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Prolonged sepsis will induce mitochondrial dysfunction and damage. As a consequence of decreased energy availability, metabolism must decrease or the cell will soon die. As cell death is not a major feature, it is thus feasible that the cells enter a hibernation-like state as a late protective response and this biochemical/physiological shutdown is manifest as multiple organ dysfunction/failure. Recovery would then be contigent upon restoration of mitochondrial function, either through repair of existing damaged mitochondria or production of new organelles. Excess production of NO and other reactive species appears likely to be the main ‘culprit’ of the initial injury and altered bioenergetics, yet, paradoxically, may provide the stimulus for eventual recovery of function. Therapeutic strategies could thus be geared towards mitochondrial protection or accelerating recovery.

As reviewed above, there is abundant evidence implicating autonomic dysfunction or cytokine excess in diseases with inflammatory pathology such as sepsis, Crohn’s disease, and rheumatoid arthritis. The identification of a vagus nerve mechanism that regulates cytokine activity and immune cell activation now suggests that some neurological or nervous system disorders may in fact manifest as inflammatory conditions, and thus alter the optimal treatment. The ability to rationally modulate vagus nerve activity through biofeedback techniques now makes it plausible to consider how to study the regulation of cytokine synthesis in volunteer subjects and patients under varying states of vagus nerve activity.

Sepsis induces profound metabolic and cardiovascular derangements. Although some indices indicate that cytopathic hypoxia may coexist, early correction of global hemodynamic alterations is essential. Regional blood flow alterations may persist after correction of systemic hemodynamics. Although a systematic increase in splanchnic blood flow may not be warranted, several arguments suggest that the maintenance of an adequate balance between oxygen supply and demand in the splanchnic area may be useful.

Severe sepsis triggers clotting, diminishes the activity of natural anticoagulant mechanisms, and impairs the fibrinolytic system. Augmented interactions between inflammation and coagulation can give rise to a vicious cycle, eventually leading to dramatic events such as manifested in severe sepsis and DIC. Unraveling the role of coagulation and inflammation in sepsis will pave the way for new treatment targets in sepsis that can modify the excessive activation of these systems. At present it remains unclear whether anticoagulant therapy improves survival in severe sepsis; in addition, it remains uncertain whether the beneficial effect of recombinant human APC derives from its anticoagulant properties. These issues will be clarified as our understanding of the interplay between coagulation and inflammation during sepsis improves further in the very near future.

HMGB1 is a novel late mediator of inflammatory responses that contributes to ALI and lethal sepsis. It appears to interact with at least three receptors, including RAGE, TLR2, and TLR4, potentially explaining the similarities in cellular activation induced by HMGB1 and bacterial products, such as LPS or peptidoglycan. However, the multiple receptors involved in HMGB1 signaling also provide insights into the differences in gene expression produced by cellular interaction with this mediator. Unlike the situation with classically described pro-inflammatory cytokines, such as TNF-α or IL-1β, where blockade is only effective in improving outcome from experimental sepsis if administered before or very early in the course of sepsis, inhibition of HMGB1 with specific antibodies or the HMGB1 A box sequence still reduces mortality even if performed up to 24 hours after the initiation of the septic insult. Such findings suggest that HMGB1 may be an appropriate therapeutic target in patients with sepsis or ALI, since it may participate in the pathogenesis of organ dysfunction and mortality even at later time points when such patients present for hospital or ICU admission.

Over the last ten years or so, a role of NO in sepsis and MOF has been established. A number of studies have been performed in animals and in patients in which the generation of NO in sepsis has been pharmacologically manipulated. While improvements in hemodynamics have generally been reported, to date none of these investigations has clearly demonstrated improved organ function or outcomes in human sepsis.

It is becoming increasingly clear that NO mediates both cytoprotective and cytopathic roles in sepsis. However, much remains to be elucidated in terms of how NO mediates these effects and also whether the consequences of NO are causative or reactive to organ dysfunction. Future therapies, better targeted towards selectively inhibiting iNOS, will no doubt help to clarify this question. In addition, it is possible that targeting downstream effects of NO, such as mitochondrial dysfunction or promoting mitochondrial biogenesis, may emerge as possible approaches to the management of this complex and widespread condition.

Reactive oxygen and nitrogen intermediates, produced by the interaction of NO with partially reduced oxygen species, affect lung function and homeostasis in a variety of different ways. They act as signaling agents and play an essential role in pathogen killing. On the other hand, they may contribute to tissue injury by upregulating genes responsible for the production of inflammatory mediators and by directly nitrating and oxidizing proteins, events known to adversely affect critical functions. A significant challenge to defining their role in lung injury results from their short biological half-lives, and lack of sensitive detection techniques, and the difficulty in deciphering the relevance of the various substrate concentrations to a particular measured response. Thus, many questions relating to the chemical, physiological, pathobiological, and clinical consequences of ROS and RNS generation remain unanswered. Therapeutic strategies, such as enhanced anti-inflammatory and antioxidant therapies are in their infancy in the clinical arena. Hence, this discussion of what is known leads one to realize how much is not known with regard to the role of RNS/ROS in lung injury.

HSPs are important mediators of a number of key intracellular reactions. Of importance to the care of the critically ill are their involvement in protein repair and tertiary structure. HSP70 is known to modulate inflammation and apoptosis. In models of acute lung injury and ARDS, over-expression of HSP70 improves outcome, ameliorates lung injury and attenuates inflammation. The involvement of HSP70 in other aspects of lung injury and in other components of MODS is under investigation.

Hyperglycemia in critically ill patients is a result of an altered glucose metabolism. Apart from the upregulated glucose production (both gluconeogenesis and glycogenolysis), glucose uptake mechanisms are also affected during critical illness and contribute to the development of hyperglycemia. The higher levels of insulin, impaired peripheral glucoseuptake and elevated hepatic glucose production reflect the development of insulin resistance during critical illness.

Hyperglycemia in critically ill patients has been associated with increased mortality. Simply maintaining normoglycemia with insulin therapy improves survival and reduces morbidity in surgical and medical ICU patients, as shown by two large, randomized controlled studies. These results obtained from clinical studies were also confirmed in ‘real-life’ intensive care of a heterogeneous patient population admitted to a mixed medical/surgical ICU.

Prevention of glucose toxicity by strict glycemic control appears to be crucial, although other metabolic and non-metabolic effects of insulin, independent of glycemic control, may contribute to the clinical benefits.

Inflammation requires clearance of the inciting pathogen, then orchestrated removal of the burden of leukocytes and other cells influxed into the inflamed site along with dissipation of the pro (or anti) inflammatory mediator cascades. We now recognize that this resolution process is strictly controlled by a number of mediators and adhesion molecules. Apoptotic cell death, when timed appropriately, allows the non-phlogistic clearance of PMNs, monocytes and eosinophils. Macrophage engulfment of these apoptotic cells signals further anti-inflammatory processes, including additional programmed cell death, anti-inflammatory mediator release, and promotes active macrophage emigration which is the final route by which cell clearance is effected. Should these processes evolve successfully, then the tissue will return to its normal structure and function, but should this not proceed effectively then the body will limit further damage by evoking a fibrotic response to ‘heal and seal’ the damaged tissue.