TY - JOUR
T1 - Inhibition of Splenic Macrophage Tumor Necrosis Factor α Secretion In Vivo by Antilipopolysaccharide Monoclonal Antibodies
AU - Battafarano, Richard J.
AU - Burd, Randall S.
AU - Kurrelmeyer, Karla M.
AU - Ratz, Craig A.
AU - Dunn, David L.
PY - 1994/2
Y1 - 1994/2
N2 - Objective: This study tried to determine whether administration of antilipopolysaccharide (LPS) murine monoclonal antibody (mAb) 2A3 to mice was associated with (1) protective capacity during experimental gram-negative bacterial sepsis, and (2) inhibition of tumor necrosis factor α (TNF-α) secretion in the systemic circulation and at the tissue level during experimental infection. Design: Mice received an initial intravenous injection of either saline or 100 μg of anti-LPS mAb 2A3, and 1 hour later underwent intraperitoneal inoculation of viable Escherichia coli 0111:B4. Mortality was assessed daily for 7 days. Separate groups of mice were treated similarly and plasma TNF-α concentrations were determined from blood samples obtained at 1, 3, 6, 10, and 16 hours after infection by enzyme-linked immunosorbent assay. Concurrently, splenocytes harvested from animals 3, 10, and 16 hours after infection were incubated in culture ex vivo and supernatant TNF-α levels were determined. Results: Pretreatment with anti- LPS mAb 2A3 prior to an intraperitoneal challenge of live E coli 0111:B4 was associated with the following: (1) significant protective capacity (100% vs 0% mortality, P<.001); (2) inhibition of plasma TNF-α levels 16 hours after infection (1257 ± 323 pg/mL vs 292 ± 254 pg/mL, P<.001); and (3) abrogation of TNF-α secretion derived from splenic macrophages isolated 16 hours after bacterial challenge (229 ± 12 pg/mL vs 107 ± 48 pg/mL, p<.05). Conclusions: These results strongly support the contention that inhibition of LPS-induced TNF-α secretion at both the tissue and systemic levels is a key mechanism by which anti-LPS mAbs provide protection during gram-negative bacterial peritonitis. We believe that in vivo monitoring of macrophage cytokine secretion will be critical for elucidating the precise role of a variety of mediators in the pathogenesis of gram-negative bacterial sepsis.
AB - Objective: This study tried to determine whether administration of antilipopolysaccharide (LPS) murine monoclonal antibody (mAb) 2A3 to mice was associated with (1) protective capacity during experimental gram-negative bacterial sepsis, and (2) inhibition of tumor necrosis factor α (TNF-α) secretion in the systemic circulation and at the tissue level during experimental infection. Design: Mice received an initial intravenous injection of either saline or 100 μg of anti-LPS mAb 2A3, and 1 hour later underwent intraperitoneal inoculation of viable Escherichia coli 0111:B4. Mortality was assessed daily for 7 days. Separate groups of mice were treated similarly and plasma TNF-α concentrations were determined from blood samples obtained at 1, 3, 6, 10, and 16 hours after infection by enzyme-linked immunosorbent assay. Concurrently, splenocytes harvested from animals 3, 10, and 16 hours after infection were incubated in culture ex vivo and supernatant TNF-α levels were determined. Results: Pretreatment with anti- LPS mAb 2A3 prior to an intraperitoneal challenge of live E coli 0111:B4 was associated with the following: (1) significant protective capacity (100% vs 0% mortality, P<.001); (2) inhibition of plasma TNF-α levels 16 hours after infection (1257 ± 323 pg/mL vs 292 ± 254 pg/mL, P<.001); and (3) abrogation of TNF-α secretion derived from splenic macrophages isolated 16 hours after bacterial challenge (229 ± 12 pg/mL vs 107 ± 48 pg/mL, p<.05). Conclusions: These results strongly support the contention that inhibition of LPS-induced TNF-α secretion at both the tissue and systemic levels is a key mechanism by which anti-LPS mAbs provide protection during gram-negative bacterial peritonitis. We believe that in vivo monitoring of macrophage cytokine secretion will be critical for elucidating the precise role of a variety of mediators in the pathogenesis of gram-negative bacterial sepsis.
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U2 - 10.1001/archsurg.1994.01420260075010
DO - 10.1001/archsurg.1994.01420260075010
M3 - Article
C2 - 8304828
AN - SCOPUS:0027979156
VL - 129
SP - 179
EP - 186
JO - Archives of Surgery
JF - Archives of Surgery
SN - 0004-0010
IS - 2
ER -