Special focus

This Virulence special focus highlights the emerging critical role of endothelial activation and dysfunction in the pathogenesis of infectious diseases and associated clinical outcomes. Infectious disease investigators might ask why endothelial biology should be of interest to them. We hope that this special focus will make the research community think otherwise. The endothelium is comprised of >60 trillion cells lining the surfaces of blood vessels to constitute a total surface area of ~4000 m, rendering it not only the largest organ in the body but also the organ that links all other organs. It represents a massive and essential surveillance organ, equipped with pathogen recognition receptors (PRRs) to recognize pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs), that contributes fundamentally to innate immunity and host response. Recent studies highlight the previously under-recognized role of the endothelium as a key innate immune effector cell capable of orchestrating profound proinflammatory responses in sepsis and influenza. Furthermore, it seems highly likely that endothelial activation/dysfunction will play a central pathogenic role in a number of critical illnesses characterized by systemic inflammation and end-organ dysfunction. Sepsis is a prime example of an infection-related clinical syndrome in which endothelial activation/dysfunction has been recently recognized to play an important mechanistic role in disease pathogenesis. Endothelial activation occurs early in the course of sepsis, and subsequent endothelial dysfunction is now recognized to contribute directly to the morbidity and mortality of sepsis. It has become increasingly clear that impaired microvascular barrier integrity leads to tissue edema, shock, and end-organ dysfunction/injury (e.g., acute respiratory distress syndrome [ARDS] and acute kidney injury [AKI]). The failure of development and translation of effective treatment strategies of sepsis prompted the Division of Blood Diseases and Resources of the National Heart, Lung and Blood Institute (NHLBI) to convene a workshop involving a multidisciplinary group of experts to address the challenges posed by sepsis and sepsis-induced multi-organ dysfunction/failure in 2010. This group concluded that sepsis represents a syndrome of severe endothelial dysfunction that causes multi-organ failure in response to intravascular or extravascular infection. The participants concluded that sepsis is fundamentally a disease of inflammation-induced endothelial activation/dysfunction and that future sepsis research should focus on the role and regulation of endothelial activation/ Special focus Endothelial activation/dysfunction