INTER-ALPHA INHIBITORS IN ADULT AND NEONATAL SEPSIS: A POTENTIAL APPLICATION AS AN INTEGRATED CLINICAL MARKER AND THERAPEUTIC AGENT

Abstract

A consistent finding in the complex pathophysiology of sepsis is evidence of excess systemic protease activity. An array of endogenous protease inhibitors counterbalances these actions. Many of these inhibitors are rapidly consumed in sepsis, often leading to a failure to appropriately regulate protease activity. A complex polypeptide family termed as Inter-alpha inhibitor proteins (IAIP) is one of the endogenous serine protease inhibitors found abundantly in human blood. IAIP have been implicated to play a role in systemic inflammation/sepsis. Studies of the IAIP levels in adult patients and infants with clinically proven sepsis indicated that IAIP decreased significantly and the plasma IAIP levels inversely correlated with the disease severity and mortality. In a longitudinal study of more than 250 severe septic patients, failure of recovery of IAIP levels over the course of sepsis was associated with a poor outcome suggesting IAIP levels are potentially useful as a clinical marker in sepsis. The rapid IAIP depletion might lead to uncontrolled proteolytic activity and exacerbates the systemic inflammation. In a preclinical study to investigate the efficacy of IAIP replacement therapy, administration of purified IAIP significantly improved outcome in experimental sepsis models. The increased survival rates were observed even when IAIP were administered at delayed timepoints in a polymicrobial sepsis rat model and in a LPS challenge neonatal mouse model. IAIP administration appeared to have immunomodulatory effects as TNF-alpha was significantly attenuated and IL-10 was augmented by IAIP treatment. Further studies in genetically altered mice pups (IL-10−/−) suggested that the beneficial effects of IAIP might be independent of the augmentation of antiinflammatory cytokines. Taken together, IAIP are potentially useful in the clinical management of sepsis as an integrated predictive marker and effective therapeutic replacement agent in reducing morbidity and mortality of this deadly disease.