Gram-negative sepsis is a major cause of morbidity and mortality in patients with liver disease. The liver is the major site for bacterial clearance and liver disease is associated with an increased incidence of bacteremia. Within the liver, the Kupffer cell is the main cell type responsible for detecting and clearing bacteria and their constituent lipopolysaccharide (LPS). Although Kupffer cells only represent 15 percent of the total cells within the liver, they constitute 80-90 percent of all the fixed tissue macrophages within the body. Strategically and uniquely located at the gateway of the portal blood flow, Kupffer cells have a crucial role in preventing Gram-negative bacteria and LPS from reaching the systemic circulation. Little is known about the molecular mechanisms involved in Kupffer cell detection, phagocytosis and killing of Gram-negative bacteria despite the critical importance of these processes. Recent investigations in monocytes have begun to shed light on the molecular interactions involved in leukocyte responses to Gram-negative bacteria. Bacterial killing is a complex process which is dependent on a series of leukocyte responses including recognition/binding, phagocytosis, and activation of intracellular microbicidal systems before bacterial killing can occur. Several lines of evidence suggest that LPS binding protein (LBP) and CD14 provide a crucial pathway which facilitates Gram-negative bacterial killing, LBP binds specifically to the lipid A portion of LPS on Gram-negative bacteria to form a complex. This LBP-LPS complex binds with high affinity to membrane CD14 found on neutrophils, monocytes and macrophages. Binding of LPS-LBP to mCD14 results in cellular activation and production of inflammatory mediators. The LPS-LBP complex is subsequently internalized by undefined mechanisms. The role of LBP and CD14 in Kupffer cell bacterial killing has not been studied, but recent evidence in LBP knockout mice suggest that they comprise a critical pathway. We hypothesize that Kupffer cells utilize LBP and CD14 to bind ingest and kill Gram-negative bacteria. Our experimental Aims are intimately related and feasible: I. Determine the mechanism by which LBP and CD14 promote attachment of Gram-negative bacteria. II. Determine the mechanism by which LBP and CD14 accelerate ingestion of Gram-negative bacteria. III. Determine the mechanisms by which LBP/CD14 mediated KC activation promote bacterial killing.
| Su, Grace L; Gong, Ke Qin; Fan, Ming Hui et al. (2005) Lipopolysaccharide-binding protein modulates acetaminophen-induced liver injury in mice. Hepatology 41:187-95 |
| Steinstraesser, Lars; Burkhard, Olaf; Fan, Ming H et al. (2005) Burn wounds infected with Pseudomonas aeruginosa triggers weight loss in rats. BMC Surg 5:19 |
| Su, Grace L; Wang, Stewart C; Aminlari, Alireza et al. (2004) Impaired hepatocyte regeneration in toll-like receptor 4 mutant mice. Dig Dis Sci 49:843-9 |
| Su, Grace L (2002) Lipopolysaccharides in liver injury: molecular mechanisms of Kupffer cell activation. Am J Physiol Gastrointest Liver Physiol 283:G256-65 |
| Nanji, Amin A; Su, Grace L; Laposata, Michael et al. (2002) Pathogenesis of alcoholic liver disease--recent advances. Alcohol Clin Exp Res 26:731-6 |
| Fan, Ming-Hui; Klein, Richard D; Steinstraesser, Lars et al. (2002) An essential role for lipopolysaccharide-binding protein in pulmonary innate immune responses. Shock 18:248-54 |
| Steinstraesser, Lars; Tack, Brian F; Waring, Alan J et al. (2002) Activity of novispirin G10 against Pseudomonas aeruginosa in vitro and in infected burns. Antimicrob Agents Chemother 46:1837-44 |
| Steinstraesser, L; Fohn, M; Klein, R D et al. (2001) Feasibility of biolistic gene therapy in burns. Shock 15:272-7 |
| Steinstraesser, L; Klein, R D; Aminlari, A et al. (2001) Protegrin-1 enhances bacterial killing in thermally injured skin. Crit Care Med 29:1431-7 |
| Su, G L; Klein, R D; Aminlari, A et al. (2000) Kupffer cell activation by lipopolysaccharide in rats: role for lipopolysaccharide binding protein and toll-like receptor 4. Hepatology 31:932-6 |
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