Project A01

Regulated Cell Death in Adrenal Inflammation and Septic Shock

Bacterial sepsis is a serious threat to homeostasis and is the most common cause of mortality in non-coronary intensive care units (ICUs). The uncompromised function of the adrenal gland is associated with the reduced development of septic shock and increased survival of ICU patients. Sepsis-triggered intra-adrenal inflammation results in dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis but the underlying mechanisms remain undefined. During the first funding period, we have demonstrated that complement and Toll-like receptor activation induced strong TUNEL positivity, which was associated with HPA-dysfunction and intra-adrenal inflammation in experimental sepsis mouse models. In the second funding period, project A01 will investigate the mechanisms involved in sepsis-driven adrenal necrosis including ferroptosis, necroptosis and pyroptosis. Our experimental approach will additionally allow us to assess the contribution of each RN-pathway to intra-adrenal inflammation during sepsis. Finally, we will perform a preclinical study to test the efficiency of ferrostatins and necrostatins for the prevention of sepsis-mediated adrenal gland dysfunction.

Aims

(I) Characterisation of regulated cell death responses of adrenal cells to inflammatory and septic stimuli.

(II) Identification of adrenal ferroptosis, necroptosis and pyroptosis in murine models of inflammation and sepsis

(III) Confirmation of necroptosis and ferroptosis during sepsis in human adrenals

© SFB/TRR 205