RESUMO
Retinopathy of prematurity (ROP) is an important cause of childhood blindness globally, and the incidence is rising. The disease is characterized by initial arrested retinal vascularization followed by neovascularization and ensuing retinal detachment causing permanent visual loss. Although neovascularization can be effectively treated via retinal laser ablation, it is unknown which children are at risk of entering this vision-threatening phase of the disease. Laser ablation may itself induce visual field deficits, and there is therefore a need to identify targets for novel and less destructive treatments of ROP. Inflammation is considered a key contributor to the pathogenesis of ROP. A large proportion of preterm infants with ROP will have residual visual loss linked to loss of photoreceptor (PR) and the integrity of the retinal pigment epithelium (RPE) in the macular region. Recent studies using animal models of ROP suggest that choroidal degeneration may be associated with a loss of integrity of the outer retina, a phenomenon so far largely undescribed in ROP pathogenesis. In this review, we highlight inflammatory and neuron-derived factors related to ROP progression, as well, potential targets for new treatment strategies. We also introduce choroidal degeneration as a significant cause of residual visual loss following ROP. We propose that ROP should no longer be considered an inner retinal vasculopathy only, but also a disease of choroidal degeneration affecting both retinal pigment epithelium and photoreceptor integrity.
Assuntos
Doenças da Coroide/metabolismo , Mediadores da Inflamação/metabolismo , Degeneração Neural/metabolismo , Retinopatia da Prematuridade/metabolismo , Animais , Doenças da Coroide/patologia , Doenças da Coroide/terapia , Humanos , Terapia a Laser/tendências , Degeneração Neural/patologia , Degeneração Neural/terapia , Epitélio Pigmentado da Retina/metabolismo , Epitélio Pigmentado da Retina/patologia , Retinopatia da Prematuridade/patologia , Retinopatia da Prematuridade/terapia , Acuidade Visual/fisiologiaRESUMO
BACKGROUND: Uterine inflammatory processes trigger prolabor pathways and orchestrate on-time labor onset. Although essential for successful labor, inflammation needs to be regulated to avoid uncontrolled amplification and resolve postpartum. During labor, myometrial smooth muscle cells generate ATP mainly via anaerobic glycolysis, resulting in accumulation of lactate. Aside from its metabolic function, lactate has been shown to activate a G protein-coupled receptor, GPR81, reported to regulate inflammation. We therefore hypothesize that lactate produced during labor may act via GPR81 in the uterus to exert in a feedback manner antiinflammatory effects, to resolve or mitigate inflammation. OBJECTIVE: We sought to investigate the role of lactate produced during labor and its receptor, GPR81, in regulating inflammation in the uterus. STUDY DESIGN: We investigated the expression of GPR81 in the uterus and the pharmacological role of lactate acting via GPR81 during labor, using shRNA-GPR81 and GPR81-/- mice. RESULTS: (1) Uterine lactate levels increased substantially from 2 to 9 mmol/L during labor. (2) Immunohistological analysis revealed expression of GPR81 in the uterus with high expression in myometrium. (3) GPR81 expression increased during gestation, and peaked near labor. (4) In primary myometrial smooth muscle cell and ex vivo uteri from wild-type mice, lactate decreased interleukin-1ß-induced transcription of key proinflammatory Il1b, Il6, Ccl2, and Pghs2; suppressive effects of lactate were not observed in cells and tissues from GPR81-/- mice. (5) Conversely, proinflammatory gene expression was augmented in the uterus at term in GPR81-/- mice and wild-type mice treated intrauterine with lentiviral-encoded shRNA-GPR81; GPR81 silencing also induced proinflammatory gene transcription in the uterus when labor was induced by endotoxin (lipopolysaccharide). (6) Importantly, administration to pregnant mice of a metabolically stable specific GPR81 agonist, 3,5-dihydroxybenzoic acid, decreased endotoxin-induced uterine inflammation, preterm birth, and associated neonatal mortality. CONCLUSION: Collectively, our data uncover a novel link between the anaerobic glycolysis and the control of uterine inflammation wherein the high levels of lactate produced during labor act on uterine GPR81 to down-regulate key proinflammatory genes. This discovery may represent a novel feedback mechanism to regulate inflammation during labor, and conveys a potential rationale for the use of GPR81 agonists to attenuate inflammation and resulting preterm birth.
Assuntos
Inflamação , Trabalho de Parto/imunologia , Ácido Láctico/imunologia , Miométrio/imunologia , Receptores Acoplados a Proteínas G/genética , Animais , Quimiocina CCL2/efeitos dos fármacos , Quimiocina CCL2/genética , Ciclo-Oxigenase 2/efeitos dos fármacos , Ciclo-Oxigenase 2/genética , Feminino , Hidroxibenzoatos/farmacologia , Imuno-Histoquímica , Técnicas In Vitro , Interleucina-1beta/efeitos dos fármacos , Interleucina-1beta/genética , Interleucina-1beta/farmacologia , Interleucina-6/genética , Trabalho de Parto/metabolismo , Ácido Láctico/metabolismo , Ácido Láctico/farmacologia , Camundongos Knockout , Miométrio/metabolismo , Gravidez , RNA Interferente Pequeno , Receptores Acoplados a Proteínas G/imunologia , Resorcinóis/farmacologia , Útero/imunologia , Útero/metabolismoRESUMO
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
RESUMO
Antenatal inflammation as seen with chorioamnionitis is harmful to foetal/neonatal organ development including to eyes. Although the major pro-inflammatory cytokine IL-1ß participates in retinopathy induced by hyperoxia (a predisposing factor to retinopathy of prematurity), the specific role of antenatal IL-1ß associated with preterm birth (PTB) in retinal vasculopathy (independent of hyperoxia) is unknown. Using a murine model of PTB induced with IL-1ß injection in utero, we studied consequent retinal and choroidal vascular development; in this process we evaluated the efficacy of IL-1R antagonists. Eyes of foetuses exposed only to IL-1ß displayed high levels of pro-inflammatory genes, and a persistent postnatal infiltration of inflammatory cells. This prolonged inflammatory response was associated with: (1) a marked delay in retinal vessel growth; (2) long-lasting thinning of the choroid; and (3) long-term morphological and functional alterations of the retina. Antenatal administration of IL-1R antagonists - 101.10 (a modulator of IL-1R) more so than Kineret (competitive IL-1R antagonist) - prevented all deleterious effects of inflammation. This study unveils a key role for IL-1ß, a major mediator of chorioamnionitis, in causing sustained ocular inflammation and perinatal vascular eye injury, and highlights the efficacy of antenatal 101.10 to suppress deleterious inflammation.
Assuntos
Inflamação/metabolismo , Interleucina-1beta/metabolismo , Retina/metabolismo , Doenças Retinianas/metabolismo , Vasos Retinianos/metabolismo , Animais , Corioamnionite/metabolismo , Corioide/metabolismo , Modelos Animais de Doenças , Feminino , Hiperóxia/metabolismo , Proteína Antagonista do Receptor de Interleucina 1/metabolismo , Camundongos , Gravidez , Receptores de Interleucina-1/metabolismoRESUMO
Preterm birth (PTB) is a leading cause of neonatal mortality and morbidity worldwide, and surviving infants are at increased risks of lifelong complications. PTB has been firmly linked to inflammation regardless of infection, specific aetiology or timing of birth. Deleterious inflammation is observed in maternal and fetal tissue, and correlates with the severity of perinatal complications. At present, PTB is treated with tocolytics as though it is exclusively a myometrial contractile disorder. These agents do not address underlying inflammatory processes and are thus vastly ineffective at improving neonatal outcomes. Of all inflammatory mediators, IL-1 is central to the pathophysiology of PTB and most adverse neonatal outcomes. We thus present herein a review of the various effects of IL-1 in utero, with a brief overview of its mechanism of action. We then discuss the potential of different IL-1-targeting agents based on pre-clinical testing in relevant models of PTB and neonatal inflammatory injuries.