Polymicrobial sepsis-induced adrenal gland dysregulation – a consequence of apoptosis and excessive inflammatory response

Introduction: Failure of the hypothalamic-pituitary-adrenal axis is a frequent event of sepsis leading to uncontrolled immune response. Several studies showed improper adrenal stress response in rodents during sepsis [1, 2], but the underlying mechanisms is still poorly understood. Here, we investigated the link of inflammation, apoptosis and adrenal impairment in mice with sepsis of different severity.

Methods: Caecal ligation and puncture (CLP) was carried out as described in [3], wherein 1/3 of the caecum was ligated and punctured once (1P) or twice (2P) with a 20-gauge needle. After 24h, adrenal glands and plasma were taken. Cytokine release (LUMINEX), apoptosis rate (TUNEL), neutrophil infiltration (immunohistology), corticosterone and ACTH levels (ELISA) were analysed.

Results: Between the two CLP groups, the mortality rate of CLP-2P is 50% higher. Both systemic and adrenal inflammatory cytokines are elevated after CLP, in which those cytokine levels are much higher in CLP-2P mice. Furthermore, there is a prominent increase in apoptosis of both chromaffin and steroid producing cells in adrenal glands as compared to sham control mice. This accompanied with an augmented neutrophil infiltration in adrenal glands, especially in CLP-2P mice. There was no marked difference in corticosterone and ACTH release in both CLP groups.

Conclusion: The severity of sepsis is characterized by enhanced tissue inflammation and cellular apoptosis in adrenal accompanied with higher risk of mortality.

References: [1] Koo DJ, et al. Crit Care Med 2001; 29(3):618 – 621. [2] Carlson DE, et al. Crit Care Med 2006; 34(4):1178 – 1184. [3] Rittirsch D, et al. Nat Protoc 2009; 4(1):31 – 36.