دانلود کتاب شوک ناشی از اندوتوکسین: یک رویکرد چند رشته ای در مراقبت های ویژه

The concept that endotoxin, an insoluble part of the bacterial cell, was a toxic sub­stance able to evoke a typical picture of bacterial infection, even without the pres­ence of living bacteria was introduced for the first time by Richard Pfeiffer in 1892. Subsequently, many years were needed to characterize the exact structure, func­tion, and mechanism of action of endotoxin, nowadays recognized as lipopolysac­charide (LPS).

LPS is the major component of the cell wall of Gram-negative bacteria, recover­ing the 75% of the surface of the outer leaflet of the outer membrane of the cell wall. It is a glycolipid composed of a hydrophobic lipid part (lipid A) anchored in the outer leaflet and a hydrophilic polysaccharide part that extends outside the cell. The polysaccharide part is divided into two domains: the core region and the O antigen (also named O-chain). The O-chain is composed of several units of oligosaccharide and is tied to lipid A through the core region. The main role of LPS molecules is to create a hydrophobic structure that results in a permeability barrier that protects bacteria from antimicrobial factors.

LPS is produced by most Gram-negative bacteria, with a few exceptions repre­sented for example by Treponema pallidum. Although the structure of LPS is well conserved, differences can be observed among species of bacteria. For exam­ple, an LPS without the O-chain is produced by some species of Gram-negative bacteria and it is called as “rough” LPS, as opposed to a “smooth” LPS, which includes the O-chain. LPS is a component of the bacterial wall essential for survival in a hostile environment. Indeed, Gram-negative bacteria that lack LPS or have LPS without an O-chain are more sensitive to antibiotics and, in general, to the host’s defense mechanisms.

Among LPS components, lipid A deserves particular attention, as it is responsi­ble for activating the immune system and for inducing pyrogenic and toxic effects. The structure of lipid A can differ among Gram-negative bacteria in the number and the length of fatty acid chains attached and the presence or absence of phosphate groups or other residues. Generally, in most cases, LPS is constituted by a diglu­cosamine backbone phosphorylated at positions 1 and 4 and acylated with 5 or 6 fatty acyl chains. The most present fatty acyl chain is the 3-hydroxy-tetra-decanoinc acid. Studies demonstrated that alterations of lipid A can cause alterations in its biological activities. Indeed, the variable structure of lipid A determines its stimula­tory or inhibitory action. For example, lipid A with a diglucosamine backbone, two phosphates, and six fatty acyl chains, is best sensed by the host’s complex of myeloid differentiation factor 2 and the toll-like receptor 4 (MD-2-TLR4).

LPS in the cell membrane of anaerobic Bacteroidales, which are present in the commensal microbiota of the human gut, has an under-acylated (tetra- or penta-acyl) lipid A that is a potent TLR4 inhibitor. Consequently, by silencing the TLR4 pathway, it facilitates the host’s tolerance of gut microbes. However, it is unknown if this phenomenon has any effect on the progression of infection. In fact, the lipid A structure of Pseudomonas aeruginosa but also of many other Gram-negative bacteria does not possess six fatty acyl chains. Yersinia pestis instead is able to produce hexa-acyl LPS at 21–27 °C and tetra-acyl LPS at 37 °C, and thus it is able to escape the host’s first-line defense in mammals. Moreover, a genetically modified strain of Yersinia pestis which produces hexa-acylated LPS at 37 °C appeared to be avirulent, as it is able to facilitate the early recognition of infection and the effective onset of immune signaling. During chronic infection, modifi­cations of LPS molecules are possible and happen to facilitate the evasion of host immune defense and biofilm adaptation.