Published online before print November 21, 2003
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
The Anlyan Center, Department of Medicine and Pathology, Yale University School of Medicine, New Haven, Connecticut
1 Correspondence: The Anlyan Center, S525, Department of Medicine and Pathology, Yale University School of Medicine, 300 Cedar St., New Haven, CT 06520. E-mail: richard.bucala{at}yale.edu
 TOP ABSTRACT INTRODUCTIONREFERENCES |
|---|
Key Words: Toll-like receptors • immunomodulatory therapy • pharmacologic therapy • cytokines
|
TOPABSTRACTINTRODUCTIONREFERENCES |
|---|
Septic shock develops because of a dysregulation in the host response, such that the mechanisms initially recruited to fight infection produce life-threatening tissue damage and death. The last several years have witnessed an explosive increase in our understanding of host-pathogen interactions, particularly in the area of innate immunity and the molecular recognition of gram-positive and gram-negative bacteria [2 ]. Important new mediators of sepsis and novel mechanisms of host-cell toxicity also have been identified. This information together with data from recently completed clinical trials targeting pathways considered central to sepsis pathogenesis provide a renewed foundation for better defining the molecular and cellular basis of sepsis and formulating new strategies for intervention [3 ].
Although not comprehensive in its scope, this series includes a selection of topics that highlight several of the conceptual advances that have been achieved in the area of septic shock. Lederer and colleagues remind us of the importance of "noninfectious" stimuli in the form of severe injury and tissue trauma in upsetting the natural balance in host-immunoregulatory pathways. As a real-life, clinical entity, septic shock is rarely a case of "simple" bacterial invasion or toxemia, and this consideration is vital to unraveling the physiologic complexity of the host response.
Sepsis not only causes a high rate of immediate mortality, but among survivors, it is associated with an increased risk of death and a poor quality of a life after hospital discharge [4 , 5 ]. Steve Kunkel and his laboratory have developed an experimental model to begin to address the immunologic suppression that can be a significant complication after recovery from sepsis. These investigators induce sepsis in mice by cecal ligation and puncture, which mimic the polymicrobial features of human intraperitoneal infection, and find that the survivors are susceptible to fungal infection with 100% mortality. This increased mortality correlates with changes in Toll-like receptor and cytokine expression in lung leukocytes, leading to the hypothesis that the lung remains vulnerable to nosocomial infection for a long time after severe sepsis.
Refinements in the clinical management of intensive care unit patients are also contributing to our scientific understanding of sepsis physiology. This "bedside-to-bench" approach is nicely illustrated by the emerging appreciation of hyperglycemia as a risk factor for sepsis mortality [6 ]. This concept was first uncovered by studies of insulin therapy for severely ill diabetic patients with myocardial infarction [7 ]. A closer examination of the role of metabolic dysfunction and insulin action in the control of inflammatory pathways is now underway in laboratory and clinical investigations, as discussed by Andersen et al.
Finally, the study of the host response to infection has long emphasized the critical role of proinflammatory mediators in initiating the lethal cascade of events producing end-organ failure. Indeed, research into new sepsis therapeutics continues to focus increasingly on interrupting the cascading, inflammatory response produced by the invasion and dissemination of pathogenic microbes. The last two contributions by the groups of Flavell and Yoshimura, respectively, teach us that there exist elaborate regulatory pathways for the control and down-regulation of proinflammatory pathways. The identification of these proteins and our understanding of their functioning are yielding increasingly to experimental investigation, largely by the power of molecular biology and genetics. These molecules and pathways are nature’s solution to our coexistence with commensual microorganisms and for this reason, may prove to be a fertile area for exploring the pharmacologic manipulation of the host response for clinical benefit.
Received October 18, 2003; accepted October 21, 2003.
|
TOPABSTRACTINTRODUCTIONREFERENCES |
|---|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
