THE NITRONE 5,5-DIMETHYL-1-PYRROLINE-N-OXIDE PREVENTS PULMONARY NEUTROPHILIC INFLAMMATION AND GENOTOXICITY IN A MOUSE MODEL OF ACUTE RESPIRATORY DISTRESS SYNDROME

CRISTOFER M. LOPEZ¹, 1,3, 2, DARIO C. RAMÍREZ3, SANDRA E. GOMEZ MEJIBA; JONATHAN M. RAMIREZ; MARIA A. MATTAR DOMINGUEZ; DARIO RAMIREZ; GOMEZ MEJIBA, SANDRA;

Congreso; SAIC; 2024

Lipopolysaccharide (LPS), is a component of the outer membraneof Gram-negative bacteria, such as Pseudomonas aeruginosa (Pa)that causes redox changes and inflammatory NF-kB-controled geneexpression. In the pulmonary microvasculature, the latest controlsthe expression of adhesion molecules which can slow down neutrophilmigration and further activation (a process known as pulmonaryneutrophilic inflammation, PNI). During PNI, myeloperoxidase(MPO) is released and can be taken up by surrounding airway epithelialcells, where it can oxidize chloride anions to HOCl. HOCl isa powerful oxidant that can damage the genomic DNA by free radical-operated mechanisms. Herein we aimed to test in vivo whetherthe nitrone 5,5,dimethyl-1-pyrroline N-oxide (DMPO) can preventDNA-centered radical formation in C57 male mice exposed to deadPa. After 24 h of oropharyngeal aspiration of Pa (5x107 cells), wefound a marked PNI, as assessed by a large infiltration of neutrophils,MPO (content and activity), and chlorotyrosine-modified proteinsin the BALF and lung parenchyma. We also found increasedexpression of ICAM-1, inducible nitric oxide synthase, and contentof nitrotyrosine-modified proteins in the lung parenchyma, as wellas increased pro-inflammatory cytokines in serum. These changeswere blocked when DMPO (2.5 mmol/mice) was administrated 1hbefore the exposure to Pa. DMPO also trapped protein and DNAradicals in the lung parenchyma forming protein- and DNA-nitroneadducts (immuno-spin trapping technique). These data indicate thatDMPO reduces Pa-induced genotoxicity and proteotoxic stress.Taken together, these data are consistent with an effect of DMPOinterfering with the LPS-triggered signaling causing inhibition of theexpression of genes under the transcriptional control of NF-kB, thusblocking PNI. The nitrone spin trap can serve as a novel structuralplatform for the design of novel drugs to reduce death associatedwith sepsis and genotoxic damage to the airways.