Nevertheless, there selleck inhibitor is a growing body of research on this important aspect of the field. Surgical/anesthesia trauma-induced stress response is mediated by a massive neuro-endocrine-hormonal flux, resulting in activation of intracellular signaling pathways and production of several molecules among which cytokines play a crucial role in regulating the function of activated cells and in preserving body homeostasis [1,2]. The intensity of such an inflammatory response is dependent on many factors, including the magnitude of tissue damage, the patient’s pre-existing diseases, the type of surgery and surgeon’s experience, as well as the anesthesia regimen [3,4].In particular, anesthetic agents are suspected of impairing the perioperative inflammatory process by affecting the host cell-mediated immune balance both directly and indirectly [5].

For example, several in vitro and in vivo investigations demonstrated the direct immunosuppressive effect of volatile and non-volatile anesthetics on various lymphocyte cell lines. Moreover, drugs employed for inducing and maintaining general anesthesia, such as opioids and muscle relaxants, as well as sevoflurane, exhibited a pro-apoptotic effect on lymphocyte cells by decreasing mitochondrial transmembrane potential or activating extrinsic cell death pathways [5,6].Recently, an endocrine family of biomolecules, termed “alarmins” by J. Oppenhaim and co-workers, is receiving growing attention as innate danger signals. High Mobility Group Box 1 (HMGB1) is a 30 KDa protein that shows all the typical features of alarmins.

HMGB1 plays a pivotal role in inducing and enhancing immune cell functions as well as in tissue injury and repair [7,8].In particular, HMGB1 was first described as a DNA-binding non-histone chromosomal protein that has been implicated in diverse cellular functions, such as stabilization of nucleosomal structure and regulation of transcription factors [9,10].Later, several research groups showed that HMGB1 exhibits an extracellular role as a cytokine, being actively secreted by peripheral blood mononuclear cells (PBMCs). In particular, recent studies have shown a delayed release of HMGB1 by activated monocytes via a non-classical vesicle-mediated secretory pathway [11]. Functionally, HMGB1 is involved in various inflammatory processes that culminate in the release of cytokines and other inflammatory mediators [12-15].

Perhaps most of these effects are initiated by the binding of HMGB1 to the receptor for advanced glycation end products (RAGE), a multi-ligand receptor of the immunoglobulin superfamily. In addition to RAGE, members of the Toll-like GSK-3 receptor (TLR) family, such as Toll-like receptor 2 and 4 have been demonstrated to participate in the HMGB1 signaling pathway [16-18].It has also been demonstrated that HMGB1 is released in the serum of subjects undergoing traumatic/surgical injury [19,20].