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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.

The understanding of sepsis-induced organ dysfunction has advanced considerably over the last few years. The interaction between signaling systems and metabolic pathways is a particularly ‘hot’ area of ongoing research. Energy production and the availability of substrates in the acute phase seem to have a crucial impact on the course of sepsis and on mortality and morbidity. Later on, during MOF, the same metabolic pathways determine outcome, but the mechanisms and clinical picture are different. Knowledge of these mechanisms is, therefore, necessary for optimal clinical practice.

The concept that apoptosis pathways are involved in the onset and long-term consequences of lung injury is important, but significant questions remain. More information is needed about the factors that control the balance between tissue injury and tissue repair in the lungs. For example, we need to know more about what determines when the Fas pathway leads to tissue injury versus when Fas activation leads to the orderly removal of excess tissue at sites of tissue repair. Cell death pathways are complex and interlocking, and more information is needed about how different cellular activation pathways interact either to enhance or inhibit cell death in the lungs. Activation of innate immunity via TLR receptors modulates Fas pathway activity, and more information is needed about the mechanisms involved. At inflammatory sites, it seems likely that receptor-mediated death pathways and mitochondrial death pathways are activated almost simultaneously, and it is not clear whether strategies to inhibit one of the death pathways will be successful without simultaneously modulating all other death pathways. Importantly, it is not clear how long apoptosis pathways should be inhibited. Nevertheless, new ideas are needed to further reduce mortality in patients with ALI. Because apoptosis pathways are a tightly regulated mode of cell death, targeting specific control points in these pathways offers new opportunities to reduce the initial severity of ALI and improve long-term outcomes.

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.

Sepsis is increasing in incidence and is commonly complicated by organ failure, of which the lung is the most common. Pronounced changes in cellular iron regulation occur in such patients, leading to dysregulation of the inflammatory response through the regulation of pro-oxidant potential and apoptotic function. The availability of heme substrate determines the nature of a range of responses to pro-inflammatory stimuli, especially in endothelial cells and neutrophils. HO-1 expression accompanies these changes and early indications suggest that fluxes in cellular iron levels direct the responses. Clinically relevant mechanical and biological stimuli result in similar pro-inflammatory responses in alveolar epithelial (like) cells, suggesting that a common signaling pathway directs iron-mediated responses. Finally, damage to alveolar epithelial cell and the microvascular endothelium leads to changes in pulmonary structure and function that characterize ALI/ARDS.

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.

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.

Development of acute renal failure during sepsis syndrome is common and portends a poor outcome. The interplay between systemic host responses, local insults in the kidney, vascular bed, and immune system, all play a role in the development of sepsis-induced acute renal failure. Despite advances in critical care, mortality rates have remained high for sepsis-associated acute renal failure. This may be, in part, a function of our poor understanding of the mechanisms of sepsis-induced acute renal failure, leading to misguided management strategies for acute renal failure. Improved understanding of various emerging mechanisms of sepsis-induced acute renal failure such as epithelial barrier dysfunction, apoptosis, and cytokine-mediated injury, should open newer avenues of therapeutic targets in this field. As has often been the case in the study of sepsis, simple universal mechanisms such as tissue perfusion, have failed to explain the diverse and complex clinical response, and therapeutic strategies aimed at single mechanisms have not been successful. The pathophysiologic mechanisms now understood to be operative in sepsis-induced acute renal failure overlap and interact at many levels. Therefore, therapeutic strategies to prevent acute renal failure or to facilitate recovery will likely need to be multifaceted.

Sepsis is often associated with CNS dysfunction that is frequently unrecognized. This dysfunction is not due to direct infection of the CNS, so is better termed ‘sepsis-associated encephalopathy’. An altered mental status may be present in the early stage of sepsis, even preceding common clinical signs of sepsis. EEG and other neurophysiologic techniques may help to detect sub-clinical alterations and to establish clinical outcome. The pathophysiological mechanism of sepsis-associated encephalopathy is not perfectly understood and is very likely multifactorial, involving direct toxicity of microorganisms or byproducts, and the effects of inflammatory mediators, metabolic alterations, and impaired cerebral circulation. There are no specific or symptomatic treatments for sepsis-associated encephalopathy.

Myocardial dysfunction is an important component in the hemodynamic collapse induced by sepsis and septic shock. A series of inflammatory cascades triggered by the inciting infection generate circulatory myocardial depressant substances, including TNF-α, IL-1β, PAF and lysozyme. Current evidence suggests that septic myocardial depression in humans is characterized by reversible biventricular dilatation, decreased systolic contractile function, and decreased response to both fluid resuscitation and catecholamine stimulation, all in the presence of an overall hyperdynamic circulation. This phenomenon is linked to the presence of a circulating myocardial depressant substance or substances which probably represents low concentrations of pro-inflammatory cytokines including TNF-α, IL-1β and perhaps IL-6 acting in synergy. These effects are mediated through mechanisms that include but are not limited to NO and cGMP generation. The mechanism through which NO depresses cardiac contractility is largely unknown. Recent data suggest that pre-apoptotic signaling involving transcription factors STAT1, IRF1 and NF-κB leading to apoptotic pathways may play a role in septic myocardial depression related to inflammatory cytokines circulating during septic shock. Links between this response and NO generation are postulated but have not been fully delineated.