Cholestatic liver injury increases circulating TNF-α and IL-6 and mortality after Escherichia coli endotoxemia

Andrew J. Lechner, Alvaro Velasquez, Karl R. Knudsen, Cheryl A. Johanns, Thomas F. Tracy, George M. Matuschak

Research output: Contribution to journalArticle

58 Citations (Scopus)

Abstract

We employed a bile duct ligation (BDL) model of cholestatic liver injury to test the hypothesis that this form of preexisting hepatic dysfunction alters the kinetics of circulating TNF-α and IL-6 after Escherichia coli endotoxemia, thereby augmenting mortality and lung injury by a TNF-α:leukotriene (LT) axis of inflammation. Male rats were catheterized 13 d after BDL or sham surgery and studied while awake 18 to 24 h later. Cholestasis after BDL was confirmed by baseline serum bilirubin (BDL = 7.34 ± 0.72 mg/dl, mean ± SEM, n = 17 versus Sham = 0.25 ± 0.07, n = 20; p < 0.005) and histopathology. Sham and BDL animals received E. coli lipopolysaccharide serotype O55:B5 (LPS, 5 mg/kg i.v.) or 0.9% NaCl (NS) ending at t = 0 and were monitored over 24 h for vital signs and hemodynamics. In parallel studies, lipoxygenase inhibition was performed using diethylcarbamazine or the 5-lipoxygenase activating-protein inhibitor MK-886. Blood was collected at baseline and at t = 1.5, 3.5, and 24 h for formed elements and for serum endotoxin, TNF-α, IL-6, bilirubin, and alanine aminotransferase (ALT). Organs were evaluated at 24 h for histopathology, including neutrophil (PMN) densities and wet/dry weight (W/D) ratios. Cholestasis reduced survival after otherwise nonlethal endotoxemia, with seven of 11 BDL + LPS rats dying within 24 h versus no deaths in BDL + NS (n = 6), Sham + LPS (n = 14), or Sham + NS (n = 6) animals (p < 0.01). Despite equivalent serum endotoxin between groups, circulating TNF-α was 8-fold higher in BDL + LPS than in Sham + LPS rats at 1.5 and 3.5 h (p < 0.001), whereas serum TNF-α did not differ between BDL + NS and Sham + NS rats. IL-6 likewise was increased differentially by 1.5 h in BDL + LPS animals (11.98 ± 2.42 ng/ml) versus Sham + LPS rats (3.05 ± 0.58 ng/ml, p < 0.05). Hypothermia, bradycardic hypotension, and leukopenia were most severe and prolonged in BDL + LPS rats, which also had significantly higher ALT values, W/D ratios, and organ PMN counts. LT inhibition failed to reduce BDL-related differences in serum cytokines or survival after endotoxemia. Thus, cholestasis augments inflammatory responses to gram-negative endotoxemia, sensitizing the host to enhanced fluid flux in multiple organs and to mortality by a LT-independent mechanism.

Original languageEnglish (US)
Pages (from-to)1550-1558
Number of pages9
JournalAmerican journal of respiratory and critical care medicine
Volume157
Issue number5 PART I
StatePublished - Dec 1 1998

Fingerprint

Endotoxemia
Bile Ducts
Ligation
Interleukin-6
Escherichia coli
Mortality
Liver
Wounds and Injuries
Leukotrienes
Cholestasis
Serum
Alanine Transaminase
L 663536
Bilirubin
Endotoxins
5-Lipoxygenase-Activating Protein Inhibitors
Diethylcarbamazine
Lipoxygenase
Organ Size
Vital Signs

All Science Journal Classification (ASJC) codes

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

Cite this

Lechner, Andrew J. ; Velasquez, Alvaro ; Knudsen, Karl R. ; Johanns, Cheryl A. ; Tracy, Thomas F. ; Matuschak, George M. / Cholestatic liver injury increases circulating TNF-α and IL-6 and mortality after Escherichia coli endotoxemia. In: American journal of respiratory and critical care medicine. 1998 ; Vol. 157, No. 5 PART I. pp. 1550-1558.
@article{99dad5fa6cbf4c5f870cded814a76276,
title = "Cholestatic liver injury increases circulating TNF-α and IL-6 and mortality after Escherichia coli endotoxemia",
abstract = "We employed a bile duct ligation (BDL) model of cholestatic liver injury to test the hypothesis that this form of preexisting hepatic dysfunction alters the kinetics of circulating TNF-α and IL-6 after Escherichia coli endotoxemia, thereby augmenting mortality and lung injury by a TNF-α:leukotriene (LT) axis of inflammation. Male rats were catheterized 13 d after BDL or sham surgery and studied while awake 18 to 24 h later. Cholestasis after BDL was confirmed by baseline serum bilirubin (BDL = 7.34 ± 0.72 mg/dl, mean ± SEM, n = 17 versus Sham = 0.25 ± 0.07, n = 20; p < 0.005) and histopathology. Sham and BDL animals received E. coli lipopolysaccharide serotype O55:B5 (LPS, 5 mg/kg i.v.) or 0.9{\%} NaCl (NS) ending at t = 0 and were monitored over 24 h for vital signs and hemodynamics. In parallel studies, lipoxygenase inhibition was performed using diethylcarbamazine or the 5-lipoxygenase activating-protein inhibitor MK-886. Blood was collected at baseline and at t = 1.5, 3.5, and 24 h for formed elements and for serum endotoxin, TNF-α, IL-6, bilirubin, and alanine aminotransferase (ALT). Organs were evaluated at 24 h for histopathology, including neutrophil (PMN) densities and wet/dry weight (W/D) ratios. Cholestasis reduced survival after otherwise nonlethal endotoxemia, with seven of 11 BDL + LPS rats dying within 24 h versus no deaths in BDL + NS (n = 6), Sham + LPS (n = 14), or Sham + NS (n = 6) animals (p < 0.01). Despite equivalent serum endotoxin between groups, circulating TNF-α was 8-fold higher in BDL + LPS than in Sham + LPS rats at 1.5 and 3.5 h (p < 0.001), whereas serum TNF-α did not differ between BDL + NS and Sham + NS rats. IL-6 likewise was increased differentially by 1.5 h in BDL + LPS animals (11.98 ± 2.42 ng/ml) versus Sham + LPS rats (3.05 ± 0.58 ng/ml, p < 0.05). Hypothermia, bradycardic hypotension, and leukopenia were most severe and prolonged in BDL + LPS rats, which also had significantly higher ALT values, W/D ratios, and organ PMN counts. LT inhibition failed to reduce BDL-related differences in serum cytokines or survival after endotoxemia. Thus, cholestasis augments inflammatory responses to gram-negative endotoxemia, sensitizing the host to enhanced fluid flux in multiple organs and to mortality by a LT-independent mechanism.",
author = "Lechner, {Andrew J.} and Alvaro Velasquez and Knudsen, {Karl R.} and Johanns, {Cheryl A.} and Tracy, {Thomas F.} and Matuschak, {George M.}",
year = "1998",
month = "12",
day = "1",
language = "English (US)",
volume = "157",
pages = "1550--1558",
journal = "American Journal of Respiratory and Critical Care Medicine",
issn = "1073-449X",
publisher = "American Thoracic Society",
number = "5 PART I",

}

Cholestatic liver injury increases circulating TNF-α and IL-6 and mortality after Escherichia coli endotoxemia. / Lechner, Andrew J.; Velasquez, Alvaro; Knudsen, Karl R.; Johanns, Cheryl A.; Tracy, Thomas F.; Matuschak, George M.

In: American journal of respiratory and critical care medicine, Vol. 157, No. 5 PART I, 01.12.1998, p. 1550-1558.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Cholestatic liver injury increases circulating TNF-α and IL-6 and mortality after Escherichia coli endotoxemia

AU - Lechner, Andrew J.

AU - Velasquez, Alvaro

AU - Knudsen, Karl R.

AU - Johanns, Cheryl A.

AU - Tracy, Thomas F.

AU - Matuschak, George M.

PY - 1998/12/1

Y1 - 1998/12/1

N2 - We employed a bile duct ligation (BDL) model of cholestatic liver injury to test the hypothesis that this form of preexisting hepatic dysfunction alters the kinetics of circulating TNF-α and IL-6 after Escherichia coli endotoxemia, thereby augmenting mortality and lung injury by a TNF-α:leukotriene (LT) axis of inflammation. Male rats were catheterized 13 d after BDL or sham surgery and studied while awake 18 to 24 h later. Cholestasis after BDL was confirmed by baseline serum bilirubin (BDL = 7.34 ± 0.72 mg/dl, mean ± SEM, n = 17 versus Sham = 0.25 ± 0.07, n = 20; p < 0.005) and histopathology. Sham and BDL animals received E. coli lipopolysaccharide serotype O55:B5 (LPS, 5 mg/kg i.v.) or 0.9% NaCl (NS) ending at t = 0 and were monitored over 24 h for vital signs and hemodynamics. In parallel studies, lipoxygenase inhibition was performed using diethylcarbamazine or the 5-lipoxygenase activating-protein inhibitor MK-886. Blood was collected at baseline and at t = 1.5, 3.5, and 24 h for formed elements and for serum endotoxin, TNF-α, IL-6, bilirubin, and alanine aminotransferase (ALT). Organs were evaluated at 24 h for histopathology, including neutrophil (PMN) densities and wet/dry weight (W/D) ratios. Cholestasis reduced survival after otherwise nonlethal endotoxemia, with seven of 11 BDL + LPS rats dying within 24 h versus no deaths in BDL + NS (n = 6), Sham + LPS (n = 14), or Sham + NS (n = 6) animals (p < 0.01). Despite equivalent serum endotoxin between groups, circulating TNF-α was 8-fold higher in BDL + LPS than in Sham + LPS rats at 1.5 and 3.5 h (p < 0.001), whereas serum TNF-α did not differ between BDL + NS and Sham + NS rats. IL-6 likewise was increased differentially by 1.5 h in BDL + LPS animals (11.98 ± 2.42 ng/ml) versus Sham + LPS rats (3.05 ± 0.58 ng/ml, p < 0.05). Hypothermia, bradycardic hypotension, and leukopenia were most severe and prolonged in BDL + LPS rats, which also had significantly higher ALT values, W/D ratios, and organ PMN counts. LT inhibition failed to reduce BDL-related differences in serum cytokines or survival after endotoxemia. Thus, cholestasis augments inflammatory responses to gram-negative endotoxemia, sensitizing the host to enhanced fluid flux in multiple organs and to mortality by a LT-independent mechanism.

AB - We employed a bile duct ligation (BDL) model of cholestatic liver injury to test the hypothesis that this form of preexisting hepatic dysfunction alters the kinetics of circulating TNF-α and IL-6 after Escherichia coli endotoxemia, thereby augmenting mortality and lung injury by a TNF-α:leukotriene (LT) axis of inflammation. Male rats were catheterized 13 d after BDL or sham surgery and studied while awake 18 to 24 h later. Cholestasis after BDL was confirmed by baseline serum bilirubin (BDL = 7.34 ± 0.72 mg/dl, mean ± SEM, n = 17 versus Sham = 0.25 ± 0.07, n = 20; p < 0.005) and histopathology. Sham and BDL animals received E. coli lipopolysaccharide serotype O55:B5 (LPS, 5 mg/kg i.v.) or 0.9% NaCl (NS) ending at t = 0 and were monitored over 24 h for vital signs and hemodynamics. In parallel studies, lipoxygenase inhibition was performed using diethylcarbamazine or the 5-lipoxygenase activating-protein inhibitor MK-886. Blood was collected at baseline and at t = 1.5, 3.5, and 24 h for formed elements and for serum endotoxin, TNF-α, IL-6, bilirubin, and alanine aminotransferase (ALT). Organs were evaluated at 24 h for histopathology, including neutrophil (PMN) densities and wet/dry weight (W/D) ratios. Cholestasis reduced survival after otherwise nonlethal endotoxemia, with seven of 11 BDL + LPS rats dying within 24 h versus no deaths in BDL + NS (n = 6), Sham + LPS (n = 14), or Sham + NS (n = 6) animals (p < 0.01). Despite equivalent serum endotoxin between groups, circulating TNF-α was 8-fold higher in BDL + LPS than in Sham + LPS rats at 1.5 and 3.5 h (p < 0.001), whereas serum TNF-α did not differ between BDL + NS and Sham + NS rats. IL-6 likewise was increased differentially by 1.5 h in BDL + LPS animals (11.98 ± 2.42 ng/ml) versus Sham + LPS rats (3.05 ± 0.58 ng/ml, p < 0.05). Hypothermia, bradycardic hypotension, and leukopenia were most severe and prolonged in BDL + LPS rats, which also had significantly higher ALT values, W/D ratios, and organ PMN counts. LT inhibition failed to reduce BDL-related differences in serum cytokines or survival after endotoxemia. Thus, cholestasis augments inflammatory responses to gram-negative endotoxemia, sensitizing the host to enhanced fluid flux in multiple organs and to mortality by a LT-independent mechanism.

UR - http://www.scopus.com/inward/record.url?scp=0031778843&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0031778843&partnerID=8YFLogxK

M3 - Article

C2 - 9603137

AN - SCOPUS:0031778843

VL - 157

SP - 1550

EP - 1558

JO - American Journal of Respiratory and Critical Care Medicine

JF - American Journal of Respiratory and Critical Care Medicine

SN - 1073-449X

IS - 5 PART I

ER -