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-PGF_1α 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 < 0.001), albumin leak 60 and 90 min after LPS (p < 0.05), plasma 6-keto-PGF_1α, TxB₂, and LTB₄ levels and BALF LTC₄ within 60 min (p < 0.05). LTB₄ and LTC₄ levels in BALF 24 h later were similarly increased (p < 0.05) as were bronchoalveolar PMNs (p < 0.001). DEC improved mortality and albumin leak (p < 0.001), reduced lung influx of PMNs and peripheral leukocytosis (p < 0.05), attenuated plasma LTB₄ and BALF LTC₄ levels 60 min after LPS (p < 0.05), and decreased BALF LTB₄ and LTC₄ at 24 h (p < 0.05), but was associated with higher plasma 6-keto-PGF_1α 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 leukotrienes by the damaged liver underlies these phenomena. We conclude that this mechanism may enhance septic lung injury during acute liver dysfunction.