Asunto(s)
Antiinflamatorios no Esteroideos/efectos adversos , Anticuerpos Monoclonales/efectos adversos , Ictiosis Lamelar/inducido químicamente , Complicaciones del Embarazo/tratamiento farmacológico , Psoriasis/tratamiento farmacológico , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Artritis Psoriásica/tratamiento farmacológico , Femenino , Humanos , Recién Nacido , Infliximab , EmbarazoRESUMEN
INTRODUCTION: Intrauterine growth restriction (IUGR) alters fetal development and is associated with neurodevelopmental abnormalities. We hypothesized that growth restriction from reduced intrauterine perfusion would predispose neonatal rats to subsequent inflammatory brain injury. METHODS: In this study, IUGR was achieved by induced placental insufficiency in pregnant rats at 14 days of gestation. IUGR offspring and sham-operated control pups were subsequently injected with intracerebral lipopolysaccharide (LPS) as a model of periventricular leukomalacia (PVL). RESULTS: LPS similarly elevates proinflammatory cytokines in the brains of both IUGR and control rat pups. However, the chemokines cytokine-induced neutrophil chemoattractant-1 (CINC-1) and macrophage chemoattractant protein-1 (MCP-1), as well as microglia activation, were significantly higher in LPS-treated IUGR rat pups as compared with LPS-treated controls. In addition to the unique brain inflammatory response, IUGR rat pups demonstrated increased brain damage with an increased number of apoptotic cells, larger lateral ventricular size, and more severe impairment of myelination. DISCUSSION: This study provides evidence that placental insufficiency may sensitize the innate immune system in the immature brain and reveals a possible link between brain inflammation and injury.
Asunto(s)
Animales Recién Nacidos/metabolismo , Encefalomalacia/patología , Retardo del Crecimiento Fetal/patología , Lipopolisacáridos/efectos adversos , Animales , Apoptosis , Quimiocina CCL2/metabolismo , Quimiocina CXCL1/metabolismo , Modelos Animales de Enfermedad , Encefalomalacia/inducido químicamente , Encefalomalacia/metabolismo , Femenino , Retardo del Crecimiento Fetal/metabolismo , Humanos , Recién Nacido , Inyecciones Intraventriculares , Leucomalacia Periventricular/inducido químicamente , Leucomalacia Periventricular/metabolismo , Leucomalacia Periventricular/patología , Lipopolisacáridos/administración & dosificación , Insuficiencia Placentaria/metabolismo , Insuficiencia Placentaria/patología , Embarazo , Ratas , Ratas Sprague-DawleyRESUMEN
Periventricular leukomalacia (PVL) is a major form of brain damage in premature infants. This study was to test whether IGF-1 can prevent PVL-like brain damage induced by lipopolysaccharide (LPS) in the neonatal rat. Intraventricular delivery of LPS resulted in an acute brain inflammatory response, i.e., rapid recruitment of polymorphonuclear leukocytes (PMNs), activation of microglia and astrocytes, and induction of IL-1beta (IL1beta) expression. Brain inflammation was associated with the loss of O4+ preoligodendrocytes (preOLs), a decrease of myelin basic protein (MBP) in the white matter and an increase of pyknotic cells in the cortex. IGF-1 at a low dose significantly prevented LPS-induced deleterious effects without alteration of IL-1beta expression and microglia/astrocytes activation. On the other hand, the low dose of IGF-1 enhanced LPS-induced PMNs recruitment and blood-brain barrier (BBB) permeability, and caused intracerebral hemorrhage. At higher doses, co-application of IGF-1 with LPS resulted in a high mortality rate. Brains from the surviving rats showed massive PMN infiltration and intracerebral hemorrhage. However, these adverse effects were not found in rats treated with IGF-1 alone. This study provides the alarming evidence that in an acute inflammatory condition, IGF-1 may have severe, harmful effects on the developing brain.