Corticosteroid therapy for patients in septic shock: Some progress in a difficult decision

Abstract

Objectives: Reversible adrenal insufficiency has been frequently diagnosed in critically ill patients with sepsis who have either low basal cortisol levels or low cortisol responses to adrenocorticotrophic hormone (ACTH) stimulation. It is generally accepted that a phenomenon called contributes to immunosuppression during sepsis. The present study was to investigate whether endotoxin tolerance occurs in the adrenal gland, leading to hyporesponsiveness of adrenal gland during sepsis. Design: Controlled laboratory experiment. Setting: University research laboratory. Subjects: Sprague-Dawley male rats 200-250 g, and primary isolated adrenal fasciculata-reticularis cells. Interventions: Rats received intra-arterial injection of purified lipopolysaccharide (LPS, 0.5 mg/kg) through indwelling femoral arterial catheters, and 24 h later the adrenocortical sensitivity to exogenous ACTH (10 ng/kg) was detected. Primary F/R cells were pretreated with LPS at 0.1-100 ng/mL or with ACTH at 0.01―10 ng/mL, and then challenged, in fresh media, with 1 μg/mL LPS or 10 ng/mL ACTH. Measurements and Main Results: Toll-like receptor 4 were expressed in adrenal gland and primary fasciculata-reticularis cells. Plasma corticosterone response to ACTH was decreased in rats receiving preinjection of LPS. LPS pretreatment caused a significant decrease in corticosterone production in response to subsequent ACTH and LPS stimulation in primary fasciculata-reticularis cells. LPS pretreatment inhibited ACTH- and LPS-induced expression of steroid metabolizing enzymes. LPS significantly decreased toll-like receptor 4 and ACTH receptor expression. Conclusions: Pre-exposure to LPS resulted in hyporesponsiveness to ACTH stimulation in rats. In vitro, LPS pretreatment impaired corticosterone production of F/R cells in response to ACTH and LPS, which was associated with decreased expression of synthetic enzymes required for corticosterone production. Our results indicate that endotoxin tolerance of adrenal gland is one of mechanisms for adrenocortical insufficiency during sepsis.