Invited review Detrimental consequences of brain injury on peripheral cells Anna Catania a, * , Caterina Lonati a , Andrea Sordi a , Stefano Gatti b a Center for Preclinical Investigation, Fondazione IRCCS Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Milano, Italy b Center for Surgical Research, Fondazione IRCCS Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Milano, Italy article info Article history: Received 27 January 2009 Received in revised form 12 March 2009 Accepted 14 April 2009 Available online 24 April 2009 Keywords: Acute-phase reaction (APR) Subarachnoid hemorrhage (SAH) Stroke Traumatic brain injury (TBI) Brain death Transplantation Immunodepression Organ inflammation Sympathetic nervous system (SNS) abstract Acute brain injury and brain death exert detrimental effects on peripheral host cells. Brain-induced impairment of immune function makes patients more vulnerable to infections that are a major cause of morbidity and mortality after stroke, trauma, or subarachnoid hemorrhage (SAH). Systemic inflam- mation and organ dysfunction are other harmful consequences of CNS injury. Brain death, the most severe consequence of brain injury, causes inflammatory changes in peripheral organs that can con- tribute to the inferior outcome of organs transplanted from brain-dead donors. Understanding of the mechanisms underlying the detrimental effects of brain injury on peripheral organs remains incomplete. However, it appears that sympathetic nervous system (SNS)-activation contributes to eli- cit both inflammation and immunodepression. Indeed, norepinephrine (NE)-induced production of chemokines in liver and other organs likely participates in local and systemic inflammatory changes. Conversely, catecholamine-stimulated interleukin-10 (IL-10) production by blood monocytes exerts immunosuppressive effects. Activation of the hypothalamic–pituitary–adrenal axis (HPA) by increased inflammatory cytokines within the brain is a significant component in the CNS-induced immune func- tion inhibition. Non-neurologic consequences of brain injury show impressive similarities regardless of the brain insult and appear to depend on altered neuroimmune circuits. Modulation of these cir- cuits could reduce extra-brain damage and improve patient outcome in both vascular and traumatic brain injury. Ó 2009 Elsevier Inc. All rights reserved. 1. Introduction Acute brain injury of traumatic or vascular origin is also marked by extra-brain damage including cardiovascular, respiratory, endo- crine, hematological, and immune disorders (Emsley et al., 2008; Kemp et al., 2008; Stevens and Nyquist, 2007). Non-neurologic or- gan involvement has great significance in that it is associated with inferior outcome. Brain death is a dire consequence of acute brain injury. Several investigations show that brain death causes alterations in periph- eral organs that can contribute to the poorer outcome of organs transplanted from brain-dead donors (Pratschke et al., 2008). In- deed, although the cadaver donor is still the primary organ source, the rate of success for these allografts remains significantly lower relative to transplants from living-related or unrelated donors. The idea is that, in addition to the commonly accepted donor fac- tors such as old age, organ pathology, or prolonged ischemia, brain death itself has a negative influence on graft survival. Therefore, it appears that acute brain injury and brain death ex- ert detrimental effects on peripheral cells (Fig. 1). Clearly, charac- terization of systemic consequences of brain injury could improve therapeutic approaches in Intensive Care and Neurosur- gery Units. Further, understanding of consequences of brain injury and brain death on donor organs could open up novel transplanta- tion strategies: treatment of the multiorgan donor before organ harvest might be a novel approach to enhance transplantation outcome. This review examines the detrimental consequences of brain injury on peripheral cells in experimental models and clinical re- search. The authors have elected to favor simply the description of established data, over and above speculation. Indeed, the mechanisms underlying extra-brain damage after brain injury have not been fully determined. The best documented hypotheses are presented while a detailed review of current theories on ex- tra-brain damage mechanisms are outside the scope of this article. 2. Extra-brain damage during acute brain injury Extra-cerebral damage in patients with acute brain injury contributes to worsen outcome. Experimental models can help 0889-1591/$ - see front matter Ó 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.bbi.2009.04.006 * Corresponding author. Address: Centro di Sperimentazione Preclinica, Padigli- one Granelli, Fondazione IRCCS Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Via F. Sforza 35, Milano 20122, Italy. Fax: +39 02 5503 3318. E-mail address: anna.catania@unimi.it (A. Catania). Brain, Behavior, and Immunity 23 (2009) 877–884 Contents lists available at ScienceDirect Brain, Behavior, and Immunity journal homepage: www.elsevier.com/locate/ybrbi