Aspirin inhibits bacterial lipopolysaccharide (LPS) stimulated release of tumor necrosis factor alpha (TNF-α) from the isolated rat heart

Walter H. Newman, Manuel R Castresana, Stefan K. Erceg, Debra J. Warejcka

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Abstract

Introduction: In heart failure and following myocardial infarction, plasma levels of TNF-α are elevated. The source of the cytokine is unknown. We hypothesized that the heart, itself, could be a source of TNF-α. Further, aspirin has recently been shown to block activation of the nuclear regulatory factor κB (NF-κB) which, in other systems, is involved in TNF-α gene transcription. We therefore tested the hypothesis that aspirin pretreatment would block TNF-α release from the heart. Methods: With IACUC approval, rats were anesthetized with pentobarbital. Hearts were removed and perfused Langendorf style at a constant pressure of 90 cm H2O with a buffer gassed with 95%O2/5%CO2. Following a 30 min. equilibration, LPS (100 ng/ml) was infused. At 30, 60, 90, 120, and 180 min. after initiation of LPS infusion, coronary flow was measured and coronary effluent analyzed for TNF-α and 6-keto-PGF. In other experiments, aspirin (2, 5 and 10 mM) or indomethacin (10 μM) was added to the perfusing buffer. TNF-α production is expressed as pg/min (concentration multiplied by flow). Data were analyzed by two-way ANOVA. Results: TNF-α was first detected at 90 min. after LPS and increased to max at 180 min. Aspirin (5 and 10 mM) inhibited LPS-stimulated TNF-α release (see Table). LPS-stimulated release of TNF-α was not affected by indomethacin. Both aspirin and indomethacin inhibited production of 6-keto-PGF. TNF-α Production by Isolated Heart (pg/min) Minutes 90 120 180 LPS 74±18 723±200 2442±600 LPS + 5 mM aspirin 157±75 675±160 1260±340*LPS + 10 mM aspirin 22±13*19±7*101±59*Values are mean ± s.d. N = 4 hearts/group.*= p<0.05 vs. LPS. Conclusion: Isolated rat hearts are a source of TNF-α. Pretreatment with aspirin significantly attenuates LPS-stimulated cytokine production. The mechanism of inhibition appears independent of cyclooxygenase blockade because both aspirin and indomethacin inhibited prostaglandin production but indomethacin had no effect on TNF-α production. A possible mechanism is inhibition of TNF-α gene transcription by aspirin blockade of NF-κB activation.

Original languageEnglish (US)
JournalCritical care medicine
Volume27
Issue number1 SUPPL.
StatePublished - Dec 1 1999

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Aspirin
Lipopolysaccharides
Tumor Necrosis Factor-alpha
Indomethacin
Buffers
Animal Care Committees
Cytokines
Pentobarbital
Prostaglandin-Endoperoxide Synthases
Genes
Prostaglandins
Analysis of Variance
Heart Failure
Myocardial Infarction
Pressure

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine

Cite this

Aspirin inhibits bacterial lipopolysaccharide (LPS) stimulated release of tumor necrosis factor alpha (TNF-α) from the isolated rat heart. / Newman, Walter H.; Castresana, Manuel R; Erceg, Stefan K.; Warejcka, Debra J.

In: Critical care medicine, Vol. 27, No. 1 SUPPL., 01.12.1999.

Research output: Contribution to journalArticle

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title = "Aspirin inhibits bacterial lipopolysaccharide (LPS) stimulated release of tumor necrosis factor alpha (TNF-α) from the isolated rat heart",
abstract = "Introduction: In heart failure and following myocardial infarction, plasma levels of TNF-α are elevated. The source of the cytokine is unknown. We hypothesized that the heart, itself, could be a source of TNF-α. Further, aspirin has recently been shown to block activation of the nuclear regulatory factor κB (NF-κB) which, in other systems, is involved in TNF-α gene transcription. We therefore tested the hypothesis that aspirin pretreatment would block TNF-α release from the heart. Methods: With IACUC approval, rats were anesthetized with pentobarbital. Hearts were removed and perfused Langendorf style at a constant pressure of 90 cm H2O with a buffer gassed with 95{\%}O2/5{\%}CO2. Following a 30 min. equilibration, LPS (100 ng/ml) was infused. At 30, 60, 90, 120, and 180 min. after initiation of LPS infusion, coronary flow was measured and coronary effluent analyzed for TNF-α and 6-keto-PGF1α. In other experiments, aspirin (2, 5 and 10 mM) or indomethacin (10 μM) was added to the perfusing buffer. TNF-α production is expressed as pg/min (concentration multiplied by flow). Data were analyzed by two-way ANOVA. Results: TNF-α was first detected at 90 min. after LPS and increased to max at 180 min. Aspirin (5 and 10 mM) inhibited LPS-stimulated TNF-α release (see Table). LPS-stimulated release of TNF-α was not affected by indomethacin. Both aspirin and indomethacin inhibited production of 6-keto-PGF1α. TNF-α Production by Isolated Heart (pg/min) Minutes 90 120 180 LPS 74±18 723±200 2442±600 LPS + 5 mM aspirin 157±75 675±160 1260±340*LPS + 10 mM aspirin 22±13*19±7*101±59*Values are mean ± s.d. N = 4 hearts/group.*= p<0.05 vs. LPS. Conclusion: Isolated rat hearts are a source of TNF-α. Pretreatment with aspirin significantly attenuates LPS-stimulated cytokine production. The mechanism of inhibition appears independent of cyclooxygenase blockade because both aspirin and indomethacin inhibited prostaglandin production but indomethacin had no effect on TNF-α production. A possible mechanism is inhibition of TNF-α gene transcription by aspirin blockade of NF-κB activation.",
author = "Newman, {Walter H.} and Castresana, {Manuel R} and Erceg, {Stefan K.} and Warejcka, {Debra J.}",
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T1 - Aspirin inhibits bacterial lipopolysaccharide (LPS) stimulated release of tumor necrosis factor alpha (TNF-α) from the isolated rat heart

AU - Newman, Walter H.

AU - Castresana, Manuel R

AU - Erceg, Stefan K.

AU - Warejcka, Debra J.

PY - 1999/12/1

Y1 - 1999/12/1

N2 - Introduction: In heart failure and following myocardial infarction, plasma levels of TNF-α are elevated. The source of the cytokine is unknown. We hypothesized that the heart, itself, could be a source of TNF-α. Further, aspirin has recently been shown to block activation of the nuclear regulatory factor κB (NF-κB) which, in other systems, is involved in TNF-α gene transcription. We therefore tested the hypothesis that aspirin pretreatment would block TNF-α release from the heart. Methods: With IACUC approval, rats were anesthetized with pentobarbital. Hearts were removed and perfused Langendorf style at a constant pressure of 90 cm H2O with a buffer gassed with 95%O2/5%CO2. Following a 30 min. equilibration, LPS (100 ng/ml) was infused. At 30, 60, 90, 120, and 180 min. after initiation of LPS infusion, coronary flow was measured and coronary effluent analyzed for TNF-α and 6-keto-PGF1α. In other experiments, aspirin (2, 5 and 10 mM) or indomethacin (10 μM) was added to the perfusing buffer. TNF-α production is expressed as pg/min (concentration multiplied by flow). Data were analyzed by two-way ANOVA. Results: TNF-α was first detected at 90 min. after LPS and increased to max at 180 min. Aspirin (5 and 10 mM) inhibited LPS-stimulated TNF-α release (see Table). LPS-stimulated release of TNF-α was not affected by indomethacin. Both aspirin and indomethacin inhibited production of 6-keto-PGF1α. TNF-α Production by Isolated Heart (pg/min) Minutes 90 120 180 LPS 74±18 723±200 2442±600 LPS + 5 mM aspirin 157±75 675±160 1260±340*LPS + 10 mM aspirin 22±13*19±7*101±59*Values are mean ± s.d. N = 4 hearts/group.*= p<0.05 vs. LPS. Conclusion: Isolated rat hearts are a source of TNF-α. Pretreatment with aspirin significantly attenuates LPS-stimulated cytokine production. The mechanism of inhibition appears independent of cyclooxygenase blockade because both aspirin and indomethacin inhibited prostaglandin production but indomethacin had no effect on TNF-α production. A possible mechanism is inhibition of TNF-α gene transcription by aspirin blockade of NF-κB activation.

AB - Introduction: In heart failure and following myocardial infarction, plasma levels of TNF-α are elevated. The source of the cytokine is unknown. We hypothesized that the heart, itself, could be a source of TNF-α. Further, aspirin has recently been shown to block activation of the nuclear regulatory factor κB (NF-κB) which, in other systems, is involved in TNF-α gene transcription. We therefore tested the hypothesis that aspirin pretreatment would block TNF-α release from the heart. Methods: With IACUC approval, rats were anesthetized with pentobarbital. Hearts were removed and perfused Langendorf style at a constant pressure of 90 cm H2O with a buffer gassed with 95%O2/5%CO2. Following a 30 min. equilibration, LPS (100 ng/ml) was infused. At 30, 60, 90, 120, and 180 min. after initiation of LPS infusion, coronary flow was measured and coronary effluent analyzed for TNF-α and 6-keto-PGF1α. In other experiments, aspirin (2, 5 and 10 mM) or indomethacin (10 μM) was added to the perfusing buffer. TNF-α production is expressed as pg/min (concentration multiplied by flow). Data were analyzed by two-way ANOVA. Results: TNF-α was first detected at 90 min. after LPS and increased to max at 180 min. Aspirin (5 and 10 mM) inhibited LPS-stimulated TNF-α release (see Table). LPS-stimulated release of TNF-α was not affected by indomethacin. Both aspirin and indomethacin inhibited production of 6-keto-PGF1α. TNF-α Production by Isolated Heart (pg/min) Minutes 90 120 180 LPS 74±18 723±200 2442±600 LPS + 5 mM aspirin 157±75 675±160 1260±340*LPS + 10 mM aspirin 22±13*19±7*101±59*Values are mean ± s.d. N = 4 hearts/group.*= p<0.05 vs. LPS. Conclusion: Isolated rat hearts are a source of TNF-α. Pretreatment with aspirin significantly attenuates LPS-stimulated cytokine production. The mechanism of inhibition appears independent of cyclooxygenase blockade because both aspirin and indomethacin inhibited prostaglandin production but indomethacin had no effect on TNF-α production. A possible mechanism is inhibition of TNF-α gene transcription by aspirin blockade of NF-κB activation.

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