Editorial [Hot Topic: Sepsis: Evolving Concepts and Therapeutic Strategies (Executive Editors: T.J. Standiford and M. Moss) ]

Sepsis is a common and devastating syndrome that causes over 200,000 deaths per year in the United States, and the incidence of sepsis is increasing at an alarming rate. The manifestations of sepsis result from the complex interaction between microbe and host. Microbial invasion triggers a robust but tightly regulated host inflammatory response. However, when this response becomes amplified and dysregulated, a cascade of maladaptive events ensue, culminating in tissue hypoperfusion, multiple organ failure, and even death. Past clinical trials targeting either selected microbial products or host inflammatory responses have produced disappointing results. However, exciting new research has provided novel insights into disease pathogenesis in sepsis, opening the door to the development of innovative therapeutic strategies in the treatment of patients with this syndrome. In this Special Issue, we will review clinical manifestations and pathogenic mechanisms in sepsis, with a particular emphasis on novel mediators and pathways involved. Drs. Hodgin and Moss [1] will discuss the changing epidemiology of sepsis and how these changes have impacted both causes of sepsis and clinical outcomes. Dr. Crouser and colleagues [2] provide an introduction to novel inflammatory targets in sepsis, including host derived molecules that activate toll receptor signaling cascades. These authors highlight the importance of other fundamental processes in disease pathogenesis, including mechanistic links between sepsis-induced inflammation, mitochondrial dysfunction, and multiple organ failure. Dr. Ayala and associates [3] discuss the critical role of apoptosis in sepsis, including effects on organ function and immunity. Activation of the coagulation cascade is a hallmark of sepsis, and compelling evidence indicates that microvascular thrombosis contributes to pathophysiologic events in sepsis. Wang and colleagues [4] outline mechanisms of abnormal coagulation in sepsis and review the findings of clinical trials aimed at disrupting coagulation cascades. The septic response is associated with a profound state of immune suppression, which is temporally associated with reprogramming of leukocyte immune responses. Putative mediators of leukocyte reprogramming in sepsis include inhibitors of pathogen recognition receptors, anti-inflammatory cytokines, ligands of nuclear hormone receptors, pro-apoptotic molecules, and epigenetic changes of key regulatory genes. Drs. Lyn-Kew and Standiford [5] discuss molecular mechanisms of impaired innate and acquired immunity in sepsis, and explore novel approaches to reverse these deleterious events in both animal models and patients with sepsis. Sepsis-induced alterations in corticosteroid responses are common and of substantial clinical importance. Dr. Annane [6] reviews causes of abnormal corticosteroid responses in sepsis, and discusses the merits of glucocorticoid therapy in this patient population. Patients with sepsis also have marked impairment in glucose metabolism, which is partially attributable to a relative state of insulin resistance. Implications of hyperglycemia include persistent inflammation, cellular toxicity, and impairment in leukocyte antimicrobial function. Dr. Van Cromphaut and colleagues [7] define mechanisms involved, and discuss the impact of insulin therapy on cellular responses and clinical outcomes in critically ill patients, including patients with sepsis. The influence of genetic variations on gene expression patterns in sepsis is an intense area of research. Dr. Wurfel [8] provides an informative summary of common sequence variations in genes involved in innate immunity, inflammation, and coagulation, and how these genetic factors influence disease susceptibility and expression in sepsis. In the final article of this Issue, Drs. Kaul, Collins, and Hyzy [9] address the important topic of antimicrobial therapy in sepsis, including an overview of evolving patterns of antimicrobial resistance and the status of new classes of antimicrobial agents in development. Collectively, this Special Issue of Current Pharmaceutical Design provides a timely and comprehensive update of new directions in sepsis research that may ultimately fuel a real paradigm shift in our approach to the treatment of this deadly disease. References [1] Hodgin KE, Moss M. The Epidemiology of Sepsis. Curr Pharm Des 2008; 14(19): 1833-1839. [2] Crouser E, Exline M, Knoell D, Wewers MD. Sepsis: Links Between Pathogen Sensing and Organ Damage. Curr Pharm Des 2008; 14(19): 1840-1852. [3] Ayala A, Perl M, Venet F, Lomas-Neira J, Swan R, Chung C-S. Apoptosis in Sepsis: Mechanisms, Clinical Impact and Potential Therapeutic Targets. Curr Pharm Des 2008; 14(19): 1853-1859. [4] Wang L, Bastarache JA, Ware LB.The Coagulation Cascade in Sepsis. Curr Pharm Des 2008; 14(19): 1860-1869. [5] Lyn-Kew K.L, Standiford TJ. Immunosuppression in Sepsis. Curr Pharm Des 2008; 14(19): 1870-1881. [6] Annane D. Adrenal Insufficiency in Sepsis. Curr Pharm Des 2008; 14(19): 1882-1886. [7] Van Cromphaut SJ, Vanhorebeek I, Van den Berghe G. Glucose Metabolism and Insulin Resistance in Sepsis. Curr Pharm Des 2008; 14(19): 1887-1899. [8] Wurfel MM. Genetic Insights into Sepsis: What Have We Learned and How Will It Help? Curr Pharm Des 2008; 14(19): 1900-1911. [9] Kaul DR, Collins C, Hyzy RC. New Development in Antimicrobial Use in Sepsis. Curr Pharm Des 2008; 14(19): 1912-1920.