory status (a type of hormetic response) can become chronic if the stimuli or tissue malfunction is present for a sustained period, causing persistent symptoms and damage to ocular surface epithelia.We review the mechanisms that characterize the transition from para-inflammation to a persistent inflammatory status of the ocular surface, including accumulation of biological waste and damaged/dysfunctional proteins, which, in normal conditions, are eliminated by autophagy, activation of the inflammasomes, and what is currently known about their role in DED pathogenesis. Furthermore, we analyze current treatments that can modulate the inflammatory response of the ocular surface and speculate about new possible therapies to treat para-inflammation.
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Síndromes de Ojo Seco/fisiopatología , Inflamación/fisiopatología , Autofagia , Hormesis/fisiología , Humanos , Lágrimas/fisiologíaRESUMEN
The pathophysiology of glaucoma is complex, multifactorial and not completely understood. Elevated intraocular pressure (IOP) and/or impaired retinal blood flow may cause initial optic nerve damage. In addition, age-related oxidative stress in the retina concurrently with chronic mechanical and vascular stress is crucial for the initiation of retinal neurodegeneration. Oxidative stress is closely related to cell senescence, mitochondrial dysfunction, excitotoxicity, and neuroinflammation, which are involved in glaucoma progression. Accumulating evidence from animal glaucoma models and from human ocular samples suggests a dysfunction of the para-inflammation in the retinal ganglion cell layer and the optic nerve head. Moreover, quite similar mechanisms in the anterior chamber could explain the trabecular meshwork dysfunction and the elevated IOP in primary open-angle glaucoma. On the other hand, ocular surface disease due to topical interventions is the most prominent and visible consequence of inflammation in glaucoma, with a negative impact on filtering surgery failure, topical treatment efficacy, and possibly on inflammation in the anterior segment. Consequently, glaucoma appears as an outstanding eye disease where inflammatory changes may be present to various extents and consequences along the eye structure, from the ocular surface to the posterior segment, and the visual pathway. Here we reviewed the inflammatory processes in all ocular structures in glaucoma from the back to the front of the eye and beyond. Our approach was to explain how para-inflammation is necessary to maintain homoeostasis, and to describe abnormal inflammatory findings observed in glaucomatous patients or in animal glaucoma models, supporting the hypothesis of a dysregulation of the inflammatory balance toward a pro-inflammatory phenotype. Possible anti-inflammatory therapeutic approaches in glaucoma are also discussed.
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Glaucoma de Ángulo Abierto , Glaucoma , Animales , Glaucoma/terapia , Humanos , Inflamación , Presión Intraocular , Enfermedades Neuroinflamatorias , Malla TrabecularRESUMEN
Neutrophils are quickly recruited to tissues in response to proinflammatory cues; however, little is known about tissue neutrophil phenotypes in health. We employ a multicolor flow cytometric approach to assess surface markers of activation on neutrophils from the bone marrow, blood, peritoneum, spleen, liver, fat, colon, and oral cavity of healthy mice. Cell preparations were promptly fixed to preserve native surface marker expression levels. Peritoneal, colonic, and oral neutrophils were also assessed in the setting of pHrodo-induced peritonitis, dextran sodium sulfate-induced colitis, and ligature-induced periodontal disease, respectively. Our results demonstrate consistent detectable neutrophil populations in various sterile and nonsterile tissues of healthy mice, and these cells had tissue-specific neutrophil immunophenotypes. Neutrophils derived from biofilm-associated mucosal tissues had 2- to 3-fold higher expression of surface markers of activation, including CD66a, CD11b, and CD62L, compared to neutrophils derived from both sterile healthy tissues as well as tissues in animals treated with broad-spectrum antibiotics. Furthermore, the unique cluster of differentiation (CD) marker activation signatures of tissue-specific neutrophils from the peritoneum, colon, and oral cavity were altered to a proinflammatory immunophenotype with the presence of an inflammatory stimulus. Based on our results, we propose a model whereby a hierarchy of tissue neutrophil immunophenotypes, based on the differential expression of CD markers of activation, correlates with sterile, healthy commensal biofilm-associated and inflamed tissue states.
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Homeostasis , Inflamación/etiología , Inflamación/metabolismo , Activación Neutrófila/inmunología , Neutrófilos/inmunología , Neutrófilos/metabolismo , Animales , Antígenos CD/metabolismo , Biomarcadores , Modelos Animales de Enfermedad , Inmunofenotipificación , Inflamación/diagnóstico , Ratones , Especificidad de ÓrganosRESUMEN
A thorough understanding of the inflammatory process has substantial biological and clinical relevance. Para-inflammation has been described as an adaptive response of the immune system to low levels of tissue stress. However, the role of para-inflammation in wound repair requires further investigation. In the present study, the expression levels of several para-inflammation genes were assessed in a murine cutaneous wound healing model. The results revealed that the expression levels of the para-inflammation genes were significantly altered. Among the genes that were examined, the expression levels of solute carrier family 7 member 11 (Slc7a11) paralleled those of the M2 macrophage-associated genes. Further investigation indicated that the Slc7a11 gene and its encoded protein cystine/glutamate transporter exhibited increased expression levels in IL-4-induced M2 macrophages. Notably, the inhibition of para-inflammation by sulindac prolonged wound healing process. The present study indicated that para-inflammation exhibited a protective effect in wound healing and provided new insight for host tissue repair.
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Allergic airway diseases are accompanied by increased permeability and an inflammatory state of epithelial barriers, which are thought to be susceptible to allergen sensitization. Although exogenous drivers (proteases, allergens) of epithelial barrier disruption and sensitization are well studied, endogenous contributors (diet, xenobiotics, hormones, and metabolism) to allergic sensitization are much less understood. Xenoestrogens are synthetic or natural chemical compounds that have the ability to mimic estrogen and are ubiquitous in the food and water supply of developed countries. By interfering with the estrogen produced by the endocrine system, these compounds have the systemic potential to disrupt the homeostasis of multiple tissues. Our study examined the potential of prototypical xenoestrogen bisphenol A (BPA) to disrupt epithelial homeostasis in vitro and promote allergic responses in vivo. We found that BPA exposure in epithelial cultures in vitro significantly inhibited epithelial cell proliferation and wound healing, as well as promoted the expression of the innate alarmin cytokine TSLP in a time-and dose-dependent manner. In vivo, the exposure to BPA through water supply or inhalation induced a systemic para-inflammatory response by promoting the expression of innate inflammatory mediators in the skin, gut, and airway. In a murine tolerogenic antigen challenge model, chronic systemic exposure to BPA was sufficient to induce airway sensitization to innocuous chicken egg ovalbumin in the complete absence of adjuvants. Mechanistic studies are needed to test conclusively whether endocrine disruptors may play an upstream role in allergic sensitization via their ability to promote a para-inflammatory state.
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Compuestos de Bencidrilo/toxicidad , Disruptores Endocrinos/toxicidad , Inflamación/inducido químicamente , Fenoles/toxicidad , Administración por Inhalación , Animales , Asma/inducido químicamente , Línea Celular , Proliferación Celular/efectos de los fármacos , Citocinas/genética , Citocinas/metabolismo , Hipersensibilidad a las Drogas , Células Epiteliales/efectos de los fármacos , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Pulmón/efectos de los fármacos , Ratones , Ratones Endogámicos BALB C , Ovalbúmina , Mucosa Respiratoria/citologíaRESUMEN
Contact lenses represent a widely utilized form of vision correction with more than 140 million wearers worldwide. Although generally well-tolerated, contact lenses can cause corneal infection (microbial keratitis), with an approximate annualized incidence ranging from ~2 to ~20 cases per 10,000 wearers, and sometimes resulting in permanent vision loss. Research suggests that the pathogenesis of contact lens-associated microbial keratitis is complex and multifactorial, likely requiring multiple conspiring factors that compromise the intrinsic resistance of a healthy cornea to infection. Here, we outline our perspective of the mechanisms by which contact lens wear sometimes renders the cornea susceptible to infection, focusing primarily on our own research efforts during the past three decades. This has included studies of host factors underlying the constitutive barrier function of the healthy cornea, its response to bacterial challenge when intrinsic resistance is not compromised, pathogen virulence mechanisms, and the effects of contact lens wear that alter the outcome of host-microbe interactions. For almost all of this work, we have utilized the bacterium Pseudomonas aeruginosa because it is the leading cause of lens-related microbial keratitis. While not yet common among corneal isolates, clinical isolates of P. aeruginosa have emerged that are resistant to virtually all currently available antibiotics, leading the United States CDC (Centers for Disease Control) to add P. aeruginosa to its list of most serious threats. Compounding this concern, the development of advanced contact lenses for biosensing and augmented reality, together with the escalating incidence of myopia, could portent an epidemic of vision-threatening corneal infections in the future. Thankfully, technological advances in genomics, proteomics, metabolomics and imaging combined with emerging models of contact lens-associated P. aeruginosa infection hold promise for solving the problem - and possibly life-threatening infections impacting other tissues.
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Antibacterianos/uso terapéutico , Bacterias/aislamiento & purificación , Lentes de Contacto/microbiología , Córnea/microbiología , Infecciones Bacterianas del Ojo/etiología , Queratitis/etiología , Infecciones Relacionadas con Prótesis/microbiología , Infecciones Bacterianas del Ojo/tratamiento farmacológico , Infecciones Bacterianas del Ojo/microbiología , Humanos , Queratitis/tratamiento farmacológico , Queratitis/microbiología , Infecciones Relacionadas con Prótesis/diagnósticoRESUMEN
Age-related Macular Degeneration (AMD) is a multifactorial disease that occurs only in senior population. According to Harman's theory (1956), senescence happens due to excessive accumulation and reduced elimination of free radicals in tissues. At the young age, intensive metabolic processes in the outer layers of the retina and pigment epithelium do not lead to the disease because the pigment epithelium itself and the antioxidant protection function well. If they do not work, the immune system becomes involved. Macrophages, microglia, complement system all contribute to the removal of toxic products. R. Medzhidov in 2008 proposed to call this phenomenon 'para-inflammation'. With aging, this protection may fail, especially if there is a genetic predisposition or aggravating environmental factors. Although AMD cannot be truly called an inflammatory disease, the factors of chronic inflammation are present in it. This is especially true for the alternative complement pathway. People carrying polymorphism of the H gene that normally blocks excessive complement activity are reliably known to have AMD more often. The normal functioning of the complement system contributes to para-inflammation, while its hyperactivation leads to more tissue damage inducing the disease. The impairment of the hemo-ophthalmic barrier caused by the defeat of RPE makes antigens of the outer layers of the retina accessible. Depending on the genetic characteristics of the patient, these antigens are represented differently to his immune system, and since they do not have immune tolerance, varying degrees of autoimmune reaction should be expected. The treatment should be aimed at reduction of the oxidative stress, and injection of inhibitors of vascular endothelial growth factors, glucocorticoids, etc. The study of para-inflammation and inflammation in AMD will help create a new generation of effective drugs that affect the key links in these processes.
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Degeneración Macular , Distribución por Edad , Humanos , Inflamación , Estrés Oxidativo , Retina , Epitelio Pigmentado de la RetinaRESUMEN
PURPOSE OF REVIEW: With the intention to summarize the currently available evidence on the pathophysiological relevance of inflammation in heart failure, this review addresses the question whether inflammation is a cause or consequence of heart failure, or both. RECENT FINDINGS: This review discusses the diversity (sterile, para-inflammation, chronic inflammation) and sources of inflammation and gives an overview of how inflammation (local versus systemic) can trigger heart failure. On the other hand, the review is outlined how heart failure-associated wall stress and signals released by stressed, malfunctioning, or dead cells (DAMPs: e.g., mitochondrial DNA, ATP, S100A8, matricellular proteins) induce cardiac sterile inflammation and how heart failure provokes inflammation in various peripheral tissues in a direct (inflammatory) and indirect (hemodynamic) manner. The crosstalk between the heart and peripheral organs (bone marrow, spleen, gut, adipose tissue) is outlined and the importance of neurohormonal mechanisms including the renin angiotensin aldosteron system and the ß-adrenergic nervous system in inflammation and heart failure is discussed. Inflammation and heart failure are strongly interconnected and mutually reinforce each other. This indicates the difficulty to counteract inflammation and heart failure once this chronic vicious circle has started and points out the need to control the inflammatory process at an early stage avoiding chronic inflammation and heart failure. The diversity of inflammation further addresses the need for a tailored characterization of inflammation enabling differentiation of inflammation and subsequent target-specific strategies. It is expected that the characterization of the systemic and/or cardiac immune profile will be part of precision medicine in the future of cardiology.
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Insuficiencia Cardíaca/complicaciones , Inflamación/complicaciones , Miocarditis/complicaciones , Enfermedad Crónica , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/fisiopatología , Hemodinámica , Humanos , Inflamación/metabolismo , Miocarditis/metabolismo , Medicina de Precisión , Sistema Renina-Angiotensina , Transducción de Señal/fisiologíaRESUMEN
Eye-care practitioners typically associate ocular inflammation during contact lens wear with serious complications such as microbial keratitis; however, more subtle mechanisms may be at play. This paper tests the notion that contact lens wear is intrinsically inflammatory by exploring whether uncomplicated contact lens wear meets the classical, clinical definition of inflammation - rubor (redness), calor (heat), tumor (swelling), dolor (pain) and functio laesa (loss of function) - as well as the contemporary, sub-clinical definition of inflammation (cellular and biochemical reactions). It is demonstrated that all of these clinical and sub-clinical criteria are met with hydrogel lens wear and most are met with silicone hydrogel lens wear, indicating that uncomplicated contact lens wear is intrinsically inflammatory. Consideration of both traditional and contemporary thinking about the role of inflammation in the human body leads to the perhaps surprising conclusion that the chronic, low grade, sub-clinical inflammatory status of the anterior eye during contact lens wear, which may be termed 'para-inflammation', is a positive, protective phenomenon, whereby up-regulation of the immune system, in a non-damaging way, maintains the eye in a state of 'heightened alert', ready to ward off any extrinsic noxious challenge. Characterisation of this inflammatory status may lead to the development of lens engineering or pharmacological strategies to modulate contact lens-induced inflammation, so as to render lens wear more safe and comfortable.
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Lentes de Contacto/efectos adversos , Oftalmopatías/etiología , Inflamación/etiología , Edema/etiología , Humanos , Hidrogel de Polietilenoglicol-Dimetacrilato , Mediadores de Inflamación/análisis , Queratitis/etiologíaRESUMEN
Age-related macular degeneration (AMD) is the most prevalent cause of blindness in the elderly. To study potential underlying mechanisms of AMD, animal models are utilized, focusing mostly on mice. Recently, genomic and phenotypic differences between the so-called control substrains, C57BL/6J and C57BL/6N, have been described in models of ocular and non-ocular diseases. In particular, the rd8 mutation of the Crb1 gene present in the C57BL/6N has been shown to impact certain ocular phenotypes and appears to augment phenotypes generally associated with inflammation. Here, we investigated angiogenic factor and cytokine expression using pathway arrays as well as the susceptibility to laser-induced choroidal neovascularization (CNV), a model of wet AMD, in the two substrains. Age-matched 3-month-old C57BL/6J and C57BL/6N animals differed in gene expression levels for angiogenic factors and cytokines, with 6N animals expressing higher levels of inflammatory markers than 6Js. Yet laser-induced CNV was comparable in size between the two substrains. This lack of difference in CNV size was correlated with a gene expression profile that was comparable between the two substrains, due to the fact that the degree of change in gene expression of inflammatory markers after CNV was blunted in 6N mice. In summary, significant gene expression differences exist between C57BL/6J and C57BL/6N animals, reinforcing the notion that appropriate litter-mate controls or genetic background controls need to be used. Contrary to our expectation, CNV was not augmented in 6N animals, suggesting that low chronic inflammation in the RPE might provide a level of pre-conditioning and protection against stress.
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Quimiocinas/genética , Neovascularización Coroidal/genética , Regulación de la Expresión Génica , ARN/genética , Animales , Quimiocinas/biosíntesis , Neovascularización Coroidal/etiología , Neovascularización Coroidal/metabolismo , Citocinas/biosíntesis , Citocinas/genética , Modelos Animales de Enfermedad , Femenino , Rayos Láser/efectos adversos , Masculino , Ratones , Ratones Endogámicos C57BL , FenotipoRESUMEN
OBJECTIVE: To investigate the role of Platelet Activating Factor (PAF) in the pathogenesis and development of Age-Related Macular Degeneration (ARMD). RESEARCH DESIGN AND METHODS: Fifty six patients with ARMD (24 patients with dry ARMD and 32 patients with wet ARMD) and 25 age-matched control participants underwent ophthalmological examination, including visual acuity measurement and evaluation of the retina. The participants were classified into three groups according to their retinal status, based on indirect fundoscopy, Optical Coherence Tomography and fluorescein angiography findings. In order to evaluate the concentrations of PAF in serum, blood samples were collected from all participants and were analyzed with ELISA technique. RESULTS: The concentrations of PAF differed significantly according to macular lesions and were found to be lower in patients with ARMD than control participants. CONCLUSIONS: PAF levels are decreased along with the severity of ARMD. Understanding the role of PAF in pathogenesis of ARMD could be the impetus for the development of new therapies field of treatment of ARMD or even other retinal diseases.