Protection against lethal polymicrobial sepsis by CNI-1493, an inhibitor of pro-inflammatory cytokine synthesis

Abstract

Polymicrobial sepsis caused by cecal ligation and puncture (CLP) in mice produces the inflammatory and pathological sequelae of lung neutrophil infiltration, adult respiratory distress syndrome (ARDS) and death. These sequelae are dependent upon the synergistic interaction between several inflammatory mediators, including tumor necrosis factor (TNF), interleukin 1 (IL-1 ), and nitric oxide (NO). The overlapping spectrum of multiple mediator toxicity has hampered efforts to develop therapies for sepsis based on selective inhibition of a single mediator. Therefore, we tested the hypothesis that inhibition of multiple pro-inflammatory mediators would abrogate lethality. Our results show that administration of a tetravalent guanylhydrazone compound (CNI-1493) protected mice against 10 day mortality in CLP. Evidence of suppression of the cytokine cascade was given by decreased serum levels of TNF and IL-6 in CNI-1493 treated animals (TNF reduced 60% as compared to controls; IL-6 reduced 90% compared to controls; P < 0.05), and decreased levels of the acute-phase protein serum amyloid A response measured 24 h after CLP. Serum nitrites/nitrates, which give an index of NO production, were also significantly reduced (50%). Protection against CLP induced lung damage was observed as attenuation of edema and alveolar neutrophil infiltration, suppression of pulmonary TNF levels, and reduction of TUNEL-positive staining in lung. We conclude that CNI-1493 effectively inhibits the synthesis of multiple pro-inflammatory mediators and protects against death during polymicrobial sepsis.