The role of Kupffer cell inhibition in porcine endotoxemia

The selective Kupffer cell inhibitor gadolinium chloride (GdCl3) has been d emonstrated to protect animals from lethality in experimental endotoxemia a nd sepsis in rodent models. This study was designed to investigate the effe ct of Kupffer cell blockade on the early response to endotoxin in a large a nimal model. Using a porcine endotoxemia model, animals were randomized to receive either GdCl3 (10 mg/kg or 30 mg/kg; n = 8 in each group) or vehicle saline (n = 8) 24 h before exposure to endotoxin. Pretreatment with GdCl3 resulted in a dose dependent reduction in early hepatic oxygen consumption as well as oxygen extraction ratio in response to continuous infusion of en dotoxin. At 5 h there was significant lower serum AST level in animals give n 30 mg/kg of GdCl3 as compared to the two other groups. Pretreatment with GdCl3 induced a dose dependent reduction of Kupffer cells in the liver sinu soids. Despite this, all animals deteriorated with continuous infusion of e ndotoxin as evidenced by the progressive reduction in cardiac output, mean arterial pressure and total liver blood flow. Also, increases in pulmonary arterial pressure, portal venous pressure and systemic, pulmonary and hepat ic vascular resistance were seen. This is consistent with activation of oth er cell populations and defense mechanisms by endotoxin, perpetuating the s eptic response. However, modulation of reticuloendothelial cell function se ems feasible also in larger animals, and our results stimulate to further r esearch on potential immunomodulatory tools in early sepsis.