Potential applications of N-terminal recombinant fragments of bactericidal/permeability-increasing protein in liver surgery

Abstract

Bactericidal/permeability-increasing protein (BPI) was first isolated by Elsbach and Weiss in 1978. 1,2 It is a natural host-defense protein of 55 kd found in the azurophilic granules of human neutrophils, which are important in the host defense against infections. The protein was named after one of its first discovered properties, the potential to kill bacteria by increasing the permeability of their cell walls. 1,2 This ability to kill bacteria has led to further studies of the functions of BPI, from which researchers have discovered several potentially useful properties. In this article, we first give a brief review of the most important in vitro and in vivo studies showing the functions and properties of BPI and then focus on the potential applications of one of the more stable recombinant BPIs, rBPI 21 , in the field of liver surgery and transplantation. The Main Effects of BPI Antibacterial ActionBPI shows antimicrobial activity against a wide range of gram-negative bacteria. 1-3 The cell envelope of gram-negative bacteria consists of the cytoplasmic membrane, peptidoglycan layer, and an additional barrier, the outer membrane, which is strictly asymmetric with respect to its lipid composition. The outer leaflet of this membrane is composed mainly of lipopolysaccharides (LPS; endotoxins). LPS consists of an oligosaccharide or polysaccharide and a covalently linked glycolipid component (lipid A) that anchors the LPS in the outer membrane. 4 The selectivity of BPI against gram-negative bacteria has been attributed to the strong attraction of BPI for this LPS in the bacterial envelope, especially the high affinity for its lipid A component. 5,6 It has become evident that the LPS structure primarily determines bacterial sensitivity. Strains bearing LPS with short polysaccharide chains in their outer membrane are the most sensitive. Long polysaccharide chains sterically hinder the access of BPI to the binding sites in the inner core and the lipid A regions of LPS, thereby reducing the affinity of BPI for the envelope LPS, necessitating higher ambient BPI concentrations to achieve the required amount of bound BPI to produce its biological effects. 3,6,7 The cytotoxic effect of BPI on gram-negative bacteria can be divided into two stages. When BPI binds to the outer membrane, several immediate effects are manifest, including arrest of bacterial growth, discrete changes in the permeability of the outer membrane, and selective activation of several envelope enzymes, which degrade phospholipids and peptidoglycans. These changes are evident despite preservation of the functional integrity of the biochemical machinery in the nongrowing bacteria. In fact, certain manipulations result in repair of the envelope alterations and resumption of growth, therefore indicating that the initial effects of BPI are not directly bactericidal. 2,8 However, when this process is continued, alterations of the cytoplasmic membrane are produced, resulting in an impairment of the energy metabolism that leads to an irreversible growth arre...

Bactericidal/Permeability-Increasing Protein Preserves Leukocyte Functions After Major Liver Resection

“…As a result of this binding, rBPI 21 not only clears endotoxin but also inhibits several endotoxin-induced humoral and cellular responses, including the generation of cytokines, free radicals, or nitric oxide, induction of tissue factor, adhesion of neutrophils to endothelial cells, and complement activation. [23][24][25][26][27][28][29] By treating the hemihepatectomy patients with this endotoxin-neutralizing agent rBPI 21 , we could estimate the effect of systemic endotoxemia in leukocyte activation after liver surgery. The effectiveness of rBPI 21 treatment was measured by assessing plasma lipopolysaccharide binding protein (LBP) levels.…”