IN A MOUSE MODELOF ACUTE-DISTRESS RESPIRATORY SYNDROME THE GENERATION OF NEUTROPHILIC INFLAMMATION INDUCES GENOTOXICITY

DARIO RAMIREZ; CRISTOFER MARTÍN LOPEZ; FLORENCIA BARRERA; FLORENCIA CLAVELES CASAS; KATHLEEN HINOJOSA VERA; MARIA DI SCIULLO; M CORTEZ; INHALEN CHACON; SANDRA GOMEZ-MEJIBA

Florida

Congreso; 2020 SfRBM's 27th Annual Meeting; 2020

Society for Redox Biology and Medicine

The model of acute respiratory distress syndrome (ARDS) caused by oropharyngeal instillation of a bolus of bacterial lipopolysaccharide (LPS) is a well-known model of neutrophilic inflammation (NI). LPS-induced activation of toll-like receptor 4 leads to activation of the nuclear factor-B (NF-B) and downstream expression of adhesion molecules, chemokines and pro-inflammatory cytokines. During NI MPO is released by activated neutrophils and taken up by surrounding cells, where it can produce HOCl close to the genomic DNA. Herein we aimed at investigating whether LPS- induced ARDS causes DNA-centered radical-mediated genotoxic damage in an in vivo mouse model of ADRS. Endotoxin instillation caused more neutrophils to be retained/activated in the lung by inducing ICAM-1 and pro-inflammatory cytokine/chemokine expression and 8-oxo-dGuo formation. This neutrophil retention/activation was prevented by instillation of the nitrone spin trap 5,5-dimethyl-1-pyrroline N-oxide (DMPO, 5 nmol/mouse) with consequent increase in DMPO-DNA nitrone adducts, and reduction in ICAM-1 and TNF-α expression, and 8-oxo-dG formation in the lung, and reduction in circulating pro-inflammatory cytokines. The nitrone DMPO spin trap, or its structural derivatives, can be used to reduce genotoxic damage linked to pulmonary NI in this ADRS 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, which expression is dependent on activation of the NF-B signaling pathway.