Am. J. Respir. Crit. Care Med.,
Volume 157, Number 5, May 1998, 1550-1558
Cholestatic Liver Injury Increases Circulating TNF-
and
IL-6 and Mortality after Escherichia coli Endotoxemia
ANDREW J.
LECHNER,
ALVARO
VELASQUEZ,
KARL R.
KNUDSEN,
CHERYL A.
JOHANNS,
THOMAS F.
TRACY Jr.,
and
GEORGE M.
MATUSCHAK
Department of Pharmacological and Physiological Science, Division of Pulmonology and Pulmonary Occupational Medicine of the
Department of Internal Medicine, and Division of Pediatric Surgery of the Department of Pediatrics, Saint Louis University School of
Medicine, and Department of Critical Care Medicine, Saint John's Mercy Medical Center, St. Louis, Missouri
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-
and IL-6 after Escherichia coli endotoxemia, thereby augmenting mortality and lung injury by a TNF-: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-, 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- 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- 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.
