NEUTROPHILIC INFLAMMATION INDUCES GENOTOXICITY IN A MOUSE MODEL OF ACUTE-DISTRESS RESPIRATORY SYNDROME

CLAVELES CASAS, FN; LOPEZ CM; HINOJOSA VERA K; CHACON I DEL V; BARRERA FS; DI SCIULLO, MARÍA PAULA; RAMIREZ DARIO; GOMEZ-MEJIBA SANDRA

San Luis

Congreso; XXXVII Reunión Científica Anual. Sociedad de Biología de Cuyo; 2019

The transit of neutrophils through pulmonary microvasculture is controlled by the expression of adhesion molecules whose expression is under the control of the nuclear factor-kB (NF-kB) and by the expression of integrins on the surface of the neutrophils. It is known that the activation of leukocytes in circulation is manifested by activation of NADPH oxidase-2 (NOX-2) and release of enzymes and proteases from their granules. Herein we aimed at investigating the mechanisms by which pulmonary exposure to bacterial endotoxin causes genotoxic damage in the lung. It was observed that intratracheal instillation of endotoxin retains more neutrophils in the lung and causes damage to macromolecules dependent on the production of HOCl by myeloperoxidase (MPO). In particular, the mechanisms of genomic DNA radicalization were investigated. Neutrophil retention is a key step in these damage processes and is controlled by the induction of adhesion molecules in the pulmonary microvasculature. This neutrophil retention was prevented by the nitrone spin trap 5,5-dimethyl-1-pyrroline N-oxide (DMPO), which, if administered before instillation of LPS, prevents induction of NF-kB-dependent chemokine and adhesion molecule expression in the pulmonary microvasculature. If DMPO is administered between 3 to 6 h after LPS, it prevents genotoxic damage by its ability to trap radical intermediaries in oxidation to DNA. It is concluded that the DMPO spin trap can be used to reduce genotoxic damage induced by acute exposure to endotoxin in this mouse model by its ability, not only to trap DNA radicals, but also to prevent the expression of pro-inflammatory factors (chemokines and cytokines) and adhesion molecules, both dependent on the signaling pathway of the NF-B. Supported by: PICT-3435, PIP-916, PROICO-100218/023418 and PUE-013.