Bactericidal/permeability-increasing protein ameliorates acute lung injury in porcine endotoxemia

Abstract

Bactericidal/permeability-increasing protein (BPI), a cationic protein isolated from human neutrophils, binds lipopolysaccharide (LPS), kills gram-negative bacteria, and neutralizes many of the effects of LPS in vitro and in vivo. We hypothesized that a recombinant 23-kDa NH2-terminal fragment of BPI (BPI23) would reduce acute lung injury in endotoxemic pigs. At -18 h, pigs received an intravenous priming dose of LPS (20 micrograms/kg). Anesthetized ventilated swine were randomized to receive 1) no further treatment (n = 4); 2) LPS (250 micrograms/kg over 50 min) and BPI23 (3-mg/kg bolus and 3 mg/kg over 60 min) (n = 6); or 3) LPS and thaumatin, a cationic protein devoid of LPS neutralizing activity that has a molecular mass and isoelectric point that are similar to that of BPI23 (n = 7). BPI23 treatment significantly ameliorated LPS-induced hypoxemia, functional upregulation of opsonin receptors on circulating phagocytes, and alveolitis but had no effect on the elaboration of tumor necrosis factor-alpha or thromboxane A2. The salutory effects of BPI23 on acute lung injury in endotoxemic pigs may be mediated, at least in part, by inhibition of direct activation of phagocytes by LPS.

Protection from endotoxemia by adenoviral-mediated gene transfer of human bactericidal/permeability-increasing protein

“…Furthermore we demonstrate that BPI gene transfer protected mice from lethal endotoxic shock. These results coincide with the observed reduction of proinflammatory mediators in published models of endotoxemia or Gram-negative sepsis using recombinant N-terminal human BPI protein, [24][25][26][27][28][29][30][31][32][33][34][35] and therefore support the use of BPI transgene as an adjunct therapeutic agent for such conditions. However, it should be pointed out that in our current study, we have evaluated only the therapeutic effect of AdhBPI in endotoxic models, and whether AdhBPI vector is effective in models of Gram-negative bacterial sepsis still remains to be determined.…”

“…31,53,54 While the majority of therapeutic strategies designed for treating sepsis have failed, 18 recent studies suggest that recombinant BPI protein is a promising therapeutic agent. [33][34][35][36][37][38][39][40] However, the production and purification of recombinant BPI have proved uneasy tasks, since BPI cannot be produced in the conventional Gram-negative bacterial strains and has to be produced in mammalian cell lines. 24 It is also difficult to maintain the integrity of purified full-length BPI protein due to its large molecular weight and complex structure.…”

“…Indeed, several studies have evaluated the effect of recombinant BPI protein in experimental models of sepsis and endotoxemia in rabbits, rats, pigs, and mice. [31][32][33][34][35][36] Furthermore, phase 1/2/3 clinical trials using recombinant BPI have been performed or are currently under way. 32,[37][38][39][40] In most cases, the regimen entails a continuous infusion of 2 to 8 mg/kg recombinant BPI for a period of 2 days.…”

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

“…In a porcine model of endotoxemic adult respiratory distress syndrome, rBPI 23 administration significantly reduced endotoxin-induced hypoxemia and alveolitis. 42 In another model, mice were intratracheally inoculated with Escherichia coli to create a gram-negative pneumonia. Correlating with the enhanced pulmonary and vascular clearance of bacteria, a significantly increased survival was found in the rBPI 23 -treated animals.…”

Role of Oxygen in Phagocyte Microbicidal Action

“…The AXIS system is ultimately designed for use in patient diagnosis and management (46,47). However, the system also has broad potential for assessing inflammation and antiinflammatory activity using in vivo and in vitro models (48).…”