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Effects of D-galactosamine-induced acute liver injury on mortality and pulmonary responses to Escherichia coli lipopolysaccharide. Modulation by arachidonic acid metabolites.

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Matuschak, GM and Pinsky, MR and Klein, EC and Van Thiel, DH and Rinaldo, JE (1990) Effects of D-galactosamine-induced acute liver injury on mortality and pulmonary responses to Escherichia coli lipopolysaccharide. Modulation by arachidonic acid metabolites. Am Rev Respir Dis, 141 (5 Pt 1). 1296 - 1306. ISSN 0003-0805

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Abstract

Multiple extrapulmonary organ system failures increase mortality, permeability edema, and alveolar inflammation during gram-negative sepsis because of abnormal regulation of host inflammatory responses. We tested the hypothesis that acute hepatocytic injury induced by the selective hepatotoxin, D-galactosamine (GalN), augments mortality and amplifies pulmonary microvascular permeability to albumin and neutrophilic influx after administering Escherichia coli lipopolysaccharide (LPS) 24 h later by impairing the metabolism of endogenously synthesized products of arachidonic acid. We determined the lung extravascular leak of 125I-human serum albumin measured at multiple time points after LPS and enumerated polymorphonuclear leukocytes (PMNs) in bronchoalveolar lavage fluid (BALF). Because the liver is important in prostaglandin (PG) and leukotriene (LT) metabolism, we measured plasma concentrations of 6-keto-PGF1 alpha and thromboxane B2 (TxB2) in addition to paired plasma BALF concentrations of LTB4 and BALF LTC4 60 min and 24 h after LPS. We further assessed the protective effects of a single 20-mg/kg injection given intraperitoneally (i.p.) of the LTA4 synthetase inhibitor, diethylcarbamazine (DEC). After 400 mg/kg GalN, LPS at 2.5 or 1.25 mg/kg i.p. increased mortality (p less than 0.001), albumin leak 60 and 90 min after LPS (p less than 0.05), plasma 6-keto-PGF1 alpha, TxB2, and LTB4 levels and BALF LTC4 within 60 min (p less than 0.05). LTB4 and LTC4 levels in BALF 24 h later were similarly increased (p less than 0.05) as were bronchoalveolar PMNs (p less than 0.001). DEC improved mortality and albumin leak (p less than 0.001), reduced lung influx of PMNs and peripheral leukocytosis (p less than 0.05), attenuated plasma LTB4 and BALF LTC4 levels 60 min after LPS (p less than 0.05), and decreased BALF LTB4 and LTC4 at 24 h (p less than 0.05), but was associated with higher plasma 6-keto-PGF1 alpha and TxB2 values at 60 min. Changes in eicosanoid levels and modulation of responses by DEC in this model suggest that impaired metabolism of endogenously synthesized leukotriences by the damaged liver underlies these phenomena. We conclude that this mechanism may enhance septic lung injury during acute liver dysfunction.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Matuschak, GM
Pinsky, MRpinsky@pitt.eduPINSKY0000-0001-6166-700X
Klein, EC
Van Thiel, DH
Rinaldo, JE
Date: May 1990
Date Type: Publication
Journal or Publication Title: Am Rev Respir Dis
Volume: 141
Number: 5 Pt 1
Page Range: 1296 - 1306
DOI or Unique Handle: 10.1164/ajrccm/141.5_pt_1.1296
Schools and Programs: School of Medicine > Critical Care Medicine
Refereed: Yes
Uncontrolled Keywords: 6-Ketoprostaglandin F1 alpha, Animals, Bronchoalveolar Lavage Fluid, Capillary Permeability, Chemical and Drug Induced Liver Injury, Escherichia coli, Galactosamine, Leukotrienes, Lipopolysaccharides, Lung, Male, Rats, Rats, Inbred Strains, Sepsis, Thromboxane B2
ISSN: 0003-0805
Funders: NHLBI NIH HHS (HL-30572), NHLBI NIH HHS (HL-32725)
Date Deposited: 16 Feb 2012 23:14
Last Modified: 30 Jan 2020 16:55
URI: http://d-scholarship.pitt.edu/id/eprint/11037

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