Mortality of Septic Mice Strongly Correlates With Adrenal Gland Inflammation.
OBJECTIVE
Sepsis and septic shock are commonly present in the ICU and accompanied by significant morbidity, mortality, and cost. The frequency of secondary adrenal insufficiency in sepsis remains open to debate and a challenge to identify and treat appropriately. Animal models of sepsis using genetic or surgical initiation of adrenal insufficiency resulted in increased mortality, but the mechanisms are still unclear. The present study investigates the impact of adrenal inflammation in septic mice challenged with cecal ligation and puncture.


METHODS
Prospective experimental study.


METHODS
University laboratory.


METHODS
C57BL/6N wild-type mice.


METHODS
Sepsis, induced by cecal ligation and puncture for 24 and 48 hours.


RESULTS
Both septic and control mice were carefully monitored (every 30 min) for up to 48 hours and divided into survivors and nonsurvivors. We observed a significant and massive increase of interleukin-6, interleukin-1β, and tumor necrosis factor-α in adrenal protein extracts of nonsurvivors compared with sham animals and survivors. This pattern was partly reflected in liver and lung but not in plasma samples. Notably, a significant increase in nonsurvivors compared with survivors was only found for lung interleukin-6. In line with these findings, we detected a higher degree of leukocyte infiltration and hemorrhage in the adrenal glands of deceased mice. Evaluation of the hypothalamic-pituitary-adrenal axis response in these animals revealed an increase of adrenocorticotropic hormone, which was only partly reflected in the corticosterone level. Notably, using the adrenocorticotropic hormone stimulation test, we found an impaired adrenocorticotropic hormone response, particularly in nonsurvivors, which significantly correlated with the number of infiltrated leukocytes.


CONCLUSIONS
Cecal ligation and puncture-induced murine sepsis induces a strong inflammatory response in the adrenal glands, which is accompanied by cell death and hemorrhage. Our data suggest that mortality and adrenal incapacitation are associated with the degree of adrenal inflammation, thereby underscoring the importance of adrenal function on survival.
1Department of Anesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Frankfurt, Frankfurt am Main, Germany. 2Department of Medicine III, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany.
Carla
C
Jennewein
Nguyen
N
Tran
Waldemar
W
Kanczkowski
Lars
L
Heerdegen
Ajith
A
Kantharajah
Stefan
S
Dröse
Stefan
S
Bornstein
Bertram
B
Scheller
Kai
K
Zacharowski
D000311:Adrenal Glands / Q000473:pathology / Q000503:physiopathology*; D000309:Adrenal Insufficiency / Q000503:physiopathology; D000324:Adrenocorticotropic Hormone / Q000097:blood; D000818:Animals; D002432:Cecum; D003345:Corticosterone / Q000097:blood; D004195:Disease Models, Animal; D007030:Hypothalamo-Hypophyseal System; D007249:Inflammation / Q000473:pathology*; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008026:Ligation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010913:Pituitary-Adrenal System; D011897:Random Allocation; D012772:Shock, Septic / Q000150:complications / Q000378:metabolism / Q000401:mortality*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D053583:Interleukin-1beta; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D000324:Adrenocorticotropic Hormone; D003345:Corticosterone