PROTECTION AGAINST LETHAL POLYMICROBIAL SEPSIS BY CNI-1493, AN INHIBITOR OF PRO-INFLAMMATORY CYTOKINE SYNTHESIS

Polymicrobial sepsis caused by cecal ligation and puncture (CLP) in mi ce produces the inflammatory and pathological sequelae of lung neutrop hil infiltration, adult respiratory distress syndrome (ARDS) and death . These sequelae are dependent upon the synergistic interaction betwee n several inflammatory mediators, including tumor necrosis factor (TNF ), interleukin 1 (IL-l), and nitric oxide (NO). The overlapping spectr um of multiple mediator toxicity has hampered efforts to develop thera pies for sepsis based on selective inhibition of a single mediator. Th erefore, we tested the hypothesis that inhibition of multiple pro-infl ammatory mediators would abrogate lethality. Our results show that adm inistration of a tetravalent guanylhydrazone compound (CNI-1493) prote cted 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 control s; IL-6 reduced 90% compared to controls; P<0.05), and decreased level s of the acute-phase protein serum amyloid A response measured 24 h af ter CLP. Serum nitrites/nitrates, which give an index of NO production , were also significantly reduced (50%). Protection against CLP induce d lung damage was observed as attenuation of edema and alveolar neutro phil infiltration, suppression of pulmonary TNF levels, and reduction of TUNEL-positive staining in lung. We conclude that CNI-1493 effectiv ely inhibits the synthesis of multiple pro-inflammatory mediators and protects against death during polymicrobial sepsis.