Endotoxemia: Pathophysiological Background
Ronco C, Piccinni P, Rosner MH (eds): Endotoxemia and Endotoxin Shock: Disease, Diagnosis and Therapy. Contrib Nephrol. Basel, Karger, 2010, vol 167, pp 14–24
______________________
Endotoxins and Other Sepsis Triggers
Steven M. Opal
Infectious Disease Division, Memorial Hospital of Rhode Island, Pawtucket, R.I., USA
______________________
Abstract
Endotoxin, or more accurately termed bacterial lipopolysaccharide (LPS), is recognized as the most potent microbial mediator implicated in the pathogenesis of sepsis and septic shock. Yet despite its discovery well over a century ago, the fundamental role of circulating endotoxin in the blood of most patients with septic shock remains enigmatic and a subject of considerable controversy. LPS is the most prominent 'alarm molecule' sensed by the host's early warning system of innate immunity presaging the threat of invasion of the internal milieu by Gram-negative bacterial pathogens. In small doses within a localized tissue space, LPS signaling is advantageous to the host in orchestrating an appropriate antimicrobial defense and bacterial clearance mechanisms. Conversely, the sudden release of large quantities of LPS into the bloodstream is clearly deleterious to the host, initiating the release of a dysregulated and potentially lethal array of inflammatory mediators and procoagulant factors in the systemic circulation. The massive host response to this single bacterial pattern recognition molecule is sufficient to generate diffuse endothelial injury, tissue hypoperfusion, disseminated intravascular coagulation and refractory shock. Numerous attempts to block endotoxin activity in clinical trials with septic patients have met with inconsistent and largely negative results. Yet the groundbreaking discoveries within the past decade into the precise molecular basis for LPS-mediated cellular activation and tissue injury has rekindled optimism that a new generation of therapies that specifically disrupt LPS signaling might succeed. Other microbial mediators found in Gram-positive bacterial and viral and fungal pathogens are now appreciated to activate many of the same host defense networks induced by LPS. This information is providing novel interventions in the continuing effots to improve the care of septic patients.
Copyright © 2010 S. Karger AG, Basel
Sepsis and the multiorgan failure that frequently accompanies severe infection remains a leading cause of mortality in the intensive care unit [1]. It is estimated that about 650,000 750,000 patients develop sepsis annually in the United States with similar incidences in Europe and around the world [2]. Nearly half of septic patients develop severe sepsis and septic shock. The mortality for septic shock remains approximately 30-45%, despite advances in supportive care and numerous efforts to improve patient outcome [1-3].
The microbiology of sepsis has significantly evolved over the past 25 years. The principal microbial pathogens in the 1970s were enteric Gram-negative bacilli and Pseudomonas aeruginosa. In the late 1980s, a transition to predominantly Gram-positive bacterial pathogens was observed [3]. The rapid transmission and acquisition of antibiotic resistance genes among Gram-positive bacteria, and their propensity to adhere and persist on vascular catheter surfaces and other implantable medical devices have contributed to the increasing incidence of Gram-positive pathogens as a cause of sepsis. Opportunistic fungal pathogens are also increasing in frequency as a cause of sepsis [3].
Remarkably, Gram-negative bacterial pathogens now appear to be staging a comeback as the predominant causative microorganisms of ICU infections in recent surveys [4].
Endotoxin, Microbial Mediators and the Recognition of Sepsis
The consensus working definitions for such clinical terms as sepsis, septic shock, systemic inflammatory response syndrome and multiple organ dysfunction syndrome have been recently updated by the surviving sepsis campaign [2]. These definitions take into account the myriad of infectious agents and microbial mediators implicated in the pathogenesis of sepsis. Actual bloodstream infection by these pathogens at the time sepsis is recognized by the clinician is documented in only about one third of patients, but the evidence of generalized inflammation and procoagulant activity is almost invariably present. The systemic inflammatory response in human sepsis is primarily initiated by micro-bial-derived, highly conserved, macromolecules that feature surface patterns not found in human tissues. The most potent of all the pathogen-associated molecular pattern (PAMP) molecules is bacterial lipopolysaccharide (LPS), also known as endotoxin. A large number of other PAMPs are expressed on Gram-positive bacteria, fungi, parasites and viral pathogens. These molecules serve as ligands for the pattern recognition receptors expressed on immune effector cells known as the Toll-like receptors (TLRs) [5, 6]. A summary of the major pathogen-derived mediators of sepsis and their respective Toll-like receptors (TLRs) is found in table 1.
The TLR family is the most important, but not the only PAMP recognition receptor complex, within the human innate immune system. TLRs are type 1 transmembrane receptors for the detection of LPS and many other microbial mediators, such as peptidoglycan, lipopeptides, flagellins, microbial nucleic acids, multiple fungal cell wall components, viral proteins and lipoteichoic acid. Ten TLRs have been identified by human genome searches thus far [5].
Table 1. PAMPs and DAMPs (danger-associated molecular patterns) and their primary pattern recognition receptors in humans
| Origin | TLR |
Bacterial PAMPs | | |
LPS-MD2 | Gram-negative bacteria | TLR4 |
Lipoteichoic acid | Gram-positive bacteria | TLR2a |
Peptidoglycan | Gram-pos./neg. bacteria | TLR2 |
Triacyl lipopeptides | Gram-pos./neg. bacteria | TLR1/TLR2 |
Diacyl lipopeptides | Mycoplasma spp. | TLR2/TLR6 |
Porins, OMPs | Neisseria spp. | TLR2 |
Flagellin | motile Gram-pos./neg. bacteria | TLR5 |
CpG DNA | bacteria, some DNA viruses | TLR9 |
Viral PAMPs | | |
dsRNA | double-stranded RNA virus | TLR3 |
ssRNA | single-stranded RNA virus | TLR7/8 |
Fungal PAMPs | | |
Zymosan | Saccharomyces cerevisiae | TLR2/TLR6 |
Phospholipomannan | Candida albicans | TLR2 |
Mannan | Candida albicans | TLR4 |
O-linked mannosyl residues | Candida albicans | TLR4 |
β-glucans | Candida albicans | TLR2/dectin-1 |
DAMPs | | |
S 100a proteins | host | RAGE |
Heat shock proteins | host | TLR4 |
Fibrinogen, fibronectin | host | TLR4 |
Hyaluronan | host | TLR4 |
Biglycans | host | TLR4 |
HMGB1 | host | TLR4, TLR2 |
OMP = Outer membrane protein CpG = cytosine-phosphate-guanine motifs RAGE = receptor for advanced glycation endproducts HMGB1 = high mobility group box-1. a For detection of LTA from some pathogens TLR6 functions as a coreceptor for TLR2. |
Microbial Virulence and the Causative Microorganisms of Sepsis
It is important to recognize that most microorganisms lack the requisite capacity to successfully invade humans. Most encounters between microbes and the human immune system results in rapid inhibition and microbial clearance by our innate and adaptive immune systems. Only a select few microbial pathogens possess a highly organized and sophisticated set of virulence properties needed to evade host defenses, invade tissues and detect stress signals within the host. Pathogens also process a series of delivery systems capable of distributing toxins to their cellular targets [7, 8]. These microorganisms have mechanisms for packaging and exchanging favorable gene arrays (e.g. antibiotic resistance ...