; for the SepNet-Critical Care Trials Group IMPORTANCE Adjunctive hydrocortisone therapy is suggested by the Surviving Sepsis Campaign in refractory septic shock only. The efficacy of hydrocortisone in patients with severe sepsis without shock remains controversial. OBJECTIVE To determine whether hydrocortisone therapy in patients with severe sepsis prevents the development of septic shock.

Systemic bacterial infections are associated with high mortality. The access of bacteria or constituents thereof to systemic circulation induces the massive release of immunomodulatory mediators, ultimately causing tissue hypoperfusion and multiple-organ failure despite adequate antibiotic treatment. Lipid A, the "endotoxic principle" of bacterial lipopolysaccharide (LPS), is one of the major bacterial immunostimuli. Here we demonstrate the biological efficacy of rationally designed new synthetic antilipopolysaccharide peptides (SALPs) based on the Limulus anti-LPS factor for systemic application. We show efficient inhibition of LPS-induced cytokine release and protection from lethal septic shock in vivo, whereas cytotoxicity was not observed under physiologically relevant conditions and concentrations. The molecular mechanism of LPS neutralization was elucidated by biophysical techniques. The lipid A part of LPS is converted from its "endotoxic conformation," the cubic aggregate structure, into an inactive multilamellar structure, and the binding affinity of the peptide to LPS exceeds those of known LPS-binding proteins, such as LPS-binding protein (LBP). Our results thus delineate a novel therapeutic strategy for the clinical management of patients with septic shock.The life-threatening clinical consequences of sepsis and septic shock arise from recognition of microbial immunostimulatory molecules by the hosts' professional immune cells and the release of hemodynamically active mediators. The most potent immunostimulatory constituents are part of the microbial cell envelope, such as lipopolysaccharide (LPS) or lipoproteins. They are released continuously due to cell growth and division and massively liberated as a consequence of the attack of the immune system. In the case of Gram-negative bacteria, the most potent factor is LPS, which, therefore, is also called an endotoxin. LPS concentrations in blood serum as low as 1 ng/ml are able to cause sepsis. Septic shock resulting from bacterial infection remains a frequent cause of death, particularly in intensive care units, with more than 200,000 people dying each year in the United States alone. Death by septic shock can happen despite appropriate broad-range antibiotic treatment, which may kill bacteria but is not only incapable of neutralizing immunostimulatory LPS but also may promote its release into circulation (11).The response of mammalian cells to LPS is initiated by its interaction with serum proteins such as lipopolysaccharidebinding protein (LBP) and specific receptors and/or binding proteins of immune cells such as soluble CD14 (sCD14) and membrane-bound CD14 (mCD14), which finally leads to cell activation through the Toll-like receptor 4 (TLR4)-MD-2 pathway (31). The hydrophobic moiety of LPS, lipid A, anchoring LPS to the bacterial outer membrane, constitutes the "endotoxic principle" of LPS (24). Enterobacterial lipid A consists of a diglucosamine backbone phosphorylated at positions 1 and 4Ј, to which six acyl chains are linked at positions 2,3 a...

Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection. The endothelial glycocalyx is one of the earliest sites involved during sepsis. This fragile layer is a complex network of cell-bound proteoglycans, glycosaminoglycan side chains, and sialoproteins lining the luminal side of endothelial cells with a thickness of about 1 to 3 μm. Sepsis-associated alterations of its structure affect endothelial permeability and result in the liberation of endogenous damage-associated molecular patterns (DAMPs). Once liberated in the circulatory system, DAMPs trigger the devastating consequences of the proinflammatory cascades in sepsis and septic shock. In this way, the injury to the glycocalyx with the consecutive release of DAMPs contributes to a number of specific clinical effects of sepsis, including acute kidney injury, respiratory failure, and septic cardiomyopathy. Moreover, the extent of glycocalyx degradation serves as a marker of endothelial dysfunction and sepsis severity. In this review, we highlight the crucial role of the glycocalyx in sepsis as a diagnostic tool and discuss the potential of members of the endothelial glycocalyx serving as hopeful therapeutic targets in sepsis-associated multiple organ failures.

In humans, the ribonuclease A (RNase A) superfamily contains eight different members that have RNase activities, and all of these members are encoded on chromosome 14. The proteins are secreted by a large variety of different tissues and cells; however, a comprehensive understanding of these proteins’ physiological roles is lacking. Different biological effects can be attributed to each protein, including antiviral, antibacterial and antifungal activities as well as cytotoxic effects against host cells and parasites. Different immunomodulatory effects have also been demonstrated. This review summarizes the available data on the human RNase A superfamily and illustrates the significant role of the eight canonical RNases in inflammation and the host defence system against infections.