Cardiac arrest and resuscitation activates the hypothalamic-pituitary-adrenal axis and results in severe immunosuppression.

Abstract

In patients who are successfully resuscitated after initial cardiac arrest (CA), mortality and morbidity rates are high, due to ischemia/reperfusion injury to the whole body including the nervous and immune systems. How the interactions between these two critical systems contribute to post-CA outcome remains largely unknown. Using a mouse model of CA and cardiopulmonary resuscitation (CA/CPR), we demonstrate that CA/CPR induced neuroinflammation in the brain, in particular, a marked increase in pro-inflammatory cytokines, which subsequently activated the hypothalamic-pituitary-adrenal (HPA) axis. Importantly, this activation was associated with a severe immunosuppression phenotype after CA. The phenotype was characterized by a striking reduction in size of lymphoid organs accompanied by a massive loss of immune cells and reduced immune function of splenic lymphocytes. The mechanistic link between post-CA immunosuppression and the HPA axis was substantiated, as we discovered that glucocorticoid treatment, which mimics effects of the activated HPA axis, exacerbated post-CA immunosuppression, while RU486 treatment, which suppresses its effects, significantly mitigated lymphopenia and lymphoid organ atrophy and improved CA outcome. Taken together, targeting the HPA axis could be a viable immunomodulatory therapeutic to preserve immune homeostasis after CA/CPR and thus improve prognosis of post-resuscitation CA patients.

• Authors: Qiang Zhao, Yuntian Shen, Ran Li, Jiangbo Wu, Jingjun Lyu, Maorong Jiang, Liping Lu, Minghua Zhu, Wei Wang, Zhuoran Wang, Qiang Liu, Ulrike Hoffmann, Jörn Karhausen, Huaxin Sheng, Weiguo Zhang, Wei Yang
• Journal: Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism (J Cereb Blood Flow Metab) Vol. 41 Issue 5 Pg. 1091-1102 (05 2021) ISSN: 1559-7016 [Electronic] United States
• PMID: 32787543 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Cytokines
• Glucocorticoids
• Hormone Antagonists
• Mifepristone

Topics

• Animals
• Brain (metabolism, physiopathology)
• Cardiopulmonary Resuscitation (adverse effects, methods)
• Case-Control Studies
• Cytokines (metabolism)
• Glucocorticoids (administration & dosage, pharmacology)
• Heart Arrest (complications, pathology, therapy)
• Homeostasis (drug effects)
• Hormone Antagonists (administration & dosage, pharmacology)
• Hypothalamo-Hypophyseal System (drug effects, immunology, metabolism, physiopathology)
• Immunosuppression Therapy (adverse effects)
• Male
• Mice
• Mice, Inbred C57BL
• Mifepristone (administration & dosage, pharmacology)
• Models, Animal
• Pituitary-Adrenal System (drug effects, immunology, metabolism, physiopathology)
• Prognosis
• Reperfusion Injury