In a mouse model of acute-distress respiratory syndrome the generation of neutrophilic inflammation induces genotoxicity

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

Modalidad Virtual

Congreso; The Society for Redox Biology and Medicine´s 27th Annual Conference; 2020

The model of acute respiratory distress syndrome (ARDS)caused by oropharyngeal instillation of a bolus of bacteriallipopolysaccharide (LPS) is a well-known model ofneutrophilic inflammation (NI). LPS-induced activation of tolllikereceptor 4 leads to activation of the nuclear factor-kB(NF-kB) and downstream expression of adhesion molecules,chemokines and pro-inflammatory cytokines. During NI MPOis released by activated neutrophils and taken up bysurrounding cells, where it can produce HOCl close to thegenomic DNA. Herein we aimed at investigating whetherLPS-induced ARDS causes DNA-centered radical-mediatedgenotoxic damage in an in vivo mouse model of ADRS.Endotoxin instillation caused more neutrophils to beretained/activated in the lung by inducing ICAM-1 and proinflammatorycytokine/chemokine expression and 8-oxodGuoformation. This neutrophil retention/activation wasprevented by instillation of the nitrone spin trap 5,5-dimethyl-1-pyrroline N-oxide (DMPO, 5 nmol/mouse) with consequentincrease in DMPO-DNA nitrone adducts, and reduction inICAM-1 and TNF-α expression, and 8-oxo-dG formation inthe lung, and reduction in circulating pro-inflammatorycytokines. The nitrone DMPO spin trap, or its structuralderivatives, can be used to reduce genotoxic damage linkedto pulmonary NI in this ADRS mouse model by its ability, notonly to trap DNA radicals, but also to prevent the expressionof pro-inflammatory factors (chemokines and cytokines) andadhesion molecules, which expression is dependent onactivation of the NF-kB signaling pathway. The model ofacute respiratory distress syndrome (ARDS) caused byoropharyngeal instillation of a bolus of bacteriallipopolysaccharide (LPS) is a well-known model of neutrophilic inflammation (NI). LPS-induced activation of tolllikereceptor 4 leads to activation of the nuclear factor-kB(NF-kB) and downstream expression of adhesion molecules,chemokines and pro-inflammatory cytokines. During NI MPOis released by activated neutrophils and taken up bysurrounding cells, where it can produce HOCl close to thegenomic DNA. Herein we aimed at investigating whether