Gastrin-Releasing Peptide Receptor Antagonism Induces Protection from Lethal Sepsis: Involvement of Toll-like Receptor 4 Signaling

Imagem de Miniatura
Arquivos
art_BARBEIRO_Gastrin_Releasing_Peptide_Receptor_Antagonism_Induces_Protection_from_2012.PDF (2.06 MB)
Citações na Scopus
14
Tipo de produção
article
Data de publicação
2012
DOI
Scopus
Web of Science
PubMed
Título da Revista
ISSN da Revista
Título do Volume
Editora
FEINSTEIN INST MED RES
Autores
PETRONILHO, Fabricia
VUOLO, Francieli
GALANT, Leticia Selinger
CONSTANTINO, Larissa
TOMASI, Cristiane Damiani
GIOMBELLI, Vinicius Renne
SOUZA, Cldudio Teodoro de
SILVA, Sabrina da
Citação
MOLECULAR MEDICINE, v.18, n.8, p.1209-1219, 2012
Projetos de Pesquisa
Unidades Organizacionais
Fascículo
Resumo
In sepsis, toll-like receptor (TLR)-4 modulates the migration of neutrophils to infectious foci, favoring bacteremia and mortality. In experimental sepsis, organ dysfunction and cytokines released by activated macrophages can be reduced by gastrin-releasing peptide (GRP) receptor (GRPR) antagonist RC-3095. Here we report a link between GRPR and TLR-4 in experimental models and in sepsis patients. RAW 264.7 culture cells were exposed to lipopolysaccharide (LPS) or tumor necrosis factor (TNF)-alpha and RC-3095 (10 ng/mL), Male Wistar rats were subjected to cecal ligation and puncture (CLP), and RC-3095 was administered (3 mg/kg, subcutaneously); after 6 h, we removed the blood, bronchoalveolar lavage, peritoneal lavage and lung. Human patients with a clinical diagnosis of sepsis received a continuous infusion with RC-3095 (3 mg/kg, intravenous) over a period of 12 h, and plasma was collected before and after RC-3095 administration and, in a different set of patients with systemic inflammatory response syndrome (SIRS) or sepsis. GRP plasma levels were determined. RC-3095 inhibited TLR-4, extracellular-signal-related kinase (ERK)-1/2, Jun NH2-terminal kinase (JNK) and Akt and decreased activation of activator protein 1 (AP-1), nuclear factor (NF)-kappa B and interleukin (IL)-6 in macrophages stimulated by LPS. It also decreased IL-6 release from macrophages stimulated by TNF-alpha. RC-3095 treatment in CLP rats decreased lung TLR-4, reduced the migration of cells to the lung and reduced systemic cytokines and bacterial dissemination. Patients with sepsis and systemic inflammatory response syndrome have elevated plasma levels of GRP which associates with clinical outcome in the sepsis patients. These findings highlight the role of GRPR signaling in sepsis outcome and the beneficial action of GRPR antagonists in controlling the inflammatory response in sepsis through a mechanism involving at least inhibition of TLR-4 signaling. Online address: http://www.molmed.org doi: 10.2119/molmed.2012.00083
Palavras-chave
URI
https://observatorio.fm.usp.br/handle/OPI/467
Referências
  1. Abraham E, 2003, CRIT CARE MED, V31, P195
  2. Alves JC, 2006, CRIT CARE MED, V34, P461, DOI 10.1097/01.CCM.0000198527.71819.E1
  3. Alves JC, 2009, P NATL ACAD SCI USA, V106, P4018, DOI 10.1073/pnas.0900196106
  4. Alves JC, 2008, SHOCK, V30, P3, DOI 10.1097/SHK.0b013e3181818466
  5. ANASTASI A, 1971, EXPERIENTIA, V27, P166, DOI 10.1007/BF02145873
  6. Andonegui G, 2003, J CLIN INVEST, V111, P1011, DOI 10.1172/JCI200316510
  7. Annane D, 2005, LANCET, V365, P63, DOI 10.1016/S0140-6736(04)17667-8
  8. Arranz A, 2008, MOL IMMUNOL, V45, P2970, DOI 10.1016/j.molimm.2008.01.023
  9. Benjamim CF, 2000, J INFECT DIS, V182, P214, DOI 10.1086/315682
  10. BONE RC, 1992, CHEST, V101, P1481, DOI 10.1378/chest.101.6.1481
  11. BRADFORD MM, 1976, ANAL BIOCHEM, V72, P248, DOI 10.1006/abio.1976.9999
  12. Brogden KA, 2005, NAT IMMUNOL, V6, P558, DOI 10.1038/ni1209
  13. Chang WJ, 2001, J BIOL CHEM, V276, P47664, DOI 10.1074/jbc.M104666200
  14. Chishti AD, 2004, INTENS CARE MED, V30, P605, DOI 10.1007/s00134-004-2175-y
  15. Committee for the Update of the Guide for the Care and Use of Laboratory Animals Institute for Laboratory Animal Research Division on Earth and Life Studies National Research Council of the National Academies, 2011, GUID CAR US LAB AN
  16. Cornelio Daniela B, 2007, Recent Pat Antiinfect Drug Discov, V2, P178, DOI 10.2174/157489107782497344
  17. Czepielewski RS, 2012, P NATL ACAD SCI USA, V109, P547, DOI 10.1073/pnas.1110996109
  18. Dal-Pizzol F, 2004, CRIT CARE MED, V32, P1971, DOI 10.1097/01.CCM.0000139620.32448.12
  19. Dal-Pizzol F, 2006, AM J RESP CRIT CARE, V173, P84, DOI 10.1164/rccm.200507-1118OC
  20. Degan S, 2008, ANN NY ACAD SCI, V1144, P136, DOI 10.1196/annals.1418.022
  21. De Souza CT, 2003, DIABETOLOGIA, V46, P1522, DOI 10.1007/s00125-003-1222-5
  22. Dickerson C, 1998, J LEUKOCYTE BIOL, V63, P602
  23. Genton L, 2003, AM J SURG, V186, P253, DOI 10.1016/S0002-9610(03)00210-1
  24. Godshall CJ, 2002, J SURG RES, V102, P45, DOI 10.1006/jsre.2001.6319
  25. Gonzalez-Rey E, 2007, TRENDS PHARMACOL SCI, V28, P482, DOI 10.1016/j.tips.2007.07.001
  26. Grimsholm O, 2005, ARTHRITIS RES THER, V7, pR416, DOI 10.1186/ar1503
  27. Guha M, 2001, CELL SIGNAL, V13, P85, DOI 10.1016/S0898-6568(00)00149-2
  28. Hedge A, 2007, J LEUKOCYTE BIOL, V82, P678
  29. Hellmich MR, 1999, J BIOL CHEM, V274, P23901, DOI 10.1074/jbc.274.34.23901
  30. Hotchkiss RS, 2003, NEW ENGL J MED, V348, P138, DOI 10.1056/NEJMra021333
  31. Ishii KJ, 2004, CURR INFECT DIS REP, V6, P361, DOI 10.1007/s11908-004-0034-1
  32. Jensen RT, 2008, PHARMACOL REV, V60, P1, DOI 10.1124/pr.107.07108
  33. Kerfoot SM, 2005, J LEUKOCYTE BIOL, V77, P862, DOI 10.1189/jlb.10044607
  34. Kuhn M, 2008, NUCLEIC ACIDS RES, V36, pD684, DOI 10.1093/nar/gkm795
  35. Kuhn M, 2010, NUCLEIC ACIDS RES, V38, pD552, DOI 10.1093/nar/gkp937
  36. LAEMMLI UK, 1970, NATURE, V227, P680, DOI 10.1038/227680a0
  37. Petronilho Fabricia, 2007, Inflammation & Allergy Drug Targets, V6, P197
  38. RADULOVIC S, 1991, INT J PEPT PROT RES, V38, P593
  39. Riedemann NC, 2003, NAT MED, V9, P517, DOI 10.1038/nm0503-517
  40. Ritter C, 2004, CRIT CARE MED, V32, P342, DOI 10.1097/01.CCM.000010954.13145.CA
  41. Roesler R., 2006, CNS & Neurological Disorders-Drug Targets, V5, P197, DOI 10.2174/187152706776359673
  42. Salomao R, 2009, CRIT CARE MED, V37, P132, DOI 10.1097/CCM.0b013e318192fbaf
  43. Schally AV, 2008, HORM METAB RES, V40, P315, DOI 10.1055/s-2008-1073142
  44. Schwartsmann G, 2006, INVEST NEW DRUG, V24, P403, DOI 10.1007/s10637-006-6886-5
  45. Secher T, 2009, J IMMUNOL, V182, P7855, DOI 10.4049/jimmunol.0804008
  46. Subramaniam M, 2003, AM J RESP CRIT CARE, V168, P601, DOI 10.1164/rccm.200212-1434OC
  47. Sugiyama K, 2008, EUR J PHARMACOL, V594, P152, DOI 10.1016/j.ejphar.2008.07.037
  48. Taylor AW, 2005, J NEUROIMMUNOL, V162, P43, DOI 10.1016/j.neuroim.2005.01.008
  49. Tsatsanis C, 2006, J IMMUNOL, V176, P1869
  50. Tsung A, 2007, SHOCK, V27, P364, DOI 10.1097/01.shk.0000239773.95280.2c
  51. Williams DL, 2003, CRIT CARE MED, V31, P1808, DOI 10.1097/01.CCM.0000069343.27691.F3

Coleções
Artigos e Materiais de Revistas Científicas - FM/MCM
Artigos e Materiais de Revistas Científicas - HC/ICHC
Artigos e Materiais de Revistas Científicas - LIM/51