Protective anti-lipopolysaccharide monoclonal antibodies inhibit tumor necrosis factor production

Cody, Carolyn S.; Burd, Randall S.; Mayoral, Jaime L.; Dünn, David L.

doi:10.1016/0022-4804(92)90109-d

Cited by 15 publications

(6 citation statements)

References 19 publications

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“…In a murine mucin peritonitis model of sepsis, antibodies against LPS were observed to inhibit TNF-␣ production. 28 Moreover, TNF-␣ has been reported to regulate in vivo NO synthesis and to induce liver injury during endotoxemia. 29 In cultured guinea pig tracheal epithelial cells, hypersecretion of mucin in response to TNF-␣ could be inhibited by NO synthase antagonist.…”

Section: Discussionmentioning

confidence: 99%

Lipopolysaccharide From Escherichia Coli Stimulates Mucin Secretion by Cultured Dog Gallbladder Epithelial Cells

et al. 1999

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Biliary infection is associated with mucin hypersecretion by the biliary epithelium. Mucins have been identified as potent pronucleators of cholesterol in bile. The aim of the present study was to determine whether lipopolysaccharides (LPS) from different bacteria are capable of stimulating mucin secretion by cultured dog gallbladder epithelial (DGBE) cells, and to investigate the mechanism by which LPS stimulate mucin secretion. Mucin secretion by confluent monolayers of DGBE cells was quantified by measuring the secretion of [3H]-N-acetyl-D-glucosamine-labeled glycoproteins. Cell viability was evaluated by measuring the leakage of the enzyme, lactate dehydrogenase (LDH), into the culture medium. LPS, derived from Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa (200 g/mL), all caused an increase in mucin secretion by the DGBE cells, without causing concomitant cell lysis. LPS from E. coli was found to be the most potent stimulator of mucin secretion, and increased mucin secretion by the DGBE cells to 252% ؎ 14% of control. LPS from E. coli had no effect on intracellular cyclic adenosine monophosphate (cAMP) levels in the DGBE cells. Addition of the nitric oxide (NO)-releasing compound, NOR-4 (0.125-1 mmol/L), to the cells did not result in increased mucin secretion, and the NO synthase inhibitor, N -nitro-L-arginine methyl ester (L-NAME) (4 or 10 mmol/L), did not inhibit the LPSstimulated mucin secretion. Exogenous tumor necrosis factor ␣ (TNF-␣) (1-10 ng/mL) did cause a minor increase in mucin secretion by the DGBE cells, but the effect of LPS from E. coli on mucin secretion could not be inhibited by preincubation with a TNF-␣ antibody (10 g/mL). We conclude that LPS stimulates mucin secretion by the gallbladder epithelium. Whether this stimulation is mediated by TNF-␣ remains to be determined. (HEPATOLOGY 1999;29:1352-1357.)Gallbladder mucin, the primary glycoprotein secreted by the gallbladder, is a densely glycosylated macromolecule with a molecular mass of approximately 2 ϫ 10 6 d. Mucin is regarded as an important contributing factor to gallstone formation. [1][2][3] Mucin has been shown to be present in the nucleus of several types of gallstones, and a macromolecular complex of mucin and bilirubin has been identified as a major structural component of the gallstone matrix. 4,5 Purified human gallbladder mucin is capable of nucleating cholesterol crystals from human bile. 6 Gallbladder mucus hypersecretion and increased mucin concentration are common findings in nearly all animal models of cholesterol gallstone disease. Mucin hypersecretion precedes crystal or stone formation. 7,8 These findings suggest that increased mucin secretion plays a role in the initial stages of gallstone formation.We have reported the succesful long-term culturing and passaging of normal, well-differentiated gallbladder epithelial cells from the dog. 9 These cells form electrically leakproof monolayers and synthesize protein and mucous glycoprotein. They have been extensively studied with regard to water and ...

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Section: Discussionmentioning

confidence: 99%

Lipopolysaccharide From Escherichia Coli Stimulates Mucin Secretion by Cultured Dog Gallbladder Epithelial Cells

et al. 1999

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“…mAb 5A5 (IgM) was purified using a DEAE disk employing a previously described technique [25], while IgG mAbs 7C5 and 1B6 were purified using a protein A or protein G column (FMC, Pine Brook, NJ). mAb binding to various Gram-negative bacteria and LPSs was characterized by Western immunotransblot analysis and enzyme-linked immunosorbent assay (ELISA) as previously described [17,24,26,27].…”

Section: Methodsmentioning

confidence: 99%

Antiendotoxin Agents Share Molecular Homology within Their Lipopolysaccharide Binding Domains

Kellogg

Weiss

Johnston

et al. 1999

Journal of Surgical Research

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“…With the advent of hybridoma technology, murine and then human anti-LPS mAbs were developed and characterized [44][45][46][47][48][49]. However, it was noted that anti-DCLA mAbs bound with lower affinity to various types of LPS and conferred less protective capacity in animal models of endotoxemia and infection compared with mAbs directed against the strainspecific O-antigen polysaccharide region of LPS [41].…”

Section: Experimental Approaches To Blocking Endotoxin Effectsmentioning

confidence: 99%

Prevention and Treatment of Multiple Organ Dysfunction Syndrome: Lessons Learned and Future Prospects

Dünn

2000

Surgical Infections

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Gram-negative bacteria commonly cause serious infections in hospitalized patients, and those that lead to bacteremic episodes and sepsis syndrome are associated with the highest mortality rate. Sepsis syndrome frequently progresses to multisystem organ dysfunction and failure, with as many as 400,000 cases occurring annually. Unfortunately, the associated mortality rate remains about 40%. Lipopolysaccharide (LPS, endotoxin), an integral component of the gram-negative bacterial outer membrane, plays a critical role in the pathophysiology of this lethal disease process. It is capable of interacting with host macrophages, a process that leads to the secretion of an increasingly well-characterized array of macrophage cytokines. Several different classes of compounds that bind directly to LPS and thereby neutralize its effects are being examined. These consist of anti-LPS monoclonal antibodies (mAbs), naturally occurring proteins and their derivatives (e.g., bactericidal/permeability-increasing protein [BPI], Limulus anti-LPS factor [LALF]), and certain antibiotics (polymyxin B, taurolidine). The molecular biology of BPI, LALF, and LPS binding protein (LBP, which augments the host response to LPS) is of considerable interest, as each demonstrates considerable genetic sequence homology. Although two anti-LPS monoclonal antibodies (HA-1A, E5) did not demonstrate efficacy during sepsis syndrome, information obtained from these clinical trials provided investigators with the ability to better understand this disease process. However, a detailed understanding of the biology of endotoxin antagonism is beginning to emerge, and the application of this knowledge in the clinical setting provides hope that it may be possible to reduce the mortality of sepsis syndrome caused by these microorganisms to a statistic well below the current 40%.

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Protective anti-lipopolysaccharide monoclonal antibodies inhibit tumor necrosis factor production

Cited by 15 publications

References 19 publications

Lipopolysaccharide From Escherichia Coli Stimulates Mucin Secretion by Cultured Dog Gallbladder Epithelial Cells

Lipopolysaccharide From Escherichia Coli Stimulates Mucin Secretion by Cultured Dog Gallbladder Epithelial Cells

Antiendotoxin Agents Share Molecular Homology within Their Lipopolysaccharide Binding Domains

Prevention and Treatment of Multiple Organ Dysfunction Syndrome: Lessons Learned and Future Prospects

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