Mortality in septic mice strongly correlates with adrenal inflammation and dysfunction

Introduction: Failure of the hypothalamic-pituitary-adrenal axis and adrenal gland insufficiency is a frequent event during sepsis. In vitro and in vivo studies demonstrate an increased adrenal inflammatory response during systemic inflammation. Still, the impact of adrenal insufficiency as well as underlying mechanisms are poorly understood. In our study, we investigated adrenal inflammation as well as its correlation with mortality rate in mice during polymicrobial sepsis.

Methods: Cecal ligation and puncture (CLP) was carried out on C57BL/6N mice as described previously, wherein 2/3 of the caecum was ligated and punctured twice (CLP-2P) with a 20-gauge needle. Control littermates underwent same surgical procedures without ligation and puncture (sham). Adrenal glands and plasma were harvested in deceased animals or after 24 and 48h respectively. Adrenal and systemic cytokine release (multiplex assay), apoptotic rate (TUNEL), neutrophil infiltration into the adrenal glands (immunohistology), and corticosterone and ACTH (ELISA) levels were investigated.

Results: In deceased CLP mice, a prominent impairment in adrenal response (corticosterone/ACTH ratio) occurs, which is accompanied by an increase in apoptosis of both chromaffin and steroid producing cells, and by an elaborated neutrophil infiltration into the adrenal glands. Furthermore, both systemic and local (within the adrenal) pro-inflammatory cytokine releases are markedly higher in CLP mice, especially in non-survivors. Notably, mortality in septic mice strongly correlates with adrenal but not systemic inflammation (s. Table 1).

Conclusion: Our data demonstrate that sepsis leads to strong inflammatory response within the adrenals, massive apoptosis as well as impaired hormonal response. They further indicate that adrenal inflammation and following insufficiency strongly contributes to mortality during sepsis.