N-methyl-D-aspartate glutamate receptor blockade attenuates lung injury associated with experimental sepsis.
BACKGROUND
The aim of this study was to examine the effects of the N-methyl-D-aspartate receptor (NMDAR) channel blocker dizocilpine (MK-801) on lung injury in rats submitted to experimental sepsis induced by cecal ligation and perforation (CLP).


METHODS
Adult male Wistar rats submitted to CLP were given a single systemic injection of MK-801 (subcutaneously at 0.3 mg/kg) administered 4 or 7 h after CLP induction. Twelve hours after CLP BAL was performed to determine total cell count, protein content, and inflammatory parameters. In addition, lung was excised for histopathologic analyses and determination of NMDAR subunits content. In a separate cohort of animals mortality was recorded for 5 days.


RESULTS
Animals submitted to sepsis induced by CLP showed an increase in the content of NMDAR subunits NR1 and NR2A in the lung. Administration of MK-801 4 h after CLP induction resulted in a decrease in BAL fluid cellular content and decreased levels of proinflammatory cytokines. In addition, MK-801 decreased lung oxidative stress markers and histopathologic alterations and improved survival.


CONCLUSIONS
These findings indicate that NMDAR blockade might represent a promising novel therapeutic strategy for the treatment of sepsis and inflammatory disorders.
da Cunha
Aline A
AA
Laboratório de Pesquisa em Biofísica Celular e Inflamação, Faculdade de Biociências, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, Brazil.
Pauli
Vânia
V
Saciura
Vasyl C
VC
Pires
Melissa G S
MG
Constantino
Leandra C
LC
de Souza
Bruna
B
Petronilho
Fabricia
F
Rodrigues de Oliveira
Jarbas
J
Ritter
Cristiane
C
Romão
Pedro R T
PR
Boeck
Carina Rodrigues
CR
Roesler
Rafael
R
Quevedo
João
J
Dal-Pizzol
Felipe
F
D000818:Animals; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000008:administration & dosage / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000627:therapeutic use*; D055370:Lung Injury / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D018805:Sepsis / Q000150:complications*; D016896:Treatment Outcome
D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D016291:Dizocilpine Maleate