New Frontiers in Cytokine Involvement during Experimental Sepsis

Despite significant advances in the antibiotic arsenal and in intensive care unit technology, including mechanical ventilation, sepsis-related morbidity and mortality remain unacceptably high. Ultimately, 25 to 50% of all septic episodes end in death. However, various subsets of septic patients, including those who experience septic peritonitis, and various secondary sequelae like the acute respiratory distress syndrome or nosocomial infections, demonstrate much higher mortality rates ranging from 60 to 95%. Although a number of strategies have been utilized to curb the progression of systemic inflammatory response syndrome with immune or inflammatory modulating therapies, none of these interventions has resulted in significant improvement in survival, and some have proven deleterious. The inability to utilize immune-modulating strategies effectively to treat septic patients likely reflects the inherent conflict that is illustrated by the two diagnostic criteria for the syndrome. The very immune/inflammatory response that has evolved to eliminate infection results in severe and life-threatening damage to host tissues. This review outlines the inflammatory pathways utilized by the host during a septic response. The basis of early immune-modulating therapies and possible reasons these approaches have failed in the treatment of sepsis are discussed. A picture of the ideal therapeutic approach for acute inflammatory diseases like sepsis is also created, and the reason therapies targeting chemokine pathways may more closely approximate the ideal therapy is proposed.