Background: Sepsis is hallmarked by an immediate and sustained decrease in total-, HDL-, and LDL- cholesterol, associated with poor outcome and suggested to be a potential contributor to adrenal failure and muscle weakness in the critically ill. Although the underlying mechanisms are unclear, this sepsis-induced hypocholesterolemia has been postulated to be due to an increased conversion of cholesterol to cortisol. We hypothesized that hydrocortisone (HC) treatment, via reduced de novo adrenal corticosterone (CORT) synthesis, can improve the cholesterol availability and as such affect the adrenal gland and skeletal muscle. Our hypothesis was tested in a validated and clinically relevant mouse model of prolonged sepsis-induced critical illness.
Methods: In a catheterized, fluid-resuscitated and antibiotics-treated mouse model of prolonged sepsis (cecal-ligation and puncture), septic mice received either HC (1.2 mg/d) or placebo (PlasmaLyte), whereas healthy mice served as controls (n=50). After five days of sepsis, plasma CORT, HDL- and LDL- cholesterol were measured, and the presence of cholesterol esters (Oil Red 0), CD68+ cells and apoptosis was assessed in the adrenal cortex. Steroidogenic capacity of ACTH (100 nM) was evaluated in an ex vivo adrenal explantation study. Total body mass loss was measured to evaluate CORT-induced wasting, in addition to ex vivo muscle force, myofiber size and mRNA expression of atrogenes (Trim63, Fbox32, Foxo3), fibrogenes (Ctgf, Tgf-B, MMP-9) and markers of muscle regeneration (Myostatin, Myf5, Myogenin). Whole body composition was performed by EchoMRl to investigate loss of lean mass, fat mass and total and free water content.
Results: Plasma CORT was normalized in HC-treated septic mice, whereas the sepsis-induced reduction in plasma HDL- and LDL-cholesterol, and adrenocortical cholesterol ester content was attenuated as compared with placebo-treated septic mice (P<0.05), but without improving the blunted ACTH- induced CORT secretion. Increased presence of CD68+ and apoptotic cells was observed in the adrenal cortex of HC-treated septic mice, as compared with healthy controls and placebo-treated septic mice, respectively (P<0.05). Total body mass was median 13% further decreased in HC-treated septic mice, as compared with placebo-treated septic mice (P<0.01), with no additional effect on sepsis-induced loss of muscle mass, force and myofiber size. The sepsis-induced rise in atrogenes and fibrogenes was not further affected by HC treatment, whereas Myostatin and Myf5lMyogenin expression was respectively increased (P<0.01) and decreased (P<0.05), as compared with placebo-treated septic mice. An increased loss of lean mass and water content was observed in HC-treated septic mice as compared with placebo-treated septic mice (P<0.05), whereas fat mass was equally reduced.
Conclusion: Hydrocortisone treatment partly restored the sepsis-induced hypocholesterolemia in prolonged septic mice, but at a cost of impaired adrenal function, exacerbated wasting of lean body mass and suppressed muscle regeneration mechanisms.