Critical care medicine · 2001
Effects of a dual inhibitor of tumor necrosis factor-alpha and interleukin-1 on lipopolysaccharide-induced lung injury in rats: involvement of the p38 mitogen-activated protein kinase pathway.
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Yoshinari D, Takeyoshi I, Koibuchi Y, Matsumoto K, Kawashima Y, Koyama T, Ohwada S, Morishita Y
Аннотация
OBJECTIVE: Sepsis is a major cause of adult respiratory distress syndrome. In this study, we evaluated the effect of FR167653, which is a potent suppressant of tumor necrosis factor (TNF)-alpha and interleukin (IL)-1 production, on lipopolysaccharide (LPS)-induced lung injury and lethality in rats, and we examined the involvement of p38 mitogen-activated protein (MAP) kinase in the action of FR167653.
DESIGN: Prospective, randomized study.
SETTING: Animal research facility in a university.
SUBJECTS: Male Sprague-Dawley rats weighing 200-270 g.
INTERVENTIONS: All the animals were assigned to one of the following four groups: control group, FR-only group, LPS-only group, and LPS/FR group. Animals in the LPS-only and LPS/FR groups received 6 mg/kg of LPS intravenously. The animals in the FR-only and LPS/FR groups also received an infusion of FR167653 at 0.2 mg x kg(-1) x hr(-1), commencing 30 mins before the LPS (or vehicle) injection and continuing for 5.5 hrs.
MEASUREMENTS AND MAIN RESULTS: LPS significantly induced the accumulation of pulmonary neutrophils and lung edema, both of which were significantly attenuated by treatment with FR167653. FR167653 also significantly decreased the LPS-induced lethality. Histologically, tissue damage was milder in the LPS/FR group than in the LPS-only group. Serum concentrations of TNF-alpha and IL-1beta and plasma concentrations of thromboxane B2 were all suppressed in the LPS/FR group compared with the LPS-only group. Western blot analysis revealed that FR167653 inhibited the phosphorylation of p38 MAP kinase in lung tissues.
CONCLUSIONS: FR167653 administration decreased serum TNF-alpha and IL-1beta concentrations, which was associated with decreased lung injury and lethality. The mechanism responsible for the decreased TNF-alpha and IL-1 may be related to the inhibitory effect of FR167653 on p38 MAP kinase activation.
DESIGN: Prospective, randomized study.
SETTING: Animal research facility in a university.
SUBJECTS: Male Sprague-Dawley rats weighing 200-270 g.
INTERVENTIONS: All the animals were assigned to one of the following four groups: control group, FR-only group, LPS-only group, and LPS/FR group. Animals in the LPS-only and LPS/FR groups received 6 mg/kg of LPS intravenously. The animals in the FR-only and LPS/FR groups also received an infusion of FR167653 at 0.2 mg x kg(-1) x hr(-1), commencing 30 mins before the LPS (or vehicle) injection and continuing for 5.5 hrs.
MEASUREMENTS AND MAIN RESULTS: LPS significantly induced the accumulation of pulmonary neutrophils and lung edema, both of which were significantly attenuated by treatment with FR167653. FR167653 also significantly decreased the LPS-induced lethality. Histologically, tissue damage was milder in the LPS/FR group than in the LPS-only group. Serum concentrations of TNF-alpha and IL-1beta and plasma concentrations of thromboxane B2 were all suppressed in the LPS/FR group compared with the LPS-only group. Western blot analysis revealed that FR167653 inhibited the phosphorylation of p38 MAP kinase in lung tissues.
CONCLUSIONS: FR167653 administration decreased serum TNF-alpha and IL-1beta concentrations, which was associated with decreased lung injury and lethality. The mechanism responsible for the decreased TNF-alpha and IL-1 may be related to the inhibitory effect of FR167653 on p38 MAP kinase activation.
Предметные рубрики MeSH
AnimalsDisease Models, AnimalDrug Evaluation, PreclinicalEscherichia coliEscherichia coli InfectionsImmunosuppressive AgentsInterleukin-1LipopolysaccharidesLungMaleMitogen-Activated Protein KinasesProspective StudiesPyrazolesPyridinesRandom AllocationRatsRats, Sprague-DawleyRespiratory Distress SyndromeSurvival AnalysisThromboxane B2Time FactorsTumor Necrosis Factor-alphap38 Mitogen-Activated Protein Kinases