REGULATION OF THE RESPONSE TO BACTERIAL LIPOPOLYSACCHARIDE BY ENDOGENOUS AND EXOGENOUS LIPOPOLYSACCHARIDE-BINDING PROTEINS

Bactericidal/permeability-increasing protein (BPI) is a natural consti tuent of human neutrophils. Recombinant BPI has been shown to bind to bacterial lipopolysaccharide (LPS), and to neutralize the ability of L PS to stimulate inflammatory cells in vitro and in vivo. BPI shares se quence homology and immunocrossreactivity with another endogenous LPS binding protein, lipopolysaccharide binding protein (LBP). Despite the homology, these proteins have opposite effects on LPS. LBP mediates c ell activation by low, otherwise nonstimulatory concentrations, while BPI neutralizes LPS bioactivity. Exogenous LPS binding proteins in the form of monoclonal antibodies have been developed with the goal of ge nerating anti-endotoxin therapeutics to treat gram-negative sepsis and related syndromes. Here we show that LPS-binding and neutralizing pro perties of BPI compare favorably with two monoclonal antibodies tested , HA-1A and XMMEN-OE5. BPI also competes effectively with LBP for LPS. Thus, BPI may represent an endogenous LPS-regulatory molecule suitabl e for use as a potent antiendotoxin therapeutic.