Immune mechanisms and potential therapeutic interventions for sepsis-induced adrenal gland inflammation

感染引起的全身性炎症常常最终导致致命性败血性休克综合征。适当的肾上腺应激反应对于应对这种危及生命的情况至关重要。在许多危重患者中，肾上腺激素产生的这种动态平衡激活受到损害，尽管其机制大多尚不清楚。在上一个资金阶段，我们证明了内毒素血症引起的SIRS和盲肠结扎和穿孔(CLP)引起的脓毒症都会导致全身和肾上腺炎症，这与免疫细胞的迅速渗透和肾上腺细胞的死亡有关。此外，我们利用组织特异性TLR信号失活的小鼠，使我们能够确定肾上腺微环境中的髓系细胞与下丘脑-垂体-肾上腺(HPA)轴激活和肾上腺炎症密切相关。在下一个资助阶段，我们计划进一步研究组织限制性TLR信号、免疫细胞渗透、线粒体功能和功能障碍在肾上腺炎症和细胞死亡中的重要性。最后，我们将研究新型抗炎和线粒体靶向治疗干预在化解肾上腺炎症和防止细胞死亡方面的保护作用。通过这些方法，我们将更好地了解脓毒症介导的肾上腺去调节的潜在机制，并在脓毒症的治疗中确定新的治疗干预措施。

Systemic inflammation resulting from infections frequently culminates in fatal septic shock syndrome. An adequate adrenal stress response is critical to cope with this life-threatening situation. In many critically ill patients, this homeostatic activation of the adrenal gland hormone production is impaired, although the mechanisms are mostly unknown. In the previous funding period, we demonstrated that both endotoxemiaprovoked SIRS and cecal ligation and puncture (CLP)-induced sepsis lead to systemic and adrenal gland inflammation which was associated with rapid immune cell infiltration and onset of cellular death of adrenal cells. Furthermore, we engaged mice with tissue-specific inactivation of TLR signaling, enabling us to identify myeloid cells in the adrenal gland microenvironment as being crucially involved in hypothalamic-pituitary-adrenal (HPA) axis activation and adrenal inflammation. In the next funding period we plan to further study the importance of tissue-restricted TLR signaling, immune cell infiltration, mitochondria function and dysfunction in the adrenal gland inflammation and cell death. Finally, we will study the protective effect of novel anti-inflammatory and mitochondria-targeted therapeutic interventions in the resolution of adrenal inflammation and prevention of cell death. With these approaches we will better understand the underlying mechanisms involved in sepsis-mediated adrenal gland deregulation and identify novel therapeutic interventions in sepsis treatments.