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The recently discovered class of Toll-like receptors (TLRs) has emerged as the central line of defense against invading pathogens. The TLR are the first to detect host invasion by pathogens, initiate immune responses and form the crucial link between the innate and adaptive immune systems. In general, the immune activation that follows TLR activation is sufficient to combat the wide variety of pathogens that daily invade the human body. However, in the case of sepsis, which can be defined as the disadvantageous systemic host response to infection , these TLR-mediated responses may exceed the threshold to maintain homeostasis of the immune system. This review focuses on new insights into the pathogenesis of sepsis gleaned from the impressive amount of research that has been conducted in the TLR research field and their potential clinical implications for intensive care medicine.

Sepsis and septic shock are the leading causes of death in intensive care units (ICUs) in developed countries despite recent advances in critical care medicine. Sepsis is the systemic inflammatory response to infection frequently associated with hypoperfusion followed by tissue injury and organ failure. Activation of monocytes/macrophages and neutrophils with consecutive release of proinflammatory mediators and activation of the coagulation cascade seem to play key roles in the pathogenesis of sepsis. This process is characterized by the massive release of proinflammatory mediators, such as tumor necrosis factor (TNF)-, interleukin (IL)-1, macrophage migration inhibitory factor (MIF), and high mobility group box-1 (HMGB-1) protein. In addition, neutrophil apoptopsis is significantly delayed by these inflammatory mediators.

Sepsis is the systemic response of the host organism to the invasion of microbial species and/or their toxins. The incidence of sepsis is steadily increasing, and, despite recent progress in intensive care research, mortality is still high, in particular when septic shock and multiple organ failure (MOF) develop [, ]. Diverse molecular mechanisms of inflammation and cellular damage have been implicated in the pathogenesis of septic shock and MOF [, ], including the excessive production of reactive oxygen species (ROS) and reactive nitrogen species (RNS).

Heat shock protein 90 (HSP90) is a molecular chaperone that ensures the correct folding and conformational maturation of specific proteins involved in a wide variety of cellular processes [, ]. Large multidomain proteins are prone to aggregation or to becoming involved in kinetically trapped intermediates; HSP90 is required for a specific set of difficult to fold proteins. When cells are stressed (e.g., because of growth at an unfavorable temperature, osmotic pressure, oxygen tension, pH, or in the presence of noxious chemicals or antibiotics), they upregulate HSP90 production in order to help combat the effects of protein degradation. HSP90 also aids protein stabilization and facilitates activation of many regulated proteins. HSPs have also been shown to be immunodominant and are major targets for the immune system in many infections [, ]. Inhibitors of HSP90 have been shown to deplete multiple proteins important in signal transduction, cell cycle regulation, apoptosis, invasion, angiogenesis, metastasis, immortalization [].

Ferruccio Ritossa first observed a novel hyperthermia-dependent puffing pattern in the giant chromosomes from the salivary glands of in 1962 []. By a chance occurrence, a colleague accidentally increased the temperature of one of the incubators in which he kept his specimens, and the following morning Ritossa discovered a new puffing pattern that had not been there on the previous day. Realizing the mistake, Ritossa conducted additional, properly controlled experiments and subsequently linked this new chromosomal puffing pattern with the expression of a specific group of proteins that he fittingly called heat shock proteins (HSP) [,]. Since Ritossa’s seminal observations in 1962, subsequent investigations into this area have continued, resulting in a growing interest in what is now commonly referred to as the heat shock response. The heat shock response is characterized by the rapid expression of a unique set of proteins collectively known as HSP [, ]. The structure, mode of regulation, and function of HSP are highly conserved among different species, and HSP have been identified in virtually all eukaryotic and prokaryotic species examined to date. While classically described as a response to thermal stress (hence the term heat shock response), HSP can be induced by a wide variety of non-thermal stressors and pharmacological agents (Table 1). These proteins range in molecular weight from 7 to 110 kDa and are found in virtually every cellular compartment, including the nucleus, cytoplasm, and mitochondria (Table 2). By convention, the stress proteins are classified according to their molecular weight, e.g. HSP25, HSP32, HSP47, HSP60, HSP70, HSP90, and HSP110.

Outcome in severe illness depends not only on adequate, goal-directed treatment, but also on the patient’s response to the treatment. In particular, the state of the immune system is crucial in cases of severe infection. Immune suppression, regardless of the underlying mechanism, is a factor adding to a poor prognosis in patients with severe infections. Existing scoring systems, designed to reflect organ failure and to give prognosis prediction for the patient, do not include any score for the status of the immune system. The reason for that is the absence of such a measure similar to those existing for respiration, circulation, coagulation, as well as for liver, kidney and mental function.

Sepsis, a systemic inflammatory response to infection, is currently the leading cause of death among critically ill patients. In the USA alone, approximately 750,000 cases of sepsis occur each year, at least 225,000 of which are fatal []. The incidence of sepsis has increased dramatically in recent decades, largely due to the advancing age of the population, an increased number of invasive procedures being performed and immunosuppressive therapy. This rising sepsis mortality is similar to that observed in Europe and the rest of the world. Despite the use of antimicrobial agents and advanced life-support care, the case fatality rate for patients with sepsis has remained between 30 and 40% for the past three decades. Several billions of dollars have been spent in efforts to improve the survival of patients with sepsis. However, results have been disappointing and many observers argue that our understanding of the underlying pathophysiology of this syndrome is grossly inadequate.

Generalized muscle weakness is increasingly recognized to be a common and serious complication after prolonged intensive care treatment. This form of muscle weakness and paralysis was initially described by Bolton as a critical illness neuropathy []. However, research has demonstrated that critical illness polyneuropathy is frequently associated with critical illness myopathy, as well as existing as the sole pathology [, ]. This chapter will focus primarily on the pathophysiology of critical illness myopathy, and the possible role of mitochondrial dysfunction as a contributing factor.

Traditionally, hyperlactatemia in critically ill patients and particularly those in shock was interpreted as a marker of secondary anaerobic metabolism due to inadequate oxygen supply inducing cellular distress []. Many arguments have since refuted this view []. With lactate metabolism being extensively described in classical biochemistry manuals, this chapter will focus only on those aspects as they relate to critically ill patients. Distinction between lactic acidosis, metabolic acidosis with hyperlactatemia, and isolated hyperlactatemia will also be addressed.

The natriuretic peptide family consists of four structurally similar but genetically distinct peptides with unique biochemical and physiologic properties (Table 1). In 1981, de Bold and colleagues infused atrial homogenate extracts into rats and noted massive diuresis and natriuresis []. The structure of atrial natriuretic peptide (ANP), the peptide hormone responsible for these actions, was identified by Kangawa and Matsuo in 1984 []. Four years later, another peptide with natriuretic and diuretic properties similar to ANP was identified in extracts of porcine brain []. Although this 32-amino acid polypeptide was called brain natriuretic peptide (BNP), it was soon determined that that the primary site of BNP synthesis was in the ventricular myocardium []. Since then, additional members of the natriuretic peptide family of extracardiac origin have been identified: