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.

Development and Evaluation of a Novel Mouse Model of Asphyxial Cardiac Arrest Revealed Severely Impaired Lymphopoiesis After Resuscitation

“…Within ≈2.5 minutes, the MAP had decreased to <20 mm Hg, the threshold for defining CA onset in our model. Moreover, adapted from mouse KCl‐mediated CA models, 16 , 17 , 18 a water‐circulating coil was used to maintain the brain temperature (38.0±0.2°C) during CA in this model, which helped to aggravate post‐CA brain injury and thus produce neurologic deficits that were readily measurable while allowing animal survival. Lastly, we calculated the dose of epinephrine based on a standard epinephrine dose used in humans.…”

“…Three days after CA/CPR, behavioral tests were performed by experimenters who were blinded to group assignments, whenever possible. 16 , 17 …”

“…Our standard protocols, as described previously, 16 were followed. Single‐cell suspensions were obtained from the spleen, thymus, bone marrow, and brain.…”

“…In this study, we developed and characterized a novel validated murine asphyxial CA model. Because the immune response is a major component of the post‐CA syndrome, 13 , 14 , 15 , 16 we further performed a detailed analysis of the immune response using this new model. Importantly, the analysis revealed severely impaired T and B lymphopoiesis after asphyxial CA and resuscitation.…”

The evaluation of pituitary damage associated with cardiac arrest: An experimental rodent model

“…The consistent data showed the increase in cortisol levels after CA from the human studies, but no study has tested the dynamics of these hormones in rats. Zhao et al used a murine CA model and reported the results of ACTH and corticosterone levels, demonstrating the overexpression of HPA with concomitant inflammatory responses observed 1-3 days after CA 40 . In our CA rat model, pars distalis showed an early recovery pattern-within 2 h after CA-and therefore, it is plausible that the anterior gland system, including HPA, can be overexpressed in the late period of post-CA responses.…”