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


METHODS
Controlled laboratory experiment.


METHODS
University research laboratory.


METHODS
Sprague-Dawley male rats 200-250 g and primary isolated adrenal fasciculata-reticularis cells.


METHODS
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.


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.
Department of Physiology, and The Key Laboratory of Molecular Neurobiology of Ministry of Education, Second Military Medical University, Shanghai, People's Republic of China.
Shujuan
S
Liu
Xiaoyan
X
Zhu
Yujian
Y
Liu
Changnan
C
Wang
Shan
S
Wang
Xiaolu
X
Tang
Xin
X
Ni
D000311:Adrenal Glands / Q000187:drug effects / Q000503:physiopathology*; D000309:Adrenal Insufficiency / Q000209:etiology / Q000503:physiopathology; D000324:Adrenocorticotropic Hormone / Q000494:pharmacology*; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D003345:Corticosterone / Q000096:biosynthesis*; D004731:Endotoxins / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D018043:Receptors, Corticotropin / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018805:Sepsis / Q000150:complications / Q000503:physiopathology*; D051197:Toll-Like Receptor 4 / Q000096:biosynthesis; D015383:Zona Fasciculata / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
D004731:Endotoxins; D008070:Lipopolysaccharides; D018043:Receptors, Corticotropin; C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4; D000324:Adrenocorticotropic Hormone; D003345:Corticosterone