MECHANISMS INVOLVED IN THE SEPTIC SHOCK SYNDROME

University Of Missouri Kansas City, Kansas City MO

Investigators

Linked publications & trials

Abstract

DESCRIPTION: (Adapted from the applicant's abstract) The investigators have analyzed the interactions of LPS with cells of the inflammatory process that can result in mortality in Gram-negative sepsis. A nontoxic lipid A derived from Rhodobacter sphaeroides (RsDPLA) that serves as a LPS antagonist in both in vivo and in vivo experimental conditions was developed. RsDPLA has the potential to be a key therapeutic adjunct to antagonize the initiating stimulus in Gram-negative sepsis, and is also a tool to study LPS-induced signal transduction. The investigators propose to: a) develop a novel, purified, and well characterized LPS crosslinking agent that will allow us to evaluate the interaction of LPS with macrophage membrane protein(s) other than CD14; b) test the hypothesis that RsDPLA blocks the interaction of LPS with a membrane-associated protein that is distinct from CD14; c) show that the cyclic guanosine monophosphate (cGMP)-dependent protein kinases and mitogen-activated protein kinases (MAPK) are involved in the LPS-induced activation of Spl using RsDPLA and several pharmacologic inhibitors; and d) develop an effective therapeutic regimen in the pig septic shock model by using a combination of RsDPLA and other drugs.