Endotoxin tolerance of adrenal gland: attenuation of corticosterone production in response to lipopolysaccharide and adrenocorticotropic hormone.

Abstract

OBJECTIVES:

Reversible adrenal insufficiency frequently has been diagnosed in critically ill patients with sepsis who have either low basal cortisol levels or low cortisol responses to adrenocorticotropic hormone (ACTH) stimulation. It is generally accepted that a phenomenon called "endotoxin tolerance" 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 (0.5 mg/kg) through indwelling femoral arterial catheters, and 24 hrs later the adrenocortical sensitivity to exogenous ACTH (10 ng/kg) was detected. Primary fasciculata-reticularis cells were pretreated with lipopolysaccharide 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 lipopolysaccharide or 10 ng/mL ACTH.

MEASUREMENTS AND MAIN RESULTS:

Toll-like receptor 4 was expressed in adrenal gland and primary fasciculata-reticularis cells. Plasma corticosterone response to ACTH was decreased in rats receiving preinjection of lipopolysaccharide. Lipopolysaccharide pretreatment caused a significant decrease in corticosterone production in response to subsequent ACTH and lipopolysaccharide stimulation in primary fasciculata-reticularis cells. Lipopolysaccharide pretreatment inhibited ACTH- and lipopolysaccharide-induced expression of steroid metabolizing enzymes. Lipopolysaccharide significantly decreased Toll-like receptor 4 and ACTH receptor expression.

CONCLUSIONS:

Pre-exposure to lipopolysaccharide resulted in hyporesponsiveness to ACTH stimulation in rats. In vitro, lipopolysaccharide pretreatment impaired corticosterone production of fasciculata-reticularis cells in response to ACTH and lipopolysaccharide, 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 the mechanisms for adrenocortical insufficiency during sepsis.

• Authors: Shujuan Liu, Xiaoyan Zhu, Yujian Liu, Changnan Wang, Shan Wang, Xiaolu Tang, Xin Ni
• Journal: Critical care medicine (Crit Care Med) Vol. 39 Issue 3 Pg. 518-26 (Mar 2011) ISSN: 1530-0293 [Electronic] United States
• PMID: 21242794 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Endotoxins
• Lipopolysaccharides
• Receptors, Corticotropin
• Tlr4 protein, rat
• Toll-Like Receptor 4
• Adrenocorticotropic Hormone
• Corticosterone

Topics

• Adrenal Glands (drug effects, physiopathology)
• Adrenal Insufficiency (etiology, physiopathology)
• Adrenocorticotropic Hormone (pharmacology)
• Animals
• Blotting, Western
• Cells, Cultured
• Corticosterone (biosynthesis)
• Endotoxins (pharmacology)
• Lipopolysaccharides (pharmacology)
• Male
• Rats
• Rats, Sprague-Dawley
• Receptors, Corticotropin (biosynthesis)
• Reverse Transcriptase Polymerase Chain Reaction
• Sepsis (complications, physiopathology)
• Toll-Like Receptor 4 (biosynthesis)
• Zona Fasciculata (cytology, drug effects, metabolism)