Predictive value of inter-alpha inhibitors in sepsis

DESCRIPTION (provided by applicant): The primary goal of this proposal is to demonstrate the feasibility of utilizing Inter-alpha Inhibitor as a novel predictive marker for adult and newborn sepsis. IaIp are natural serine protease inhibitors found in relatively high concentration in human adult and newborn plasma (ranges between 600-1200 mg/L). IaIp have been implicated to play roles in inflammation, wound healing and cancer metastasis. The high level of IaIp circulating normally in plasma indicates that the proteins are essential for life and no person with complete absence of IaIp has ever been detected. Our preliminary results demonstrate a significant decrease of plasma IaIp levels in plasma of adult patients with severe sepsis and septic shock and the decrease correlates with the mortality suggesting the potential clinical utility of IaIp as a predictive marker in sepsis. A similar decrease of IaIp levels was found also in clinically proven neonatal sepsis. Furthermore, in our animal studies using a polymicrobial sepsis rat model of cecal ligation and puncture (CLP), we have demonstrated the beneficial effects of IaIp in maintaining hemodynamic stability, preventing organ injury, and improving survival during the progression of sepsis in adult animals. Taken together, the data strongly suggest the involvement of IaIp in the pathogenesis of sepsis. In this Phase I application, we will develop a standardized and validated immunoassay that is reliable and capable of accurately determining IaIp levels in biological fluids. This validated assay will be used to confirm our initial findings that IaIp levels in plasma constitute a valuable diagnostic, prognostic and theranostic marker for adult and neonatal sepsis.