دورية أكاديمية
P2X7 Receptor Signaling Contributes to Sepsis-Associated Brain Dysfunction.
| العنوان: | P2X7 Receptor Signaling Contributes to Sepsis-Associated Brain Dysfunction. |
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| المؤلفون: | Savio LEB; Laboratory of Immunophysiology, Biophysics Institute Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.; Department of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Harvard University, Boston, MA, USA., Andrade MGJ; Laboratory of Immunophysiology, Biophysics Institute Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil., de Andrade Mello P; Department of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Harvard University, Boston, MA, USA.; Laboratory of Biochemical and Cytological Analysis, Faculty of Pharmacy, Federal University of Rio Grande do Sul, Porto Alegre, Brazil., Santana PT; Laboratory of Immunophysiology, Biophysics Institute Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil., Moreira-Souza ACA; Laboratory of Immunophysiology, Biophysics Institute Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil., Kolling J; Laboratory of Neuroprotection and Metabolic Diseases, Department of Biochemistry, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil., Longoni A; Laboratory of Neuroprotection and Metabolic Diseases, Department of Biochemistry, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil., Feldbrügge L; Department of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Harvard University, Boston, MA, USA., Wu Y; Department of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Harvard University, Boston, MA, USA., Wyse ATS; Laboratory of Neuroprotection and Metabolic Diseases, Department of Biochemistry, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil., Robson SC; Department of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Harvard University, Boston, MA, USA., Coutinho-Silva R; Laboratory of Immunophysiology, Biophysics Institute Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil. rcsilva@biof.ufrj.br.; Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Edifício do Centro de Ciências da Saúde, Bloco G. Av. Carlos Chagas Filho, 373, Cidade Universitária, Ilha do Fundão, Rio de Janeiro, RJ, 21941-902, Brazil. rcsilva@biof.ufrj.br. |
| المصدر: | Molecular neurobiology [Mol Neurobiol] 2017 Oct; Vol. 54 (8), pp. 6459-6470. Date of Electronic Publication: 2016 Oct 11. |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Humana Press Country of Publication: United States NLM ID: 8900963 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1559-1182 (Electronic) Linking ISSN: 08937648 NLM ISO Abbreviation: Mol Neurobiol Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Clifton, NJ : Humana Press, c1987- |
| مواضيع طبية MeSH: | Antigens, CD/*metabolism , Apyrase/*metabolism , Brain/*metabolism , Receptors, Purinergic P2X7/*metabolism , Sepsis/*metabolism , Signal Transduction/*genetics, Animals ; Antigens, CD/genetics ; Apyrase/genetics ; Brain/pathology ; Catalase/metabolism ; Cytokines/metabolism ; Inflammation/genetics ; Inflammation/metabolism ; Inflammation/pathology ; Male ; Mice ; Mice, Knockout ; Oxidative Stress/physiology ; Receptors, Purinergic P2X7/genetics ; Sepsis/genetics ; Sepsis/pathology ; Superoxide Dismutase/metabolism |
| مستخلص: | Sepsis results in unfettered inflammation, tissue damage, and multiple organ failure. Diffuse brain dysfunction and neurological manifestations secondary to sepsis are termed sepsis-associated encephalopathy (SAE). Extracellular nucleotides, proinflammatory cytokines, and oxidative stress reactions are associated with delirium and brain injury, and might be linked to the pathophysiology of SAE. P2X7 receptor activation by extracellular ATP leads to maturation and release of IL-1β by immune cells, which stimulates the production of oxygen reactive species. Hence, we sought to investigate the role of purinergic signaling by P2X7 in a model of sepsis. We also determined how this process is regulated by the ectonucleotidase CD39, a scavenger of extracellular nucleotides. Wild type (WT), P2X7 receptor (P2X7 -/- ), or CD39 (CD39 -/- ) deficient mice underwent sham laparotomy or CLP induced by ligation and puncture of the cecum. We noted that genetic deletion of P2X7 receptor decreased markers of oxidative stress in murine brains 24 h after sepsis induction. The pharmacological inhibition or genetic ablation of the P2X7 receptor attenuated the IL-1β and IL-6 production in the brain from septic mice. Furthermore, our results suggest a crucial role for the enzyme CD39 in limiting P2X7 receptor proinflammatory responses since CD39 -/- septic mice exhibited higher levels of IL-1β in the brain. We have also demonstrated that P2X7 receptor blockade diminished STAT3 activation in cerebral cortex and hippocampus from septic mice, indicating association of ATP-P2X7-STAT3 signaling axis in SAE during sepsis. Our findings suggest that P2X7 receptor might serve as a suitable therapeutic target to ameliorate brain damage in sepsis. |
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| معلومات مُعتمدة: | K08 DK092281 United States DK NIDDK NIH HHS; P01 HL107152 United States HL NHLBI NIH HHS |
| فهرسة مساهمة: | Keywords: Brain; CD39; Il-1β; P2X7 receptor; STAT3; Sepsis |
| المشرفين على المادة: | 0 (Antigens, CD) 0 (Cytokines) 0 (Receptors, Purinergic P2X7) EC 1.11.1.6 (Catalase) EC 1.15.1.1 (Superoxide Dismutase) EC 3.6.1.5 (Apyrase) EC 3.6.1.5 (CD39 antigen) |
| تواريخ الأحداث: | Date Created: 20161013 Date Completed: 20180709 Latest Revision: 20191216 |
| رمز التحديث: | 20240628 |
| DOI: | 10.1007/s12035-016-0168-9 |
| PMID: | 27730511 |
| قاعدة البيانات: | MEDLINE |
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Full Text Finder | تدمد: | 1559-1182 |
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| DOI: | 10.1007/s12035-016-0168-9 |