RESUMEN
BACKGROUND & AIMS: Hepatic encephalopathy (HE) is a serious neurologic complication in patients with liver cirrhosis. Very little is known about the role of the meningeal lymphatic system in HE. We tested our hypothesis that enhancement of meningeal lymphatic drainage could decrease neuroinflammation and ameliorate HE. METHODS: A 4-week bile duct ligation model was used to develop cirrhosis with HE in rats. Brain inflammation in patients with HE was evaluated by using archived GSE41919. The motor function of rats was assessed by the rotarod test. Adeno-associated virus 8-vascular endothelial growth factor C (AAV8-VEGF-C) was injected into the cisterna magna of HE rats 1 day after surgery to induce meningeal lymphangiogenesis. RESULTS: Cirrhotic rats with HE showed significantly increased microglia activation in the middle region of the cortex (P < .001) as well as increased neuroinflammation, as indicated by significant increases in interleukin 1ß, interferon γ, tumor necrosis factor α, and ionized calcium binding adaptor molecule 1 (Iba1) expression levels in at least 1 of the 3 regions of the cortex. Motor function was also impaired in rats with HE (P < .05). Human brains of patients with cirrhosis with HE also exhibited up-regulation of proinflammatory genes (NFKB1, IbA1, TNF-α, and IL1ß) (n = 6). AAV8-VEGF-C injection significantly increased meningeal lymphangiogenesis (P = .035) and tracer dye uptake in the anterior and middle regions of the cortex (P = .006 and .003, respectively), their corresponding meninges (P = .086 and .006, respectively), and the draining lymph nodes (P = .02). Furthermore, AAV8-VEGF-C decreased microglia activation (P < .001) and neuroinflammation and ameliorated motor dysfunction (P = .024). CONCLUSIONS: Promoting meningeal lymphatic drainage and enhancing waste clearance improves HE. Manipulation of meningeal lymphangiogenesis could be a new therapeutic strategy for the treatment of HE.
Asunto(s)
Sistema Glinfático/patología , Encefalopatía Hepática/inmunología , Cirrosis Hepática/complicaciones , Trastornos Motores/inmunología , Factor C de Crecimiento Endotelial Vascular/metabolismo , Animales , Línea Celular , Corteza Cerebral/inmunología , Corteza Cerebral/patología , Cisterna Magna/inmunología , Cisterna Magna/patología , Dependovirus/genética , Modelos Animales de Enfermedad , Vectores Genéticos/administración & dosificación , Vectores Genéticos/genética , Sistema Glinfático/inmunología , Encefalopatía Hepática/patología , Humanos , Cirrosis Hepática/inmunología , Linfangiogénesis/inmunología , Masculino , Microglía/inmunología , Microglía/patología , Trastornos Motores/patología , Ratas , Factor C de Crecimiento Endotelial Vascular/genéticaRESUMEN
IL-1RA has been used intra-cerebrally to ameliorate neuroinflammatory responses. The present study explored the possibility that the bioactivity of IL-1RA administered intra-cerebrally may be prolonged in the CNS. hIL-1RA was detected in hippocampus from 2h to 14d post-ICM treatment. hIL-1RA ameliorated both the hippocampal cytokine (TNFα and NFκBIα) and sickness response to peripheral LPS administered 4d after hIL-1RA. Four days post treatment, hIL-1RA reduced the basal expression of IL-1R1, Iba-1, MHCII, and TLR4 and blunted the microglial IL-1ß and IL-6 response to LPS ex vivo. IL-1RA might be administered prophylactically to prevent the neuroinflammatory effects of trauma.
Asunto(s)
Cisterna Magna/efectos de los fármacos , Encefalitis/prevención & control , Proteína Antagonista del Receptor de Interleucina 1/administración & dosificación , Animales , Conducta Animal/efectos de los fármacos , Cisterna Magna/inmunología , Cisterna Magna/patología , Encefalitis/inmunología , Encefalitis/patología , Ensayo de Inmunoadsorción Enzimática , Lipopolisacáridos/inmunología , Masculino , Ratas , Ratas Sprague-Dawley , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
A new approach was developed to minimize inevitable damage to nervous and meningeal tissue due to implantation of a sampling tube allowing multiple withdrawal of cerebrospinal fluid (CSF) from the cisterna magna in adult rats. A tube was secured on the atlanto-occipital membrane. Thereafter, a hole was cut through the membrane, allowing flow of CSF from the cisterna magna to the tube. CSF could be sampled repeatedly for at least 1 week. There was no blood-brain barrier damage. The pressure in the cisterna magna remained normal as did the estimated rate of CSF formation. Very few blood cells contaminated the CSF. There was very little evidence of inflammation. The nervous tissue was undamaged as shown by exclusion of a dye-protein complex. The CSF concentrations of the cytosolic neuronal protein neuron-specific enolase (NSE), and of the astrocyte protein S-100 were very low. The pattern of amino acids remained within normal limits. Scanning electron microscopy revealed that clot and reactive changes were restricted to the vicinity of the connecting hole. We conclude that our approach to positioning a tube on the atlanto-occipital membrane and then connecting it to the cisterna magna reproducibly and reliably enables 'atraumatic' multiple sampling of CSF.
Asunto(s)
Barrera Hematoencefálica/fisiología , Líquido Cefalorraquídeo/química , Cisterna Magna/cirugía , Fosfopiruvato Hidratasa/metabolismo , Proteínas S100/metabolismo , Aminoácidos/líquido cefalorraquídeo , Animales , Líquido Cefalorraquídeo/citología , Líquido Cefalorraquídeo/metabolismo , Presión del Líquido Cefalorraquídeo , Derivaciones del Líquido Cefalorraquídeo , Cisterna Magna/inmunología , Cisterna Magna/lesiones , Inflamación , Meninges/lesiones , Microscopía Electrónica de Rastreo , Neuronas/citología , Fosfopiruvato Hidratasa/líquido cefalorraquídeo , Ratas , Ratas Sprague-Dawley , Proteínas S100/líquido cefalorraquídeo , Manejo de EspecímenesRESUMEN
Intracisternal (IC) transfer of cerebrospinal fluid (CSF) mononuclear cells from multiple sclerosis (MS) patients has been reported by others to induce an 'MS-like pathology' in severe combined immunodeficient (SCID) mice. We injected cells from several sources intracisternally into SCID mice and assessed the recipients for clinical and histological disease. CSF cells and myelin basic protein (BP)-specific T lymphocytes from MS patients failed to induce clinical or histological disease following IC injection in SCID mice. Similarly, encephalitogenic BP-specific T cells from Lewis rats were unable to induce disease after IC injection in either SCID mice or Lewis rats, even at cell numbers which induced experimental autoimmune encephalomyelitis in Lewis rats following intraperitoneal (IP) injection. In contrast, naive Lewis rat splenocytes, which were capable of inducing lethal graft-versus-host (GVH) disease following IP transfer in SCID mice, induced paralysis and histopathological changes following IC transfer in SCID mice. We conclude that MS CSF cells do not typically transfer disease into SCID mice following IC injection. Furthermore, it appears likely that neuropathological disease following IC transfer of cells reflects the potential of the transferred cells for inducing GVH disease. Specific recognition of neuroantigens by T cells, as occurs in EAE, is probably not involved in the transfer of paralytic disease by IC transferred MS patient CSF cells.