oa Editorial [Hot topic: Sepsis Pathogenesis: How Many Pieces are There in the Puzzle? (Guest Editor: Luciano Cesar Pontes Azevedo)]

Sepsis remains a challenge for intensive care physicians and is one of the leading causes of death nowadays. This syndrome comprises a spectrum of conditions ranging from systemic inflammatory response syndrome (SIRS) to septic shock and multisystem organ failure (MSOF), the deadly forms of the disease. Although definite advances have been made in the knowledge regarding its pathogenesis and treatment and a decline in mortality has been observed, the annual incidence of the disease is increasing 8.7% in the United States, which results in augmented health care costs. The economic burden of sepsis is nearly $17 billion annually in the United States, with mortality ranging from 20% to 50% of severely affected patients. This enhance in the incidence in recent years is probably due to progressive aging of the population, improvements in critical care support and in immunosuppressive therapies so that individuals with immunosuppression now have increased life expectancy [1]. Thus, there is a clear need to further investment in order to better understand the integrative mediator pathways of inflammation, vascular dysfunction and cellular repair amenable to therapeutic intervention in sepsis. The pathogenesis of sepsis is complex and a fascinating area of investigation; our understanding of its underlying mechanisms has improved markedly in recent years, despite several pieces of the sepsis' puzzle are yet to be discovered. In sepsis, protective and deleterious responses are closely related. Certainly, this is an important reason for the failure of many pathogenesis-oriented target adjunctive therapies. It is now well accepted that this disease results from a triggering of body's defense mechanisms by pathogens and their products. The extension of this activation as well as the regulation of this complex pathogen-host interaction is the key for poor outcome or survival [2]. The mechanisms implicated in development of organ dysfunction during sepsis are progressively being revealed. Compounds such as cytokines, eicosanoids and more recently, nitric oxide (NO) and reactive oxygen species (ROS) have been clearly related to MSOF [3]. In sepsis, large amounts of NO are present in vasculature and may be partially responsible for vascular hiporeactivity and microvascular damage which are common features of this condition. In addition, new players have been described in the field of vascular dysfunction, such as platelet-derived microparticles, which are associated with apoptosis of vascular cells and cardiac failure [4]. However, the correlation of these pathways to outcome is so far poorly understood. Mitochondria seem to be another important piece in the puzzle of sepsis' pathogenesis. Patient studies have shown that the degree of mitochondrial dysfunction relates to eventual outcome [5]. Associated mechanisms may include damage to mitochondria or inhibition of the electron transport chain enzymes from NO and other reactive oxygen species (the effects of which are amplified by co-existing tissue hypoxia). During sepsis, a decrease in energy supply due to mitochondrial inhibition or injury may trigger this hibernation/estivation-like state with organ “shut-down” as an adaptation to harmful environment. Likewise, organ recovery may depend on restoration of normal mitochondrial respiration (mitochondrial biogenesis), which seems to be related to NO production. The pathway that correlates the same molecule to organ injury and recovery is another attractive aspect of sepsis' pathogenesis. Therefore, stimulation of mitochondrial biogenesis could offer a new therapeutic approach for patients in MSOF. In this issue of Endocrine, Metabolic & Immune Disorders - Drug Targets journal we intend to provide an update on the most recent discoveries regarding sepsis pathogenesis. Mechanisms of sepsis-related organ dysfunction such as the ones described above and several others will be discussed by the invited authors, which will support most of the topics discussed on their own research data, thus offering a wide scope of information concerning several pathogenetic and therapeutic aspects of this disease.