Mechanism of the effects of 5,5-dimethyl 1-pyrroline n-oxide in a mouse model of acute respiratory distress syndrome

SANDRA E. GOMEZ MEJIBA, OLIVERA VARGAS JORGE AGUSTIN, LOPEZ CRISTOFER, DI SCIULLO PAULA, DARÍO RAMIREZ

MEDICINA (BUENOS AIRES)

MEDICINA (BUENOS AIRES)

Lugar: Buenos Aires; Año: 2018 vol. 78 p. 272 - 273

0025-7680

The nitrones spin trap 5,5-dimethyl-1-pyrroline N-oxide (DMPO) was developed for the study of free radicals. Later it was used to visualize protein- and DNA-centered radicals in cells, tissues and whole animals in animal models of diseases. Recently we found that DMPO blocks lipopolysaccharide (LPS)-triggered signaling in macrophages primed with LPS, traps protein- and DNA-centered radicals, and also decreases systemic inflammation and death in mice exposed to an overdose of LPS. Herein we aimed at determining the mechanism by which DMPO can protect the lung in a mouse model of acute-distress respiratory syndrome (ADRS) triggered by bacterial LPS. We hypothesize that these protective effects of DMPO can either be due to blocking quimiotaxis/homing and activation of neutrophils, myeloperoxidase (MPO) activity or other enzyme sources of reactive biochemical species o by trapping protein radicals and thus reducing their decay to end-oxidation products. We used male C57 mice (7 weeks-old, 9/group) and exposed them, under light anesthesia, to oropharyngeal aspiration of 50 ul of either vehicle (PBS) or 1 ug/ul LPS. Another group of animals (9/group) were pre-treated 30 min before LPS challenge with vehicle or vehicle containing 50 mM DMPO (2.5 nmol DMPO/mice). We found that LPS treatment increased ICAM-1 and iNOS expression, neutrophil in lung parenchyma (NIMP-14+ cells); and markers of tissue damage in BALF (LDH leakage); MPO protein and activity in lung parenchyma and BALF; and chlorotyrosine, nitrotyrosine and carbonyls in the lung parenchyma. These effects were prevented by pretreatment with DMPO which trapped some protein radicals. DMPO did not affect MPO, iNOS or NOX-2 activity. Taking together our data are consistent with DMPO reducing LPS-induced neutrophil recruitment into the lung parenchyma, thus downstream effects are blocked. DMPO or its derivatives may prove to be effective anti-LPS treatments in ADRS and also sepsis. PICT-3369, PIP916 , PROICO 10-0218- PROICO 02-3418.