Glucocorticoids Inhibit the Cerebral Microvascular Dysfunction Associated with Sepsis in Obese Mice

Abstract

Objectives: Obesity is associated with increased morbidity and mortality in critically ill patients. It is unclear whether this increase is due to exaggerated inflammatory response alone or due to lack of response to therapeutic agents used. The objective of this study was to determine whether low‐dose steroid therapy, which has proven effective in clinical setting, affords any benefit in the increased morbidity to sepsis in genetically obese (ob/ob) mice. Methods: Intravital videomicroscopy was used to monitor and quantify the adhesion of platelets and leukocytes in the brain microcirculation of lean (WT) and ob/ob mice subjected to cecal ligation and puncture (CLP) with or without dexamethasone 4 mg/kg within 15 min of surgery. The dual radiolabeled monoclonal antibody method was used to measure P‐selectin expression in the microcirculation, while the sepsis‐induced behavioral deficit was quantified using a multicompartment chamber test. Results: Dexamethasone completely prevented the accumulation of adherent leukocytes and platelets observed at 4 h after CLP in both WT and ob/ob mice. The steroid also prevented the CLP‐induced upregulation of P‐selectin in the brain and other vascular beds, and it attenuated the behavioral deficit in ob/ob, but not in lean, mice. Conclusion: Low‐dose glucocorticoid therapy is beneficial in experimental sepsis in obese animals compared to lean animals.