Cecal Ligation and Puncture Alters Glucocorticoid Receptor Expression


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Abstract

Objectives:Interventional trials on glucocorticoids in sepsis have yielded capricious results. Recent studies have identified multiple glucocorticoid receptor isoforms. The relative abundance of these isoforms in septic patients and following murine cecal ligation and puncture is unknown. The objective of this study is to determine the effects of cecal ligation and puncture on glucocorticoid receptor isoform abundance.Design:Determination of effects of cecal ligation and puncture on glucocorticoid receptor isoform subtype abundance in C57BL/6 mice. Examination of glucocorticoid receptor isoform abundance in tissues harvested from patients immediately after death from sepsis or nonseptic critical illness.Setting:Research laboratory.Subjects:C57BL/6 mice and human tissue sections from recently deceased critically ill patients.Interventions:C57BL/6 mice were subjected to cecal ligation and puncture or sham operation. Abundance of the activating glucocorticoid receptor α and the inactivating glucocorticoid receptor β isoforms was determined in mouse and human tissue using immunoblotting. Cardiac output with or without stimulation with dexamethasone was assessed using echocardiography. The expression of the gene encoding the glucocorticoid-dependent enzyme glucose-6-phosphatase was identified using polymerase chain reaction. Statistical significance (p < 0.05) was determined using analysis of variance.Measurements and Main Results:Results in baseline and sham operation mice were identical. At baseline, glucocorticoid receptor αA predominated in heart, lung, and skeletal muscle; abundance was decreased post cecal ligation and puncture. All glucocorticoid receptor α subtypes were identified in liver. Cecal ligation and puncture decreased the summed abundance of hepatic glucocorticoid receptor α subtypes and those of glucocorticoid receptors αA, B, and D. However, glucocorticoid receptor αC abundance was unchanged. Cecal ligation and puncture increased glucocorticoid receptor β protein abundance in the heart and lung. Relative to T0, cecal ligation and puncture decreased cardiac output and attenuated the cardiac output response to dexamethasone. Cecal ligation and puncture also decreased expression of glucose-6-phosphatase. Compared with nonseptic patients, human sepsis decreased the abundance of glucocorticoid receptor α and increased the abundance of glucocorticoid receptor β in heart and liver biopsies.Conclusions:Cecal ligation and puncture altered glucocorticoid receptor α and glucocorticoid receptor β isoform expression in tissues and decreased functional responses in heart and liver. Decreases in glucocorticoid receptor α and increases in glucocorticoid receptor β might explain the diminished glucocorticoid responsiveness observed in sepsis.

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