Limulus Antilipopolysaccharide Factor Protects Rabbits from Meningococcal Endotoxin Shock

Abstract

Limulus antilipopolysaccharide factor (LALF), an 11.8-kDa peptide isolated from amebocytes of Limulus polyphemus, neutralizes meningococcal lipooligosaccharide (LOS)-induced gelation of limulus amebocyte lysate. Rabbits challenged with an LD90 of LOS (10 micrograms/kg) premixed with LALF in vitro (n = 10) had significantly higher mean arterial pressure, arterial pH, serum bicarbonate concentrations, and survival (90% vs. 8%, P = .005) than did rabbits challenged with LOS alone. Relative to untreated controls, rabbits pretreated with LALF intravenously (iv) at 1.2 mg/kg (n = 21) also had significant improvements in physiologic measurements and higher survival (52% vs. 8%, P = .003). Even when LALF (1.2 mg/kg iv) was given 1/2 h after LOS challenge, animals showed significant improvements in physiologic measurements and survival (33% vs. 8% in untreated controls P = .028). LALF-treated animals also had significantly lower circulating endotoxin activity and tumor necrosis factor concentrations. Thus, LALF attenuates the toxic effects of meningococcal LOS in rabbits even when administered after LOS challenge and deserves further evaluation as a potential therapeutic agent for treating gram-negative septic shock.

Mechanisms of bacterial lipopolysaccharide-induced endothelial apoptosis

“…Lipid A alone is capable of eliciting EC responses identical to those induced by LPS (16,50,193). Agents that specifically target the lipid A moiety of LPS inhibit EC activation (16,52) and protect against the development of vascular complications in endotoxin shock models (6,210). Similar to activation, the lipid A moiety is also responsible for the proapoptotic properties of the LPS molecule (84).…”

“…Second, administration of LPS alone to experimental animals reconstitutes the EC injury seen after gram-negative bacterial challenge (27,201). Third, immunological and pharmacological interventions that specifically target the LPS molecule protect against these same vascular complications (6,210,211,225). Finally, LPS directly elicits several of the EC responses in vitro that are similarly evoked during sepsis, including: 1) the production of the proinflammatory cytokines IL-6 (77,109), IL-8 (7,77,223), and IL-1␤ (57,138); 2) the increased surface expression of the adhesion molecules E-selectin, intercellular adhesion molecule (ICAM)-1, and vascular cell adhesion molecule (VCAM)-1 (34,59,77,108); and 3) increased expression of tissue factor (42,75).…”

Update on Meningococcal Disease with Emphasis on Pathogenesis and Clinical Management

“…Shock is caused by capillary leakage, inappropriate vascular tone, intravascular microthrombi, and myocardial dysfunction. The central activator that elicits these derangements is meningococcal endotoxin (6,69,212), and the severity of shock correlates with the degree of endotoxinemia (54,55,57,495).…”

Synthetic Endotoxin-Binding Peptides Block Endotoxin- Triggered TNF-α Production by Macrophages In Vitro and In Vivo and Prevent Endotoxin-Mediated Toxic Shock

“…Several candidate molecules with endotoxin-binding and neutralizing capability are known and bactericidal/permeability increasing protein (BPI) may be until now the most promising candidate (14 -16). Limulus anti-LPS factor (LALF) is a protein from the horseshoe crab with high potential to block endotoxin-mediated activities in animals (17)(18)(19)(20). Both BPI and LALF crystal structures are known, and the LALF analysis revealed a detailed view of a potential endotoxin-binding site (21).…”