Orexinergic activity modulates altered vital signs and pituitary hormone secretion in experimental sepsis.

OBJECTIVES: Sepsis is a common, lethal poorly understood disorder affecting nearly a million Americans annually. The syndrome is characterized by altered cardiodynamics, respiration, metabolism, pituitary function, arousal, and impaired interaction among organ systems. The immunologic and endocrine systems, which are in part responsible for organ-organ communication, have been studied extensively in sepsis. However, little is known about sepsis-induced changes in central nervous system activity. HYPOTHESIS: A defect in hypothalamic neurons secreting the neurotransmitter orexin modulates physiologic derangements in sepsis.
DESIGN: Animal study.
SETTING: University Research Laboratory.
INTERVENTIONS: Male C57Bl6 mice were made septic using cecal ligation and puncture. Data were collected 24 or 48 hours later, blood was collected, animals were killed, and brain tissue was harvested, fixed, and sectioned. Hypothalamic sections were subjected to immunohistochemistry using antibodies to orexin and c-Fos, a marker of neuronal activity. In a separate cohort of mice, cannulas were placed in the right lateral cerebral ventricle. Cecal ligation and puncture was performed 1 week later. At 24 or 48 hours post-cecal ligation and puncture, vital signs were measured, and1 µL of saline with or without 3 nmol orexin-A was infused. Vital signs were repeated at 25 or 49 hours post-cecal ligation and puncture, blood was collected, animals were killed, and brains were removed, fixed, sectioned, and stained.
MEASUREMENTS AND MAIN RESULTS: Orexinergic activity decreased six-fold following cecal ligation and puncture. This change was associated with decreases in arousal, temperature, and heart and respiratory rates. Levels of selected pituitary hormones increased 24 hours post-cecal ligation and puncture but were significantly lower than baseline at 48 hours. Injection of orexin-A increased vital signs to baseline levels. Hormone levels were unaffected at 25 hours but increased to supranormal levels at 49 hours.
CONCLUSIONS: Sepsis-induced changes in activity, vital signs, and pituitary hormones are modulated by the orexinergic system. This finding implicates central nervous system dysfunction in the pathogenesis of sepsis, suggesting further study of neurological dysfunction to identify novel approaches to management.