TY - JOUR
T1 - Regulation of tumor necrosis factor-α production in the isolated rat heart stimulated by bacterial lipopolysaccharide or reactive oxygen
AU - Jennings, G. Russell
AU - Castresana, Manuel R.
AU - Newman, Walter H.
PY - 2004/12/1
Y1 - 2004/12/1
N2 - Reperfusion after cardiopulmonary bypass causes induction of reactive oxygen species (ROS), elevated plasma levels of bacterial lipopolysaccharide (LPS), and production of tumor necrosis factor-α (TNF) by the heart. Nuclear factor-κB (NF-κB) regulates the expression of TNF. Because NF-κB is activated by both LPS and ROS, we hypothesized that an inhibitor of NF-κB, pyrrolidine dithiocarbamate (PDTC), would block release of TNF from the heart stimulated by these two agents. With Institutional animal care and use committee (IACUC) approval, rat hearts were perfused Langendorf style. LPS was infused and ROS were generated with a hypoxanthine/xanthine oxidase system. PDTC was added to the perfusion buffer. Other hearts were treated with forskolin in order to elevate cyclic AMP. Timed collections of coronary effluent were made for the determination of coronary flow and measurement of TNF. LPS stimulated TNF release to a maximum of 2247 ± 133 pg/min at 150 minutes. PDTC inhibited LPS-stimulated TNF release. For instance, at 150 minutes, LPS-stimulated TNF release was 449 ± 49 pg/min with 100 μM PDTC and was 70 ± 65 pg/mL with 250μM PDTC (P < 0.05 vs LPS alone). ROS stimulated TNF release was 1494 ± 130 pg/min at 150 minutes and was not affected by PDTC. Forskolin almost completely blocked TNF release stimulated by LPS or ROS. These data are consistent with the notion that inhibitors of NF-κB block cytokine production stimulated by some agents but not others.
AB - Reperfusion after cardiopulmonary bypass causes induction of reactive oxygen species (ROS), elevated plasma levels of bacterial lipopolysaccharide (LPS), and production of tumor necrosis factor-α (TNF) by the heart. Nuclear factor-κB (NF-κB) regulates the expression of TNF. Because NF-κB is activated by both LPS and ROS, we hypothesized that an inhibitor of NF-κB, pyrrolidine dithiocarbamate (PDTC), would block release of TNF from the heart stimulated by these two agents. With Institutional animal care and use committee (IACUC) approval, rat hearts were perfused Langendorf style. LPS was infused and ROS were generated with a hypoxanthine/xanthine oxidase system. PDTC was added to the perfusion buffer. Other hearts were treated with forskolin in order to elevate cyclic AMP. Timed collections of coronary effluent were made for the determination of coronary flow and measurement of TNF. LPS stimulated TNF release to a maximum of 2247 ± 133 pg/min at 150 minutes. PDTC inhibited LPS-stimulated TNF release. For instance, at 150 minutes, LPS-stimulated TNF release was 449 ± 49 pg/min with 100 μM PDTC and was 70 ± 65 pg/mL with 250μM PDTC (P < 0.05 vs LPS alone). ROS stimulated TNF release was 1494 ± 130 pg/min at 150 minutes and was not affected by PDTC. Forskolin almost completely blocked TNF release stimulated by LPS or ROS. These data are consistent with the notion that inhibitors of NF-κB block cytokine production stimulated by some agents but not others.
UR - http://www.scopus.com/inward/record.url?scp=16544393891&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=16544393891&partnerID=8YFLogxK
M3 - Article
C2 - 15481297
AN - SCOPUS:16544393891
SN - 0003-1348
VL - 70
SP - 797
EP - 800
JO - American Surgeon
JF - American Surgeon
IS - 9
ER -